Essentials of Anatomic Pathology, Third Edition

Essentials of Anatomic Pathology Third Edition

Essentials of Anatomic Pathology Third Edition Edited by

Liang Cheng, MD Professor of Pathology and Urology Director of Molecular Diagnostics Service Chief of Genitourinary Pathology Division Director, Fellowship in Urologic Pathology Indiana University School of Medicine Indianapolis, Indiana

David G. Bostwick, MD Chief Medical Officer Bostwick Laboratories Glen Allen, Virginia

Editors Liang Cheng, MD Professor of Pathology and Urology Director of Molecular Diagnostics Service Chief of Genitourinary Pathology Division Director, Fellowship in Urologic Pathology Indiana University School of Medicine Indianapolis, Indiana, USA [email protected]

David G. Bostwick, MD Chief Medical Officer Bostwick Laboratories Glen Allen, Virginia, USA [email protected]

ISBN 978-1-4419-6042-9 e-ISBN 978-1-4419-6043-6 DOI 10.1007/978-1-4419-6043-6 Springer New York Dordrecht Heidelberg London © Springer Science+Business Media, LLC 2002, 2006, 2011 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter ­developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface to the Third Edition

It is our privilege to present the Third Edition of Essentials of Anatomic Pathology. This edition has been substantially revised to include the most current knowledge and understanding of pathologic processes and to provide contemporary, comprehensive, evidence-based practice information in a consistent and user-friendly outline format. It is our sincere hope that this new edition will serve the educational and reference needs of both trainees and practicing pathologists. This work has been greatly expanded and enhanced with the addition of seven new chapters: Immunohistochemistry for the Surgical Pathologist, Tumors of Unknown Primary, Biomedical Informatics for Anatomic Pathology, Quality Assurance and Regulations for Anatomic Pathology, Molecular Pathology of Solid Tumors, and others. The addition of these chapters reflects the increased importance of these topics in the modern practice of pathology. The most recently published TNM staging classifications (2010 revision) by the American Joint Committee on Cancer (AJCC) and the World Health Organization (WHO) classification of tumors have been incorporated. This new edition includes 2083 full color photographs and 235 tables, making it an even more useful visual reference than previous editions. Additional emphasis has been placed on newly discovered biomarkers and histologic variants. A limited number of “Suggested Readings” rather than an exhaustive list of references are included with each chapter. The text, authored by leading international experts, will serve as an evidence- and criterion-based reference that fully outlines

the current scope of our specialty. This new edition details in a clear and concise manner the most important aspects of anatomic pathology, and the topics presented herein constitute the fundamentals and core base of knowledge that is required for the daily practice of surgical pathology. We hope that this updated edition will continue to serve as a frontline resource for trainees and practicing pathologists. Our profound gratitude goes to all who have been involved in the development and production of this new edition. We are indebted to the contributing authors for sharing their knowledge and experiences with our readers and with us. We also express our appreciation to the excellent production staff at Springer Publishing whose efforts made this project possible. In particular, we would like to thank Ryan P. Christy from the Multimedia Education Division of the Department of Pathology at Indiana University, who edited the digital images for this book, and Tracey Bender, who provided superior editorial assistance. Finally, we thank our readers who have made many insightful suggestions that have enhanced the quality of this work. As always, we welcome the opinions of our readers to ensure greater usability in future editions. Liang Cheng, MD Indianapolis, Indiana David G. Bostwick, MD Glen Allen, Virginia

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Preface to the First Edition

The past decade has witnessed remarkable progress in surgical pathology. The ability of contemporary surgical pathologists to reach a definite diagnosis has been enhanced greatly by innovative immunohistochemical techniques and biomarkers. The information that is useful for pathology practice may not be readily accessible in the daily signout. An up-to-date handbook that contains relevant information to establish an accurate diagnosis would be of practical value. Therefore, we have concentrated on diagnostic criteria and differential diagnosis to ensure an accurate diagnosis. The purpose of Essentials of Anatomic Pathology is to provide a concise review of anatomic pathology for pathologists in training and practicing pathologists, integrating recent advances in diagnostic surgical pathology. This book is organized to allow easy reference for daily practice, and is intended to aid residents who are preparing for Anatomic Pathology Boards and in-service examinations. It will be a useful resource for medical students and for anyone interested in pathology. Part I covers general anatomic pathology, including diagnostic molecular pathology, medical cytogenetics, human genetic disorders,

microbiology for surgical pathologists, forensic pathology, and cytopathology. Part II is classified by organ system, and covers important diagnostic features of common medical diseases and tumors. The pertinent clinical information, salient diagnostic features, relevant ancillary data (for example, immunohistochemical profiles), main differential diagnoses of each disease, and most recent tumor staging information are presented in a consistently user-friendly format. We believe that this format will provide easy access to essential information necessary for sign-out. It is not meant as a substitute for lavishly illustrated, comprehensive textbooks, but to complement them as a practical aid. We hope that this text will materially aid in continuing efforts to recognize, understand, and accurately interpret the gross and light microscopic findings in anatomic pathology specimens. We earnestly solicit constructive criticism from colleagues so that the utility of this text can be expanded and improved to its maximum potential. Liang Cheng, MD David G. Bostwick, MD

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Contents

Preface to the Third Edition.................................................. v Preface to the First Edition.................................................vii Contributors.........................................................................xi

Part I General Pathology   1 Cytopathology Fadi W. Abdul-Karim, Jennifer Brainard, and Claire W. Michael...........................................3

  2 Immunohistochemical Diagnosis in Surgical Pathology Nancy Klipfel, Raul Simental-Pizarro, and Clive R. Taylor............................................103

  3 Tumors of Unknown Primary Nancy Klipfel, Raul Simental-Pizarro, and Clive R. Taylor............................................203

  4 Diagnostic Electron Microscopy Jean L. Olson..........................................................247

  5 Transplantation Pathology Oscar W. Cummings...............................................267

  6 Microbiology for the Surgical Pathologist Deborah E. Blue and Stephen D. Allen.................315

  7 Forensic Pathology Frank P. Miller III and Jeffrey J. Barnard..........407

  8 Autopsy Dean A. Hawley.....................................................455

  9 Biomedical Informatics for Anatomic Pathology Waqas Amin, Uma Chandran, Anil V. Parwani, and Michael J. Becich...........469

10 Quality Assurance and Regulations for Anatomic Pathology Maxwell L. Smith and Stephen S. Raab................481

11 Molecular Diagnostic Pathology James Huang and Richard D. Press......................489

12 Molecular Pathology of Solid Tumors Franklin R. Moore and Richard D. Press.............515

13 Human Genetic Disorders Teresa M. Kruisselbrink, Noralane M. Lindor, Elyse B. Mitchell, Brittany C. Thomas, Cassandra K. Runke, Katrina E. Kotzer, Rajiv K. Pruthi, Devin Oglesbee, Elyse M. Grycki, and Ralitza H. Gavrilova.......535

Part II Organ Systems 14 Neuropathology Eyas M. Hattab, Matthew C. Hagen, Bernd W. Scheithauer, and Arie Perry..............601

15 Lymph Node Ellen D. McPhail and Paul J. Kurtin....................681

16 Spleen

Dennis P. O’Malley and Attilio Orazi.................. 723

17 Bone Marrow Dennis P. O’Malley................................................751

18 Neoplasms of the Skin and Immunodermatology Daniel P. Vandersteen, Melanie Triffet-Treviño, and Chris H. Jokinen........................................797

19 Nonneoplastic Skin Diseases Steven D. Billings and Antoinette F. Hood............875

20 Endocrine Pathology Lori A. Erickson.....................................................903

21 Bone and Joints Jasvir S. Khurana and Guldeep Uppal..................955

22 Soft Tissue Tumors Leona A. Doyle and Alessandra F. Nascimento..........................995

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Contents

23 Tumor of the Salivary Glands Diana M. Bell and Adel K. El-Naggar................1047

24 Head and Neck John D. Henley and Don-John Summerlin.........1081

25 Eye and Ocular Adnexae Jose M. Bonnin.....................................................1123

26 Mediastinum and Thymus Chung-Che (Jeff) Chang, Munir Shahjahan, and Joseph F. Tomashefski Jr.........................1161

27 Cardiovascular Pathology Eric A. Pfeifer.......................................................1193

28 Lung and Pleura Carol F. Farver and Andrea V. Arrossi................1211

29 Breast Mohiedean Ghofrani and Fattaneh A. Tavassoli...............................1263

30 Vulva and Vagina Sharon X. Liang and Wenxin Zheng...................1309

31 Uterus and Fallopian Tube Maritza Martel and Fattaneh A. Tavassoli..........1343

32 Ovary and Peritoneum Robert E. Emerson...............................................1397

33 Placenta and Gestational Trophoblastic Disease Raymond W. Redline............................................1431

34 Nonneoplastic Renal Diseases Geoffrey A. Talmon and Donna J. Lager............1455

35 Tumors of the Kidney Gregory T. MacLennan and Liang Cheng..........1487

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36 Urinary Bladder Liang Cheng, Antonio Lopez-Beltran, and David G. Bostwick....................................1515

37 Renal Pelvis, Ureter, and Urethra Antonio Lopez-Beltran, Sean R. Williamson, and Liang Cheng.............................................1567

38 Prostate David G. Bostwick and Liang Cheng..................1581

39 Testis and Testicular Adnexa Kenneth A. Iczkowski and Thomas M. Ulbright.................................1617

40 The Penis Alcides Chaux, Gustavo Ayala, and Antonio L. Cubilla....................................1647

41 Esophagus and Stomach Thomas P. Plesec and John R. Goldblum............1681

42 Small Intestine, Appendix, Colorectum, and Anus Stephen C. Lawhorn and Shuan C. Li................1717

43 Pancreas Olca Basturk and N. Volkan Adsay.....................1747

44 Nonneoplastic Hepatobiliary Disease Romil Saxena........................................................1771

45 Neoplasms of the Liver and Biliary System Romil Saxena.......................................................1829

Index. ............................................................................1855

Contributors

Fadi W. Abdul-Karim, md Professor of Pathology, Case Western Reserve University, Director of Anatomic Pathology, University Hospitals Case Medical Center, Cleveland, OH, USA

N. Volkan Adsay, md Professor and Vice Chair, Director of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

Stephen D. Allen, md James Warren Smith Professor of Clinical Microbiology, Director, Division of Clinical Microbiology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Waqas Amin, md Research Associate, Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA

Andrea V. Arrossi, md Assistant Professor of Pathology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

Gustavo Ayala, md, phd R. Clarence and Irene H. Fulbright Chair in Pathology, Professor, Director HTAP, Department of Pathology and Scott Department of Urology, Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

Jeffrey J. Barnard, md Chief Medical Examiner, Dallas County, Director, Southwestern Institute of Forensic Sciences, Dallas, TX, USA

Olca Basturk, md Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Michael J. Becich, md, phd Chair, Professor of Biomedical Informatics, Pathology, Information Sciences and Telecommunications, Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Diana M. Bell, md Assistant Professor, Pathology-Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Steven D. Billings, md Co-Director of Dermatopathology Section, Associate Professor of Pathology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

Deborah E. Blue, md Associate Professor, Division of Translational Science and Molecular Medicine, Division of Human Pathology, Department of Physiology, Michigan State University College of Human Medicine, Grand Rapids, MI, USA

Jose M. Bonnin, md Professor of Pathology, Ophthalmology, and Neurology, Director of Neuropathology Service, Indiana University School of Medicine, Indianapolis, IN, USA

David G. Bostwick, md Chief Medical Officer, Bostwick Laboratories, Glen Allen, VA, USA

Jennifer Brainard, md Section Head, Cytopathology and Staff Pathologist, Gynecologic Pathology, Cleveland Clinic, Cleveland, OH, USA

Uma Chandran, phd Co-Director, Department of Biomedical Informatics, Cancer Informatics Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

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Contributors

Chung-Che (Jeff) Chang, md, phd Professor of Pathology, Department of Pathology, The Methodist Hospital, Baylor College of Medicine, Weill Medical College of Cornell University, Houston, TX, USA

Alcides Chaux, md Associated Member, Instituto de Patología e Investigación, Asunción, Paraguay

Liang Cheng, md Professor of Pathology and Urology, Director of Molecular Diagnostics Service, Chief of Genitourinary Pathology Division, Director, Fellowship in Urologic Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

Antonio L. Cubilla, md Professor of Pathology, Universidad Nacional de Asunción, Director, Instituto de Patología e Investigación, Asunción, Paraguay

Oscar W. Cummings, md Professor of Pathology, Director of Surgical Pathology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Leona A. Doyle, md Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

Adel K. El-Naggar, md, phd Professor of Pathology, Chief, Section-Head and Neck Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Robert E. Emerson, md Associate Professor of Pathology, Director of Anatomic Pathology, Wishard Memorial Hospital, Indiana University School of Medicine, Indianapolis, IN, USA

Lori A. Erickson, md Associate Professor of Laboratory Medicine and Pathology, Mayo Clinic, Mayo Clinic College of Medicine, Rochester, MN, USA

Carol F. Farver, md Vice-chair for Education, Director of Pulmonary Pathology, Cleveland Clinic, Pathology and Laboratory Medicine Institute, Cleveland, OH, USA

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Ralitza H. Gavrilova, md Senior Associate Consultant, Instructor in Medical Genetics and Neurology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Mohiedean Ghofrani, md Staff Pathologist, Southwest Washington Medical Center, Vancouver, WA, USA

John R. Goldblum, md Chairman, Professor of Pathology, Department of Anatomic Pathology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

Elyse M. Grycki Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Matthew C. Hagen, md, phd Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Eyas M. Hattab, md Associate Professor, Director of Immunohistochemistry, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Dean A. Hawley, md Professor of Pathology, Forensic Pathologist, Director of Autopsy Service, Indiana University School of Medicine, Indianapolis, IN, USA

John D. Henley, md Staff Pathologist, Columbus Regional Hospital, Columbus, IN, USA

Antoinette F. Hood, md Professor and Chair, Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA, USA

James Huang, md Clinical Associate Professor, Department of Clinical Pathology, William Beaumont Hospital, William Beaumont School of Medicine, Royal Oak, MI, USA

Kenneth A. Iczkowski, md Associate Professor, Department of Pathology, University of Colorado Denver, Aurora, CO, USA

Contributors

Chris H. Jokinen, md Staff Pathologist/Dermatopathologist, Department of Pathology, St. Mary’s Hospital/Duluth Clinic Health System, Duluth, MN, USA

Jasvir S. Khurana, md Associate Professor, Department of Pathology, Temple University School of Medicine, Philadelphia, PA, USA

Nancy E. Klipfel, md Assistant Professor of Pathology, Associate Director of Surgical Pathology Fellowship, Department of Pathology and Laboratory Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

Katrina E. Kotzer Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Teresa M. Kruisselbrink Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Paul J. Kurtin, md Consultant in Hematopathology and Anatomic Pathology, Professor of Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Donna J. Lager, md Director of Renal Pathology, ProPath Laboratories, Clinical Associate Professor of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

Stephen C. Lawhorn, md Bostwick Laboratories, Glen Allen, VA, USA

Shuan C. Li, md Staff Pathologist and Director of Residency Program, Department of Pathology and Laboratory Medicine, Orlando Health, Orlando, FL, USA

Sharon X. Liang, md, phd Associate Professor, Hofstra University School of Medicine, Director of Gynecologic Pathology, North Shore-LIJ Health System, New Hyde Park, NY, USA

Noralane M. Lindor, md Consultant, Professor of Medical Genetics, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Antonio Lopez-Beltran, md, phd Professor of Anatomic Pathology, Department of Surgery, Unit of Anatomic Pathology, Cordoba University School of Medicine, Cordoba, Spain

Gregory T. MacLennan, md Professor of Pathology, Urology and Oncology, Case Western Reserve University, Director of Surgical Pathology, University Hospitals Case Medical Center, Cleveland, OH, USA

Maritza Martel, md Staff Pathologist, Department of Pathology, Providence St. Vincent Medical Center, Portland, OR, USA

Ellen D. McPhail, md Consultant in Hematopathology and Anatomic Pathology, Associate Professor of Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Claire W. Michael, md Professor of Pathology, Director of Cytopathology, Department of Pathology, University of Michigan, Ann Arbor, MI, USA

Frank P. Miller iii, md Forensic Pathologist, Coroner, Cuyahoga County, OH, USA; Instructor of Pathology, Case Western Reserve University, Cleveland, OH, USA

Elyse B. Mitchell Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Franklin R. Moore, md, phd Department of Pathology, Oregon Health & Science University, Portland, OR, USA

Alessandra F. Nascimento, md Associate Pathologist, Assistant Professor, Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

Devin Oglesbee, phd Senior Associate Consultant, Assistant Professor of Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Jean L. Olson, md Professor of Pathology, Director of Electron Microscopy, Department of Pathology, University of California San Francisco, San Francisco, CA, USA

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Contributors

Dennis P. O’Malley, md Pathologist, Clarient Inc., Aliso Viejo, CA; Adjunct Associate Professor, Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Attilio Orazi, md, frcpath Professor of Pathology and Laboratory Medicine, Director, Division of Hematopathology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA

Anil V. Parwani Division Director, Pathology Informatics, Staff Pathologist, University of Pittsburgh School of Medicine and Shadyside Hospital, Pittsburgh, PA, USA

Arie Perry, md Professor of Pathology and Neurological Surgery, Vice Chair, Director of Neuropathology Division and the Neuropathology Fellowship Program, Department of Pathology, University of California San Francisco, San Francisco, CA, USA

Eric A. Pfeifer, md Consultant in Anatomic Pathology and Forensic Medicine, Mayo Clinic, Rochester, MN, USA

Thomas P. Plesec, md Assistant Professor of Pathology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

Richard D. Press, md, phd Professor of Pathology, Director of Molecular Pathology, Oregon Health & Science University, Portland, OR, USA

Rajiv K. Pruthi, mbbs Consultant, Assistant Professor of Medicine, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Stephen S. Raab, md Professor of Pathology, Vice Chair of Quality, Director of Anatomic Pathology, University of Colorado Denver, Aurora, CO, USA

Raymond W. Redline, md Professor of Pathology and Reproductive Biology, Co-Director, Pediatric and Perinatal Pathology, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA

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Cassandra K. Runke Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Romil Saxena, mbbs, frcpath Associate Professor of Pathology, Associate Professor of Medicine, Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA

Bernd W. Scheithauer, md Consultant in Pathology, Professor of Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Munir Shajahan, md Department of Pathology, The Methodist Hospital, Houston, TX, USA

Raul G. Simental-Pizarro, md Assistant Professor, Department of Pathology and Laboratory Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

Maxwell L. Smith, md Assistant Professor, Director of Liver and Transplant Pathology, Departments of Pathology and Medicine, University of Colorado Denver, Aurora, CO, USA

Don-John Summerlin, md, ms Professor of Pathology, Director of Head & Neck Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

Geoffrey A. Talmon, md Assistant Professor, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

Fattaneh A. Tavassoli, md Professor of Pathology and Obstetrics, Gynecology, and Reproductive Sciences, Director, Women’s Health Program/Gynecologic and Breast Pathology, Yale University School of Medicine, New Haven, CT, USA

Clive R. Taylor, md, phd Professor and Chairman, Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

Contributors

Brittany C. Thomas Genetic Counselor, Instructor in Laboratory Medicine and Pathology, Mayo Clinic, Mayo College of Medicine, Rochester, MN, USA

Joseph F. Tomashefski, jr., md Professor and Chairman, Department of Pathology, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, OH, USA

Melanie Triffet-Trevino, md Staff Dermatopathologist, Dermatopathology of Wisconsin, Brookfield, WI, USA

Thomas M. Ulbright, md Lawrence M. Roth Professor of Pathology and Laboratory Medicine, Director of Anatomic Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

Guldeep Uppal, md Department of Pathology, Temple University School of Medicine, Philadelphia, PA, USA

Dan Vandersteen, md Staff Pathologist/Dermatopathologist, Department of Pathology, St. Mary’s Hospital/Duluth Clinic Health System, Duluth, MN, USA

Sean R. Williamson, md Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

Wenxin Zheng, md Professor of Pathology and Gynecology, Director of Gynecologic Pathology, Director of Molecular Pathology, The University of Arizona, Tucson, AZ, USA

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Part I General Pathology

1 Cytopathology Fadi W. Abdul-Karim, md, Jennifer Brainard, md, and Claire W. Michael, md

Contents PART A:  GYNECOLOGIC CYTOLOGY........1-5

I. The 2001 Bethesda System..................1-6 Specimen Type....................................................1-6 Specimen Adequacy...........................................1-6 General Categorization......................................1-6 Interpretation/Result.........................................1-6 Negative for Intraepithelial Lesion or Malignancy...........................................1-6 Organisms.................................................1-6 Other Nonneoplastic Findings.................1-6 Epithelial Cell Abnormalities..................1-6 Ancillary Testing................................................1-6 Automated Review.............................................1-6 Educational Notes and Suggestions (Optional).......................................................1-6

II. Specimen Adequacy Terminology/ Reporting.............................................1-7 Adequate Pap Test..............................................1-7 Endocervical/Transformation Zone Component...........................................1-7 Unsatisfactory Specimen...................................1-8

III. Organisms............................................1-8 Trichomonas vaginalis........................................1-8 Candida albicans.................................................1-8 Bacterial Vaginosis.............................................1-9 Actinomyces.........................................................1-9 Herpes Simplex Virus......................................1-10 Chlamydia trachomatis.....................................1-10 Döderlein Bacilli (Lactobacillus acidophilus)...... 1-10 Leptothrix..........................................................1-10 Molluscum Contagiosum (Pox Virus).............1-10

Enterobius vermicularis (Pinworm).....................................................1-10 Entamoeba histolytica.......................................1-10 Cytomegalovirus...............................................1-10

IV. Contaminants.....................................1-10 V. Reactive Changes...............................1-11 Typical Repair..................................................1-11 Radiation Effect................................................1-12 IUD-Associated Change...................................1-12 Atrophy.............................................................1-13 Other Reactive Changes..................................1-13 Hyperkeratosis........................................1-13 Parakeratosis...........................................1-13 Chronic Follicular (Lymphocytic) Cervicitis.............................................1-13 Folic Acid Deficiency..............................1-14 Navicular Cells........................................1-14 Decidual Cells..........................................1-14 Trophoblasts............................................1-14

VI. Squamous Cell Abnormalities............1-15 Atypical Squamous Cells.................................1-15 Atypical Squamous Cells of Undetermined Significance...........1-15 Atypical Squamous Cells: Cannot Exclude HSIL.......................1-16 Squamous Intraepithelial Lesions..................1-17 Low Grade Squamous Intraepithelial Lesion........................1-17 High Grade Squamous Intraepithelial Lesion........................1-18 Cervical Squamous Cell Carcinoma...............1-19

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_1, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Essentials of Anatomic Pathology, 3rd Ed.

VII. Normal and Reactive Endocervical Cytology............................................1-21 Endocervical Tubal Metaplasia.......................1-21 Microglandular Endocervical Hyperplasia..................................................1-22 Arias-Stella Reaction.......................................1-22 Benign Glandular Cells in the Specimens from Posthysterectomy Women..................1-22

VIII. Glandular Cell Abnormalities.............1-22 Atypical Endocervical Cells............................1-22 Atypical Endocervical Cells Favor Neoplastic.....................................................1-23 Endocervical Adenocarcinoma In Situ...........1-23 Endocervical Adenocarcinoma.......................1-25

IX. Endometrial Cytology........................1-26 Cytologically Normal Endometrial Cells........................................1-26 Atypical Endometrial Cells.............................1-27 Endometrial Adenocarcinoma........................1-28 Papillary Serous Adenocarcinoma..................1-29 Extrauterine Metastatic Adenocarcinoma..........................................1-29 Malignant Mixed Müllerian Tumor...............1-30 Lymphoma/Leukemia Cervix..........................1-30

X. Pap Test and Hpv Testing...................1-30 XI. Asc-Us Low Grade Triage Study (Alts Trial)..........................................1-30 HPV Prevalence................................................1-30 HPV Testing and Management Guidelines.....................................................1-30

Benign Lesions..................................................1-37 Pneumonia...............................................1-37 Creola Bodies (Bronchial Cell Hyperplasia).......................................1-38 Pneumocyte Type II Hyperplasia..........1-38 Pulmonary Infarct..................................1-38 Cigarette and Habitual Marijuana Smoking..............................................1-39 Radiation and ChemotherapyInduced Atypia...................................1-39 Amiodarone Induced Changes..............1-39 Hemosiderin-Laden Macrophages........1-40 Lipid-Laden Macrophages in Bronchial Lavage...........................1-40 Corpora Amylacea..................................1-40 Alveolar Proteinosis................................1-41 Sarcoidosis...............................................1-41 Miscellaneous Findings..........................1-42 Infectious Processes..........................................1-42 Viral Infection.........................................1-42 Fungal Infections....................................1-42 Tuberculosis.............................................1-43 Pneumocystitis jirovecii (Formerly Known as Pneumocystis carinii (PCP))..............1-43 Neoplastic Lesions............................................1-43 Keratinizing Squamous Cell Carcinoma..........................................1-43 Nonkeratinizing Squamous Cell Carcinoma..........................................1-44 Adenocarcinoma.....................................1-44 Large Cell Undifferentiated Carcinoma..........................................1-46 Pulmonary Neuroendocrine Tumors................................................1-46 Metastatic Carcinoma............................1-48

XII. The American Society for Colposcopy and Cervical Pathology (Asccp) Guidelines (2006)..............................1-31 XVI. Salivary Gland and Head/Neck Cytology............................................1-49 XIII. Noncorrelating Pap and Biopsy..........1-31 PART B: NONGYNECOLOGIC CYTOLOGY.................................1-33 XIV. Overview...........................................1-34 Overall Evaluation of Cytologic Smear..........1-34 Key Cellular Features......................................1-34 Cellular Patterns..............................................1-35

XV. Respiratory Cytology..........................1-36 Overview...........................................................1-36 Normal Cellular Components of Lung Cytology...............................1-36 Types of Pulmonary Specimens.............1-36 Spectrum of Cytologic Changes in Various Preparations.....................1-37

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Statistics............................................................1-49 Salivary Glands................................................1-49 Normal Findings.....................................1-49 Nonneoplastic Lesions............................1-49 Benign Neoplastic Lesions.....................1-50 Malignant Neoplasms.............................1-51 Head and Neck..................................................1-54 Nonneoplastic Lesions............................1-54 Neoplastic Lesions..................................1-54

XVII. Thyroid..............................................1-55 Overview...........................................................1-55 Benign Lesions..................................................1-56 Thyroid Cysts..........................................1-56 Thyroiditis...............................................1-56 Black Thyroid Nodule............................1-57

Cytopathology

Nodular Goiter and Colloid Nodules....1-57 Toxic Diffuse Hyperplasia (Graves Disease)...............................................1-58 Neoplastic Lesions............................................1-58 Follicular Neoplasm................................1-58 Hürthle Cell Neoplasm...........................1-59 Papillary Carcinoma..............................1-59 Medullary Carcinoma............................1-60 Anaplastic Carcinoma............................1-60 Metastatic Carcinoma............................1-61

XVIII. Breast.................................................1-61 Overview...........................................................1-61 Benign Lesions..................................................1-61 Fat Necrosis.............................................1-61 Subareolar Abscesses.............................1-62 Lactational Changes...............................1-62 Fibrocystic Changes...............................1-62 Fibroadenoma.........................................1-63 Gynecomastia..........................................1-64 Intraductal Papilloma............................1-64 Ductal Carcinoma In Situ and Invasive Carcinoma....................................................1-64 Ductal Carcinoma In Situ......................1-64 Lobular Carcinoma In Situ...................1-65 Intracystic Papillary Carcinoma...........1-65 Invasive Ductal Carcinoma....................1-65 Lobular Carcinoma................................1-66 Mucinous (Colloid) Carcinoma.............1-66 Medullary Carcinoma............................1-67 Tubular Carcinoma................................1-67 Apocrine Carcinoma..............................1-67 Phyllodes Tumor.....................................1-67 Metaplastic Carcinoma..........................1-67

XIX. Lymph Node.......................................1-68 Reactive Hyperplasia.......................................1-68 Acute Lymphadenitis.......................................1-68 Necrotizing Granulomatous Lymphadenitis.............................................1-68 Cat Scratch Disease..........................................1-68 Nonnecrotizing Granulomatous Lymphadenitis.............................................1-68 Infectious Mononucleosis.................................1-68 Malignant Lymphoma.....................................1-69 Common Variants of Lymphoma..........1-69

XX. Skin, Soft Tissue, Bone, and Cartilage.....................................1-71 Skin....................................................................1-71 Pilomatrixoma (Calcifying Epithelioma of Malherbe).................1-71 Squamous Cell Carcinoma....................1-71 Basal Cell Carcinoma.............................1-71 Malignant Melanoma.............................1-71

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Merkel Cell Carcinoma..........................1-72 Soft Tissue.........................................................1-72 Adipose Tissue Tumors..........................1-72 Fibrous and Fibrohistiocytic Lesions................................................1-72 Neural Tumors........................................1-73 Miscellaneous..........................................1-74 Bone and Cartilage...........................................1-75 Chondroma.............................................1-75 Chondroblastoma...................................1-75 Giant Cell Tumor....................................1-75 Chondrosarcoma....................................1-76 Osteosarcoma..........................................1-76 Ewing Sarcoma and PNET....................1-76 Langerhans Cell Histiocytosis (Eosinophilic Granuloma).................1-76

XXI. Esophagus, Stomach, Colon, Liver, and Pancreas......................................1-76 Esophagus.........................................................1-76 Normal Components..............................1-76 Infection...................................................1-76 Reflux Esophagitis..................................1-77 Radiation Change...................................1-77 Barrett Esophagus..................................1-77 Dysplasia..................................................1-77 Squamous Cell Carcinoma....................1-77 Adenocarcinoma.....................................1-78 Stomach.............................................................1-78 Normal Cytology.....................................1-78 Gastric Ulcer...........................................1-78 Chronic Gastritis....................................1-78 Hyperplastic or Regenerative Polyp.....1-78 Adenocarcinoma.....................................1-78 Lymphoma...............................................1-79 Colon..................................................................1-79 Normal Cytology.....................................1-79 Adenomatous Polyp................................1-79 Adenocarcinoma.....................................1-79 Liver...................................................................1-79 Normal Components..............................1-79 Benign Lesions........................................1-79 Malignant Lesions..................................1-80 Pancreas............................................................1-81 Normal Components..............................1-81 Acute Pancreatitis...................................1-82 Chronic Pancreatitis...............................1-82 Cystic Mass Lesions................................1-82 Solid Masses............................................1-83

XXII. Ovary.................................................1-84 Overview...........................................................1-84 Selected Lesions................................................1-84 Follicular Cyst.........................................1-84 Corpus Luteum Cyst..............................1-84

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Essentials of Anatomic Pathology, 3rd Ed.

Endometriotic Cyst.................................1-84 Mature Cystic Teratoma........................1-84 Cystic Granulosa Cell Tumor................1-84 Serous Cystadenoma..............................1-85 Mucinous Cystadenoma.........................1-85 Papillary Serous Cystadenocarcinoma.........................1-85 Mucinous Cystadenocarcinoma............1-85 Endometrioid Carcinoma......................1-85 Clear Cell Carcinoma.............................1-85 Granulosa Cell Tumor............................1-85 Brenner Tumor.......................................1-85 Fibrothecoma..........................................1-85 Carcinoid.................................................1-85 Dysgerminoma........................................1-85

XXIII. Kidney................................................1-86 Simple Cyst.......................................................1-86 Oncocytoma......................................................1-86 Angiomyolipoma...............................................1-86 Clear Cell Renal Cell Carcinoma...................1-86 Chromophobe Renal Cell Carcinoma............1-87 Papillary Renal Cell Carcinoma.....................1-87 Collecting Duct Carcinoma.............................1-87 Wilms Tumor....................................................1-88

XXIV. Urinary Bladder.................................1-88 Overview...........................................................1-88 Benign Lesions and Mimics of Malignancy..............................................1-89 Reactive Urothelial Cells........................1-89 Instrument Artifact and Lithiasis.......................................1-89 Decoy Cells..............................................1-89 Ileal Conduit............................................1-89 Treatment Effect.....................................1-89

6

Urothelial Neoplasm.........................................1-90 Urothelial Adenocarcinoma...................1-91

XXV. Pleural and Peritoneal Fluid...............1-92 Benign Quiescent Mesothelial Cells................1-92 Reactive Mesothelial Cells...............................1-92 Rheumatoid Pleuritis/Pericarditis..................1-93 Tuberculosis......................................................1-93 Malignant Mesothelioma.................................1-93 Metastatic Adenocarcinoma............................1-94

XXVI. Cerebrospinal Fluid and Central Nervous System.................................1-96 Specimen Preparation of CSF.........................1-96 Normal Components of CSF...........................1-96 Ependymal Cells.....................................1-96 Choroid Plexus Cells..............................1-97 Pia-Arachnoid (Leptomeningeal) Cells.....................................................1-97 Brain Parenchyma..................................1-97 Primitive (Blast-Like) Cells of Neonates................................1-97 Inflammatory Conditions................................1-97 Acute Lymphocytic Leukemia/Malignant Lymphoma...................................................1-97 Astrocytoma......................................................1-97 Ependymomas..................................................1-98 Choroid Plexus Papilloma...............................1-98 Craniopharyngioma.........................................1-98 Germinoma.......................................................1-98 Meningioma......................................................1-98 Retinoblastoma.................................................1-98 Medulloblastoma..............................................1-98 Metastatic Carcinoma......................................1-99

XXVII. Suggested Reading............................1-99

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Part A Gynecologic Cytology

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Essentials of Anatomic Pathology, 3rd Ed.

THE 2001 BETHESDA SYSTEM Specimen Type

Other

♦♦ Indicate conventional smear (Pap smear) vs. liquid-based preparation vs. other

♦♦ Endometrial cells (in a woman ≥ 40 years of age) −− Specify if negative for squamous intraepithelial lesion

Specimen Adequacy

Epithelial Cell Abnormalities Squamous Cell

♦♦ Satisfactory for evaluation (describe presence or absence of endocervical/transformation zone component (TZ) and any other quality limiting factors, e.g., partially obscuring blood, inflammation, etc.) ♦♦ Unsatisfactory for evaluation (specify reason) −− Specimen rejected/not processed (specify reason) −− Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality because of (specify reason)

General Categorization (Optional) ♦♦ Negative for intraepithelial lesion or malignancy ♦♦ Other: See “Interpretation/Result” (e.g., endometrial cells in a woman ≥ 40 years of age) ♦♦ Epithelial cell abnormality: See “Interpretation/Result” (specify “squamous” or “glandular” as appropriate)

Interpretation/Result Negative for Intraepithelial Lesion or Malignancy ♦♦ When there is no cellular evidence of neoplasia, state this in the General Categorization above and/or in the “Interpretation/Result” section of the report, whether or not there are organisms or other nonneoplastic findings

Organisms

♦♦ Atypical squamous cells −− Of undetermined significance (ASC-US) −− Cannot exclude HSIL (ASC-H) ♦♦ Low grade squamous intraepithelial lesion (LSIL) −− Encompassing: HPV/mild dysplasia/CIN1 ♦♦ High grade squamous intraepithelial lesion (HSIL) −− Encompassing: moderate and severe dysplasia, CIS; CIN2 and CIN3 −− With features suspicious for invasion (if invasion is suspected) ♦♦ Squamous cell carcinoma

Glandular Cell ♦♦ Atypical −− Endocervical cells (NOS or specify in comments) −− Endometrial cells (NOS or specify in comments) −− Glandular cells (NOS or specify in comments) ♦♦ Atypical endocervical glandular cells, favor neoplastic ♦♦ Endocervical adenocarcinoma in situ (AIS) ♦♦ Adenocarcinoma −− Endocervical −− Endometrial −− Extrauterine −− Not otherwise specified (NOS)

♦♦ Trichomonas vaginalis ♦♦ Fungal organisms morphologically consistent with Candida spp ♦♦ Shift in vaginal flora suggestive of bacterial vaginosis ♦♦ Bacteria morphologically consistent with Actinomyces spp ♦♦ Cellular changes associated with Herpes simplex virus (HSV)

Other Malignant Neoplasms (Specify) Ancillary Testing

Other Nonneoplastic Findings (Optional to Report; not Inclusive)

Automated Review

♦♦ Reactive cellular changes associated with −− Inflammation (includes typical repair) −− Radiation −− Intrauterine contraceptive device (IUD) ♦♦ Glandular cells status post hysterectomy ♦♦ Atrophy

Educational Notes and Suggestions (Optional)

8

♦♦ Provide a brief description of the test method(s) and report the result so that it is easily understood by the clinician

♦♦ If the case is examined by automated device, specify the device and result

♦♦ Suggestions should be concise and consistent with clinical ­followup guidelines published by professional organizations (references to relevant publications may be included)

Cytopathology

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SPECIMEN ADEQUACY TERMINOLOGY/REPORTING Adequate Pap Test (Figs. 1.1 and 1.2) ♦♦ An adequate test has well-visualized and well-preserved squamous cells with an estimated minimum of 8–13,000 cells (conventional Pap) and >5,000 (liquid-based Pap). This minimum cell range should be an estimate aided by published diagrams of representations of microscopic fields with different parameters of microscope objectives/oculars/field number and number of cells ♦♦ Describe presence or absence of endocervical/transformation component and any other quality indicators immediately after

Fig.  1.1. Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Superficial squamous cells, metaplastic cells, and intermediate squamous cells. LBP liquid-based preparation.

Fig. 1.2. Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Superficial, intermediate, and metaplastic squamous cells. LBP liquid-based preparation.

Satisfactory and Unsatisfactory terms. The list of quality indicators might include: absence of pertinent clinical information (such as LMP, age, etc.), air drying, or poor preservation of cellular material, excessive blood/mucous/exudates, thick cell groups, scant cellularity, and excessive cytolysis ♦♦ Any specimen with abnormal cells is by definition satisfactory for evaluation

Endocervical/Transformation Zone Component (Figs. 1.3 and 1.4) ♦♦ At least 10 well-preserved endocervical and/or squamous metaplastic cells should be observed to report that a transformation zone component (TZ) is present. In a negative Pap test, its absence does not necessarily mean that the patient requires early repeat testing especially if the patient has a negative Pap

Fig. 1.3. Satisfactory for evaluation. Endocervical-transformation zone component present. Normal endocervical cells. CP Conven­ tional preparation.

Fig. 1.4. Satisfactory for evaluation. Endocervical transformation zone component present. Immature and mature metaplastic cells. CP Conventional preparation.

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Essentials of Anatomic Pathology, 3rd Ed.

history. However, attention to regular screening is suggested. If there is a history of abnormal Pap, incomplete visualization of cervix, immunocompromised status, or poor screening history, repeat in 6 months is suggested

Unsatisfactory Specimen (Fig. 1.5) ♦♦ Clarify laboratory’s role in processing/evaluation of specimen in the report ♦♦ Suggested wording to clarify report −− Rejected Pap (a) Specimen rejected (not processed) because of the following: specimen not labeled, slide broken, etc −− Fully evaluated unsatisfactory Pap (a) Specimen processed and examined, but is unsatisfactory for evaluation of epithelial abnormality because of obscuring blood, inflammation (>75% of the cells are obscured), etc ♦♦ Additional comments or recommendations are suggested, as appropriate: An excessively bloody or inflamed Pap test may mask the screener’s ability to detect an underlying abnormality and a repeat examination/evaluation is suggested

Fig. 1.5. Unsatisfactory for evaluation, obscuring exudate. The specimen is totally obscured by acute inflammatory cells precluding evaluation. Greater than 75% obscuring is considered unsatisfactory if no abnormal cells are identified. CP Conventional preparation.

ORGANISMS Trichomonas vaginalis (Figs. 1.6 and 1.7) ♦♦ Approximately 25% of women are carriers of Trichomonas vaginalis. Trichomonas vaginalis often coexist with leptothrix and other coccoid bacteria. The organisms are small, “pear or kite-shaped,” and faintly stained with small, oval, eccentric pale nuclei and red cytoplasmic granules. Rare flagella may be observed in LBP. Cannonball cells with agglom-

Fig.  1.6. Trichomonas vaginalis. Pear-shaped organisms with eccentrically located nucleus and granular cytoplasm. LBP liquid-based preparation.

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eration of neutrophils onto squamous cells maybe observed. The squamous cells may show vacuolization, polychromasia, and “moth eaten” appearance. Granular debris and inflammation is usually present in the background

Candida albicans (Figs. 1.8 and 1.9) ♦♦ Approximately 10% of females are carriers of Candida organisms. The incidence of Candida infection increases with pregnancy, oral contraceptive use, and diabetes. The organisms

Fig. 1.7. Trichomonas vaginalis. LBP liquid-based preparation.

Cytopathology

Fig.  1.8. Fungal organisms morphologically consistent with Candida species. Pseudohyphae and spores are present. LBP liquid-based preparation.

Fig.  1.9. Fungal organisms morphologically consistent with Candida species. LBP liquid-based preparation.

are yeast forms with long pseudohyphae. “Spearing” of epithelial cells by the pseudohyphae may be observed. Inflammatory cells are generally present in the background. Torulopsis glabrata lack the pseudohyphae observed in Candida, but the two organisms may be difficult to separate on Pap test

Bacterial Vaginosis (Fig. 1.10) ♦♦ Bacterial vaginosis occurs in 10–30% of the general population. Patients have exponentially more anaerobes per ml of vaginal fluid than normal. The etiologic agents for bacterial vaginosis include Gardnerella vaginalis, anaerobic lactobacilli, and Bacteroides and Mobiluncus species. G. vaginalis (haemophilus-corynebacterium-vaginalis) may be cultured in 30–50% of asymptomatic women

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Fig. 1.10. Shift in flora suggestive of bacterial vaginosis. Clue cells with cocobacilli covering the cytoplasm. LBP liquid-based preparation.

Fig. 1.11. Bacteria morphologically consistent with Actinomyces species. A cluster of thin filamentous bacilli are present. LBP liquid-based preparation. ♦♦ A combination of Pap test, wet prep, and other tests ­including vaginal PH and “Whiff” test on KOH preparation, which is positive in symptomatic women, can establish the diagnosis. The organisms are gram variable bacilli, including numerous coccobacilli, curved bacilli, or mixed organisms imparting a “filmy” appearance to the ­preparation. Lactobacilli are absent. “Clue cells” refer to the presence of squamous cells covered by adherent, small, and uniformly spaced coccobacilli. This finding is neither specific nor sufficient for the diagnosis of bacterial vaginosis

Actinomyces (Fig. 1.11) ♦♦ Actinomyces organisms are gram positive filamentous bacteria. They are associated with the use of IUD and vaginal pessaries. Actinomyces organisms are recognized by the presence of isolated tangled aggregates of long basophilic filamentous structures with a radiating pattern

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may be associated with follicular cervicitis. The Pap test has no role in the diagnosis of this infection

Döderlein Bacilli (Lactobacillus acidophilus) ♦♦ Döderlein bacilli represent a heterogeneous group of bacilli whose function is to maintain an acid vaginal pH (3.5–4.5). They are the only species of bacteria that are capable of causing cytolysis or dissolution of cytoplasm of intermediate squamous cells by hydrolyzing intracytoplasmic glycogen, and they result in cytolysis of intermediate squamous cells

Leptothrix ♦♦ Leptothrix are filamentous rods with or without branching. They are often associated with the presence of another organism (Trichomonas, Candida) Fig. 1.12. Cellular changes consistent with herpes simplex virus. Multinucleated giant cell with molding, ground-glass nuclei, and intranuclear inclusions. LBP liquid-based preparation.

Molluscum Contagiosum (Pox Virus) ♦♦ Molluscum contagiosum is characterized by the presence of large cells with eosinophilic intracytoplasmic inclusions and pyknotic degenerative nuclei

Enterobius vermicularis (Pinworm)

Herpes Simplex Virus (Fig. 1.12) ♦♦ 80% of exposed females develop Herpes simplex virus (HSV) infection following exposure and the recurrence rate is 60%. Herpetic infection is characterized by the presence of multinucleation, molding of nuclei, groundglass nuclei, margination of chromatin, and eosinophilic intranuclear inclusions. Type I and type II (genital) herpes, or primary or secondary infections cannot be distinguished cytologically

Chlamydia trachomatis ♦♦ Intracytoplasmic vacuoles containing eosinophilic dots (elementary particles) are not specific for C. trachomatis, as they probably represent mucinous or other vacuoles. C. trachomatis

♦♦ Enterobius vermicularis has ovoid-shaped eggs with a ­double-walled shell which is flattened on one side

Entamoeba histolytica ♦♦ Entamoeba histolytica organisms are large trophozoites with large nuclei and a dot-like central karyosome. Their cytoplasm is vacuolated and contains ingested RBCs

Cytomegalovirus ♦♦ Cytomegalovirus infection in immunocompetent women is usually transient and asymptomatic. The infected cells are enlarged with a solitary basophilic intranuclear inclusion surrounded by a halo. Intracytoplasmic small granular inclusions may also be observed

CONTAMINANTS ♦♦ Alternaria. Alternaria are air-borne contaminant fungi that have short yellow brown conidiospores and transversely and longitudinally septate macroconidia (snow shoe-like) ♦♦ Pollen ♦♦ Vegetable cells. Vegetable cells have dense cell walls and structureless nuclei. They may be observed in patients with rectovaginal fistulas along with goblet cells, inflammation, and necrotic debris ♦♦ Graphite-pencil markings ♦♦ Lubricant jelly. Not recommended for gynecologic examination prior to Pap smear ♦♦ Cotton, cardboard, and tampon fibers ♦♦ Trichome. “Octopus-like” or star-shaped structure derived from leaves of arrow-wood plant

12

♦♦ Carpet beetle parts. Arrow-shaped structures that may have origin from tampon or gauze pads ♦♦ Cockleburs. Cockleburs are associated with IUD, oral ­contraceptive use, and second half of pregnancy. They are related to cellular degeneration and composed of nonimmune glycoprotein, lipid, and calcium. Cytologically they are identified as golden refractile orange crystalline rays surrounded by histiocytes. They have no clinical significance ♦♦ Hematoidin crystals. Hematoidin crystals are indicative of previous hemorrhage. They are composed of bile-like pigment formed from hypoxic tissue, but do not contain iron. Cytologically they are identified as having finer crystalline rays than cockleburs with variable shapes ♦♦ Talc particles

Cytopathology

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♦♦ Ferning. Represents arborizing palm leaves-like pattern of cervical mucus that occurs at ovulation ♦♦ “Corn flakes.” A refractile brown cell artifact representing air-trapping between the superficial squamous cell nuclei and the cover slip. It can be resolved by reprocessing

♦♦ Sperm. Sperm may be identified in the Pap test a few days after intercourse. In HIV-infected patients, the presence of sperm is indicative of unprotected intercourse

REACTIVE CHANGES (FIGS. 1.13 and 1.14) Typical Repair (Figs. 1.15 and 1.16) ♦♦ Typical repair is characterized by the presence of cohesive sheets of cells with rare or absence of isolated cells

Fig. 1.13. Reactive cellular changes associated with inflammation. Sheet of cells with slightly enlarged uniform nuclei and abundant cytoplasm. Polymorphonuclear leukocytes are present in the sheet. Elsewhere in this slide fungal organisms consistent with Candida species were observed. LBP liquid-based preparation.

Fig. 1.14. Reactive cellular changes associated with inflammation. Sheet of squamous cells with distinct borders, abundant cytoplasm, enlarged uniformly round nuclei and nucleoli. Isolated atypical cells are not observed. CP Conventional preparation.

♦♦ The sheets show cellular streaming and pseudopodia. The nuclei are enlarged with fine chromatin and smooth nuclear contours. There are prominent nucleoli that are often ­multiple

Fig. 1.15. Reactive cellular changes associated with inflammation. Typical repair characterized by a sheet of cells with distinct borders, abundant cytoplasm, and slightly enlarged nuclei with uniform chromatin pattern and nucleoli. CP Conventional preparation.

Fig. 1.16. Reactive cellular changes associated with inflammation. Typical repair. LBP liquid-based preparation.

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Fig.  1.17. Reactive cellular changes associated with radiation effect. Large intermediate and metaplastic cells with enlarged nuclei and abundant cytoplasm. Note the polymorphous staining and vacuolization. LBP liquid-based preparation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  1.18. Reactive cellular changes associated with radiation effect. LBP liquid-based preparation.

and regular. The cells have a delicate, cyanophilic cytoplasm without differentiation ♦♦ No tumor diathesis is present

Differential Diagnosis ♦♦ The differential diagnosis of typical repair includes, among others, squamous cell carcinoma (SCC) and acantholytic cells in pemphigus vulgaris ♦♦ SCC presents as discohesive abnormal cells. The tumor cells have an irregular chromatin distribution and multiple irregular nucleoli. A tumor diathesis is present ♦♦ Acantholytic cells in pemphigus vulgaris are usually observed in vaginal smears. Isolated single cells are present: referred to as tombstone cells – Tzank cells. Correlation with clinical history is essential for accurate interpretation of cells derived from pemphigus vulgaris

Radiation Effect (Figs. 1.17 and 1.18) ♦♦ Radiated cells manifest cellular enlargement (macrocytosis), and nuclear enlargement, but the N/C ratio remains normal. The cells show nuclear and cytoplasmic vacuoles and large perinuclear halos. Cellular chromatin is finely granular or degenerative (“smudged”). Karyorrhexis and karyopyknosis are observed ♦♦ Binucleation and multinucleation, and micro- and macronucleoli are typical of radiated cells. Large bizarre cells with polychromasia, cytoplasmic vacuolization, peripheral cytoplasmic projections (pseudopodia), and cytophagocytosis including intracytoplasmic neutrophils are observed

IUD-Associated Change (Fig. 1.19) ♦♦ Small clusters of hypersecretory endocervical cells are observed. The cells have abundant cytoplasm with distinct cell borders. Large cytoplasmic vacuoles (bubble-gum cytoplasm) are observed

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Fig. 1.19. Reactive cellular changes associated with intrauterine contraceptive device. Glandular cells with cytoplasmic vacuoles displacing the nuclei. CP Conventional preparation.

♦♦ The nuclei are large, uniform and may contain prominent nucleoli. Inflammatory/reparative squamous changes may be present. The background is generally clean or inflammatory ♦♦ Actinomycotic colonies and calcified debris may be observed in the background

Differential Diagnosis ♦♦ The differential diagnosis of IUD is mainly endometrial adenocarcinoma ♦♦ Adenocarcinoma of endometrium, unlike IUD-associated changes occurs in older patients (postmenopausal). Generally endometrial adenocarcinoma is characterized by the presence of many abnormal cells with associated tumor diathesis. Cells derived from adenocarcinoma have an irregular chromatin pattern and prominent nucleoli

Cytopathology

Atrophy (Figs. 1.20 and 1.21) ♦♦ Basal and parabasal cells, either as single cells or in sheets, predominate in atrophy. Tissue-like fragments/sheets of parabasal cells may be seen in severe atrophy ♦♦ Atrophic cells show generalized uniform mild nuclear enlargement with smooth contours and bland smudgy or mildly hyperchromatic chromatin ♦♦ Air drying and degeneration may result in autolysis (bare nuclei), orangophilic change in the cytoplasm (pseudoparakeratosis), and a granular background. These changes are more common in CP than in LBP ♦♦ “Blue blobs” which represent inspissated mucus or nuclear material are often seen in atrophic smears and may mimic atypical cells

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Other Reactive Changes Hyperkeratosis (Fig. 1.22) ♦♦ Hyperkeratosis (HK) may represent a nonspecific reaction to chronic cervicitis, uterine prolapse. It may occur in reaction to previous biopsy, cryosurgery, or instrumentation, or as a manifestation of in utero diethylstilbestrol (DES) exposure ♦♦ HK may represent a reactive surface reaction overlying SIL (approximately 10%), usually LSIL or a reaction to persistent or recurrent disease in patients with prior biopsy/­ cytology-proven SIL. The presence of anucleated squamous cells during pregnancy suggests ruptured fetal membranes

Cytologic Features ♦♦ HK cells are characterized by the presence of clusters or groups of anucleated and granular superficial polygonal squamous cells. Rare, isolated anucleated cells probably represent contaminants from vulva or vagina

Parakeratosis (Fig. 1.23) ♦♦ Parakeratosis (PK) represents a reactive surface process ­similar to HK. Persistence of PK without a known etiology may warrant further investigation to exclude an associated squamous intraepithelial lesion

Cytologic Features ♦♦ PK cells present as isolated or loose sheets of miniature round to oval superficial cells with dense orangophilic cytoplasm. They possess small uniform pyknotic nuclei

Chronic Follicular (Lymphocytic) Cervicitis (Fig. 1.24)

Fig.  1.20. Negative for intraepithelial lesion or malignancy. Atrophy. Maturation is not observed. Smear consists predominantly of parabasal cells. LBP liquid-based preparation.

Fig.  1.21. Negative for intraepithelial lesion or malignancy. Atrophy. Granular backround, basal cells, and “blue blobs” (CCP).

♦♦ Cells originating from chronic follicular (lymphocytic) cervicitis (CLC) represent a polymorphous population of mature lymphocytes, plasma cells, and histiocytes. The presence of “tingible” body macrophages is characteristic of CLC. CLC has no clinical significance and reporting is optional

Fig. 1.22. Reactive cellular changes. Hyperkeratosis. Anucleated mature squamous cells with absent ghost-like nuclei. LBP ­liquid-based preparation.

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Fig.  1.23. Reactive cellular changes. Parakeratosis. Miniature brightly orangophilic cells with small hyperchromatic nuclei. LBP liquid-based preparation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 1.25. Decidua. These cells were observed on a Pap smear from a pregnant woman. They show abundant eosinophilic to amphophilic cytoplasm and enlarged nuclei with smudged chromatin pattern. CP Conventional preparation.

menstrual cycle, pregnancy, and in the setting of high progesterone medications. Cytolysis may be prominent under those same conditions

Decidual Cells (Fig. 1.25) ♦♦ Decidual cells may be seen in Paps from pregnant women and women on birth control pills or progesterone therapeutic agents. Clinical history is important for accurate interpretation

Cytologic Features ♦♦ Decidual cells usually present as isolated cells or loose sheets of large, polygonal or round cells. They have abundant granular eosinophilic or amphophilic cytoplasm. Slight to moderate nuclear enlargement is present, but the N/C ratio remains low. The nuclei are round with vesicular or smudged chromatin and degenerative changes. Nucleoli may be prominent Fig. 1.24. Reactive cellular changes. Chronic lymphocytic cervitis. Polymorphous population of lymphoid cells with tingible body macrophages. LBP liquid-based preparation.

Folic Acid Deficiency ♦♦ The cytologic findings in folic acid deficiency are similar to those of early radiation effect. There is nuclear and cellular enlargement; nuclear enfolding; binucleation and multinucleation. The nuclei are hypochromatic with smooth contours. Cytoplasmic vacuolization and cytoplasmic polychromasia are usually observed

Navicular Cells ♦♦ Navicular cells are observed with pregnancy. They are boatlike intermediate cells with ecto-endoplasmic differentiation and glycogen. Navicular cells can also be seen late in the

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Trophoblasts ♦♦ Trophoblasts are rarely seen in normal pregnancy. Their presence may indicate threatened abortion (6% of patients) when observed in the first trimester. Partial premature separation of the placenta should be suspected when trophoblasts are observed in the third trimester of pregnancy ♦♦ Retained placental tissue should be suspected when trophoblasts are observed 4 weeks after termination of pregnancy

Cytologic Features ♦♦ Syncytiotrophoblasts have abundant cyanophilic cytoplasm and distinct cell borders. Their multiple nuclei (20+) are round to oval with nuclear overlapping but without molding. The chromatin is finely granular and evenly distributed with inconspicuous nucleoli ♦♦ Cytotrophoblasts are large cells with uniformly amphophilic cytoplasm and large irregular nuclei that may be lobulated and vacuolated

Cytopathology

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SQUAMOUS CELL ABNORMALITIES Atypical Squamous Cells Definition ♦♦ Cytologic changes suggestive of a squamous intraepithelial lesion (SIL) that are quantitatively or qualitatively insufficient for a definitive interpretation. Atypical squamous cell (ASC) does not represent a single biologic entity. ASC is subdivided: ASC-US and ASC-H

Atypical Squamous Cells of Undetermined Significance

♦♦

♦♦

♦♦ Atypical squamous cells of undetermined significance (ASC-US) represents approximately 90% of all ASC. The ALTS trial showed that approximately 50% have oncogenic (high risk) HPV types

Cytologic Features ♦♦ ASC-US may manifest a wide range of cytologic features. The cytologic interpretation for all of these variations remains ASC-US. Designation by cell type of origin is not used; however, these are listed below to assure recognition of ASC-US and to separate it from other often overlapping manifestations of normal/reactive cells or more advanced cytologic epithelial abnormalities ♦♦ ASC-US resembling intermediate or superficial squamous cells represents the most common pattern (Figs.  1.26 and 1.27). The cells are usually isolated and few in number. Their size and shape are that of superficial or intermediate cells. Nuclear size is 2–3× (or 2½–3×) size of an intermediate cell nucleus or 2× size of the nucleus of an immature squamous metaplastic cell. There is a slight increase in N/C ratio. Minimal nuclear hyperchromasia, irregularity, clumping, smudging,

Fig.  1.26. ASC-US (LBP). Atypical intermediate squamous cells with round hypochromatic nuclei that are at 2–3 times the size of the adjacent normal intermediate cell nuclei. ASC-US atypical squamous cells of undetermined significance, LBP ­liquid-based preparation.

♦♦

♦♦

or multinucleation may be observed. ASC-US cells do not include inflammatory or reparative/reactive “atypia” ASC-US cells originating from squamous metaplastic cells have similar enlarged nuclei to ASC-US of intermediate or superficial cells (70–120  mm2). They have finely granular, evenly distributed chromatin. Their cytoplasm has metaplastic cell features in that it is less abundant and more cyanophilic. The cells are more round with an N/C ratio higher than in conventional ASC-US in intermediate or superficial squamous cells Atypical repair has all the essential features of typical repair. However, focally there may be some cellular overlap and slight discohesiveness. There is some loss of nuclear polarity, slight anisonucleosis, and slight irregularity of nuclear contour. Prominent single or multiple nucleoli are present as well as mitotic figures and an inflammatory background. Atypical repair is generally considered under the ASC-US category. However, if the “atypia” described above is prominent and concerning for HSIL or a more advanced lesion, then atypical repair can be considered under the ASC-H category ASCs in an atrophic smear show nuclear enlargement with concomitant hyperchromasia. They may manifest more marked irregularities in cell shape, nuclear contours, or chromatin distribution Atypical parakeratosis cells are generally considered as ASC-US cells (Fig. 1.28). These cells demonstrate nuclear abnormalities noted above and are associated with dense orangophilic cytoplasm. Spindled and variable/irregular outlines may be observed. The cells show high N/C ratio with irregular nuclear contours. Dark nuclei with dense or smudged chromatin may be observed

Fig. 1.27. ASC-US. Intermediate cells with nuclear enlargement (2–3×) intermediate cell nuclei and minimal hyperchromasia. No inflammation is present in the background. ASC-US atypical squamous cells of undetermined significance, LBP liquid-based preparation.

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Fig.  1.28. ASC-US. Atypical parakeratosis. Spindled and slightly pleomorphic orangophilic parakeratotic cells with mild nuclear enlargement. ASC-US atypical squamous cells of undetermined significance, LBP liquid-based preparation. ♦♦ Cells with equivocal changes for HPV are placed in the ASC-US category. These cells manifest partial koilocytosis/ perinuclear halos. Bi- or multinucleation may be observed. The nuclei are spindled with mild hyperchromasia ♦♦ Cells that manifest drying artifact, especially in conventional smears, may have features that mimic ASC-US. This phenomenon has been lessened by LBC ♦♦ ASC-US differs from LSIL in that the latter show more marked nuclear enlargement (>×3 size of intermediate cell nucleus, often ×5–6 the size of an intermediate cell nucleus), more hyperchromasia, more irregularities of nuclear contour, bi- or multinucleation, and perinuclear halos with sharp borders (koilocytes)

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  1.29. ASC-H. Atypical immature metaplastic cells with enlarged nuclei and nuclear irregularity. The findings are not diagnostic of HSIL. Only rare atypical cells were present. ASCH atypical squamous cells cannot exclude high grade squamous intraepithelial lesion, HSIL high grade squamous intraepithelial lesion, LBP liquid-based preparation.

Atypical Squamous Cells: Cannot Exclude HSIL (Figs. 1.29 and 1.30) ♦♦ Atypical squamous cells: cannot exclude HSIL (ASC-H) constitutes approximately 5% of all ASC. ASC-H is defined as having cytologic changes that are suggestive of high grade squamous intraepithelial lesion (HSIL), but lack criteria for definitive interpretation ♦♦ The association of ASC-H with underlying CIN2 and CIN3 for ASC-H (30–40%) is lower than for HSIL, but sufficiently higher than for ASC-US to warrant consideration of different management recommendations. A few cases of ASC-H may have invasive carcinoma (2–3%) ♦♦ The ALTS trial noted that approximately 70–80% have oncogenic (high risk) HPV types. In common practice, this percentage would be expected to be lower as a variety of other cellular change mimicking ASC-H are commonly included under this interpretation

Cytologic Features ♦♦ ASC-H may be observed as “atypical immature metaplastic cells.” These cells are small cells that usually mani-

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Fig. 1.30. ASC-H. Atypical immature metaplastic cells. ASC-H atypical squamous cells cannot exclude high grade squamous intraepithelial lesion, LBP liquid-based preparation. fest singly or in tight clusters of usually less than ten cells. The nuclear size of ASC-H cells is 1.5–2× that of metaplastic cells. The nucleus is usually round to oval and has dense amphophilic cytoplasm. Ectoplasm and endoplasm may be distinctive. The cells have a high N/C ratio similar to HSIL with mildly hyperchromatic nuclei. The presence of numerous cells with nuclear hyperchromasia, chromatin irregularity, and abnormal nuclear shapes favors HSIL

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♦♦ Clusters of cells demonstrating markedly atypical repair can also be included under the ASC-H category if the differential interpretation raises the possibility of or includes carcinoma. These cells occur in cohesive sheets with nuclear pleomorphism or some loss of cohesion ♦♦ An interpretation of ASC-H can be rendered for thick tissue fragments/crowded sheet pattern. These fragments resemble a microbiopsy of crowded cells. The cells show loss of polarity or are difficult to see. Rare isolated atypical small cells that do not necessarily show features of immature metaplastic cells can also be designated as ASC-H. These cells demonstrate high N/C ratio, nuclear irregularities/grooves, and hyperchromasia

Differential Diagnosis ♦♦ ASC-US cells are mature squamous cells with lower N/C ratio ♦♦ Immature metaplastic cells have regular round nuclei and uniform finely granular chromatin ♦♦ HSIL cells are usually more numerous, often occurring in syncytial aggregates and demonstrate more pronounced increased N/C ratio, more marked nuclear irregularities, and coarser granular chromatin than ASC-H ♦♦ Endometrial cells are smaller, exfoliate in 3D clusters, and have a round eccentric nucleus with finely granular chromatin ♦♦ Histiocytes have foamy cytoplasm, bean-shaped nuclei, and low N/C ratio

Fig. 1.31. LSIL (mild dysplasia with HPV effect). Intermediate cells with mild nuclear enlargement and nuclear contour irregularities. Perinuclear hollows consistent with HPV effect are present. HPV human papillomavirus, LSIL low grade squamous intraepithelial lesion, LBP liquid-based preparation.

Squamous Intraepithelial Lesions ♦♦ Squamous intraepithelial lesions (SIL) encompasses a spectrum of noninvasive cervical epithelial abnormalities traditionally classified as flat condyloma, dysplasia/carcinoma in situ, and CIN. Low grade lesions include the cellular changes associated with HPV cytopathic effect and mild dysplasia/ CIN1. High grade lesions encompass moderate dysplasia, severe dysplasia, and carcinoma in situ (CIS) (CIN2, 3)

Low Grade Squamous Intraepithelial Lesion (Figs. 1.31–1.33) ♦♦ The transition from ASC-US to low grade squamous intraepithelial lesion (LSIL) involves increase in nuclear size, nuclear hyperchromasia, N/C ratio, and nuclear envelope irregularities. HPV cytopathic effect is synonymous with SIL and not with ASC ♦♦ LSIL is characterized by the presence of single or sheets of large polygonal cells with nuclear enlargement that is approximately 3–6× the size (usually 4–5× the size; >150 mm2) of the normal intermediate cell nucleus or 2–4× the size of the normal immature squamous metaplastic cell nucleus ♦♦ The nuclei of LSIL exhibit nuclear hyperchromasia and moderate variation in nuclear size. Mild nuclear envelope irregularities may be observed in some nuclei. Binucleation/ multinucleation may be present. The chromatin pattern is usually finely granular and uniformly distributed. Nucleoli are generally absent. LSIL typically includes koilocytes with perinuclear halos surrounded by dense peripheral cytoplasm.

Fig. 1.32. LSIL (mild dysplasia). Intermediate squamous cells with mildly enlarged nuclei and slight hyperchromasia. LSIL low grade squamous intraepithelial lesion, LBP liquid-based preparation.

The nuclei of koilocytes are enlarged and hyperchromatic and with slight irregular contour ♦♦ Dyskeratosis, binucleation, multinucleation, and nuclear pleomorphism may be observed in these cells. The cytologic features of LSIL in liquid-based cytology are similar to those of conventional preparations. There may be, however, decreased hyperchromasia, increased visualized nuclear detail, and more apparent nuclear membrane irregularities

Differential Diagnosis ♦♦ HSIL exhibits significant increase in N/C ratio, hyperchromasia, and marked chromatin abnormalities and irregularities. The cells are usually arranged in syncytial aggregates

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Fig. 1.33. CIN 1; Mild dysplasia with evidence of HPV infection. Disordered proliferation of dysplastic cells in the lower third of the epithelium and HPV effect toward the surface (histology). CIN cervical intraepithelial neoplasia, HPV human papillomavirus.

Fig.  1.34. HSIL (moderate dysplasia). Sheet of cells with enlarged nuclei, irregularities of nuclear contour, and coarse chromatin pattern. HSIL high grade squamous intraepithelial lesion, LBP liquid-based preparation. ♦♦ ASC-US cells tend to be few in number and there is only slight nuclear enlargement (×2–3 intermediate cell nucleus). The chromatin pattern in ASC-US is stippled in contrast to the coarse chromatin pattern of HSIL, and the nuclear membranes are smooth

High Grade Squamous Intraepithelial Lesion (Figs. 1.34–1.38) ♦♦ Compared with LSIL, HSIL cells show increased frequency of cell aggregates and syncytial-like arrangements, immature cytoplasmic characteristics or pleomorphic keratinized configurations, and increased nuclear hyperchromasia. There is, in addition, an increase in chromatin clumping and coarsening

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Fig.  1.35. HSIL (moderate dysplasia). Metaplastic cells with enlarged nuclei, irregular nuclear contours, and coarse chromatin pattern. HSIL high grade squamous intraepithelial lesion, LBP liquid-based preparation.

Fig. 1.36. HSIL (severe dysplasia-cis). Syncytial cluster of small cells with very high nuclear to cytoplasmic ratio, markedly irregular nuclear contours, and coarse but equally distributed chromatic pattern. HSIL high grade squamous intraepithelial lesion, LBP liquid-based preparation.

of chromatin, irregularities of nuclear outline, and N/C ratio (the overall cell and nuclear size, however, are smaller than LSIL). Generally, HSIL cells tend to be round to oval with lacy, delicate, or metaplastic cytoplasm. Tumor diathesis is absent in SIL ♦♦ In liquid-based cytology, HSIL cells may be fewer in number than CP smears and the cells tend to be more isolated or present in small groups. The nuclear membrane irregularities are distinctly prominent, and hyperchromasia is often observed as coarsening of chromatin material rather than the typical darkening of the nuclear stain in CP smears

Cytopathology

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keratinizing dysplasia is usually viewed as HSIL to assure that a biopsy is obtained to evaluate severity of the lesion and to exclude the presence of invasive carcinoma

Differential Diagnosis ♦♦ Unlike HSIL, invasive SCC is characterized by marked ­cellular pleomorphism, irregular chromatin pattern, prominent nucleoli, and the presence of tumor diathesis ♦♦ Endocervical adenocarcinoma in situ is characterized by a picket-fence arrangement of columnar cells with peripheral palisading (“feathering”) and granular cytoplasm. The nuclei are usually oval, monotonous, and hyperchromatic. This contrasts with the disorderly syncytial arrangement of HSIL cells, which are smaller and exhibit variation in nuclear size and shape Fig.  1.37. HSIL (severe dysplasia-cis). Loose arrangement of small immature cells with high nuclear to cytoplasmic ratio, markedly irregular nuclear contours, and coarsely granular chromatic pattern. HSIL high grade squamous intraepithelial lesion, CP Conventional preparation.

Cervical Squamous Cell Carcinoma ♦♦ Squamous cell carcinoma (SCC) is characterized by the presence of many discohesive abnormal cells. There is loss of cellular and nuclear polarity. The carcinoma cells are about 1/5 or less the size of normal superficial or intermediate squamous cells. The nuclear size is about 2–4× nucleus of that of intermediate squamous cell nucleus. The N/C ratio is very high and the chromatin is coarse and irregularly distributed with parachromatic clearing. Tumor diathesis, which consists of the host response of lysed blood, cellular debris, inflammatory cells, and protein precipitate, is generally observed in over 50% of SCC ♦♦ In liquid-based cytology, SCC cells may demonstrate a greater depth of focus of cell groups. The nuclei maintain features indicative of malignancy but are usually less hyperchromatic when compared to CP smears. In addition, ­nucleoli are more prominent and there is a distinctive necrotic background pattern consisting of debris immediately surrounding individual cells or clusters of cells ­(clinging diathesis)

Classification of SCC Fig. 1.38. CIN 3; Severe dysplasia-cis (histology). Full-thickness disordered maturation with dysplastic cells showing hyperchromatic nuclei and high nuclear: cytoplasmic ratio. CIN cervical intraepithelial neoplasia.

♦♦ “Keratinizing dysplasia” refers to the pleomorphic appearance of the cells rather than cytoplasmic staining. The cells exhibit pleomorphism with marked anisonucleosis, caudate (spindle, elongated, tadpole, or bizarre forms), coarsely granular or smudged chromatin, dense orangophilic cytoplasm with distinct borders. The severity of keratinizing dysplasia is usually reflected by degree of pleomorphism rather than cytological atypia and as such may be difficult to predict. It may be also more difficult to distinguish keratinizing dysplasia from keratinizing squamous cell carcinoma (KSCC), although KSCC generally has more discohesive cells and more marked nuclear pleomorphism. As such,

♦♦ SCC is subtyped into keratinizing (KSC) and large cell nonkeratinizing (LCNK) squamous cell carcinoma. Each type exhibits some variation in cytologic features ♦♦ KSCC cells show significant pleomorphism with spindle, bizarre, tadpole, and caudate cells (Figs.  1.39 and 1.40). They have a dense keratinizing orangophilic cytoplasm with distinct cell borders. Their nuclei are pleomorphic and hyperchromatic with coarsely clumped chromatin and inconspicuous nucleoli. Anucleated squamous cells and atypical parakeratotic cells may be present in the background. KSC lacks tumor diathesis ♦♦ Large cell nonkeratinizing squamous cell carcinoma cells show less anisocytosis and anisonucleosis than KSC (Figs. 1.41 and 1.42). There are numerous abnormal single cells and syncytial groups of cells with dense cytoplasm, and indistinct borders. The N/C ratio is high. The nuclei tend to be round to oval with nuclear overlapping, coarse granular chromatin with chromatin clearing, and macronucleoli. Tumor diathesis is present in LCNK carcinoma

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Fig. 1.39. Squamous cell carcinoma, keritinizing type. Markedly pleomorphic orangophilic cells are present. The nuclei are irregular with enlarged hyperchromatic nuclei and irregular coarse chromatin pattern. CP Conventional preparation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  1.41. Squamous cell carcinoma, large cell nonkeratinizing type. Cluster of malignant cells with pleomorphic nuclei, irregular chromatin pattern and nucleoli. LBP liquid-based preparation.

Fig. 1.40. Invasive squamous cell carcinoma, keratinizing type. Keratin pearls are present in this invasive moderately differentiated squamous cell carcinoma (histology).

♦♦ Small cell carcinomas are usually of neuroendocrine origin (Figs.  1.43 and 1.44). The neoplastic cells are generally small, cuboidal or round, and present as single cells or in small tight syncytial aggregates. The tumor cells have scant cyanophilic cytoplasm, a high N/C ratio and round to oval nuclei with hyperchromatic and coarsely granular chromatin. Nucleoli are not observed. Nuclear molding, necrosis, and crush artifact are prominent

Differential Diagnosis ♦♦ Endometrial cells generally occur in three-dimensional clusters of cells that have kidney bean-shaped nuclei, evenly

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Fig. 1.42. Squamous cell carcinoma, large cell nonkeratinizing type. Invasive squamous cell carcinoma that lacks squamous pearls (histology).

distributed chromatin, and smooth nuclear contours. Their cytoplasm tends to be foamy. Macronucleoli are not observed and there is a lack of tumor diathesis ♦♦ HSIL cells present as aggregates and syncytial-like arrangements. Their nuclei are round to oval with delicate cytoplasm. Unlike SCC, HSIL cells do not exhibit significant nuclear molding, chromatin clearing, or tumor diathesis

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Fig. 1.43. Small cell carcinoma. Malignant small cells with high nuclear: cytoplasmic ratio, molding, and single file arrangement. LBP liquid-based preparation.

Fig. 1.44. Small cell carcinoma. Small blue cells with molding and necrosis (histology).

NORMAL AND REACTIVE ENDOCERVICAL CYTOLOGY ♦♦ Normal endocervical cells may occur singly or in strips, rosettes, or sheets. They are usually elongated and columnar. When viewed on end, they are smaller, polygonal or cuboidal, and demonstrate the typical “honeycomb” arrangement. The cytoplasm of endocervical cells is usually described as granular, but it may show fine vacuolization. The nuclei are round to oval and are often indented or possess a nuclear nipple protrusion of the nuclear contents at one end. The nuclear chromatin is finely granular and evenly dispersed. Multiple small chromocenters and one or more small eosinophilic nucleoli may be present. Binucleation or multinucleation is not uncommon. Variability is observed in cells derived from various regions of the endocervical canal ♦♦ Endocervical cells with reactive/reparative changes occur in sheets and strips with minor degrees of nuclear overlap. They may exhibit nuclear enlargement, up to three to five times the area of normal endocervical nuclei. Mild variation in nuclear size and shape occurs. Slight hyperchromasia is frequently evident. Nucleoli are often present. The cells usually have abundant cytoplasm. Distinct cell borders are discernible

Endocervical Tubal Metaplasia (Figs. 1.45–1.47) ♦♦ Tubal metaplasia (TM) is a normal finding especially in the upper endocervical canal. TM may be related to unopposed estrogen. Cells derived for TM tend to be present as small crowded cellular strips, clusters, or flat honeycomb sheets. They have evenly spaced uniform and basally oriented round to oval nuclei. Large stripped nuclei may be observed. The nuclei are finely granular, with evenly distributed or washed-out

Fig. 1.45. Endocervical cells, tubal metaplasia. A strip of ciliated columnar endocervical cells. CP Conventional preparation.

chromatin. Small inconspicuous nucleoli may be observed. The presence of terminal bars/cilia, and mucus depletion are characteristic features of TM. Ciliocytophthoria may be present

Differential Diagnosis ♦♦ AIS cells lack terminal bars or cilia, show nuclear hyperchromasia and a coarse chromatin pattern and demonstrate nuclear feathering and rosettes. Apoptosis is only observed in AIS

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Essentials of Anatomic Pathology, 3rd Ed.

Microglandular Endocervical Hyperplasia ♦♦ Microglandular endocervical hyperplasia (MGH) is related to progesterone effect and may be observed in pregnancy, birth control pills, and postmenopausal women on estrogen. The cytologic features of MGH are usually indistinguishable from those of reactive hyperplasia and regeneration/ repair ♦♦ Associated endocervical changes may include the presence of large sheets of polygonal or columnar cells with minimal stratification, pseudoparakeratotic degenerative changes, and the presence of spindle and elongated metaplastic cells ♦♦ Terminal bars and cilia may be present Fig. 1.46. Endocervical cells, tubal metaplasia. Columnar endocervical cells, one multinucleated, with cilia. CP Conventional preparation.

Arias-Stella Reaction ♦♦ Arias-Stella reaction (ARS) is a nonneoplastic hormonerelated phenomenon that is usually observed in pregnancy ♦♦ Clinical correlation is essential for diagnosis ♦♦ The cytologic features of ARS are nondiagnostic and the cytologic interpretation is that of atypical endocervical cells. Single or small groups of “atypical” glandular cells with low N/C ratio and abundant clear or faintly eosinophilic cytoplasm may be observed. Nuclear enlargement, hyperchromasia, pleomorphism, and nuclear grooves can be observed. The nuclear chromatin is usually granular, with evenly distributed chromatin. Nuclei are often smudged with groundglass appearance

Benign Glandular Cells in the Specimens from Posthysterectomy Women

Fig. 1.47. Tubal metaplasia. Ciliated tubal epithelium lines an endocervical gland (histology).

♦♦ The likely sources of these benign cells include prolapse of uterine tube, vaginal endometriosis, fistula, vaginal adenosis not associated with DES exposure, or glandular metaplasia associated with prior radiation or chemotherapy ♦♦ These findings are considered benign and do not warrant an interpretation/diagnosis of “atypical glandular cells” (AGC)

GLANDULAR CELL ABNORMALITIES ♦♦ Whenever possible, atypical glandular cells should be qualified as endocervical or endometrial in origin ♦♦ When the distinction cannot be made, the cytology report of atypical glandular cells indicates the uncertainty as to the source of these cells ♦♦ Atypical glandular cell rates in the typical cytology laboratory are usually infrequent, with compiled data showing means between 0.3 and 1%

Atypical Endocervical Cells ♦♦ Atypical endocervical cells are defined as having changes beyond those encountered in reactive processes, but are

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insufficient for favoring neoplasia or an unqualified diagnosis of AIS. These changes include mild cellular crowding without nuclear pseudo stratification, and nuclear enlargement, hyperchromasia, and anisocytosis ♦♦ Followup of atypical endocervical cells reveals the following: 20–40% are normal, reactive or benign process, 35–80% are derived from squamous lesions, and 0–11% represent endocervical abnormalities. This points to the difficulties inherent in interpretation of these lesions. SIL may involve endocervical gland necks and mimic glandular cells. Features that should favor SIL include the presence of syncytial groups, opaque hyperchromatic nuclei, dense cytoplasm, and the presence of individual SIL cells

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Atypical Endocervical Cells Favor Neoplastic (Figs. 1.48 and 1.49) ♦♦ An interpretation of atypical endocervical cells favor neoplastic is rendered when the atypical endocervical cells have some but not all the criteria as outlined for AIS or other “atypical” presentation which should be individually and specifically categorized in a qualifying statement

Endocervical Adenocarcinoma In Situ (Figs. 1.50–1.54) Cytologic Features ♦♦ The cytologic features of “the endocervical type” of AIS in conventional smears include Fig.  1.50. AIS. Hyperchromatic endocervical cells with pseudostratification, rosette-like arrangement, and feathering. AIS adenocarcinoma in situ.

Fig.  1.48. Atypical endocervical cells, favor neoplastic. Crowding and pseudostratification of two strips of atypical endocervical cells. Followup biopsy showed AIS. AIS adenocarcinoma in situ, LBP liquid-based preparation.

Fig. 1.49. Atypical endocervical cells, favor neoplastic. A strip of pseudostratified atypical endocervical cells and a disorganized cluster of similar cells. The findings fall short of those characteristic of AIS. AIS adenocarcinoma in situ, LBP liquidbased preparation.

Fig.  1.51. AIS. Pseudostratified hyperchromatic endocervical cells with rosette-like arrangement and feathering. AIS adenocarcinoma in situ, CP Conventional preparation.

Fig. 1.52. AIS. Crowded three-dimensional clusters of endocervical cells with enlarged elongated nuclei and coarsely granular chromatin. Feathering is noted. AIS adenocarcinoma in situ, LBP liquid-based preparation.

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Fig. 1.53. AIS. Endocervical gland with stratified neoplastic lining (histology, low power). AIS adenocarcinoma in situ.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 1.55. Lower uterine segment endometrium can mimic AIS. Branching fragment of epithelial and stromal cells. AIS adenocarcinoma in situ, CP Conventional preparation. have dense immature cytoplasm, nuclear overlap, and hyperchromasia, with increased difficulty in visualization of individual nuclei in the groupings. A “disordered honeycomb” arrangement may be the only feature present in some cases −− The key architectural features may be more subtle than in conventional smears. The margins of the groups become smoother and sharper with low degrees of nuclear protrusion (feathering). Pseudostratified strips of cells are often the most prominent architectural arrangement of AIS in LBC specimens

Differential Diagnosis Fig. 1.54. AIS. Endocervical gland with pseudostratification of enlarged hyperchromatic elongated nuclei and mitotic figures (histology, high power). AIS adenocarcinoma in situ.

−− The presence of a moderate to highly cellular smear composed of tight clusters and cohesive sheets of glandular cells showing pseudo stratification, rosette formation, and feathering at the edge of sheets. The abnormal endocervical cells have uniform nuclear enlargement, hyperchromasia, nuclear irregularities, and crowding with an elongate configuration ♦♦ The nuclear chromatin is coarsely granular and evenly distributed. Mitoses, apoptotic bodies, and micronucleoli may be observed. The cytoplasm is delicate and finely vacuolated with diminished mucin production. The background is usually clean or inflammatory. Approximately 50% of AIS cases are associated with SIL

Cytologic Features ♦♦ The cytologic features of AIS in liquid-based preparations are characterized by −− The presence of “hyperchromatic/dark crowded cell ­clusters.” These crowded hyperchromatic cell clusters

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♦♦ Tubal metaplasia is characterized by the presence of terminal bars and cilia. The nuclei are more evenly spaced than those observed in AIS, and resemble a honeycomb pattern. Mitoses, apoptosis, and nuclear hyperchromasia are not observed ♦♦ Cells derived from lower uterine segment endometrium typically occur as cohesive aggregates of a mixture of glandular and stromal cells (Fig. 1.55). The cell aggregates are large with tubular branched glands that may fold and appear three-dimensional. Cell polarity is retained. The nuclei are smaller and more uniform than those of AIS and have finely granular chromatin ♦♦ Repair/reactive processes are characterized by the presence of flat sheets of polygonal cells in a honeycomb arrangement. Single atypical cells are absent. The cells have abundant cytoplasm and distinct cell borders. They are uniform cells with low N/C ratios. Minor degrees of nuclear overlap may be observed in reactive/reparative processes as well as nuclear enlargement, up to three to five times the area of normal endocervical nuclei, and mild variation in nuclear size and shape. Unlike AIS, the hyperchromasia in reactive/ reparative processes is slight and nucleoli are often present ♦♦ HSIL involving endocervical glands may show feathering, however, it is often restricted to one end of a crowded sheet.

Cytopathology

HSIL cells are usually arranged in large syncytial aggregates, with ill defined cell borders, and loss of polarity. HSIL cells have dense cytoplasm and hyperchromatic nuclei with nuclear membrane irregularities. Strips, rosettes, or pseudostratified atypical columnar cells that are characteristic of AIS are not observed in HSIL. Unlike AIS, numerous normal endocervical cells and individual dysplastic squamous cells are typically present in the background in HSIL. Since AIS is much less frequent than HSIL, the latter interpretation should statistically more likely represent the true cervical abnormality (Figs. 1.56 and 1.57)

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In addition, adenocarcinoma shows isolated strips and single or discohesive sheets of columnar or cuboidal cells often in three-dimensional clusters. The nuclei of adenocarcinoma are round to oval with coarse granular chromatin, chromatin clearing, and marconucleoli. An increase in nuclear size and nuclear pleomorphism is noted in less differentiated tumors. Multinucleation and mitotic figures may be present. The cytoplasm of adenocarcinoma cells is more abundant foamy or finely vacuolated cytoplasm than AIS. Necrotic granular (tumor) diathesis is usually present

Endocervical Adenocarcinoma (Figs. 1.58 and 1.59) ♦♦ Endocervical adenocarcinomas present as highly cellular specimens that demonstrate all cytologic features of AIS.

Fig. 1.58. Adenocarcinoma, endocervical. Columnar cells with eccentric large round to oval nuclei, irregular chromatin pattern, nucleoli, and eosinophilic granular cytoplasm. Tumor diathesis is present in the background. CP Conventional preparation. Fig. 1.56. HSIL involving endocervical glands mimicking AIS. Syncytial cluster of HSIL in a tight cluster with rounded contour. AIS adenocarcinoma in situ, HSIL high grade squamous intraepithelial lesion, LBP liquid-based preparation.

Fig. 1.57. CIN 3; severe dysplasia/carcinoma in situ involving endocervical glands. The endocervical glands are occupied by dysplastic squamous cells extending from the surface (histology). CIN cervical intraepithelial neoplasia.

Fig.  1.59. Adenocarcinoma, endocervical. Adenocarcinoma cells with suggestion of a columnar configuration and glandular foundation. The nuclei are elongated and hyperchromatic with irregularly distributed chromatin pattern and nucleoli. The cytoplasm is basophilic and granular. Tumor diathesis is present in the background. CP Conventional preparation.

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♦♦ Minimal deviation adenocarcinoma (adenoma malignum) can be a very difficult cytologic diagnosis. In the proper clinical context, the presence of hypercellular specimens with strips, honeycomb sheets, and three-dimensional clusters of cells with distinct cell borders, abundant lacy cytoplasm, round to oval nuclei (rather than elongated) with coarse granular

chromatin, and occasional nucleoli may suggest the possibility of minimal deviation adenocarcinoma

Differential Diagnosis ♦♦ The differential diagnosis of endocervical adenocarcinoma includes mainly endometrial adenocarcinoma (see Table 1.1)

Table 1.1. Endocervical Adenocarcinoma vs. Endometrial Adenocarcinoma Endocervical adenocarcinoma* (Endocervical type)

Endometrial adenocarcinoma (Endometrioid type)

Younger patients

Elderly patients

Strips, rosette, and feathering arrangement

Syncytial arrangement

Larger columnar cells

Smaller cell with indistinct cell border

Granular cytoplasm

Amphophilic cytoplasm

Solitary macronucleoli

Multiple small nucleoli

Necrotic dirty background

Watery diathesis

*Note: the cytologic findings of moderately and poorly differentiated endocervical adenocarcinoma often overlap with those of endometrial adenocarcinoma. Other histologic types are identical to their endometrial counterpart

ENDOMETRIAL CYTOLOGY Cytologically Normal Endometrial Cells (Figs. 1.60–1.62) ♦♦ Endometrial epithelial cells usually present as loose clusters and cell balls. The cells are small and cuboidal to round. They have scant amphophilic and often finely vacuolated cytoplasm. The nuclei are round or bean shaped and slightly eccentric. The nuclear size of normal endometrial cells is similar to that of an intermediate cell nucleus. The nuclei have a uniform finely powdered chromatin pattern ♦♦ Superficial endometrial stromal cells individually resemble and may be indistinguishable from histiocytes. They are identified as stromal cells when numerous and loosely clustered. They have round, oval or reniform nuclei which are usually centrally located but may be eccentric. Their chromatin is finely granular, and micronucleoli may be observed ♦♦ Deep endometrial stromal cells present as loose aggregates late in the menstrual flow. The cells are spindle or oval with ill defined cytoplasmic borders. The nuclei of deep endometrial cells are reniform or cigar shaped, often with nuclear enfolding (grooves). The nuclear chromatin is finely granular, but at times may be hyperchromatic. Small chromocenters may be observed ♦♦ Exodus represents cell balls composed of stromal cells surrounded by peripheral larger epithelial cells. Exodus clusters are usually observed on days 6–10 of the menstrual cycle ♦♦ The cytologic features of endometrial cells are related to their site of origin in the endometrium, menstrual cycle day,

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the environment into which they are shed, interval that has elapsed since the cells were shed, the collection method, and the processing techniques

General Comments ♦♦ The significance of endometrial cells is in part dependent on the age of the patient, day of last menstrual cycle, menopausal state, and hormonal usage. Endometrial cells peak at

Fig. 1.60. Endometrial cells cytologically normal. LBP liquidbased preparation.

Cytopathology

Fig. 1.61. Endometrial cells, cytologically normal-Exodus. A tight ball of cells with central epithelial and peripheral stromal cells. LBP liquid-based preparation.

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Fig. 1.63. Atypical endometrial cell. A cluster of atypical endometrial cells with slight variation in size and shape, loss of polarity, and mild nuclear enlargement. LBP liquid-based preparation.

♦♦ Because of the lack of clinical impact and the unreliable clinical data often supplied with the sample, cytologically normal endometrial cells need not be reported in women less than 40 years

Bethesda 2001 Reporting of Endometrial Cells

Fig. 1.62. Endometrial cells, present in 40 years and older. Tight cluster of small glandular cells with eccentric nuclei and scant cytoplasm. The nuclei are uniformly round and have regularly distributed chromatic pattern. LBP liquid-based preparation. day 4–5 and may persist until day 12–14 of a 28 day menstrual cycle. The presence of endometrial cells after day 12–14 or in menopausal women is associated with an agedependent increased detection of endometrial pathology (endometrial polyp, hyperplasia, or adenocarcinoma) ♦♦ Abnormal shedding of cytologically normal endometrial cells may be associated with a 35–40% risk of endometrial pathology of any kind. There is advancing risk with age especially over the age of 40 years. Changes/lesions that may be associated with endometrial cells may include IUD use, hormonal effect, immediate postpartum period, impending or early abortion, acute and chronic endometritis, recent intrauterine instrumentation, endometriosis, polyps, and submucosal leiomyoma

♦♦ Cervical/vaginal cytology is a screening tool for SCC and its precursor lesions. It is not a sensitive or accurate screening test for detection of endometrial lesions and should not be used to evaluate suspected endometrial abnormalities ♦♦ TBS suggests reporting of benign appearing endometrial cells in all women from the age of 40 onward, regardless of hormonal therapy using the following format −− General categorization: negative for squamous intraepithelial lesion −− Descriptive interpretation: endometrial cells present. See “Comment” ♦♦ An educational comment appropriate for the local laboratory practice, such as the following, may be used. For example, “Endometrial cells after age 40, particularly out of phase or after menopause, may be associated with benign endometrium, hormonal alterations, and less commonly, endometrial/ uterine abnormalities. Clinical correlation is recommended”

Atypical Endometrial Cells (Figs. 1.63 and 1.64) ♦♦ There are no well-defined criteria to separate reactive vs. preneoplastic endometrial cells, and atypical endometrial cells are not subdivided into categories ♦♦ Atypical endometrial cells may originate from endometrial polyps, acute and chronic endometritis, endometrial metaplasia, endometrial hyperplasia, or well-differentiated adenocarcinoma (FIGO grade 1)

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Fig. 1.64. Atypical endometrial cells. Tight cluster of endometrial cells with loss of polarity, variation in nuclear size and shape, coarse chromatin pattern, and scattered small nucleoli. LBP liquid-based preparation.

Fig.  1.65. Adenocarcinoma, endometrial. Three-dimensional cluster of malignant glandular cells with round eccentric nuclei, vacuolated basophilic cytoplasm, and nucleoli. LBP liquidbased preparation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 1.66. Adenocarcinoma, endometrial. A cluster of pleomorphic malignant glandular cells with eccentric irregular nuclei, irregular chromatin pattern of nucleoli. LBP liquid-based preparation.

Fig.  1.67. Adenocarcinoma, endometrial. Malignant glandular cells in a papillary configuration. LBP liquid-based preparation.

Cytologic Features ♦♦ Atypical endometrial cells occur in small groups, usually 5–10 cells per group. They show mild cellular crowding without nuclear pseudostratification. Their nuclei are slightly enlarged with mild hyperchromasia and anisocytosis. Small nucleoli may be present. The cell borders are ill-defined and when compared with endocervical cells, these cells have scant cytoplasm, which occasionally is vacuolated

Endometrial Adenocarcinoma (Figs. 1.65–1.68) Cytologic Features ♦♦ Shedding of neoplastic cells is generally sparse and irregular especially for low grade tumors. The cells are usually small

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cells and may be difficult to detect. The cell size increases from low to high grade tumors ♦♦ Cells derived from endometrial adenocarcinoma tend to have a scant cyanophilic cytoplasm with fine vacuolization. There is loss of cell polarity. The nuclei are enlarged (>70 mm2) and the N/C ratio is high. Nuclear crowding and overlapping (3D cell ball) is typical of endometrial adenocarcinoma. The nuclear chromatin is not usually hyperchromatic, but tends to be powdery with parachromatin clearing. Nucleolar enlargement is proportional to grade of tumor ♦♦ Single or loose clusters of foamy histiocytes and lipophages may be present in the background as well as a watery granular tumor diathesis

Cytopathology

Fig. 1.68. Adenocarcinoma, not otherwise specified. The cluster of high grade adenocarcinoma has papillary features. The primary carcinoma was endometrial with secondary involvement of the endocervix. LBP liquid-based preparation.

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Fig.  1.69. Vaginal specimen. Adenocarcinoma, metastatic to vagina from primary ovarian papillary serous carcinoma. Threedimensional cluster of malignant glandular cells with prominent nucleoli. LBP liquid-based preparation.

♦♦ In liquid based cytology, the endometrial adenocarcinoma cell groups may be more spherical or clustered than CP. The nuclei present in these groups may show less visual accessibility due to overlap and increased cytoplasmic thickening. The nuclear features are usually well preserved. Nucleoli are prominent. The distinction between endometrial and endocervical adenocarcinoma may be more difficult in LBP than CP, especially for high grade tumors

Differential Diagnosis ♦♦ Normal endometrial cells have a round nucleus that is similar in size to the intermediate squamous cell nucleus. There are no cytological features of malignancy. The cytological changes of atypical endometrial cells may overlap with those of low grade endometrial adenocarcinoma ♦♦ Atypical endometrial cells maintain cell polarity and their nuclear size is less than that of adenocarcinoma. Tumor diathesis is not observed with atypical endometrial cells ♦♦ The cytologic differences between endometrial and endocervical adenocarcinoma are shown in Table 1.1

Papillary Serous Adenocarcinoma (Figs. 1.67 and 1.68) ♦♦ Cytologic features: Cells derived from papillary serous adenocarcinoma are usually shed in papillary aggregates and have all the features of a poorly differentiated carcinoma. Small compact cell balls, elongated groups with peripheral molding, or irregular tight clusters of cells may be identified. Occasionally, the central connective tissue core may be seen. Psammoma bodies can be observed ♦♦ The cytologic features of papillary serous carcinoma of the endocervix, endometrium, or tubes/ovaries are indistinguishable. Poorly differentiated endometrioid adenocarcinoma, FIGO grade III and extrauterine papillary serous carcinoma cannot be distinguished cytologically

Fig. 1.70. Vaginal specimen. Adenocarcinoma, metastatic from primary adenocarcinoma of endometrium. A cluster of malignant glandular cells. The patient had previously a hysterectomy for deeply invasive endometrial adenocarcinoma. LBP liquidbased preparation.

Extrauterine Metastatic Adenocarcinoma (Figs. 1.69 and 1.70) ♦♦ The clinical history of a nongynecologic malignancy is essential for an interpretation of extrauterine adenocarcinoma. Most extrauterine carcinomas are poorly differentiated adenocarcinomas ♦♦ Ovarian carcinoma is the most common primary site (papillary serous carcinomas) of extrauterine carcinoma. Other sites include fallopian tubes, gastrointestinal tract, pancreas, and breast. The presence of ascites and patent fallopian tubes increases yield for extrauterine carcinoma

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♦♦ Cytologic Features: Cells derived from extrauterine carcinoma present as three-dimensional, tubular, spherical, or papillary tissue fragments. The malignant cells are large cells with high N/C ratios, nuclear hyperchromasia, and macronucleoli. Generally, no specific cytological features point to the primary site. Exceptions may include the presence of psammoma bodies (favor ovarian), columnar cells with brush borders (favor GI), and cords of cells (favor breast). Tumor diathesis is absent in extrauterine carcinoma, provided implantation has not occurred

Malignant Mixed Müllerian Tumor ♦♦ Malignant mixed müllerian tumor is characterized by the presence of two distinct tumor cell populations: a malignant poorly differentiated glandular component with or without squamous differentiation, and a pleomorphic spindle or multinucleated sarcomatous component. Hetero­ logous elements are rare and are cytologically difficult to recognize

♦♦ The malignant epithelial component usually sheds as single cells or in aggregates, whereas the sarcomatous cells usually occur as single cells and, rarely, in aggregate ♦♦ Tumor diathesis is usually evident

Lymphoma/Leukemia Cervix ♦♦ The cytologic features of lymphoma cells vary with the type of lymphoma. There is complete lack of intercellular cohesion among the tumor cells. Some of the cells may appear to cluster, but no true aggregates are present. The tumor cell population is generally monomorphic and the lymphoma cells have high N/C ratios. In most lymphoma cells, the cytoplasm is barely visible; however, a minority have a plasmacytoid appearance with more abundant cytoplasm. The nuclear membrane usually shows marked convolutions and may show a nipple-like protrusion. The chromatin is coarse with regular clumps. Nucleoli are not common, except in the immunoblastic lymphoma category ♦♦ The cytologic sub typing of lymphomas is not reliable

PAP TEST AND HPV TESTING ♦♦ HPV “testing” refers to a DNA test for high-risk HPV types. Studies have found no clinical role for low-risk HPV testing in cancer prevention. The management guidelines on the use of HPV testing are based on controlled trials using validated HPV assays. Similar results cannot be assumed when man-

agement is based on results of assays not similarly validated ♦♦ Only HPV tests validated to ensure reproducibility and accuracy in identifying cancer precursors, must be used by laboratories

ASC-US Low grade TRIAGE STUDY (ALTS TRIAL) HPV Prevalence ♦♦ HR-HPV is positive in 85% HSIL; 75–85% LSIL; 70–80% ASC-H; 50% ASC-US; and a variable % normal Paps (10–20%) ♦♦ The probability of CIN 2/3 is approximately 15% in ASC-US; 40–50% in ASC-H; 25–30% in LSIL; 50–90% in HSIL; and 30–50% in HSIL with negative colposcopic biopsy

HPV Testing and Management Guidelines 1. HPV “Reflex” testing for equivocal ASC-US Cytology HPV testing provides effective triage for ASC-US. HPV triage virtually captures all HSIL The cumulative probability of HSIL/CIN 2+ in 2 years for ASC-US HPV positive is 25–30%, ASCUS if HPV negative is <1% , and ASC-US if HPV is unknown is 15%. The negative predictive value for the HPV test is 99% (98.9–99.3%) −− If the cytology is ASC-US and HPV test is negative there is still a small chan5ce of CIN 2 or 3. Of the 0.7–1.1% cases there are 3–5% cases which

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are false negative (Eventually proved to have CIN 2/3 on 1–24 months followup period). The causes of false negative results include few HSIL cells/or any of the right cells, low HPV DNA load below cut off for test, methodological or reproducibility errors, and histological interpretation errors −− If the Pap test is negative and the HPV test is positive, then there is a 4% chance of having high grade dysplasia over a 24 months followup period 2. LSIL is associated with HR-HPV and is not amenable to triage. HR-HPV is positive in 83% of LSIL. LSIL and ASCUS/HPV positive are managed in a similar manner. 3. Postcolposcopy followup of women with abnormal cytology found to have less than a high grade lesion 4. Posttreatment (LEEP or Cold knife cone) followup to assess the risk of recurrence 5. As an adjunct to cytology in primary cervical cancer screening in ³30 years 6. Used adjunctively with (5) to assess for specific (HPV16 and HPV18) HPV types

Cytopathology

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THE AMERICAN SOCIETY FOR COLPOSCOPY AND CERVICAL PATHOLOGY (ASCCP) GUIDELINES (2006) ♦♦ The 2006 Consensus Guidelines for the Management of Women with Cervical Cytological Abnormalities and Cervical Intraepithelial Neoplasia, and current updates are available at http://www.asccp.org ♦♦ These guidelines should not be construed as directing an exclusive course of treatment. Some of the main guidelines for initial evaluation of abnormal Pap test are listed below ♦♦ In general, women are divided into three groups; Adolescents (20 years and younger), nonadolescents under 30 years and women of 30 years and older. There are also guidelines for “special population” categories ♦♦ Triage or followup with HPV DNA testing is not recommended for ASC-US in adolescents ♦♦ LSIL and ASC-US/HPV positive are managed in a similar manner ♦♦ ASC-H necessitates colposcopy/biopsy ♦♦ For pregnant women the only indication for therapy is invasive cancer. Colposcopy is deferred in pregnant women at low risk for having cancer. ECC is contraindicated

♦♦ HSIL necessitates colposcopy/biopsy. The need for having a complete review of the cytology, colposcopy, and histology was de-emphasized for HSIL and CIN 1 or less on biopsy and the option of reevaluating these patients at 6-month intervals for 1 year was introduced; “adolescents” with discordant cytology/colposcopy results should be managed conservatively ♦♦ Colposcopy with endocervical sampling is recommended for all subcategories of AGC–AIS. Endometrial sampling is added to colposcopy for AGC >35 years and <35 years with irregular bleeding. Endometrial sampling is recommended for atypical endometrial cells ♦♦ Repeat cytology is not acceptable for AGC ♦♦ Guidelines for use of HPV DNA testing as an adjunct to cervical cytology for screening in women of 30 years of age and older were adopted in 2006. Women (30 years and older) who test negative for HR-HPV and have negative cytology should be re-screened at 3 years and not before. Data support the triage of cytology negative HPV DNA positive women using assays that identify HPV-16 and 18

NONCORRELATING PAP AND BIOPSY ♦♦ Sampling error is a major cause of noncorrelation. Even with specialized training and experience, colposcopic biopsy frequently misses the most significant pathology, including 66% of the CIN 3 ♦♦ The cytologic LSIL is not equivalent to histologic CIN1 (and cytologic HSIL is not equivalent to histologic CIN2/3) A biopsy diagnosis of CIN1 carries a lower risk than LSIL cytology or ASC-US / HPV positive because CIN1 implies that colposcopy biopsy has ruled out the most evident precancerous lesions

♦♦ There appears to be no difference in CIN3 capture with nurse practitioner, gynecologic oncology fellow, generalist, or gynecologic oncologist ♦♦ The 2-year cumulative CIN3+ capture correlates with the number of biopsies taken ♦♦ At least five levels are required to ensure 100% diagnostic accuracy when initial slide are negative (colposcopic/ histopathologic discrepancy)

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Part B Nongynecologic Cytology

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Essentials of Anatomic Pathology, 3rd Ed.

OVERVIEW Overall Evaluation of Cytologic Smear ♦♦ Cellularity: high, moderate or low ♦♦ Are the cells representative of a lesion? ♦♦ Type of the lesional cells (epithelial, mesenchymal, or lymphopoietic) ♦♦ Architectural arrangement of tissue fragments: clusters, sheets, papillary structures, etc ♦♦ Relationship of cells: honeycomb arrangement, crowded, overlapping, disordered arrangement ♦♦ Cellular changes: Nuclear to cytoplasmic (N/C) ratio, cytoplasm, nuclear change (chromatin, nuclear membrane, and nucleoli) ♦♦ Background: bloody, granular, watery, proteinaceous, inflammatory, granuloma, mucoid, diathesis, etc

Key Cellular Features Benign Cellular Features ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Centrally located, single or multiple, round to oval nuclei Chromatin finely granular and evenly distributed Nuclear membrane smooth Single or multiple, small, rounded nucleoli Normal N/C ratio Well defined cytoplasmic border Tissue fragments are one to two cell layers with good polarity or honeycomb pattern

Reactive Cellular Features Due to Inflammation

♦♦ Normal N/C ratio ♦♦ Background may or may not be inflamed

Degenerative Features Due to Irreversible Injury ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Nucleus wrinkled and decreased in size Loss of chromatin detail Pyknotic and smudged chromatin Fragmentation and condensation of chromatin (karyorrhexis) Hyperchromasia Nucleolus invisible Cytoplasmic borders not well defined and disintegrated N/C ratio may be increased due to loss of cytoplasm or decreased due to nuclear shrinkage

Cellular Features of Repair (Fig. 1.71) ♦♦ Monolayer sheets of well-organized cells and very few single cells ♦♦ Cells bear striking resemblance to each other ♦♦ Little or no cellular overlap ♦♦ Enlarged cells with centrally located round nuclei ♦♦ Enlarged nuclei ♦♦ Prominent nucleoli/cherry red single macronucleoli ♦♦ Marginated chromatin (swelling) ♦♦ Well defined, uniform, and thick nuclear membrane ♦♦ Well defined cell borders ♦♦ Cytoplasm may be streaming in the same direction (school of fish)

♦♦ ♦♦ ♦♦ ♦♦

Centrally located, single or multiple, round to oval nuclei Nuclei enlarged with slightly enlarged nucleoli N/C ratio normal or slightly increased Chromatin slightly more granular and may be hyper­ chromatic ♦♦ Nuclear membrane may be wavy but uniform in thickness ♦♦ Background with inflammation, granular and cellular debris

Degenerative Changes Due to Reversible Injury ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Nuclear enlargement due to swelling (karyolysis) Chromatin smudged or washed out Nuclear membrane may be uneven in thickness Nucleoli may be indistinct Cells may become more rounded due to swelling Cytoplasmic disintegration and fraying (moth-eaten appearance) ♦♦ Cell borders not well defined

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Fig. 1.71. Repair, gastric brush. Monolayer sheet of well-organized cells with striking resemblance to each other. No cellular overlap. The nuclei are enlarged with prominent nucleoli and marginated, pale chromatin. The cell borders are well defined, and the cytoplasm shows streaming in the same direction. Papanicolaou stain, high power view.

Cytopathology

Atypical Repair ♦♦ Areas of atypical repair usually merge or coexist with typical repair ♦♦ Anisonucleosis within the monolayer sheet ♦♦ Increased cellular overlap within the sheet ♦♦ Increased number of single cells ♦♦ Increase chromatin granularity ♦♦ Altered nuclear polarity ♦♦ Hyperchromasia ♦♦ Cell borders blurred

General Features of Malignancy ♦♦ Increased N/C ratio (with few exceptions) ♦♦ Nuclei are round to oval, single or multiple, and frequently irregular ♦♦ Marked variation in nuclear size and shape (anisonucleosis) ♦♦ Chromatin is crisp and may vary from finely granular and evenly distributed to coarsely granular and unevenly distributed ♦♦ Chromatin rim may be irregular in thickness ♦♦ Nuclear membrane may be smooth but frequently irregular with grooves and sharp notches ♦♦ Nucleoli may vary from inconspicuous to prominent. They may be angulated or irregular ♦♦ Cellular discohesion with many single cells ♦♦ Cells within aggregates lose their polarity and form pseudosyncytia (cells blend with each other and lose their well defined borders) ♦♦ Background may contain tumor diathesis which appears as granular material with cellular debris and old blood

Cellular Patterns Mixture of Epithelial Cells/Lymphocytes ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Branchial cleft cyst Sialadenitis Lymphoepithelial lesion Warthin tumor Hashimoto thyroiditis Thymoma Seminoma Medullary carcinoma of the breast Nasopharyngeal lymphoepithelioma-like carcinoma

Mixture of Epithelial Cells/Spindle Cells (Biphasic) ♦♦ ♦♦ ♦♦ ♦♦

Pleomorphic adenoma Tumors with marked stromal fibrosis Neuroendocrine tumors (e.g., carcinoid) Synovial sarcoma

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Malignant schwannoma Mesothelioma (biphasic) Phyllodes tumor Brenner tumor Malignant mixed müllerian tumor Leiomyoblastoma Wilms tumor Hepatoblastoma Epithelioid sarcoma Epithelioid leiomyosarcoma Melanoma

Plasmacytoid Cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Multiple myeloma Lymphoma (lymphoplasmacytic and Waldenstrom lymphoma) Carcinoid Medullary thyroid carcinoma Islet cell tumor Breast carcinoma, lobular and ductal Urothelial carcinoma Melanoma

Tumor with Discohesive Pattern ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Lymphoma Melanoma Sarcoma Squamous cell carcinoma Signet-ring carcinoma Lobular carcinoma of the breast Seminoma Neuroendocrine tumors Small blue cell tumors: Ewing sarcoma, primitive neuroectodermal tumor (PNET), neuroblastoma, and rhabdo­ myosarcoma

Tumors with Acinar Pattern ♦♦ Prostate carcinoma ♦♦ Thyroid follicular tumor ♦♦ Carcinoid and neuroendocrine tumor

Tumor with Trabecular Pattern ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hepatic tumor (hepatocellular carcinoma, hepatic adenoma) Thyroid follicular tumor Breast carcinoma Carcinoid Merkel cell carcinoma

Granuloma ♦♦ Infectious (e.g., fungal, mycobacterium, etc.) ♦♦ Noninfectious (e.g., sarcoidosis, Wegener granuloma­ tosis, etc.)

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♦♦ Reaction to foreign body (e.g., keratin, amyloid, and suture material) ♦♦ Tumors with granulomatous component −− Squamous cell carcinoma (most common) −− Other carcinomas with extracellular material, e.g., mucin −− Seminoma −− Hodgkin lymphoma −− T-cell lymphoma

Intranuclear Cytoplasmic Inclusions ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Papillary thyroid carcinoma Medullary carcinoma of the thyroid Hurthle cell neoplasm Hyalinizing trabecular adenoma of the thyroid Parathyroid adenoma Bronchioalveolar carcinoma Hepatocellular carcinoma Melanoma Meningioma Sclerosing hemangioma Breast carcinoma Adrenal cortical carcinoma

Intracytoplasmic Inclusions/Hyaline Globules ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Papillary thyroid carcinoma (septate vacuoles) Bronchioalveolar carcinoma, clara cell type (surfactant) Squamous cell carcinoma (keratin) Adenocarcinoma (mucin droplets) Hepatocellular carcinoma (Mallory bodies or inspissated secretions) ♦♦ Melanoma ♦♦ Yolk sac tumor (alpha-fetoprotein) ♦♦ Pleomorphic liposarcoma (sarcoma bodies)

♦♦ Rhabdoid tumor (intermediate filaments)

Extracellular Hyaline Globules ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Corpora amylacea Collagenous spherules Liesegang rings Alveolar proteinosis Amyloid (irregular and thick) Mesothelial hyperplasia and mesothelioma (collagen balls) ♦♦ Clear cell carcinoma of the kidney or ovary ♦♦ Adenoid cystic carcinoma (smooth globules) ♦♦ Monomorphic adenoma (irregular globules)

Signet-Ring Cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Goblet cells Mesothelial cells (degenerative change) Gastrointestinal tract carcinoma Mucinous carcinoma of the breast and ovary Mucin-producing carcinoid

Mucinous/Myxoid Background ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Mucinous carcinoma Pleomorphic adenoma Chondroid hamartoma Chondroid tumors Myxoid tumors

Psammoma Bodies ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Papillary carcinoma of thyroid, breast and ovary Bronchoalveolar carcinoma (BAC) Malacoplakia Meningioma Endosalpingiosis Mesothelial hyperplasia and mesothelioma

RESPIRATORY CYTOLOGY Overview Normal Cellular Components of Lung Cytology ♦♦ Squamous cells: Oral origin or due to squamous meta­ plasia ♦♦ Alveolar macrophages primarily dust cells ♦♦ Bronchial epithelial cells (ciliated columnar cells interspersed with goblet cells) ♦♦ Terminal bronchiolar and alveolar lining cells (pneumocytes)

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♦♦ Inflammatory cells ♦♦ Megakaryocytes and mesothelial cells

Types of Pulmonary Specimens ♦♦ Exfoliative specimens include sputum, bronchial brushing (BB), bronchial washing (BW), and bronchoalveolar lavage (BAL) ♦♦ Fine needle aspiration (FNA) include CAT scan-guided aspiration of pulmonary deep-seated masses and transbronchial aspiration

Cytopathology

Spectrum of Cytologic Changes in Various Preparations Sputum ♦♦ Best used to diagnose centrally located masses and has highest sensitivity for detecting SCC ♦♦ An adequate sample must contain alveolar macrophages (exception: acute pneumonia where severe acute inflammation predominates) ♦♦ May contain numerous benign squamous cells, candida, actinomyces, and food particles originating from the oropharynx. The presence of such elements in high numbers indicates saliva rather than deep cough sputum and renders it unsatisfactory for diagnosis ♦♦ A positive specimen often shows a small number of single or small tight clusters of tumor cells with frequent degenerative changes. Tumor diathesis is indistinguishable from inflammatory exudate or pneumonia

Bronchial Brushing and Washing Clinical ♦♦ Useful in sampling mucosal and submucosal lesions that are directly visualized by the bronchoscope. They are also used to map the sites involved with tumor. Bronchial washing (BW) rather than bronchial brushing (BB) provides the best cost efficiency particularly in well-visualized masses. Also useful in sampling peripheral lesions

Microscopic ♦♦ BB presents as large number of cells and tissue fragments with few macrophages. The predominant cells are columnar ciliated bronchial epithelial cells with or without reactive change. Profuse mucus can be present. Tumor diathesis if present is well demonstrated ♦♦ BW presents as large number of alveolar macrophages and scattered bronchial cells. Positive samples tend to contain small numbers of tumor cells

Bronchoalveolar Lavage Clinical ♦♦ Samples the distal airway spaces and intraalveolar contents. Useful in the workup of lung infiltrate and opportunistic infections

Microscopic ♦♦ Consists predominantly of alveolar macrophages (pigmented, single, and multinucleated cells) and few ciliated cells. Inflammatory or infectious lesions will present with a considerable component of inflammatory cells depending on the disease

Fine Needle Aspiration of Lung Nodules Clinical ♦♦ Fine needle aspirations (FNAs) are useful in the workup of lung nodules particularly the peripheral ones. Can be more accurate in typing tumors and in distinguishing a benign, e.g., granuloma or hamartoma from a malignant mass

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Microscopic ♦♦ A diagnostic sample will consist predominantly of the lesional cells admixed with few macrophages, bronchial epithelium, and rare mucus. Pneumocytes may be abundant with reactive changes ♦♦ Lesional cells could be aspirated in large numbers and may present with a pattern that reflects the original architecture of the lesion, e.g., papillae, single discohesive cells or large sheets, etc. Tumor diathesis is well demonstrated ♦♦ Well-prepared smears have excellent cellular preservation and good representation of lesion ♦♦ Mesothelial cells may be seen (picked up by the needle in its path)

Transbronchial FNA (Wang) Clinical ♦♦ Performed to sample a bronchial mass for primary diagnosis or hilar lymph nodes for staging and/or primary diagnosis

Microscopic ♦♦ A bronchial mass FNA will consist of the lesional cells admixed with bronchial cells, histiocytes, and mucin ♦♦ Aspirates of positive hilar lymph nodes will consist of the lesional cells admixed with bronchial cells and histiocytes. Lymphocytes may be present in the background in variable numbers depending on degree of replacement of the lymph node by the metastatic tumor ♦♦ Aspirate of a negative lymph node should contain lymphocytes to document adequate sampling of the node when the aspirate is negative

Benign Lesions Pneumonia Microscopic ♦♦ Specimens from bacterial pneumonia are cellular and consist predominantly of numerous polymorphonuclear leukocytes that may obscure other elements such as native respiratory cells. The background may contain cellular debris that mimics tumor diathesis and careful screening of smears with purulent material is warranted to rule out a necrotic tumor ♦♦ The presence of bacterial colonies is significant only in FNA samples and additional passes should be requested for cultures ♦♦ Specimens from fungal pneumonia particularly blastomycosis can contain severe acute inflammation, and smears need to be carefully screened to detect the spores ♦♦ Specimens from viral pneumonia will have high lymphocytic background ♦♦ Smears representing either viral or fungal pneumonia may contain scattered highly atypical squamous cells ♦♦ Other cellular changes such as reactive, e.g., creola bodies or repair and degenerative features may be present

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Differential Diagnosis ♦♦ Unsatisfactory exfoliative specimen due to oropharyngeal contamination. These samples tend to contain other contaminants such as squamous cells, actinomyces, and candida ♦♦ KSCC, when ASCs are present. Carcinoma usually presents with higher numbers of malignant cells with well-preserved hyperchromatic nuclei while those in pneumonia tend to show evidence of degenerative changes. The presence of viral inclusions or fungal elements is a clue to the nature of the atypia

Creola Bodies (Bronchial Cell Hyperplasia) (Fig. 1.72) Clinical ♦♦ Originally described in asthmatic patients. The term “Creola” was coined in honor of the patient whose sputum contained such clusters. Now it is established that such clusters can be seen in a variety of reactive conditions

Microscopic ♦♦ The smears can be very cellular and contain numerous tight clusters of benign reactive columnar ciliated cells. Florid cases may contain papillary tissue fragments or three-dimensional cell balls ♦♦ These clusters are characterized by the presence of peripheral palisading cells with terminal plates and cilia sometimes intermixed with an occasional goblet cell. Central cells are smaller, less differentiated, and difficult to visualize clearly

Differential Diagnosis ♦♦ Adenocarcinoma −− Clusters of highly atypical cells with nuclei situated at the borders. There is usually evidence of cell discohesion, mitotic activity, and apoptotic figures. Bronchial hyper-

Essentials of Anatomic Pathology, 3rd Ed.

plasia, despite the cellularity, does not exhibit any of these malignant features. The presence of goblet cells and terminal cilia are clues to the benign nature of the cells

Pneumocyte Type II Hyperplasia Clinical ♦♦ These cells are the result of regeneration after injury replacing the pneumocyte type I. Injury could have resulted from a variety of conditions including pneumonia, pulmonary infarction, diffuse alveolar damage (DAD) etc

Microscopic ♦♦ The number of cells may vary from few to numerous. The atypical pneumocytes may present as single cells, small clusters, or many large clusters. The latter is mainly encountered in cases with DAD ♦♦ The clusters are tightly cohesive with scalloping borders due to protruding nuclei at the periphery. The cells may have slightly enlarged nuclei but relatively normal or slightly increased N/C ratio ♦♦ The cells can be highly vacuolated and the vacuoles are frequently out of proportion with the cellular size ♦♦ Background may contain evidence of other reactive changes such as repair

Differential Diagnosis ♦♦ Bronchial cell hyperplasia −− Clusters have focal areas with well-visualized terminal bars and cilia. Clusters may be in continuation with rows of reactive bronchial cells ♦♦ Adenocarcinoma −− Present with more obvious atypia and evidence of discohesion. They tend to be finely vacuolated, rather than the large out of proportion vacuoles seen in pneumocyte hyperplasia

Pulmonary Infarct Clinical These are usually aspirates performed when a localized lesion is seen in a patient with a clinically undetected embolic event

Microscopic ♦♦ Smears are variable in cellularity and content depending on the area sampled. Sheets and papillary groups of reactive pneumocytes may be seen if the periphery of the lesion is sampled, while atypical squamous metaplastic cells are seen when the center is sampled ♦♦ Hemosiderin-laden macrophages may be present in the background and are a clue to the diagnosis ♦♦ Maximum atypia is seen during second to third postinfarction weeks

Differential Diagnosis Fig.  1.72. Creola body, bronchoalveolar lavage. Threedimensional, tightly cohesive clusters bordered by cilia. Papanicolaou stain, high power view.

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♦♦ Adenocarcinoma −− The cells are more pleomorphic and discohesive with obvious disorganized arrangement within the sheets or clusters

Cytopathology

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Fig.  1.73. Reserve cell hyperplasia, bronchial wash. Tightly cohesive small blue cells with no cytologic atypia or discohesion. The presence of contiguous goblet cells is a clue of their origin. Papanicolaou stain, high power view.

Fig. 1.74. Radiation therapy change, lung, FNA. Cytomegallic cells arranged in a syncytium. The cells are bizarre with amphophilic, frequently vacuolated cytoplasm and ingested neutrophils. The chromatin is frequently smudged and difficult to read. Papanicolaou stain, high power view.

Cigarette and Habitual Marijuana Smoking

−− Nuclear degeneration (karyorrhexis and karyolysis), hyperchromasia, and prominent nucleoli −− Smudged chromatin and poor nuclear detail

♦♦ The smears of exfoliative samples are generally cellular with features of irritation and consequent reactive changes ♦♦ The earliest change is reserve cell hyperplasia, which presents as tight clusters of uniform small cells with hyperchromatic nuclei. This is followed by squamous metaplasia (Fig. 1.73) ♦♦ Background of numerous multinucleated histiocytes frequently containing anthracotic pigment

Radiation and Chemotherapy-Induced Atypia (Fig. 1.74) Clinical ♦♦ Patients undergoing treatment for a malignant disease ♦♦ Acute radiation therapy changes are seen within 6 months of initiating treatment, while chronic changes may persist for a long time. Chemotherapy changes resemble those of chronic radiation and subside within a month of terminating therapy

Microscopic ♦♦ Acute Radiation Therapy −− Cytomegaly, nucleomegaly, multinucleation, and normal N/C ratio −− Cytoplasmic vacuolization and neutrophil ingestion (vacuoles may be prominent) and cytoplasmic polychromasia −− Syncytial sheets with blurred cell borders. Cytoplasm may be very fragile and blend with the background ♦♦ Chronic radiation and chemotherapy changes −− Cytomegaly, nucleomegaly, multinucleation, and normal N/C ratio −− Syncytial sheets with blurred cell borders −− Bizarre cells with amphophilic cytoplasm, indistinct cell border, and cytophagocytosis of neutrophils

Differential Diagnosis ♦♦ Poorly Differentiated Carcinoma −− These malignant cells will have increased N/C ratio. The nuclei are hyperchromatic and frequently contain prominent nucleoli. The chromatin is well preserved and nuclear detail is evident

Amiodarone Induced Changes Clinical ♦♦ Patients treated with amiodarone for supraventricular arrhythmia ♦♦ Patients present with nonspecific symptoms such as cough, shortness of breath, etc. and frequently have bilateral diffuse lung infiltrates

Microscopic ♦♦ Cellular smears consisting of numerous foamy alveolar macrophages with uniform, well-defined, and distended vacuoles. These cells are negative for oil red O stain ♦♦ Atypical pneumocytes with increased N/C ratio, hyperchromasia, and nuclear pleomorphism ♦♦ Background of increased lymphocytes, neutrophils, and eosinophils

Electron Microscopy ♦♦ Osminophilic lamellar cytoplasmic inclusions

Differential Diagnosis ♦♦ Lipoid Pneumonia (Fig. 1.75) −− Patient presentation is different and lack history of amiodarone therapy (see below) −− Vacuoles are less defined and positive for oil red O

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Essentials of Anatomic Pathology, 3rd Ed.

Fig.  1.75. Lipoid pneumonia, bronchoalveolar lavage. Highly vacuolated cytoplasm of these lipid-ladened macrophages. Papanicolaou stain, high power view.

Fig. 1.76. Corpora amylacea, bronchial wash. Thick amorphous material with internal rings. Note the crack induced during preparation and the surrounding giant cell. Papanicolaou stain, high power view.

Hemosiderin-Laden Macrophages Clinical

Differential Diagnosis

♦♦ Pediatric Patients −− Idiopathic pulmonary hemosiderosis (isolated) −− Pulmonary hemosiderosis associated with sensitivity to cow’s milk −− Glomerulonephritis −− Collagen vascular and pruritic disease −− Cardiac diseases, intravascular lesions, or malformations ♦♦ Adult Patients −− Diffuse interstitial pulmonary disease −− Congestive heart failure (heart failure cells) −− Hypersensitivity pneumonitis −− Fibrosis associated with rheumatoid arthritis −− Radiation or chemotherapy

Microscopic ♦♦ Smears contain many pigmented histiocytes. Hemosiderin appears as refractile particles that vary in size and stains as golden brown with Papanicolaou and as greenish brown with Diff-Quik stain

Quantitation of Hemosiderin-Laden Macrophages ♦♦ Percentage of cells containing hemosiderin (Prussian blue or Perl stain) −− Result of >20% has a sensitivity of 10% and specificity of 92% for detecting pulmonary hemorrhage and hemosiderosis ♦♦ Hemosiderin score −− Adding staining intensity score (0–3) for each 100 cells measured −− A score of >50 has a high sensitivity and specificity in the proper clinical setting

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♦♦ Carbon-laden histiocytes (dust cells) −− These cells are commonly seen in all samples and are particularly increased in smokers. They contain anthracotic pigment which is nonrefractile and shows minimal variation in size. The pigment stains dark brown or black on both Papanicolaou and Diff-Quik stains ♦♦ Melanophages −− These cells are seen in patients with history of melanoma but are not always associated with the malignant cells. The pigment varies from fine dust like quality to globular droplets and stains brown to black

Lipid-Laden Macrophages in Bronchial Lavage Clinical ♦♦ Associated with tracheal aspiration in children with gastroesophageal reflux (GER) or lobular consolidation distal to an obstructed bronchus. In adults it may also be associated with aspiration of mineral oil

Microscopic ♦♦ Smears with finely vacuolated histiocytes admixed with bronchial cells. Vacuoles are fine and ill-defined ♦♦ Fresh specimens should be stained with oil red O to confirm the diagnosis ♦♦ Quantitation/percentage of oil red O positive cells may be of value for predicting recurrent aspiration

Corpora Amylacea (Fig. 1.76) Clinical Their presence has no particular clinical significance and is seen in patients with ♦♦ Older age ♦♦ Heart failure

Cytopathology

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♦♦ Pulmonary infarction ♦♦ Chronic bronchitis

Microscopic ♦♦ Variably sized round to oval dense bodies that stain amphophilic with Papanicolaou stain. They have concentric laminations and a radiating array arising from a central nidus. They frequently crack during smearing and can be seen phagocytosed by giant cells ♦♦ They are positive for periodic acid-Schiff (PAS) stain and resist digestion and weakly positive with Congo red stain

Differential Diagnosis ♦♦ Alveolar proteinosis −− Patients are symptomatic with dyspnea, dry cough, and fever. Radiologically, these patients have extensive bilateral consolidation. The material stains strongly positive with PAS and resists digestion and is also positive to oil red O stain but negative to mucin stains ♦♦ Amyloid −− Patients may have systemic amyloidosis or history of lymphoma or carcinoid. Amyloid is rarely detected in exfoliative samples. It appears as flocculent irregularly shaped material that stains eosinophilic or cyanophilic with Papanicolaou stain and blue with Diff-Quik stain. Amyloid stains with Congo red and exhibits apple green birefringence upon polarization. It can be weakly reactive to PAS

Alveolar Proteinosis Clinical ♦♦ This autoimmune disease is characterized by accumulation of phospholipoproteinaceous material within the alveolar spaces. Patients present with nonspecific symptoms such as cough or dyspnea but radiologically they may present with bilateral extensive consolidation that is way out of proportion with their symptoms. In up to 50%, the patients may present with patchy and perihilar infiltrate “bat wing pattern”

Microscopic ♦♦ The lavage is usually thick and grossly opaque ♦♦ Microscopically it appears as amorphous thick material with irregular shapes that stains basophilic with Diff-Quik and amphophilic with Papanicolaou stain. The material is also strongly positive to PAS and oil red O (on fresh smears) but negative to all mucin stains and Congo red

Differential Diagnosis ♦♦ Corpora amylacea (see above) ♦♦ Amyloid (see above)

Sarcoidosis (Fig. 1.77) Clinical ♦♦ This is a multiorgan disease that frequently affects the lung. Radiologically patients present with bilateral hilar and mediastinal lymphadenopathy and nodular lung infiltrate.

Fig. 1.77. Sarcoidosis, FNA of lung. (A) Clusters of epithelioid histiocytes mixed with lymphocytes, Papanicolaou stain. (B) Diff-Quik stain, high power view. The nodules are particularly numerous along the bronchi and vessels

Microscopic ♦♦ On FNA, may see loose clusters of epithelioid cells and giant cells intermingled with lymphocytes. These represent the noncaseating granulomata seen on histology ♦♦ BAL findings are not specific but generally the number of lymphocytes and histiocytes are increased and many multinucleated giant cells can be detected. Schaumann bodies may be noted in the giant cells. Asteroid bodies are not specific. All microorganism stains are negative

Differential Diagnosis ♦♦ Other infectious diseases such as tuberculosis −− Acid fast bacilli may be detected by Ziehl–Nelson stain in up to 40% of cases ♦♦ Other granulomatous diseases −− Fungal infections: Granulomas are usually less cohesive and there may be evidence of necrosis and suppurative reaction especially with Blastomycosis. Fungal spores and hyphae are detected and will stain with Gomori methenamine silver (GMS) ♦♦ Rheumatoid granulomas

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−− Lung nodules are usually seen in severe cases and ­frequently associated with pleuritis and effusion. FNA will contain necrotic debris, scattered epithelioid ­histiocytes, and lymphocytes

Miscellaneous Findings Ferruginous Bodies (Fig. 1.78) Clinical ♦♦ General term applied to a variety of mineral fibers that have been inhaled and sheathed with golden brown iron–protein complex. Asbestos bodies are indicative of occupational asbestos exposure

Microscopic ♦♦ Consist of a clear colorless central fiber of uniform thickness within a golden brown iron–protein complex

Differential Diagnosis ♦♦ Nonasbestos bodies: have a black or yellowish center that is not uniform in thickness

Ciliocytophthoria Clinical ♦♦ The presence of this finding is usually suggestive of viral infection (e.g., respiratory syncytial virus)

Microscopic ♦♦ Scattered anucleated cytoplasmic fragments bearing cilia are seen among the normal component of an exfoliative specimen such as bronchial cells and histiocytes. These fragments represent detached bronchial cilia

Asthma Clinical ♦♦ The following findings are frequently encountered in asthmatic patients although they are by no means specific to asthma −− Curschmann spirals

Essentials of Anatomic Pathology, 3rd Ed.

(a)  A  ppear as coiled strands of inspissated mucus frequently associated with bronchial cell hyperplasia −− Charcot–Leydin crystals (a) Elongated red crystalline structure derived from eosinophil phospholipase B, involved in prostaglandin metabolism −− Bronchial cell hyperplasia (a) Also known as “Creola bodies” (see description above). This entity was first described as a characteristic of status asthmaticus, but it is believed now that it is rather a feature of chronic irritation and injury to the bronchial mucosa

Infectious Processes Viral Infection Clinical ♦♦ Symptomatic patients usually present with significant symptoms, however, viral inclusions can be detected in cytologic smears from asymptomatic patients with no active disease

Microscopic ♦♦ General background features seen in the company of viral infections include ciliocytophthoria, necrosis, inflammation, and bronchial/alveolar cell hyperplasia ♦♦ Squamous metaplasia with nuclear atypia can be detected ♦♦ Cellular features include multinucleation, intranuclear or cytoplasmic inclusion bodies, and loss of nuclear chromatin detail due to the inclusion bodies

Differential Diagnosis ♦♦ Carcinoma −− Malignant cells are usually more numerous and present with well-preserved chromatin detail compared with the ground-glass or smudged chromatin encountered with viral infections −− The ASCs could be mistaken for SCC. However, the clinical presentation is different and the reviewer should search diligently for viral inclusions or fungal hyphae when encountering few scattered highly atypical squamous cells when cancer is not clinically suspected

Fungal Infections Clinical ♦♦ Patients are usually immunocompromised or experienced massive exposure to the organism

Microscopic

Fig.  1.78. Asbestos body, bronchial wash. Fiber with a clear, colorless center, and uniform thickness. Papanicolaou stain, high power view.

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♦♦ Aspergillosis −− The presence of aspergillus should always be reported although on rare occasions it may be a contaminant. It presents as thick, uniform, septate hyphae 3–6 mm in width, and showing dichotomous branching at 45° angle. Fruiting heads form in aerobic conditions, e.g., ruptured abscess connecting with a bronchial wall. Birefringent needle-like crystals ­(calcium oxalate) can be produced by A. niger and others. It stains with Papanicolaou, PAS, and Grocott methods ♦♦ Cryptococcosis

Cytopathology

♦♦

♦♦

♦♦

♦♦

♦♦

−− Presents as yeast cells 5–10  mm in size surrounded by thick mucoid capsule (clear zone) that can be seen extracellularly or intracellularly within macrophages. It is characterized by single narrow-based budding with a tear drop appearance. The cytoplasm stains green with clear capsule on Papanicolaou. PAS, alcian blue, and mucicarmine stain the capsule. GMS stains the organism. A background of inflammation varies from mild to necrosis Histoplasmosis −− Presents as oval, single budding, yeast like organism (2–5 mm) in macrophages and neutrophils. The organism is readily recognized on methenamine silver stain Phycomycosis/zygomycetes (mucor, rhizopus, etc) −− Infection with this organism occurs in severely immunocompromised, diabetics, renal failure, and patients with severe burns. It presents as nonseptated broad hyphae of variable width (5–20 mm), resembling ribbons with irregular branching at up to 90º angles. It shows pale staining with most staining methods Coccidioidomycosis −− This organism is endemic in western and southern states. It presents as intact or collapsed large thick-walled spherules 20–60 mm in diameter (empty or contain endospores, resembling a bag of marbles). Endospores are round, nonbudding, and 2–5 mm in size. It stains eosinophilic in Papanicolaou preparations and strongly stains by Grocott method Blastomycosis −− Presents as yeast cells 8–15  mm in diameter that have refractile thick cell wall (double contour) and single broad-based budding but no hyphae. It stains poorly in Papanicolaou ­samples and strongly with Grocott method. Suppurative granulomatous inflammation in the background may be prominent Candidiasis −− Candida species are part of the normal flora of the oropharynx. Diagnosis of pathologic candidiasis requires histologic demonstration of pulmonary parenchymal invasion or identification of materials from FNA. It presents as small spherical to oval yeast like cells 2–6 mm in diameter, pseudohyphae, and spores (sticks and stones)

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♦♦ The capsule/cyst stains with GMS, PAS, and toluidine blue. Romanowsky (includes Diff-Quik, Giemsa and Wright stains) results in empty spaces against a purple background. Trophozoites stain with Gram and Romanowsky stains as tiny purple dots

Neoplastic Lesions Keratinizing Squamous Cell Carcinoma (Fig. 1.79) Clinical ♦♦ This carcinoma is highly associated with history of smoking and high-risk occupations. It presents as a central mass that invades the bronchial wall and therefore can be detected in sputum and transbronchial sampling

Microscopic ♦♦ The smears are usually cellular and contain discohesive squamous cells with abnormal keratinization, pearls, and intercellular bridges. The cells have abundant waxy cytoplasm that stains orangeophilic by Papanicolaou stain and pure blue by Diff-Quik stain. There is marked nuclear and

Tuberculosis ♦♦ The specimen consists of a mixed inflammatory exudate, epithelioid histiocytes, and giant cells. Langerhans giant cells (peripheral nuclei) are infrequently found. Fragmented granuloma may be seen in FNA material. Caseation ranges from absent to conspicuous. The organism may be demonstrated by acid fast staining on FNA samples and the yield is higher when necrosis is present

Pneumocystitis jirovecii (Formerly Known as Pneumocystis carinii (PCP)) ♦♦ The specimen is rich in eosinophilic foamy alveolar exudate that contain clusters of organisms with round clear spaces within the eosinophilic material (overlapping ringlets). Tiny basophilic dots are frequently seen in the clear spaces. The cysts are 4–8  mm, spherical or cup shaped, and the trophozoites are 8/cyst

Fig.  1.79. Well-differentiated squamous cell carcinoma, lung, FNA. (A) Atypical cells with moderate orangeophilic cytoplasm indicating keratinization, Papanicolaou stain, medium power view. (B) The keratinizing cells have a robin blue cytoplasm. Diff-Quik stain, high power view.

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cellular pleomorphism with variable N/C ratio as well as bizarre cell shapes including caudate and tadpole cells. The nuclei are irregular with marked hyperchromasia ♦♦ Tumor diathesis is seen in the background and can be prominent particularly in FNA specimens

Differential Diagnosis ♦♦ Atypical squamous metaplasia −− These metaplastic cells tend to be few and lack cellular and nuclear pleomorphism. There is usually evidence of other pathology such as reactive changes or the presence of microorganisms ♦♦ Pap cells −− These cells are derived from squamous metaplasia/parakeratosis in pharynx or upper respiratory tract. They present as small angulated cells with degenerative nuclei (pseudokeratosis). The presence of inflammation or other oral/pharyngeal contaminants such as actinomyces are a clue to their origin ♦♦ Vegetable cell contaminants −− Present as few groups or sheets with rectangular cells surrounded by a well-defined refractile cellulose cell wall and containing amorphous nuclei ♦♦ Pulmonary infarct −− The smears contain other features suggestive of reactive changes such as reactive type II pneumocytes. Hemosiderinladen macrophages can be scattered in the background ♦♦ Coagulative Necrosis −− Cells undergoing coagulative necrosis, whether benign or malignant, may acquire cytoplasmic orangeophilia and mimic keratinization (look for viable cells and evidence of other differentiation)

Nonkeratinizing Squamous Cell Carcinoma Microscopic

Essentials of Anatomic Pathology, 3rd Ed.

Adenocarcinoma (Fig. 1.80) ♦♦ Depending on the degree of differentiation, the malignant cells may present as sheets, rosettes, acini, cell balls, and papillary structures with a smooth community border in well-differentiated tumors and as syncytial grouping in poorly differentiated ones ♦♦ Cellular features may vary depending on the origin of adenocarcinoma (ADC). For example metastatic colon adenocarcinoma may present as isolated cells in columnar configuration with altered polarity while mucin-producing adenocarcinoma will present as tight cell clusters or sheets of plasmacytoid cells in pools of mucin etc ♦♦ Adenocarcinoma cells in general tend to have abundant pale or vacuolated cyanophilic cytoplasm. The cells may exhibit intracytoplasmic lumens or pseudo-inclusions in certain types such as papillary or bronchoalveolar carcinoma. The nuclei are frequently eccentrically located, enlarged with high N/C ratio, more vesicular chromatin than that of SCC, and contain a prominent nucleolus

Variants Bronchoalveolar Carcinoma Clinical ♦♦ Based on the latest WHO classification, BAC represents an AIS that lacks evidence of invasion, pleural involvement, and metastasis. Consequently it is not possible to make such diagnosis by cytology; however in cases where the pattern of bronchoalveolar growth is predominant, the following features are seen

Microscopic ♦♦ The smears can be highly cellular and present as sheets of slightly atypical cells in FNA samples. In addition, the cells can be seen as cell balls or papillae particularly in exfoliative

The smears contain irregular cohesive sheets of highly atypical cells with prominent nucleoli. These features could be difficult to distinguish from poorly differentiated adenocarcinoma ♦♦ Clues to squamous differentiation −− The cells have dense cytoplasm and well-defined cell borders. The nuclei are central and the cytoplasm forms the peripheral border of the sheets. The nuclear chromatin is coarse and varies in density among the cells. The nucleoli vary in size and number

Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma −− Most adenocarcinomas have vacuolated cytoplasm and syncytial appearance with ill-defined cell borders. Nucleoli are prominent and nuclei tend to be more monotonous with more vesicular chromatin ♦♦ Large cell undifferentiated carcinoma −− The smears are cellular and contain highly atypical and very discohesive population of undifferentiated cells

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Fig. 1.80. Adenocarcinoma, bronchial brushing. Atypical cells arranged in sheets with a common cell border and areas with depth of focus. The nuclei are enlarged with prominent nucleoli. Compare the cytologic features of these malignant cells to the neighboring bronchial epithelium with ciliated cells in the center of the field. Papanicolaou stain, medium power view.

Cytopathology

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samples. Characteristically, the clusters have flower-like knobby borders with hobnail nuclei and lack any cilia ♦♦ The neoplastic cells tend to be bland with mild cytologic atypia and an overall monotonous appearance with occasional out of proportion atypical cells. The N/C ratio is slightly increased and the nuclei tend to be round to oval and eccentrically located, slightly hyperchromatic, and contain small prominent nucleoli. Nuclear grooves can be seen in some cases. Some BACs exhibit numerous intranuclear pseudoinclusions and/or psammoma bodies ♦♦ Mucinous variants often display vacuolated or abundant foamy cytoplasm and pools of mucin and can be negative to TTF-1

Differential Diagnosis ♦♦ Mesothelioma −− While mesothelioma is included in this differential, it is rarely encountered as a mass within the lung parenchyma and has to invade the bronchial mucosa before it is encountered in exfoliative specimens. In aspirates, mesothelioma will present as flat sheets of uniform population of cells with dense two-tone cytoplasm. The periphery of sheets exhibit scalloped borders, thick cell membranes, and cytoplasmic blebs. The nuclei are usually centrally located, bland, and contain prominent nucleoli. Myxoid stroma when seen in the background will stain with Alcian blue and digest with hyaluronidase −− Stains are summarized in Table 1.2 ♦♦ Squamous cell carcinoma (see nonkeratinizing SCC) −− Poorly differentiated squamous carcinoma can be difficult to separate from ADC, however, it presents with much higher nuclear pleomorphism while BAC presents with less pleomorphism ♦♦ Hyperplastic type II pneumocyte proliferations and reactive/ reparative changes

−− Clusters of hyperplastic pneumocytes can be numerous in sputum and BAL specimens rendering it the most important differential diagnosis encountered with ADC, particularly that with a predominant BAC growth pattern. These hyperplastic pneumocytes present as smooth outlined spherical clusters and cohesive sheets of cells. The clusters frequently have scalloped borders and intercellular windows (gap) typical of reactive type II pneumocytes −− Characteristically, the cells can be highly vacuolated and some of the vacuoles are out of proportion with the cell size causing a deformity of the cell appearance. This is in contrast with the fine vacuoles encountered in ADC. The cells have normal N/C ratio with abundant cytoplasm, uniform nuclei, and prominent nucleoli. The chromatin may be smudged due to degenerative changes −− The background contains a spectrum of reactive and /or degenerative changes. Pneumocyte reactive clusters can be seen in continuity with recognizable benign cells. Also there is no necrosis or tumor diathesis in the background −− Rectangular or columnar cells with cilia and terminal plates could be encountered in cases related to therapy effect ♦♦ Creola body −− Creola bodies also present as papillary tissue fragments or three-dimensional cell balls. They represent benign reactive columnar cell hyperplasia, often seen in asthma and other causes of chronic irritation such as smoking. Look for the peripheral palisading cells with terminal plates and cilia. Another helpful feature is the presence of goblet cells admixed with the peripheral ciliated cells ♦♦ Granular cell tumor −− This rare tumor originates from the bronchial wall and can be encountered in bronchial samples and rarely in an FNA. The smears contain isolated or small clusters of round or

Table 1.2. Staining characteristics of mesothelioma and adenocarcinoma Stain

Mesothelioma

Adenocarcinoma

Routine stains

•  Two-tone appearance with Papanicolaou •  Peripheral blebs with Diff-Quik

•  Homogeneously distributed stain •  No peripheral blebs noted

Special stains

•  PAS + digestible material (glycogen) •  Coalesced vacuoles may appear sausage-shaped •  Extracellular alcian blue+ material removable by hyaluronidase

•  Glycogen content is small •  PAS + material not digested •  No hyaluronic acid present

Immunostains •  CEA •  EMA

Consistently negative Variably positive with frequently “thick” membrane

•  LMWK and HMWK •  Leu M1 •  HBME-1 •  Calretinin

Positive for both Invariably negative Positive in many cases (cytoplasmic or membranous) Positive in many cases

Consistently positive Frequently positive in cytoplasm and cell periphery Positive only for LMWK Occasionally positive Occasionally positive Occasionally positive

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Essentials of Anatomic Pathology, 3rd Ed.

spindled cells with a finely granular cytoplasm, uniform round to oval nuclei that are frequently eccentrically located, and small nucleoli. The fragile cytoplasm may break during manual smearing (not a feature with liquid based preparations) and numerous granules are seen in the background. The cells are S-100 protein positive

Mucinous Adenocarcinoma Microscopic ♦♦ These present as tight cell clusters or large sheets of Signetring or plasmacytoid type cells in a background of mucin. Despite their apparent low pleomorphism, the cells have enlarged nuclei with increased N/C ratio. There is also evidence of cellular discohesion with scattered single or loosely associated atypical cells

Differential Diagnosis ♦♦ Metastatic mucinous carcinoma −− This differential is usually resolved based on a known history of carcinoma or immunostains characteristic of other primary such as CD-X2 for colon primary, etc. but not based on morphology alone. It is important to note that lung mucinous carcinoma may not express TTF-1 ♦♦ Goblet cell hyperplasia −− Goblet cells may also appear as sheets of plasmacytoid or signet-ring cells. However, contrary to mucinous carcinoma, goblet cells exhibit normal N/C ratio, no discohesion and are frequently admixed with ciliated cells

Large Cell Undifferentiated Carcinoma (Fig. 1.81) Clinical ♦♦ This neoplasm constitutes 10–15% of lung carcinomas and has a strong association with smoking

Microscopic ♦♦ This carcinoma lacks definitive evidence of differentiation whether adeno or squamous. The smears are cellular and contain predominantly single or disorganized groups of large malignant cells with high degree of pleomorphism. The N/C ratio is high with variable cytoplasm and intracytoplasmic ingested neutrophils. The nuclei are markedly enlarged with multiple large prominent nucleoli, thickened irregular nuclear membranes, and coarse clumped chromatin pattern. The cytoplasm is cyanophilic and without evidence of squamous or glandular differentiation. These tumors may contain giant cells (<25% of total cells). Tumor diathesis and necrosis can be prominent ♦♦ Immunostain expression can be variable with over 50% coexpressing cytokeratin, EMA, and vimentin. About 50% will express adenocarcinoma phenotype including positive reaction to CK7 and TTF-1. These tumors may also variably expresses a variety of other antibodies such as B72.3, CEA and NSE

Differential Diagnosis ♦♦ Giant cell carcinoma −− This is a poorly differentiated neoplasm with multinucleated cells constituting more than 25% of the total cell population.

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Fig.  1.81. Large cell anaplastic carcinoma, lung, FNA. Large single, disorganized malignant cells with pleomorphic nuclei and abundant cytoplasm. (A) Papanicolaou stain, (B) Diff-Quik stain, high power view. Neutrophil infiltrate and emperipolesis are present. As in large cell carcinoma, pronounced nuclear pleomorphism with multiple nuclei and nucleoli are characteristic ♦♦ Metastatic melanoma −− Melanoma has to be ruled out whenever large cell carcinoma is in the differential. The smears are cellular and contain predominant single scattered large cells with high N/C ratio, eccentric nuclei with intranuclear pseudoinclusions. The cytoplasm is moderate in amount and has a dusty appearance. Melanin pigment may be detected in some cases. The cells are negative to keratin and positive to S-100 protein, HMB 45, and Melan-A (Mart1)

Pulmonary Neuroendocrine Tumors ♦♦ ♦♦ ♦♦ ♦♦

Typical carcinoid Atypical carcinoid Large cell neuroendocrine carcinoma (LCNE) Small cell carcinoma

Clinical ♦♦ Carcinoid is the most common lung tumor in childhood but constitutes 1–2% of adult lung tumors. Typical and atypical

Cytopathology

carcinoids commonly present as a central endobronchial mass. However, bronchial brushes and washes are usually negative unless the overlaying mucosa is ulcerated ♦♦ Typical and atypical carcinoids are not associated with smoking, while small cell and large cell neuroendocrine carcinomas are highly associated with smoking

Microscopic ♦♦ All neuroendocrine tumors express neuroendocrine markers to a variable degree. Such markers include chromogranin-A, synaptophysin, NSE, and CD56. They are also positive to pancytokeratin. A large proportion of small cell carcinoma expresses TTF-1

Typical Carcinoid (Fig. 1.82) ♦♦ The smears are highly cellular and consist of a monotonous population of small round to oval cells. Cohesive clusters, loosely cohesive sheets, and single cells are seen. The cellular aggregates can present as acinar structures, papillae, cords of cells, interconnecting trabeculae, and palisading groups. The cells can be plasmacytoid with a moderate amount of cytoplasm and low N/C ratio. The nuclear chromatin is finely

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granular “salt and pepper” and a small but obvious nucleolus is present. Characteristically there is no chromatinic smearing. Occasional intranuclear inclusions are encountered and the background may contain fine or prominent capillaries. Mitotic figures are usually absent in cytology or extremely rare

Atypical Carcinoid ♦♦ The smears are cellular and appear similar to that of typical carcinoid at low magnification. Higher magnification reveals slight to moderate nuclear pleomorphism with more prominent nucleoli, occasional mitotic activity, and single cell necrosis

Differential Diagnosis ♦♦ Adenocarcinoma −− Contrary to carcinoids, adenocarcinoma exhibits a higher N/C ratio, more pleomorphism, more prominent nucleoli, and generally more necrosis. The chromatin is usually coarser than that of carcinoid. It is important to note that some carcinoids can be mucin producing (rare variant) and therefore the presence of mucin alone is not reliable in the differential

Spindle Cell Carcinoid ♦♦ This variant is more commonly seen in peripheral carcinoid and can be typical or atypical. The smears are cellular and contain a monotonous population of fusiform cells forming arches and comma shapes appearing as single cells or loose aggregates ♦♦ The cells have moderate cytoplasm with elongated processes appearing like a whip and may fold on themselves forming comma shapes and arches. The nuclear chromatin is finely granular and may have an indentation. A single small nucleolus is evident. Prominent capillaries can also be seen in the background. Mitotic activity and single cell necrosis are dependent on whether it is a typical or atypical carcinoid

Differential Diagnosis

Fig. 1.82. Typical carcinoid, lung, FNA. (A) Monotonous population of small plasmacytoid-appearing cells with a moderate amount of cytoplasm. Chromatin has a salt and pepper appearance. Papanicolaou stain. (B) Occasional binucleation and multinucleation. Diff-Quik stain, high power view.

♦♦ Spindle cell tumors −− Spindle cell carcinoid can be very cellular and mimic sarcomas. It is important to note that cytologically sarcoma is not always very pleomorphic. Immunostains in carcinoid will show the keratin and neuroendocrine markers expression in contrast to the negative reaction of sarcomas ♦♦ Epithelioid histiocytes −− These cells tend to be spindled and contain an elongated carrot-shaped nucleus with small indentation and fine chromatin thus mimicking spindle cell carcinoid. Epithelioid histiocytes however are generally occurring as part of a disease and may accompany other features of such disease, e.g., in sarcoidosis they appear as tight granulomas infiltrated with lymphocytes, in infections they may be accompanied by necrosis or organisms, etc ♦♦ Bronchial cells −− Both bronchial cells and spindle carcinoid have an elongated appearance and oval eccentrically placed nuclei with small nucleoli. The nuclear size is not much different although spindle cell carcinoid tends to be slightly larger (about 1.5 times that of a bronchial cell). Closer

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Essentials of Anatomic Pathology, 3rd Ed.

examination should reveal the terminal bar and cilia characteristic of bronchial cells

Large Cell Neuroendocrine Carcinoma ♦♦ The smears are variably cellular and frequently contain a considerable amount of necrotic debris. The malignant cells are large polygonal to oval in appearance with evidence of extensive discohesion. It is important to remember that according to the WHO classification, large cell neuroendocrine carcinoma (LCNE) carcinoma is defined as having nuclei that are more than three times the size of a resting lymphocyte ♦♦ Nuclei are variable in size and shape and may present as large vesicular nuclei with prominent nucleoli mimicking adenocarcinoma or coarse stippled nuclei and occasional nucleoli mimicking small cell carcinoma. There is usually obvious mitotic activity and necrosis. Nuclear molding, while not a feature in histology, can be seen focally in cytology and the cells tend to focally organize as rosettes or cords with palisaded nuclei

Differential Diagnosis ♦♦ Adenocarcinoma −− It is common to mistake LCNE carcinoma for adenocarcinoma. The nuclear rosetting and palisading could be a clue to neuroendocrine origin and immunostains could assist in the differential ♦♦ Small cell carcinoma −− It is also common to mistake LCNE for small cell carcinoma. The larger cell size and lack of chromatin smearing could be a clue to the differential

Small Cell Carcinoma (Fig. 1.83) ♦♦ Cellular smears depicting a dimorphic population of large cohesive sheets in a background of small blue cells with discohesion. The background contains single cells, doublets, and short cords. The cells are small and the nuclei are equal to or do not exceed three times the size of a resting lymphocyte. The N/C ratio is very high with scant cytoplasm and coarsely clumped, “salt and pepper” chromatin with no nucleoli. Paranuclear cytoplasmic inclusions (blue bodies) can be seen in some cells. Extensive nuclear molding within the clusters and cellular cords are a characteristic feature of small cell carcinoma ♦♦ The background contains many bare nuclei and elongated cells with pointed and angulated nuclei. At times the chromatinic smearing of these fragile nuclei is very prominent. Mitotic activity can be very high and necrotic debris is always present, although in variable degrees

Differential Diagnosis ♦♦ Reserve and bronchial cell hyperplasia −− Present as cohesive, uniform cuboidal cells with smooth nuclear contours. Peripheral cells may have columnar configuration with cilia or terminal bars in bronchial hyperplasia. The clusters contain round uniform nuclei sometimes with very tight molding. There is distinctive absence of discohesion or single cells as well as tumor diathesis. Other reactive changes such as repair may be seen in the background

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Fig. 1.83. Small cell carcinoma, lung, FNA. (A) Small cells with extensive molding, salt and pepper nuclei, and no distinct nucleoli. Chromatin smearing and apoptotic cells in the background. Papanicolaou stain. (B) Highly cellular smear showing extensive molding, focal palisading of the nuclei, and chromatin smearing. Diff-Quik stain, medium power view.

♦♦ Benign lymphocytes and follicular bronchitis −− These present as few collections of small lymphocytes without anisonucleosis. The cellular chromatin shows sharp demarcation of the euchromatin from heterochromatin ♦♦ Lymphoma/leukemia −− These present as increased numbers of loosely aggregated lymphoid cells with intact cytoplasm, vesicular nuclei, and visible nucleoli, but no molding. Note that the morphology will vary depending on the specific type. Subtyping can be enhanced in BAL and FNA material utilizing immunostains on the cell block and/or flow cytometry of fresh material

Metastatic Carcinoma ♦♦ A wide range of malignant neoplasms can metastasize to the lungs and can be detected either by exfoliative specimens or by FNA depending on the location of the metastatic nodules. The following are just examples of the commonly encountered metastases

Cytopathology

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♦♦ Metastatic colon carcinoma −− The malignant cells are frequently seen as geographic sheets in a background of extensive necrosis. The cells are columnar in appearance with elongated hyperchromatic nuclei in a picket-fence or rosette pattern. Cytoplasmic vacuoles and prominent nucleoli may be seen ♦♦ Renal cell carcinoma −− Metastatic renal cell carcinoma present as discohesive sheets of monotonous cells with uniform nuclei in a frequently bloody background (high vascularity of the tumor). The cytoplasm may be clear or granular depending on the variant of

renal cell carcinoma. Numerous bare nuclei (due to fragile cytoplasm) are noted in the background ♦♦ Prostatic adenocarcinoma −− The cells are uniform and form acinar arrangements with prominent nucleoli ♦♦ Breast carcinoma −− Breast carcinoma presents as either tight cellular clusters or isolated cells with eccentric nuclei imparting a plasmacytoid appearance. Breast carcinoma frequently shows short cords or single filing cells. Occasional cytoplasmic vacuoles and signet-ring cells are also common

SALIVARY GLAND AND HEAD/NECK CYTOLOGY Statistics ♦♦ Most common salivary gland tumor −− Pleomorphic adenoma −− Warthin tumor (second most common) ♦♦ Most common parotid cancer in adults −− Mucoepidermoid carcinoma ♦♦ Most common malignancy of salivary glands other than parotid location −− Adenoid cystic carcinoma −− Polymorphous low grade adenocarcinoma (second most common) ♦♦ Most common salivary gland malignancy in child −− Mucoepidermoid carcinoma −− Acinic cell carcinoma (second most common) ♦♦ Most common cystic lesions of salivary glands −− Warthin tumor −− Mucoepidermoid carcinoma (second most common) ♦♦ Most common bilateral tumors of salivary glands −− Warthin tumor −− Acinic cell carcinoma (second most common) ♦♦ Most common bilateral cancer of salivary glands −− Acinic cell carcinoma ♦♦ Most common radiation induced malignancy −− Mucoepidermoid carcinoma

Salivary Glands Normal Findings ♦♦ Acinar cells (serous or mucinous) −− Appear as cohesive tissue fragments of spherical acini outlined by their basement membrane, often held together by a small amount of fibrovascular tissue and may be connected by a small ductular structure. Admixed fat cells are easily identified. The parotid glands consist mainly of serous acinar glands, the submandibular glands have a mixture of both serous and mucinous

while the sublingual glands have predominantly mucinous glands ♦♦ Serous glands −− They have a moderate amount of finely vacuolated granular cytoplasm and small round basal nuclei. The cytoplasm stains basophilic with Papanicolaou stain. The cytoplasm is fragile and may break down during manual smearing resulting in numerous bare nuclei (not to be confused with lymphocytes) ♦♦ Mucinous glands −− They have more abundant vacuolated cytoplasm and small round basal nuclei. Cytoplasm may stain eosinophilic or basophilic by Papanicolaou stain ♦♦ Ductal cells −− Appear as small cohesive flat sheets with a honeycomb pattern when seen en face. The cells are small and have dense eosinophilic cytoplasm by Papanicolaou stain and round to oval nuclei

Nonneoplastic Lesions Sialadenosis Clinical ♦♦ Sialadenosis often present as bilateral enlargement of the parotid glands in patients with known history of long standing autonomic neuropathy such as chronic alcoholism and diabetes mellitus

Microscopic ♦♦ Moderately cellular aspirates consisting predominantly of benign appearing acinar epithelial groups with hypervacuolated and swollen cytoplasm. These groups tend to aggregate and appear as bunches of grapes. Many bare nuclei are detected in the background

Differential Diagnosis ♦♦ Normal acinar glands −− Normal glands have less vacuolated cytoplasm and less bare nuclei in the background

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♦♦ Acinic cell carcinoma −− The aspirates are highly cellular and consist of large sheets and solid groups of acinar glands. The cells can be deceptively bland and confused with benign acini. However, acinic cell carcinoma characteristically lacks any evidence of ductal architecture or interspersed fat cells

Sialadenitis Acute Sialadenitis Clinical ♦♦ Acute sialadenitis can be due to either viral or bacterial infections and result in tender swollen glands

Microscopic ♦♦ Viscous aspirate that consists of purulent material comprised of neutrophils, foamy cells, and endothelial cells

Chronic Sialadenitis Clinical ♦♦ Nonspecific inflammation that usually results from sialolithiasis or as a complication of postsurgical scarring

Microscopic ♦♦ The smears are hypocellular due to the interstitial fibrosis and atrophy and consist of few cohesive clusters of epithelial cells with reactive changes admixed with fibroblasts and mixed inflammatory cells including lymphocytes, neutrophils, and macrophages. Metaplastic squamous or oncocytic cells may be seen (may have some atypia)

Differential Diagnosis ♦♦ Benign lymphoepithelial lesion and Sjogren syndrome −− The smears contain a mixture of polymorphous lymphoid cells and myoepithelial islands. Few oncocytes and multinucleated histiocytes can also be present. Notable is the absence of acute inflammatory cells. In Sjögren syndrome, the lacrimal gland may also be affected ♦♦ Malignant lymphoma −− The smears are cellular and consist predominantly of a monotonous population of lymphoid cells. Other salivary gland elements may be absent or scant ♦♦ Intraparotid lymph node −− The smears are cellular and consist of a polymorphous population of lymphocytes. Germinal centers (grouped lymphocytes with tingible body macrophages) may be evident

Benign Neoplastic Lesions Pleomorphic Adenoma (Benign Mixed Tumor) (Fig. 1.84) Microscopic ♦♦ A droplet of very thick material is retrieved. The smears are variable in cellularity and consist of a biphasic population of epithelial cells admixed with a myxoid stromal component.

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Fig.  1.84. Pleomorphic adenoma, parotid gland, FNA. (A) Cluster of epithelial cells with plasmacytoid appearance in a background of cyanophilic staining myxoid stroma. Papanicolaou stain. (B) Myxoid stroma staining as dark magenta. Diff-Quik stain, medium power view.

The low magnification is characteristic and small islands of myoepithelial cells are seen intimately associated with myxoid or chondromyxoid stroma that characteristically feathers at the periphery of these groups ♦♦ The epithelial component appears as trabeculae, acinar, and solid branching arrangement of epithelial cells with moderate amount of amphophilic ill-defined cytoplasm. The myoepithelial cells are seen as singly scattered cells with a plasmacytoid or vacuolated cytoplasm (sometimes signetring) with well-defined cytoplasmic border. The nuclei are round with finely granular chromatin. When myoepithelial cells are seen within the myxoid stroma they may have fusiform or spindled appearance ♦♦ The stromal component ranges from very loose myxoid material that stains metachromatic with Diff-Quik and amphophilic or cyanophilic with Papanicolaou to dense chondromyxoid material that stains deep blue with Diff-Quik and Papanicolaou stain ♦♦ Tyrosine-rich crystals and metaplastic goblet or squamous cells may be seen

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Differential Diagnosis ♦♦ Malignant mixed tumor −− The smears appear at low magnification similar to pleomorphic adenoma, however at higher magnification atypical cells representing the malignant components (glandular, squamous, small cell, or sarcomatous) are identified ♦♦ Epithelial-myoepithelial carcinoma −− This is a rare neoplasm that also consists of a biphasic population of dark and clear cells admixed with stroma. The cells may be plasmacytoid, round, or oval in appearance and the cytoplasm may be clear or dense. Numerous bare nuclei or bipolar cells may be seen. The myoepithelial groups may appear as tubular fragments. The stromal component may be prominent however, it lacks the irregular feathery border characteristic of the pleomorphic adenoma ♦♦ Mucoepidermoid carcinoma −− The mucin component of a low grade mucoepidermoid carcinoma can mimic the loose myxoid stroma. However, mucin tends to have a more stringy appearance and lacks the feathery pattern. The epithelial component consists of goblet like cells, columnar cells and intermediate type cells. Low grade squamous component is also usually detected in welldifferentiated tumors while a higher grade squamous component tends to dominate as the tumor becomes higher grade ♦♦ Well-differentiated adenoid cystic carcinoma −− Occasionally the myxoid stroma in pleomorphic adenoma appears as cylindrical stroma and mimics adenoid cystic carcinoma. However, in adenoid cystic carcinoma the cells are smaller with high N/C ratio, hyperchromatic nuclei, and more scant cytoplasm ♦♦ Basal cell (monomorphic) adenoma −− This adenoma presents as numerous epithelial clusters and few single cells. The cells have finely granular chromatin and scant cytoplasm. Variable amount of stromal material can be seen in the background and associated with the cells −− Membranous variant presents as clusters surrounded by hyaline material (opposite to what is seen in adenoid cystic carcinoma)

Warthin Tumor (Papillary Cystadenoma Lymphomatosum) (Fig. 1.85) Microscopic ♦♦ This benign cystic neoplasm usually produces few droplets of hazy viscous fluid. The smears contain orderly cohesive flat sheets and clusters of oncocytes intermixed with many lymphocytes. The background consists of amorphous material and scattered histiocytes. Occasional aspirates may be dominated by lymphocytes and mistaken for a lymph node or lymphoma

Differential Diagnosis ♦♦ Branchial cleft cyst −− This cyst is commonly encountered in the lateral neck and is believed to arise from the second branchial cleft. The cyst is lined by squamous epithelium with abundant lymphoid tissue beneath the epithelium. Occasionally columnar cells

Fig. 1.85. Warthin tumor, salivary gland, FNA. A tight cluster of oncocytic cells with abundant granular cytoplasm in the background of numerous lymphocytes and mucoid background. Papanicolaou stain, medium power view.

♦♦

♦♦

♦♦

♦♦

line the cyst. An aspirate usually produces benign squamous cells and in some cases numerous lymphocytes Benign lymphoepithelial lesions −− Myoepithelial islands and less frequent oncocytes (see above) Acinic cell carcinoma −− Acinic cells have very fragile cytoplasm that breaks during manual smearing resulting in numerous bare nuclei that mimic lymphocytes. This neoplasm produces more cellular aspirates containing sheets and acinar glandular structures in addition to the many bare nuclei. The acinic cells are PAS positive and diastase resistant Oncocytoma −− When oncocytic cells are numerous in FNA of a Warthin tumor, it can be easily confused with oncocytoma. In the latter, the cells have more abundant eosinophilic cytoplasm and the lymphocytes are inconspicuous if present Low grade mucoepidermoid carcinoma −− The coexistence of glandular and squamous components with intermediate cells is a diagnostic feature in this tumor. The presence of mucin in the background is also a clue to its nature

Malignant Neoplasms Mucoepidermoid Carcinoma (Fig. 1.86) Microscopic ♦♦ The microscopic appearance of this carcinoma can be variable depending on its grade. Aspirates from low grade mucoepidermoid carcinoma produce predominantly a glandular component that may or may not be admixed with cells of intermediate differentiation (transitional cells) and a welldifferentiated squamous component. The amount of mucin in the background is variable and some cases are dominated by the mucin with few admixed columnar cells

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Fig. 1.86. Well-differentiated mucoepidermoid carcinoma, salivary gland, FNA. (A) Cellular aggregate of intermediate cells and glandular cells. Glandular differentiation is evidenced by the appearance of intracytoplasmic vacuoles and attempt to form glands (microacinar formation). Background mucin staining light pink. Papanicolaou stain. (B) Most of the cells are showing intermediate differentiation; note the fine vacuolization in some of these cells and the intracellular mucin seen in the center. Diff-Quik stain, medium power view.

♦♦ High grade mucoepidermoid carcinoma produces aspirates with a predominant squamous component and obvious pleomorphism. A definitive diagnosis can only be established if a glandular component is present. In some cases this is impossible as the glandular component could be scant

Differential Diagnosis ♦♦ Mucocele and mucous cyst −− Aspirates of mucoepidermoid carcinoma with a predominant mucinous component are difficult to differentiate from these cysts. Hypocellularity and abundant mucin are common features, and the histiocytes seen with these benign cysts are difficult to separate from the singly scattered columnar cells of the carcinoma. As a general rule, benign cysts tend to collapse or drastically decrease in size upon aspiration contrary to cystic carcinomas that either do not disappear or recur within a short duration

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♦♦ Warthin tumor −− It is important to distinguish between the amorphous background in Warthin tumor and the stringy mucin in mucoepidermoid carcinoma. Look for the clusters of oncocytic cells and lymphocytes characteristic of the former ♦♦ Chronic Sialadenitis with prominent mucin or squamous metaplasia −− Aspirates of this lesion are usually hypocellular. In addition to the rare clusters of glandular or squamous cells there are usually inflammatory cells and few fibroblasts ♦♦ Necrotizing sialometaplasia −− Sialometaplasia involves primarily the minor salivary glands and is usually a result of ischemia to the gland. There is considerable squamous metaplasia of the ducts and hyperplasia thus producing aspirates with mixed squamous and glandular components. The clinical history may be helpful in separating it from mucoepidermoid carcinoma ♦♦ Pleomorphic adenoma −− The abundant mucin admixed with bland columnar cells in mucoepidermoid carcinoma may be confused with the myxoid stroma of pleomorphic adenoma. However, the feathering stroma intimately admixed with the myoepithelial cells in pleomorphic adenoma is different from the clusters and small sheets simply swimming in the pools of mucin of the carcinoma. When in doubt, a positive mucin stain would confirm the suspicion of carcinoma ♦♦ Primary or Metastatic squamous cell carcinoma −− These neoplasms can be difficult to separate from high grade mucoepidermoid carcinoma, since all of them consist of malignant squamous cells with variable differentiation. A mucin stain may help to highlight the glandular component in a poorly differentiated mucoepidermoid carcinoma. A history of SCC in another site may favor a metastasis

Adenoid Cystic Carcinoma (Fig. 1.87) Microscopic ♦♦ The majority of aspirates are highly cellular and consist of tight three-dimensional cell balls and branching cylindrical structures surrounding an acellular hyaline well-defined globular material recapitulating the histologic appearance. The cells are small, basaloid, and hyperchromatic. The long axis of the cells tends to be aligned along the border of the clusters. While the cells appear deceptively bland, a closer examination will reveal the high N/C ratio, coarse chromatin, and small nucleoli. While some authors suggest that nuclei in adenoid cystic carcinoma can be distinguished by their atypia from those of adenomas, others maintain that such distinction is impossible and nuclear features do not aid in the differential ♦♦ In poorly differentiated tumors, the aspirate consists of small clusters of predominantly small atypical cells and may completely lack the hyaline material

Differential Diagnosis ♦♦ Monomorphic adenoma (basal cell adenoma) −− This adenoma also presents as cylindrical and branching tubular structures consisting of small cells with round to

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Fig.  1.87. Adenocystic carcinoma, salivary gland. Cylindrical material appearing as rounded globules with well-defined borders surrounded by small, uniform basaloid hyperchromatic cells. Papanicolaou stain, medium power view.

oval uniform nuclei and inconspicuous nucleoli. The stroma may appear focally globular and mimic adenoid cystic carcinoma. However, closer evaluation will reveal an irregular interface between neoplastic cells and collagenous stroma. Focal stroma appears interdigitating with the epithelial cells. The stroma generally contains fibroblasts and small capillaries and is not completely acellular as that of adenoid cystic carcinoma ♦♦ Monomorphic adenoma (membranous) −− This adenoma is also known as dermal analogue type. The smears consist of clusters and tubular structures made of small cells outlined by membranous material ♦♦ Basal cell adenocarcinoma −− The smears consist of branching trabeculae made of small highly atypical blue cells with hyperchromasia and prominent nucleoli. The cells are palisaded at the periphery of the trabeculae. Mitotic activity can be prominent. A myxoid background can be seen. Morphologically this could mimic the solid adenoid cystic carcinoma

Acinic Cell Carcinoma (Fig. 1.88) Microscopic ♦♦ This carcinoma can be solid, cystic, or papillary cystic. The smears are usually cellular and contain a monomorphic ­population of large cells with abundant finely granular cytoplasm. The cells occur in large and small fragments as well as poorly formed acini. Prominent capillaries can be seen traversing the large fragments. Because of the cytoplasmic fragility, many bare nuclei are present in the background and can be confused with lymphocytes. Ductal sheets and adipose cells are not detected among the acinic cells. The background is generally clean particularly in solid cases; however, histiocytes and amorphous debris could be present in cystic cases

Fig. 1.88. Acinic cell carcinoma, salivary gland, FNA. (A) Sheets of monotonous cells with enlarged nuclei and moderate to abundant cytoplasm. Papanicolaou stain. (B) similar cells with obvious granular cytoplasm. Diff-Quik stain, high power view.

Differential Diagnosis ♦♦ Benign salivary gland acini and adenosis −− The aspirates are usually less cellular. In adenosis the numerous acini appear in large cohesive groups that appear like a bunch of grapes. Ductal sheets and adipose cells are detected among the acinar structures. There is no evidence of discohesion of sheets of monomorphic cells ♦♦ Warthin tumor and oncocytoma −− The oncocytic sheets in these neoplasms may be confused with the granular acinic cells particularly in Warthin tumor where the lymphocytic background can be similar to the numerous bare nuclei of stripped acinic cells. Oncocytic cell granules (large number of mitochondria) are negative to PAS with diastase while acinic cell granules (zymogen granules) are positive to PAS and resist digestion

Polymorphous Low Grade Adenocarcinoma Microscopic ♦♦ The smears contain cohesive groups or loosely cohesive clusters of small cells with moderate amount of cytoplasm admixed with a stromal component sometimes appearing as

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small hyaline oval globules. Tyrosine crystals have been reported in some aspirates

Differential Diagnosis ♦♦ This carcinoma is cytologically very difficult to separate from pleomorphic adenoma and adenoid cystic carcinoma. The cells are bland in appearance and lack mitotic activity or necrosis. The loosely cohesive cells tend to have central nuclei contrary to the eccentrically located nuclei of myoepithelial cells in pleomorphic adenoma

Salivary Duct Carcinoma Microscopic ♦♦ Cytologic findings resemble those of comedocarcinoma of the breast. The smears are cellular and contain sheets of obviously malignant cells with high N/C ratio and pleomorphic nuclei. Extensive necrosis and calcifications may be present

Head and Neck Nonneoplastic Lesions Thyroglossal Duct Cyst Clinical ♦♦ This cyst is located at midline of the neck and is movable in a cranial direction when swallowing

Microscopic ♦♦ The smears are hypocellular and may contain squamous and glandular cells admixed with lymphocytes. Thyroid follicular epithelium and variable colloid may be seen as well as rare scattered ciliated columnar respiratory epithelium

Differential Diagnosis ♦♦ Tracheal mucosa −− This may occur particularly in palpable nodules performed without ultrasound guidance. The needle may erroneously reach the trachea. The patient usually coughs immediately which should be a clue. Also these aspirates will lack other features noted in cystic contents such as the histiocytes or lymphocytes

Epidermal Inclusion Cyst (Epidermoid Cyst) Microscopic ♦♦ The aspirates, while cellular, consist predominantly of abundant anucleated squames and few benign keratinizing squamous cells. Some aspirates particularly when ruptured may have a considerable number of multinucleated giant cells. In cases with superimposed infection, numerous neutrophils and multinucleated histiocytes are seen

Differential Diagnosis ♦♦ Cystic squamous cell carcinoma −− This carcinoma can be very low in cellularity and the squamous cells may exhibit very subtle atypia. Clinical and radiologic findings are helpful in this differential

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Branchial Cleft Cyst (Lymphoepithelial Cyst) Microscopic ♦♦ Aspirate results in a thick yellow fluid consisting of an admixture of numerous anucleated squamous cells and squamous cells of variable maturity, cholesterol clefts, and elements of reactive lymphoid tissue, foamy histiocytes, and acellular debris. Occasionally columnar cells are present

Differential Diagnosis ♦♦ Squamous cell carcinoma with cystic degeneration −− Diagnosis rests on finding few highly atypical or bizarre cells with abnormal keratinization ♦♦ Thyroglossal duct cyst −− Distinguished by the anatomic site ♦♦ Epidermal inclusion cyst −− Lack the lymphocytic component

Neoplastic Lesions Paraganglioma (Carotid Body and Glomus Jugulare Tumors) Clinical ♦♦ Presents as a painless firm mass that is attached to the sheath of the artery or nerve. Those situated in the head and neck are rarely functional although few may secrete catecholamines. Carotid body tumor is usually situated deep below the sternocleidomastoid muscle at the level of bifurcation. A bruit can be heard by auscultation over the nodule. Paragangliomas are usually situated along the nerve branches and may surround the nerve

Microscopic ♦♦ The aspirate tends to be hypocellular and consists mainly of blood with scattered single or poorly cohesive cells with a vague follicular pattern. The cells (chief cells) have abundant pale cytoplasm with fine red granules on Diff-Quik and round to oval nuclei with finely granular chromatin. In some cases, the cells may have well-defined dense cytoplasm mimicking oncocytes or carcinoid type cells, while other cells may be predominantly spindled, mimicking neurilemmoma, or other spindle cell neoplasms. The chief cells are strongly argyrophilic and positive with chromogranin

Differential Diagnosis ♦♦ Medullary carcinoma of the thyroid −− The aspirates are usually more cellular and less bloody and consist of numerous plasmacytoid cells with a moderate amount of granular cytoplasm. Amyloid may be seen and can be confirmed by Congo red stain. The epithelial cells are positive to calcitonin ♦♦ Carcinoid tumor −− The tumor location is usually helpful in the differential. Carcinoid tends to produce cellular smears with prominent capillaries yet not necessarily bloody

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Neurilemmoma/Schwannoma Clinical

Microscopic

♦♦ Frequently occur in the head and neck (45%) particularly the lateral aspect, more often in women than men and should always be included in the differential of head and neck lesions. Aspiration of a schwannoma can be painful and sometimes very difficult in those with ancient changes due to the considerable collagen deposits

Microscopic ♦♦ Aspirates tend to be low in cellularity and contain few cohesive fragments of spindled cells (Antoni type A), small fragments of myxoid material (Antoni type B), and singly scattered spindled cells. The nuclei are oval with fine chromatin and inconspicuous nucleoli. Mitotic activity and necrosis are absent. Occasionally a small core of fibrillar material surrounded by two rows of palisaded cells (Verocay bodies) may be detected. In cases with ancient changes, few scattered highly atypical cells are present and should not be confused with malignancy

Squamous Cell Carcinoma Clinical

♦♦ Three microscopic variants have been described: the keratinizing squamous, nonkeratinizing squamous, and the undifferentiated type. Cytologic features of the former two variants are similar to those in other body sites. The undifferentiated variant also known as lymphoepithelioma presents with smears containing both undifferentiated malignant cells and a rich benign lymphoid background. The malignant cells occur in small clusters and single cells and have ill defined cytoplasm. The nuclei are enlarged, vesicular, and contain prominent nucleoli

Differential Diagnosis ♦♦ Hodgkin lymphoma or large cell lymphoma −− These could be confused with the undifferentiated type. Immunostains including pancytokeratin are helpful

Olfactory Neuroblastoma Clinical ♦♦ Occurs in the upper nasal cavity and may metastasize to cervical lymph nodes

Microscopic

♦♦ This is the most common carcinoma in the head and neck and can be either primary or metastatic to lymph nodes. Lymph node metastasis of well-differentiated carcinoma has a tendency for cystic degeneration

Microscopic ♦♦ Cytologic features are similar to those described in the respiratory section. Few atypical cells in a dirty background may be all that are seen in a cystic or necrotic mass (look for abnormal dense keratin and bizarre shaped cells)

Nasopharyngeal Carcinoma Cytologic Features Clinical ♦♦ This carcinoma arises from the epithelial lining of the nasopharynx and is first discovered as a metastasis to the cervical lymph nodes

♦♦ The smears contain small blue cells in clusters, sheets, and singly scattered. The cytoplasm is scant and ill defined with fibrillary processes. Pseudorosettes may be seen in well-differentiated tumors with fibrillary material seen in the center of rosettes. The nuclei are bland with coarse granular chromatin and small inconspicuous nucleoli. Nuclear molding is frequent

Differential Diagnosis ♦♦ Small cell carcinoma −− The aspirates are more cellular with evidence of high mitotic activity and necrosis. Nuclear molding is more prominent and the cells are more pleomorphic in appearance. Chromatinic smearing is usually a prominent feature in small cell carcinoma but completely absent in neuroblastoma. When in doubt immunostaining including pancytokeratin can help in the differential

THYROID Overview Adequacy and Reporting terminology ♦♦ The specimen should be properly prepared and technically ­adequate for proper evaluation. The criteria for adequacy may not apply to all specimens since it depends on the intrinsic nature of the mass ♦♦ Specimens with inflammation such as thyroiditis do not require a minimum number of follicular cells

♦♦ Colloid cysts with abundant watery colloid do not require a minimum number of follicular cells ♦♦ Cystic aspirates with numerous histiocytes and no or rare follicular cells should be diagnosed as “cystic contents” only. These aspirates are categorized as nondiagnostic rather than unsatisfactory ♦♦ Solid nodules require a minimum of 5–6 clusters of follicular cells with ten cells each

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Recommended Diagnostic Terminology

Microscopic

♦♦ Benign (low risk of malignancy) ♦♦ Follicular lesion of undetermined significance/Atypia of undetermined significance (5–10% risk of malignancy). These aspirates are not convincingly benign but atypia is not sufficient to render a diagnosis of neoplasia ♦♦ Follicular neoplasm/suspicious for follicular ­neoplasm (20–30% risk for malignancy). This ­category does not apply to papillary carcinoma ♦♦ Specify if oncocytic (Hürthle cell) ♦♦ Suspicious for malignancy −− Suspicious for papillary carcinoma −− Suspicious for medullary carcinoma (material not sufficient for immunostaining) −− Suspicious for other malignancies or metastasis −− Suspicious for neoplasm with extensive necrosis ♦♦ Malignant ♦♦ Nondiagnostic ♦♦ Specimen processed and evaluated but deemed nondiagnostic due to low cellularity, lack of follicular cells, or poor preservation

♦♦ The smears contain abundant neutrophils, macrophages, cellular debris, and fibrin. Follicular cells are scant

Benign Lesions Thyroid Cysts Clinical ♦♦ The majority of these cysts are benign and result from degeneration, necrosis, or hemorrhage within an adenomatous nodule or neoplasm. Benign cysts collapse after aspiration

Microscopic ♦♦ The smears are variable in cellularity and contents. They frequently contain numerous histiocytes however, they tend to be devoid of epithelial cells in the majority of these cysts and in such situation they should be diagnosed as “cystic contents.” ♦♦ Columnar or squamous cells can be seen in midline thyroglossal duct cysts along with the histiocytes. Hemosiderin-laden macrophages are seen in cysts with internal bleeding, and multinucleated giant cells can be seen particularly in cysts that ruptured resulting in surrounding tissue reaction

Differential Diagnosis ♦♦ Cystic papillary carcinoma −− Large cystic nodules (4  cm or above) with numerous hemosiderin-laden macrophages (particularly when arranged as sheets) should be examined and diagnosed with caution as they could represent a cystic papillary carcinoma

Thyroiditis Acute Thyroiditis Clinical ♦♦ Enlarged gland with multiple abscesses

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Differential Diagnosis ♦♦ Infected thyroglossal duct cyst −− Columnar ciliated or squamous cells are detected along with the inflammatory cells. The epithelial cells may show some atypia that should not be confused with malignancy ♦♦ Carcinoma with necrosis −− The smears may contain necrotic debris only and the epithelial component may be absent or scant. The background is usually that of tumor diathesis with cellular debris and old blood rather than the predominant acute inflammation in acute thyroiditis

Subacute Thyroiditis Clinical ♦♦ Common in middle aged women and resolves spontaneously in most cases

Microscopic ♦♦ Initial stage: degenerated follicular cells, multinucleated giant cells, epithelioid histiocytes, lymphocytes, and neutrophils; background dirty ♦♦ Late stage: low cellularity aspirates with few inflammatory cells and active fibroblasts

Subacute Lymphocytic Thyroiditis Clinical ♦♦ Painless swelling that resolves spontaneously. May develop in postpartum women

Microscopic ♦♦ Smears contain a moderate number of lymphocytes and no Hürthle cells

Chronic Thyroiditis Clinical ♦♦ Chronic granulomatous thyroiditis, e.g., tuberculous, mycotic, etc ♦♦ Reidel thyroiditis −− Chronic fibrosing multifocal inflammation probably of autoimmune etiology. Presents as a sudden painless enlargement of a long standing mass and may cause dysphagia or dyspnea

Microscopic ♦♦ Aspirates are poorly cellular and frequently nondiagnostic. The smears may contain lymphocytes, degenerated follicular cells and fibroblasts

Hashimoto Thyroiditis (Fig. 1.89) Clinical ♦♦ Middle aged women present with hypothyroidism and a moderate generalized enlargement. Micronodules can develop in late lesions

Cytopathology

Fig.  1.89. Lymphocytic thyroiditis (Hashimoto). A cluster of Hürthle cells in a background of numerous lymphocytes and plasma cells. Papanicolaou stain, medium power view.

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Fig. 1.90. Nodular hyperplasia (goiter): Large monolayer sheet of follicular/Hürthle cells showing a well-organized, honeycombed arrangement with abundant cytoplasm in a background of metachromatically stained colloid. Diff-Quik stain, high power view.

Microscopic ♦♦ In the acute phase, the smears contain mostly lymphocytes in variable numbers. In the hypertrophic phase, the smears contain an admixture of lymphocytes and Hürthle cells. In the atrophic phase the smears contain an admixture of cells but much lower in cellularity ♦♦ Hürthle cells may present as small clusters or large fragments that predominate the aspirate. This represents the Hürthle cell hyperplastic nodules commonly seen in histologic sections. Frequently the clusters are infiltrated by lymphocytes. Hürthle cells may exhibit variable degree of cytologic atypia ♦♦ The background lymphocytes may vary in number from few to highly cellular and almost appearing as a touch imprint of a lymph node. Characteristically, it is an admixture of inflammatory cells with germinal center (immature) lymphocytes, small lymphocytes, plasma cells, and histiocytes ♦♦ Colloid may be absent or inconspicuous and multinucleated histiocytes are frequently seen

Differential Diagnosis ♦♦ Hürthle cell neoplasm −− Smears are highly cellular and contain large sheets of Hürthle cells with syncytial arrangement or as numerous completely discohesive cells. The background lacks the lymphocytes. Capillaries traversing the sheets may be detected and reflect the high vascularity of these tumors −− Prominent Hürthle cell nodules that do not have lymphocytes can be indistinguishable from Hürthle cell neoplasms ♦♦ Riedel thyroiditis −− The smears contain fewer follicular center cells. Squamous metaplasia or Hürthle cells are absent. Neutrophils and eosinophils are more abundant rather than lymphocytes ♦♦ Subacute (De Quervain) granulomatous thyroiditis −− Smears contain admixtures of follicular epithelium, small lymphocytes, epithelioid histiocytes, and foreign-body giant cells. Follicular center (immature) lymphocytes and

Hürthle cells are uncommon. Foreign body giant cells with evidence of ingested colloid may be seen in both lesions. Fibroblast and inflammatory debris are also present ♦♦ Graves disease −− Hypercellular smear with hyperplastic follicular epithelium and abundant colloid. The inflammatory component is inconspicuous. The cells characteristically have more eosinophilia at the luminal surface thus described as “Flame cells”

Black Thyroid Nodule Clinical ♦♦ Associated with administration of minocycline and tetracycline

Microscopic ♦♦ Moderately cellular aspirates containing follicular cells with intracytoplasmic deposits of brown pigment. The nuclei are small and nucleoli are inconspicuous. The pigment is comprised of neuromelanin and lipofuscin

Differential Diagnosis ♦♦ Melanoma −− Smears are cellular and contain singly scattered plasmacytoid cells with brown to black pigment. The nuclei are enlarged, eccentrically located, and contain macronuclei. Nuclear pseudo-inclusions are common

Nodular Goiter and Colloid Nodules (Fig. 1.90) Microscopic (see Table 1.3) ♦♦ The smears contain variable numbers of follicular cells in a background of abundant colloid and histiocytes. Colloid is primarily of watery type although some cases may contain numerous fragments of hard colloid

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Table 1.3. Differential diagnosis follicular lesions Colloid nodule/goiter

Follicular neoplasm

Abundant colloid and scanty cellularity

Cellular specimen with scant colloid

Honeycomb sheets of follicular cells

Syncytial sheets and microfollicles

Regenerative and degenerative changes

♦♦ Watery colloid appears as a thin film of pink material on Papanicolaou stain and blue on Diff-Quik. The colloid frequently exhibits a mosaic pattern, a wrinkled-sheet appearance or a rolling border. Occasionally, the colloid falls off the slide during processing leaving behind a lacy network appearance ♦♦ Follicular cells appear as variable sized sheets, intact follicles or small clusters. Microfollicles may be seen in the background but are usually few and not within the sheets. The cells within the sheets are orderly arranged “honeycomb pattern.” The follicular cells are cuboidal, have a small amount of blue cytoplasm, and a central nucleus with fine chromatin and small nucleoli. There is usually minor variation in nuclear size ♦♦ In some cases, the smears also contain Hürthle cells which may be the predominant population. Hürthle cells appear mostly as sheets of orderly arranged cells with slightly larger nuclei than the follicular cells and more prominent nucleoli. The cytoplasm is oncocytic in appearance and heavily granular. It stains eosinophilic by Papanicolaou stain and blue by Diff-Quik. Hürthle cells tend to be more common in older patients, women, and in long standing nodules ♦♦ Degenerative/involutional changes are common. The smears contain numerous histiocytes with or without hemosiderin and occasionally giant cells and fibroblasts. Occasional cases may also contain sheets with classic features of repair. Stromal calcifications can also be seen

Toxic Diffuse Hyperplasia (Graves Disease) Microscopic ♦♦ The smears are highly cellular and consist of colloid and hypertrophied follicular cells. Flame cells are the key feature and they appear as follicular cells with metachromatic materials in apical cytoplasm best seen by Diff-Quik stain. This material is secondary to hyperfunctioning of the endoplasmic reticulum ♦♦ Follicular cells are well organized and appear as honeycomb sheets

Differential Diagnosis ♦♦ Follicular neoplasm (see Table 1.3) −− Cellular aspirates contain numerous syncytial sheets or clusters of follicular cells with little or absent colloid.

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Fig.  1.91. Follicular neoplasm (adenoma), thyroid, FNA. (A) Syncytial fragment of follicular cells with disordered arrangement and some nuclear variation. Notice the small microfollicles in the upper right corner. (B) Papanicolaou stain. Diff-Quik stain, medium power view.

There are many loose microfollicles and clusters with scalloped borders (due to microfollicle formation within the clusters) ♦♦ Follicular variant of papillary carcinoma −− Sheets and clusters with disordered arrangement and evidence of microfollicle formation within the sheets. Nuclear features of papillary carcinoma are preserved

Neoplastic Lesions Follicular Neoplasm (Fig. 1.91) Microscopic (See Table 1.3) ♦♦ The smears are cellular and consist of follicular cells forming syncytial sheets with loss of honeycomb pattern, microfollicles, and microfollicular complexes. The clusters may have a scalloping contour formed by the borders of the microfollicles ♦♦ Rarely markedly atypical or bizarre cells may be observed in atypical adenoma

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♦♦ The colloid is generally scant except in macrofollicular adenomas (these are very difficult to separate from ­hyperplastic nodules) ♦♦ Due to the high vascularity of these neoplasms, aspirates may be extremely bloody and scarce in cellularity ♦♦ Well-differentiated carcinoma may be indistinguishable from adenoma. Some of the features described in association with carcinoma include: disordered cellular pattern with crowding; nucleomegaly with coarse granular chromatin and prominent nucleoli, and loss of polarity within the cell aggregates

Differential Diagnosis ♦♦ Parathyroid adenoma −− Smears are highly cellular and the cells are small cuboidal forming microfollicles. Morphologically parathyroid cells are very similar to follicular cells and the best clue is the site of the aspirate (usually at the posterior border of the thyroid) ♦♦ Nodular goiter (see Table 1.3) −− Admixture of colloid, histiocytes, and follicular epithelial cells that are orderly arranged. The cells have small nuclei and normal N/C ratio

Fig.  1.92. Papillary carcinoma, thyroid, FNA. Follicular cells with monotonously enlarged nuclei and disordered arrangement of the cells. Notice the frequent overlapping and molding of cells, the intranuclear inclusions, and the frequent nuclear grooves. Papanicolaou stain, high power view.

Papillary Carcinoma (Fig. 1.92) Microscopic

♦♦ Cellular smears containing microtissue fragments of monolayer sheets, syncytium, and papillae with or without fibrovascular ♦♦ Highly cellular smears containing exclusively a monomorcores. Follicular structures are observed especially in follicular phic population of Hürthle cells with obvious discohesion variant. Dispersed cell pattern is less frequent ♦♦ The cells are arranged in sheets or as single isolated large ♦♦ The cells are overcrowded within the sheets with nuclear oval or polygonal cells with abundant granular eosinophilic molding. The nuclei are oval with irregular nuclear memcytoplasm (rich in mitochondria). The nuclei are enlarged, branes (nuclear grooves imparting a coffee bean appearance). uniform and have finely granular chromatin and prominent The chromatin is finely granular and small nucleoli can be nucleoli seen frequently touching the nuclear membrane. Intranuclear pseudoinclusion is another feature frequently associated with ♦♦ Adenomas may not be reliably distinguished from well-­ papillary carcinoma (also described in medullary and anadifferentiated carcinoma on FNA biopsies plastic carcinomas). Papillary carcinomas of the Hürthle cell ♦♦ Carcinomas are often more discohesive with numerous isolated variant exhibit all the nuclear features described in the usual smaller cells with high N/C ratio, nuclear pleomorphism, type nuclear overlapping, coarsely granular chromatin and multiple nucleoli. Features described in association with carcinoma ♦♦ The cytoplasm is moderate in amount and well defined. Septated cytoplasmic vacuoles are seen on Diff-Quik stain. include small cell dysplasia (monotonous population of small Occasional cells with squamous differentiation exhibit dense Hürthle cells with high N/C ratio), large cell dysplasia (monotmetaplastic cytoplasm onous population of markedly enlarged Hürthle cells with marked atypia, or a mixture of small and large cells). Bizarre ♦♦ The background may contain numerous hemosiderin-laden cells with nuclei at least three times of the size of nuclei in macrophages. Psammoma bodies appear as red laminated adjacent cells, cytoplasmic inclusions and transgressing vessels structures on Papanicolaou stain or as colorless and refractile are other described features structures on Diff-Quik, although laminations can still be appreciated. Other elements may include variable number of Differential Diagnosis lymphocytes and giant cells with epithelioid cytoplasm ♦♦ Hyperplastic Hürthle cells in hashimoto thyroiditis ♦♦ Colloid is usually present and appears as metachromatic on −− The cells are more cohesive and generally smaller in Diff-Quik stain and stringy on Papanicolaou stain (sticky and size. Lymphoplasmacytic infiltrate is usually present in stretched out) thus coined the term “bubble gum” the background. The sheets may be pleomorphic and ♦♦ The cells are positive to thyroglobulin and TTF-1 infiltrated by the lymphocytes. Giant cells are frequently seen Differential Diagnosis ♦♦ Hyperplastic nodule of predominantly Hürthle cells ♦♦ Hürthle cell neoplasm −− The aspirates will contain all the classic findings of hyper−− The characteristic nuclear features of papillary carcinoma plasia including the abundant colloid and histiocytes namely, nuclear grooves, molding, and pseudo-inclusions

Hürthle Cell Neoplasm

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are absent or inconspicuous in Hürthle cell neoplasm. In contrast these features are easily identified in papillary carcinoma of Hürthle cell variant ♦♦ Follicular cell neoplasm −− Follicular variant of papillary carcinoma may not be easily recognized and can be mistaken for a follicular neoplasm particularly in cases where the nuclear features are not prominent and should always be considered in the differential. Follicular neoplasms tend to exhibit a more prominent microfollicular pattern and the nuclear chromatin tends to be coarser and contain a small but conspicuous nucleoli

Medullary Carcinoma (Fig. 1.93) Microscopic ♦♦ Cellular smears containing discohesive clusters and isolated spindle or plasmacytoid cells. The cytoplasm is moderate in amount, pale with red azurophilic cytoplasmic granules (calcitonin). Fine red metachromatic (neurosecretory) granules

Essentials of Anatomic Pathology, 3rd Ed.

can be seen on Diff-Quik stain. The nuclei are eccentric, round to oval, with salt and pepper chromatin, and small nucleoli. Bi- or multinucleation and intranuclear cytoplasmic inclusions are common. Occasional large atypical cells and giant cells may be scattered among the other cells. The cells are positive to calcitonin, and neuroendocrine markers such as chromogranin and synaptophysin ♦♦ Fluffy, granular or acellular amyloid stroma may be admixed with the cellular component and can be confirmed by a positive Congo red stain

Differential Diagnosis ♦♦ Malignant lymphoma −− The numerous plasmacytoid cells may be mistaken for lymphoma. However, lymphoma presents as a monotonous population of lymphoid cells that, while variable in morphology depending on the type of lymphoma, usually have far less cytoplasm. Lymphoglandular bodies on Diff-Quik stain representing broken cytoplasm is a very helpful feature in identifying a lymphocytic population. Lymphocytes also lack the salt and pepper chromatin characteristic of medullary carcinoma ♦♦ Hurthle cell neoplasm −− Medullary carcinoma may have abundant granular cytoplasm mimicking Hürthle cells. However, the latter when appearing as a single cell pattern, usually are much larger cells with coarser chromatin and a prominent nucleolus

Anaplastic Carcinoma (Fig. 1.94) Microscopic ♦♦ Cellular smears contain isolated or discohesive clusters of cells. The cells are markedly pleomorphic with enlarged hyperchromatic nuclei and prominent nucleoli. Many cells are noted ingesting large numbers of neutrophils. The background is dirty containing tumor diathesis and blood. Anaplastic carcinoma could also present as a spindle cell

Fig. 1.93. Medullary carcinoma, thyroid, FNA. (A) Discohesive small plasmacytoid cells with round to oval nuclei, and occasional binucleation. Chromatin is finely granular and evenly distributed. Papanicolaou stain. (B) Occasional out of proportion enlarged nuclei consistent with neuroendocrine lesions. Note also the palisading of nuclei in the upper right corner attempting to form rosettes. Diff-Quik stain, high power view.

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Fig.  1.94. Anaplastic carcinoma, thyroid, FNA. Discohesive, large, markedly pleomorphic cells. Papanicolaou stain, high power view.

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variant. The cells are positive to low molecular keratin, vimentin, and P53. TTF-1 may be focally positive

carcinoma. A positive calcitonin favors medullary carcinoma

Metastatic Carcinoma

Differential Diagnosis ♦♦ Medullary carcinoma ♦♦ The spindle cell variant may not exhibit prominent atypia and may be confused with spindle cell variant of medullary

♦♦ It is rare to encounter metastasis to the thyroid without a known primary; however metastatic tumor should always be considered when the cytologic features are not consistent with conventional thyroid neoplasms

BREAST Overview Stromal and Epithelial Cells

Reporting Terminology (Diagn Cytopathol 1997;16:295–311)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Benign: no evidence of malignancy ♦♦ Atypical/indeterminate: cellular findings are not diagnostic, clinical and radiologic correlation is warranted ♦♦ Suspicious/probably malignant: Highly suggestive of malignancy, recommend tissue biopsy ♦♦ Malignant: findings diagnostic of malignancy. Qualify further with specific diagnosis ♦♦ Unsatisfactory (due to) −− Scant cellularity −− Air drying or distortion artifact −− Obscuring blood or inflammation −− Other

Fibroadenoma Phyllodes tumor Periductal stromal sarcoma Carcinosarcoma Adenocarcinoma with marked stromal fibrosis

Squamous Cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Subareolar abscess Fibrocystic change (rare) Phyllodes tumor (rare) Gynecomastia Infarcted papilloma (rare) Cysts (epidermal inclusion cyst and fibrocystic change) Metaplastic carcinoma

Apocrine Cells ♦♦ ♦♦ ♦♦ ♦♦

Fibrocystic changes Fibroadenoma Benign phyllodes tumor Apocrine carcinoma

Benign Lesions Fat Necrosis (Fig. 1.95) Clinical ♦♦ This is a benign lesion that can simulate malignancy clinically and radiologically. Rarely the patient gives the history of trauma

Giant Cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Duct ectasia Granulomatous mastitis Foreign body reaction (e.g., suture material, silicon) Fat necrosis Medullary carcinoma

Small Cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Ductal carcinoma Tubular carcinoma Lobular carcinoma Lymphoma Carcinoid

Fig. 1.95. Fat necrosis, breast, FNA. Disrupted fat surrounded by histiocytes and hemosiderin-laden macrophages. Diff-Quik stain, high power view.

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Microscopic

Differential Diagnosis

♦♦ Moderate to low cellular smears containing disrupted fat and dystrophic calcifications admixed with isolated atypical fibroblasts with enlarged nuclei and fine vesicular chromatin. The background may contain inflammatory cells including neutrophils, lymphocytes and plasma cells, and foreign body reaction with foamy histiocytes and giant cells. Hemosiderinladen macrophages may or may not be present and their presence indicates old blood. Occasionally atypical ductal cells with reparative changes may also be present

♦♦ Acute abscess or mastitis −− A specific diagnosis of subareolar abscess results in proper management of the patient. However, if the significance of anucleated squames is not recognized or presumed to be skin surface contamination, the diagnosis will be missed

Differential Diagnosis ♦♦ Adenocarcinoma −− The slight cytological atypia that may be seen in the reactive fibroblasts, histiocytes (granulation tissue components), and reactive ductal cells combined with the suspicious clinical presentation may cause the overcall of fat necrosis. However, contrary to adenocarcinoma the cytologic atypia is usually subtle, the cells are mostly singly scattered and do not aggregate as in carcinoma, and the smears are low in cellularity. The presence of inflammatory background and hemosiderin-laden macrophages point to the traumatic etiology

Subareolar Abscesses (Fig. 1.96) Clinical ♦♦ The result of local inflammation of the lactiferous ducts beneath the nipple causing squamous metaplasia and subsequent obstruction. Drainage of the abscess usually results in temporary relief and the abscess recurs shortly. Therefore, the appropriate treatment includes surgical intervention

Microscopic ♦♦ The aspirated material is thick and contains suppurative granulomatous inflammation and numerous anucleated squamous cells in granular, necrotic dirty inflammatory background. Additional findings may include mature metaplastic or parakeratotic cells and reactive and reparative epithelial changes

Lactational Changes Clinical ♦♦ Pregnancy and lactational breast changes may result in de novo lesions namely lactating adenoma or lactational changes in ­preexisting lesions most commonly a fibroadenoma

Microscopic ♦♦ The smears are of moderate cellularity containing more ductal mammary epithelium than normally encountered in normal breast. There is usually a uniform cell population of discohesive cells with prominent nucleoli and foamy vacuolated cytoplasm. The background contains numerous bare nuclei (fragile hypervacuolated cytoplasm) in a granular proteinaceous material (milky). Because of cellular hypertrophy, the ductal cells appear to have larger nuclei with prominent nucleoli; however, since the cytoplasm is abundant the N/C ratio remains low ♦♦ Cases of fibroadenoma with superimposed lactational changes are almost cytologically identical, however the former will also contain numerous naked bipolar myoepithelial cells in the background

Differential Diagnosis ♦♦ Lobular carcinoma and signet-ring cell carcinoma −− Overcalling lactational change is a well known pitfall since the fragile cytoplasm frequently breaks leaving behind what appears to be discohesive atypical cells. However, closer evaluation will reveal the monotonous appearance of the bare nuclei with occasional cells having intact highly vacuolated cytoplasm in contrast to the significant cytologic atypia, nuclear pleomorphism, necrosis, and loss of polarity encountered in carcinoma

Fibrocystic Changes (Figs. 1.97 and 1.98) Microscopic

Fig.  1.96. Subareolar abscess, breast, FNA. Purulent exudate admixed with numerous anucleated squames. Papanicolaou stain, medium power view.

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♦♦ The aspirates are characterized by a triad of epithelial hyperplasia, cyst formation, and stromal fibrosis. The mammary epithelium presents as cohesive sheets of ductal epithelial cells with honeycomb arrangement or sheets of apocrine metaplastic cells. In cases with hyperplasia, larger ductal sheets with folded appearance may also be seen. Myoepithelial cells can be seen within the sheets ♦♦ The background contains variable number of bipolar/ myoepithelial cells and occasional fibroblasts depending on the extent of fibrosis, and histiocytes representing cystic contents ♦♦ The presence of a polymorphous population of cells is therefore a key feature for the diagnosis of fibrocytic changes

Cytopathology

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Fig. 1.97. Apocrine metaplasia, breast, FNA. Monolayer sheet of large cells with enlarged nuclei, prominent nucleoli, and abundant granular cytoplasm. Papanicolaou stain, high power view.

Fig. 1.99. Fibroadenoma, breast, FNA. Cellular smear with tight branching, cohesive sheets of cells forming antler horn and papillary-like fronds in a background of numerous small stripped nuclei. Papanicolaou stain, low power view.

Fig. 1.98. Fibrocystic changes, breast, FNA. Large folded sheet of benign mammary epithelium in a background of few stripped nuclei. Diff-Quik stain, medium power view.

Fig.  1.100. Fibroadenoma, breast, FNA. Fibromyxoid stroma admixed with few clusters of benign mammary epithelium. Papanicolaou stain, medium power view.

Differential Diagnosis

Fibroadenoma (Figs. 1.99 and 1.100) Microscopic

♦♦ Fibroadenoma −− This benign lesion is characterized by a triad of branching complex sheets, myoepithelial cells, and fibromyxoid stroma. The number of myoepithelial cells tends to be much more than fibrocystic changes ♦♦ Well-differentiated ductal carcinoma −− The cytologic presentation of this carcinoma may overlap with that of fibroadenoma when the invasive trabeculae are aspirated intact and present as cohesive sheets in a background of stripped or spindled small fibroblasts of desmoplastic origin mimicking myoepithelial cells. The former usually have more irregular sheets with frayed edges and pointed borders. Closer examination will reveal more pronounced nuclear atypia in the carcinoma cells and some evidence of disordered arrangement

♦♦ The smears can vary in cellularity depending on the ratio of epithelial to stromal component within the fibroadenoma. Cellular smears characteristically contain a triad of complex epithelial fragments, myoepithelial cells, and fibromyxoid stroma. The background is usually clean ♦♦ The epithelial component is presented as tight branching cohesive sheets of polymorphous cells forming antler horn or mitten-like papillary fronds. They may also form large monolayer and folded sheets. Large sheets of apocrine metaplastic cells can also be seen. Mild nuclear and nucleolar enlargement and rare mitotic figures may be encountered in some cases ♦♦ The background contains numerous stripped bipolar naked myoepithelial cells and fragments of fibromyxoid stroma.

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Occasional multinucleated giant cells (stromal origin) may be noted. The presence of foamy histiocytes indicates cystic change within the fibroadenoma

Differential Diagnosis ♦♦ Phyllodes tumor −− Also result in aspirates containing dimorphic population of epithelium and stroma. Epithelial fragments are similar to those of fibroadenoma. Squamous metaplasia may be more frequently seen than in fibroadenoma. Stromal fragments tend to be more cellular than fibroadenoma with transgressing blood vessels. Cytologic atypia can be recognized in the naked bipolar cells and stromal fragments ♦♦ Well-differentiated ductal carcinoma −− Rarely the aspirates may mimic fibroadenoma due to the intact trabeculae and the background of stripped fibroblasts mimicking bipolar cells. Ductal carcinoma fragments will present as epithelial fragments with pointed edges and irregular borders. Cytologic atypia with nuclear overlapping and nuclear membrane irregularity can also be detected ♦♦ Tubular carcinoma −− The smears tend to be low in cellularity and contain few three-dimensional tubular structures with angulated appearance and less frequent bipolar cells (stripped fibroblasts not myoepithelial cells) ♦♦ Fibromatosis, nodular fasciitis, and mammary fibrosis −− These aspirates are often similar on FNA biopsy to fibroadenoma. The smears are hypocellular and contain few isolated spindle fibroblasts and syncytial stromal fragments. Contrary to fibroadenoma they lack an epithelial component. Myxoid stroma in an inflammatory background is more common in nodular fasciitis, while fragments of mature adipose tissue admixed with the stromal fragments are more common in mammary fibrosis ♦♦ Fibrocystic changes −− While the aspirates of fibroadenoma and fibrocystic changes contain very similar elements, the latter lacks the numerous bipolar cells and the complex tissue fragments

Gynecomastia (Fig. 1.101) Microscopic ♦♦ These aspirates contain findings similar to fibroadenoma, but they tend to be less cellular. The epithelial component presents as branching, cohesive sheets of hyperplastic polymorphous cells in a background of few naked bipolar cells. Frequent ­discohesive isolated columnar cells are present and epithelial cytologic atypia may be striking

Differential Diagnosis ♦♦ Invasive ductal carcinoma −− The cytologic atypia in gynecomastia can be mistaken for carcinoma. However, the overall pattern and the clinical information including the gender (male) should be a clue to the diagnosis

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Fig. 1.101. Gynecomastia, male breast, FNA. Several tight clusters of benign mammary epithelium in a background of few stripped nuclei and a small fragment of myxoid stroma in the center. Diff-Quik stain, low power view.

Intraductal Papilloma Microscopic ♦♦ Aspirates are moderate to high in cellularity and contain sheets of polymorphous cells, papillary fragments and feather like fragments lined by columnar cells with eccentric nuclei. The cells exhibit minimal nuclear pleomorphism and nuclear membrane irregularity. Typically the aspirate contains a mixture of apocrine metaplasia, foamy macrophages, and sheets of hyperplastic ductal cells as well. Singly scattered cells are few

Differential Diagnosis ♦♦ Intracystic papillary carcinoma −− These aspirates are cellular and contain branching three-­ dimensional papillae with more complex architecture lined by columnar cells. There are numerous scattered single papillae and obvious discohesiveness with numerous singly dispersed columnar cells, nuclear pleomorphism, and mitotic figures

Ductal Carcinoma In Situ and Invasive Carcinoma ♦♦ CIS cannot be reliably separated from invasive carcinoma by cytology. The following are characteristic features suggested by the literature

Ductal Carcinoma In Situ Microscopic ♦♦ Cellular aspirates containing three-dimensional clusters of cells with papillary, solid, or cribriform configuration. Rare bipolar cells or bare nuclei may be present ♦♦ Evidence of discohesiveness is noted with isolated cells often >10% of the atypical cell population ♦♦ Cytologic atypia with nuclear pleomorphism, nuclear hyperchromasia, coarsely granular chromatin, prominent macronucleoli, and necrosis in comedo-type ductal carcinoma in situ (DCIS)

Cytopathology

Differential Diagnosis ♦♦ Ductal hyperplasia without atypia −− Smears contain clusters and crowded sheets of cells in a complex arrangement with cellular streaming, nuclear spindling, and irregular lumen formation. Bipolar bare nuclei are present within the clusters and in the background ♦♦ Atypical ductal hyperplasia −− These aspirates are often indistinguishable from low grade DCIS. The smears contain clusters and flat sheets of epithelial cells with regular lumen formation. There is loss of polarity and cell cohesion with increased isolated monotonous cells. Nuclear enlargement, crowding, and overlapping are more evident. Additionally there may be an admixture of benign stromal cells and apocrine metaplastic cells ♦♦ Low grade ductal carcinoma −− These aspirates are cellular and exhibit evidence of increased discohesion in the form of isolated monotonous cells. Benign cellular components are absent

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♦♦ Fibroadenoma −− Cellular smears containing a dimorphic population of cells without cytologic atypia. The cellular fragments are larger and formed of many flat sheets in addition to the complex branching fragments that characteristically have a rounded smooth tip. There are numerous stripped-­ bipolar nuclei and fibromyxoid stroma

Invasive Ductal Carcinoma (Fig. 1.102) Microscopic ♦♦ Cellular smears composed of sheets and syncytial fragments of malignant cells with cytologic atypia, obvious discohesion and disordered arrangement. The cells have high N/C ratio, enlarged hyperchromatic nuclei that are frequently eccentrically located (plasmacytoid), irregular nuclear membrane, and prominent nucleoli. There are many singly scattered abnormal cells. Mitotic activity and necrosis may be prominent. Myoepithelial cells are absent. Background of necrosis and tumor diathesis (nuclear and cytoplasmic debris, ghosts of cells, and old blood) is conspicuous

Lobular Carcinoma In Situ Microsopic ♦♦ Hypocellular smears containing few singly isolated uniform small cells and three-dimensional cell balls. Indian filing and nuclear molding of cells may be noted. The small cells have high N/C ratio, eccentrically locate nuclei, and intracytoplasmic vacuoles (signet-ring cells). The nuclei are hyperchromatic with irregular nuclear membranes and inconspicuous nucleoli

Differential Diagnosis ♦♦ Atypical lobular hyperplasia −− Often indistinguishable from LCIS ♦♦ Invasive lobular carcinoma −− The smears tend to be more cellular and exhibit evidence of more discohesion and more cytologic atypia

Intracystic Papillary Carcinoma Microscopic ♦♦ Highly cellular aspirates containing numerous branching papillae, single papillae, and feather like fragments lined by tall columnar cells with cytologic atypia and nuclear pleomorphism. There is evidence of discohesion with numerous isolated monomorphic columnar cells admixed with many histiocytes and hemosiderin-laden macrophages in a bloody background. The nuclei are atypical with irregular nuclear membranes and increased mitotic activity. Arborizing thinwalled blood vessels may be seen within the fragments

Differential Diagnosis ♦♦ Intraductal papilloma −− The epithelial fragments are less complex, more cohesive and lack the cytologic atypia seen in carcinoma. The smears tend to contain apocrine metaplasia, foamy histiocytes and small bipolar bare nuclei

Fig.  1.102. Invasive ductal carcinoma, breast FNA. (A) Small cluster and trabeculae of atypical cells with enlarged nuclei and prominent nucleoli. Note the presence of numerous atypical discohesive single cells. Papanicolaou stain. (B) Diff-Quik stain, medium power view.

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Differential Diagnosis ♦♦ Cellular fibroadenoma −− Dimorphic populations of bipolar naked cells and branching tight clusters and sheets of epithelial cells with fenestration. Prominent nucleoli and nuclear overlapping are absent while the cellular polarity is preserved

Lobular Carcinoma (Fig. 1.103) Microscopic ♦♦ These aspirates tend to be low to moderately cellular due to its scirrhous nature. The smear contains singly scattered small discohesive cells. Cells may be depicted, arranged in a single file “Indian filing” ♦♦ The cells have high N/C ratio, hyperchromatic nuclei with irregular nuclear membranes and small nucleoli. Targetoid intracytoplasmic vacuoles with eccentric nuclei, imparting signet-ring appearance are frequent

Differential Diagnosis ♦♦ Mucinous (colloid) carcinoma −− Although the mucinous carcinoma cells are plasmacytoid in appearance, these aspirates tend to be more cellular and

Fig.  1.103. Invasive lobular carcinoma, breast, FNA. (A) Discohesive atypical single cells, some with intracytoplasmic vacuoles (signet-ring cells). Papanicolaou stain. (B) Single cells have a plasmacytoid appearance. Diff-Quik stain, high power view.

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contain clusters and single mildly atypical cells swimming in a pool of mucin

Mucinous (Colloid) Carcinoma (Fig. 1.104) Microscopic ♦♦ Cellular smear contains numerous isolated cells, discohesive sheets, and cell balls in a mucoid background (pink by Papanicolaou and blue by Diff-Quik stain). The cells are slightly atypical and the N/C ratio is slightly increased with eccentric uniform nuclei and intracytoplasmic vacuoles. Closer examination will reveal the cytological atypia commonly encountered in carcinoma. Arborized thin-walled blood vessels within the mucus are common

Differential Diagnosis ♦♦ Mucocele −− These aspirates are scant in cellularity and contain few clusters and cohesive flat sheets of cells in a background of abundant extracellular mucin and scattered histiocytes and fibroblasts. There is no cytologic atypia and it lacks the three-dimensional cell balls and arborized thin-walled blood vessels

Fig. 1.104. Mucinous carcinoma, breast, FNA. (A) Tight and discohesive clusters of malignant cells in a background of abundant mucin. Papanicolaou stain, low power view. (B) Another presentation with numerous single plasmacytoid cells. Notice the occasional binucleation and the mild nuclear atypia. The background is rich in pale-staining mucin. Papanicolaou stain, high power view.

Cytopathology

♦♦ Cystic hypersecretory duct carcinoma −− This is very rarely aspirated and the smear contains scattered isolated, clusters and sheets of epithelial cells in a background of pink bubbling secretions with cracked artifact imparting a mosaic plate appearance. The cells have a large hypervacuolated cytoplasm and nuclei that exhibit cytologic atypia

Medullary Carcinoma Microscopic ♦♦ Cellular smears contain syncytial fragments, discohesive clusters, and numerous single cells. The cells are large and highly pleomorphic with nucleomegaly, anisonucleosis, and prominent nucleoli (may be bizarre). Inflammatory cells including lymphocytes and plasma cells and sometimes neutrophils are numerous in the background

Differential Diagnosis ♦♦ Intramammary lymph node with metastatic carcinoma −− The background of benign lymphocytes from the lymph node mimics that of medullary carcinoma. The later tend to have more dirty back ground and tumor diathesis

Tubular Carcinoma Microscopic ♦♦ The smears are low in cellularity and contain three-dimensional angulated tubular structures with occasional central lumens against a background of discohesive isolated monotonous cells and bipolar cells present in 25–50% of the cases (most likely stripped fibroblasts). While the overall appearance of the cells is bland, closer examination reveals loss of polarity within the groups, and the single cells have small nucleoli

Differential Diagnosis ♦♦ Fibroadenoma −− The three-dimensional groups of tubular carcinoma mimic the complex branching sheets of fibroadenoma. However, the later exhibits flat branching sheets with honeycomb pattern, staghorn configuration with rounded borders. The presence of myxoid stroma can also help in separating the bipolar bare nuclei in fibroadenoma from the stripped nuclei and fibrous stroma fragments of tubular carcinoma

Apocrine Carcinoma Microscopic ♦♦ Cellular smears contain numerous syncytial fragments, discohesive clusters, and isolated cells. The cells are large and demonstrate apocrine differentiation with dense waxy eosinophilic cytoplasm and apocrine snouts. They have abundant heavily granular cytoplasm (rich in mitochondria). The nuclei are markedly enlarged, with nuclear pleomorphism and prominent nucleoli (macronucleoli)

Differential Diagnosis ♦♦ Fibrocystic change/apocrine metaplasia −− The smears are less cellular, more cohesive, and lack the cytologic atypia or anisonucleosis encountered in carci-

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noma. Other findings indicative of fibrocystic changes are also present such as histiocytes and benign ductal sheets

Phyllodes Tumor Microscopic ♦♦ Cellular smears contain two cell populations representing the epithelial and stromal components. The epithelial component presents as complex branching tight clusters very similar to those of fibroadenoma. Squamous metaplasia can be seen. The stromal component presents as fibromyxoid stroma that tends to be more abundant and cellular than that of fibroadenoma, with many spindle cells embedded in metachromatic staining stroma. These spindled cells have large nuclei with nuclear membrane irregularity and prominent nucleoli. Numerous bipolar naked nuclei with cytologic atypia are present in the background. Stromal overgrowth and/or stromal atypia with increased mitosis suggest malignancy

Differential Diagnosis ♦♦ Fibroadenoma −− The stromal fragments are fewer and far less in cellularity and lack the spindled atypical cells encountered in phyllodes tumor ♦♦ Juvenile cellular fibroadenoma −− Stromal and epithelial elements may be abundant; however, they lack any significant cytologic atypia ♦♦ Ductal carcinoma −− Phyllodes with atypical epithelial component may mimic invasive ductal carcinoma with desmoplastic fibrous stroma. However, ductal carcinoma lacks the bipolar cells and the hypercellular stromal fragments with atypical spindled cells

Metaplastic Carcinoma Microscopic ♦♦ Cytologic findings will vary depending on the type of metaplasia. Generally the smears are hypercellular containing mixtures of poorly differentiated malignant cells and areas of squamous, sarcomatous, chondroid, or osseous metaplasia ♦♦ Squamous metaplasia is the most common type of metaplasia. The smears contain large cohesive sheets as well as numerous single cells. The cells are enlarged and have dense waxy eosinophilic cytoplasm and enlarged hyperchromatic nuclei. The background contains anucleated keratinous debris, and multinucleated giant cells with intracytoplasmic vacuoles and phagocytic debris ♦♦ Spindled cell metaplasia will present as groups of spindled cells indistinguishable from sarcoma. The cells are positive to high molecular weight kertins (K903)

Differential Diagnosis ♦♦ Fibromatosis and nodular fasciitis −− The smears are less cellular and lack cytologic atypia

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LYMPH NODE Reactive Hyperplasia (Fig. 1.105) Clinical

Necrotizing Granulomatous Lymphadenitis Clinical

♦♦ In general, the specific cause of reactive hyperplasia cannot be determined on the basis of cytologic features alone. If cytologic evaluation does not match the clinical or flow cytometry result, the lymph node should be excised

♦♦ The etiology of necrotizing granulomatous adenitis includes cat scratch disease, mycobacterial infection, Yersinia, tularemia, brucellosis, and fungal infection

Cytologic Findings ♦♦ An aspirate from a reactive lymph node consists of a polymorphous cell sample with a predominance of mature small lymphocytes admixed with tingible body macrophages, plasmacytoid lymphocytes/plasma cells, and immunoblasts (all parts of lymph node are sampled). The lymphoid cells are dispersed with lymphoglandular bodies in the background. Lymphohistiocytic aggregates (follicle center fragments) are also present and consist of dendritic cells associated with centroblasts and centrocytes ♦♦ Reactive plasma cells may show intracytoplasmic inclusions (Russell bodies). Mott cells are plasma cells with large numbers of Russell bodies which appear as hyaline globules (immunoglobulin within the endoplasmic reticulum)

Differential Diagnosis ♦♦ Granuloma, Hodgkin lymphoma, and follicular lymphoma (see below)

Acute Lymphadenitis ♦♦ Smears show sheets of neutrophils and heterogeneous lymphoid cells in a variably necrotic background. Bacteria and fungi may be identified in routine preparations or on special stains

Cytologic Findings ♦♦ Aspirate samples consist of varying numbers of granulomas: loose or tightly clustered epithelioid histocytes. There is a variable degree of acute inflammation and necrosis in the background

Cat Scratch Disease ♦♦ Aspirate samples consist of a polymorphous population of lymphocytes, plasma cells, and neutrophils in a dirty necrotic background. Poorly formed granulomas with scattered epithelioid histiocytes may be seen. Some granulomas show a stellate configuration with central neutrophils

Nonnecrotizing Granulomatous Lymphadenitis Clinical ♦♦ Etiologies of nonnecrotizing granulomatous inflammation include: sarcoidosis, toxoplasmosis, infectious mononucleosis, tuberculosis, drug reactions, syphilis, berylliosis, foreign body reaction, lymphoma (especially Hodgkin lymphoma and T-cell lymphoma), and lymph node ­draining malignancies (especially SCC and seminoma). Microbiologic cultures are essential to exclude an infectious etiology

Cytologic Findings ♦♦ Aspirate samples consist of loose clusters of epithelioid histiocytes with elongate nuclei and fibrillar cytoplasm associated with variable numbers of small lymphocytes. The background of the smears is clean ♦♦ Multinucleated giant cells are characteristically present. Isolated multinucleated giant cells should prompt a thorough search for granulomas in the sample

Infectious Mononucleosis

Fig. 1.105. Reactive lymph node, FNA. A polymorphic population of lymphocytes and tingible body macrophages. Small blue droplets represent broken lymphocytic cytoplasm, i.e., lymphoglandular bodies. Diff-Quik, medium power view.

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♦♦ FNA samples are highly cellular with increased numbers of immunoblasts in a background of reactive hyperplasia including germinal center fragments and plasmacytoid lymphocytes ♦♦ Immunoblasts are smaller than Reed–Sternberg cells and lack the inclusion-like nucleoli of Reed–Sternberg cells. Immunoblasts have round nuclei, fine chromatin, and regular prominent nucleoli with abundant deeply basophilic cytoplasm ♦♦ A specific diagnosis of infectious mononucleosis requires serologic confirmation

Cytopathology

Malignant Lymphoma (see Chapter 15) Clinical ♦♦ Accurate lymphoma diagnosis by FNA requires close communication with clinicians and colleagues in hematopathology. Familiarity with role of ancillary studies, proper methods of specimen collection, and immediate assessment of specimen adequacy is essential for appropriate triage

Cytologic Finding ♦♦ Lymphomas generally produce highly cellular smears with a discohesive cell population. Usually, there is a relatively monomorphic population of abnormal lymphocytes ♦♦ Lymphoglandular bodies are fragments of lymphocyte cytoplasm. They are best appreciated in Romanowsky stained preparations as light blue or blue-gray globular or flake-like structures. Lymphoglandular bodies are seen in both benign and malignant conditions, but are rare in T-cell lymphoma ♦♦ Dutcher bodies are intranuclear inclusion bodies in plasma cells (versus Russell bodies: intracytoplasmic inclusions, nonspecific). Dutcher bodies are often seen in Waldenström macroglobulinemia and may indicate a neoplastic process. Flame cells are often seen in IgA producing plasma cell myeloma

Common Variants of Lymphoma Small Lymphocytic Lymphoma (Fig. 1.106) Cytologic Findings ♦♦ Aspirates from Small Lymphocytic Lymphoma (SLL) show a cellular, monomorphic population of small round lymphocytes. The neoplastic lymphocytes have uniform round nuclei with regular nuclear borders, coarsely granular chromatin, and inconspicuous nucleoli. Cytoplasm is scant and basophilic. Tingible body macrophages and mitotic figures are absent

Differential Diagnosis

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Follicular Lymphoma (Fig. 1.107) ♦♦ Aspirates from follicular lymphoma are highly cellular. In general, there is a predominance of small lymphocytes with minimal cytoplasm (centrocytes). Large cells (centroblasts) are present in variable numbers depending on grade. The small lymphocyte nuclei have condensed chromatin with irregular contours and clefts or grooves and inconspicuous nucleoli. The malignant large cells are often noncleaved with open chromatin and multiple small nucleoli applied to the nuclear membrane ♦♦ In follicular lymphoma, aggregates of lymphoid cells may be seen. Follicular architecture may be preserved in cell block preparations

Mantle Cell Lymphoma ♦♦ Mantle cell lymphoma is an aggressive lymphoma with deceptively “low grade” cytology. This lymphoma has a characteristic monotonous population of lymphocytes slightly larger than mature lymphocytes. Large transformed lymphocytes, prolymphocytes, plasmacytoid lymphocytes, and tingible body macrophages are absent ♦♦ The nuclei of the malignant lymphocytes show slight nuclear membrane irregularity, condensed chromatin, and high nuclear/cytoplasmic ratios. Epithelioid histiocytes are often scattered individually throughout the infiltrate ♦♦ The blastoid variant of mantle cell lymphoma consists of larger lymphoid cells with fine “blast-like” chromatin, nuclear membrane irregularities, and conspicuous often multiple nucleoli. Mitoses and apoptotic bodies may be seen

Burkitt Lymphoma (Fig. 1.108) Cytologic Findings ♦♦ Aspirates from Burkitt lymphoma produce a monotonous population of intermediate sized lymphocytes 2–3× larger

♦♦ The cytologic differential diagnosis includes reactive lymphoid processes (characteristically polymorphous), and other small B-cell lymphomas (requires ancillary studies)

Fig. 1.106. Small lymphocytic lymphoma, FNA. A monotonous population of small lymphocytes. Papanicolaou stain, medium power view.

Fig. 1.107. Follicular center lymphoma, follicular grade II. The smear consists of a mixture of follicle center cells, consisting of centrocytes (cleaved follicle center cells) and centroblasts (large noncleaved follicle center cells). Diff-Quik stain, high power view.

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Fig. 1.108. Burkitt lymphoma, abdominal mass, FNA. Monoto­ nous population of predominantly enlarged cells with round nuclei, and a rim of cytoplasm with peripheral vacuoles. Diff-Quik stain, high power view.

than mature lymphocytes in a “dirty” background with apoptotic bodies and necrosis. Tingible body macrophages and mitoses are seen ♦♦ The malignant lymphocytes have predominantly round nuclei with finely clumped immature blastic chromatin. Nucleoli are small but conspicuous and often multiple. There is a moderate amount of deeply basophilic cytoplasm with variable numbers of well-defined “punched out” lipid vacuoles

Differential Diagnosis ♦♦ Cytologic differential: other diffuse aggressive B-cell lymphomas, including lymphoblastic lymphoma, diffuse large B-cell lymphoma, blastoid variant of mantle cell lymphoma

Diffuse Large B-Cell Lymphoma (Fig. 1.109) ♦♦ Aspirates from diffuse large B-cell lymphoma show sheets of large cells 2–3× larger than mature lymphocytes. There is an absence or paucity of small lymphocytes. Tingible body macrophages are often seen in the background. Mitotic figures are variable ♦♦ The nuclei of the malignant lymphocytes are round or convoluted and may have projections (nipple). The chromatin pattern is variable, from open and blastic to coarse. Nucleoli are invariably present and prominent with variable number and size. Cytoplasm is moderate to abundant and may be vacuolated. Cytoplasmic vacuoles are nonspecific

Adult T-Cell Lymphoma ♦♦ Aspirates from T-cell lymphoma consist of malignant lymphocytes with round to variably convoluted nuclei. The cells are approximately 2× larger than mature lymphocytes. The chromatin pattern is delicate and nucleoli are inconspicuous. Cytoplasm is scant and may be vacuolated. Hand-mirror cells are often seen in lymphoblastic lymphoma and Ki-1 lymphoma. Numerous mitotic figures are seen. There are variable numbers of tingible body macrophages and necrosis

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Fig. 1.109. Large B-cell lymphoma. Monotonous population of large atypical lymphocytes with obvious nuclear irregularity and high N/C ratio. Diff-Quik stain, high power view.

Anaplastic Large Cell Lymphoma Cytologic Findings ♦♦ Aspirate samples from anaplastic large cell lymphoma are highly cellular and populated by large markedly pleomorphic cells with irregular nuclear contours, coarsely granular chromatin, and prominent nucleoli. The smear background may show necrosis but tingible body macrophages/germinal center fragments are not present. The neoplastic lymphoid population is polymorphous with a mixture of small and large cells. Occasional cells with horseshoe- or kidneyshaped nuclei and prominent macronucleoli may be present. Bi- or multinucleation and wreath-like nuclei are often seen. Intranuclear pseudo-­inclusions are common and cells may resemble Reed–Sternberg cells. The cells have moderate amounts of pale to basophilic cytoplasm with projections (hand-mirror cells)

Differential Diagnosis ♦♦ Cytologic differential diagnosis: other pleomorphic large cell malignancies including carcinoma, melanoma, sarcoma, and in particular Hodgkin lymphoma

Hodgkin Lymphoma Cytologic Findings ♦♦ Cytologic diagnosis relies on identification of Reed– Sternberg cells and variants in a benign inflammatory background. Scattered large cells stand out due to cell size at low magnification. Stripped large nuclei may be seen. Granulomas, eosinophils, and/or suppurative acute inflammation may be present in the background ♦♦ Classic Reed–Sternberg cells have gray cytoplasm, bilobed mirror-image nuclei, irregular nuclear membrane, coarse chromatin, and prominent inclusion-like nucleoli that approximate the size of a red-blood cell. Mononuclear Reed– Sternberg variants may be slightly smaller, about 3–4 times the size of a small lymphocyte, nuclei may be polylobated and nucleoli are variable

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♦♦ Aspirates from nodular sclerosis Hodgkin lymphoma often show low cellularity, even in the setting of a markedly enlarged lymph node. This may result in a false negative FNA interpretation

Differential Diagnosis ♦♦ Cytologic differential diagnosis includes benign reactive processes, including infectious mononucleosis, as well as lymphoid and nonlymphoid malignancies

SKIN, SOFT TISSUE, BONE, AND CARTILAGE Skin Pilomatrixoma (Calcifying Epithelioma of Malherbe) ♦♦ Aspirates from pilomatrixoma yield sheets of degenerated, anucleated squamous cells (ghost cells), cytologically bland basaloid cells, and foreign body-type giant cells. Calcification, nuclear debris, and inflammation are present in the background. Cell block preparations may enhance diagnostic yield by ­making ghost cells more readily apparent

Squamous Cell Carcinoma ♦♦ See previous discussion

Basal Cell Carcinoma Cytologic Findings ♦♦ Basal cell carcinomas produce tight cell aggregates and some discohesive cells. Palisading nuclei may be seen at the periphery of the aggregates. The small basaloid cells have scant cyanophilic cytoplasm (Pap stain) and indistinct cell borders. The nuclei are small with inconspicuous nucleoli. Nuclear molding is not observed

Differential Diagnosis ♦♦ Basaloid squamous cell carcinoma: These tumors tend to exhibit more discohesion. Occasional cells have dense cytoplasm and prominent nucleoli ♦♦ Merkel cell carcinoma: These tumors consist of a predominantly discohesive cell population. The tumor cells have neuroendocrine features. Nuclear molding is seen

Malignant Melanoma (Fig. 1.110) ♦♦ This tumor should be considered in the differential diagnosis of every tumor of unknown primary

Fig. 1.110. Malignant melanoma. (A) Amelanotic variant with single discohesive, markedly atypical cells with plasmacytoid appearance and occasional intranuclear inclusion. Notice the binucleation and multinucleation. Papanicolaou stain. (B) In this aspirate, the melanin is seen both intracellularly and as loose pigment in the background. Diff-Quik stain, high power view.

Cytologic Findings ♦♦ Melanoma produces aspirate smears that are highly cellular with a predominantly discohesive population with numerous single cells. Occasional clusters of tumor cells are seen. Individual cells may have a plasmacytoid appearance with eccentric nuclei. There is generally marked nuclear pleomorphism. Bi- and multinucleated cells are common. Nucleoli are characteristically prominent ♦♦ Cytoplasm is abundant and dense to slightly vacuolated with a dusty quality. Melanin pigment may be obvious in the cytoplasm of tumor cells, in histiocytes, or loose in

the background. Intranuclear cytoplasmic inclusions are frequent ♦♦ The spindle cell variant of melanoma presents with numerous spindle cells, sometimes intermixed with few classic cells. Myxoid stroma may be seen in occasional cases. The small cell variant consists of relatively smaller cells than the classic epithelioid variant ♦♦ Melanoma cells are positive to S-100, HMB 45, and Melan-A/ Mart-1. A cell block may be helpful for immunohistochemical staining in all tumors of unknown primary

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Differential Diagnosis ♦♦ Cytologic differential: spindle cell tumors, anaplastic large cell carcinomas, myxoid soft tissue tumors, and small cell tumors

Merkel Cell Carcinoma ♦♦ Aspirates from Merkel cell carcinoma are highly cellular and consist of a predominantly discohesive monomorphic population of small cells, resembling small cell undifferentiated carcinoma of the lung. Nuclear molding, pseudorosettes and acinar formations may be seen. Individual tumor cell nuclei are round with finely dispersed chromatin and inconspicuous nucleoli ♦♦ Cytoplasm is scant and intracytoplasmic red granules may be seen in Romanowsky-stained preparations. Discrete intracytoplasmic dots may be present (keratin buttons by electron microscopy). Cytokeratin 20 immunostain shows a characteristic dot pattern corresponding to these keratin buttons

Soft Tissue (See Chapter 22) Adipose Tissue Tumors Lipoma ♦♦ Microtissue fragments and tight clusters of adipocytes ♦♦ Round cells with single large clear cytoplasmic vacuoles and distinct cell borders ♦♦ Small round to oval nuclei, often eccentrically located ♦♦ Background of lipid droplets

Differential Diagnosis ♦♦ Normal subcutaneous tissue −− Indistinguishable from lipoma, clinical findings important ♦♦ Well-differentiated liposarcoma −− Atypical lipocytes (lipoblasts) with irregular and enlarged hyperchromatic nuclei −− Prominent plexiform capillary network

Liposarcoma Cytologic Findings ♦♦ Lipoblasts in a finely vascular stroma ♦♦ Lipoblasts often arranged around a delicate branching capillary network ♦♦ Lipoblasts may have variable cytologic appearance: spindle or stellate cells with small lipid droplets, single large cytoplasmic vacuoles (signet-ring type), or multivacuolated cytoplasm ♦♦ Nuclei may show indentation or scalloping ♦♦ Lipid droplets are usually sharply outlined and best appreciated on Romanowsky ♦♦ Myxoid liposarcoma contains a matrix rich in acid mucopolysaccharide that appears magenta to purple on Romanowsky and is alcian blue positive and mucin negative ♦♦ Round cell liposarcomas composed of densely packed small round cells with finely vacuolated cytoplasm and pleomorphic nuclei

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♦♦ Pleomorphic liposarcoma often yields highly cellular smears composed of bizarre microvacuolated pleomorphic giant cells

Differential Diagnosis ♦♦ Lipid-laden histiocytes (lipophages) −− Foamy cytoplasm with fine vacuoles and indistinct vacuoles −− Bean-shaped nuclei that are rounded rather than scalloped −− Background of hemorrhage, necrosis, inflammation, ­lipids, and giant cells −− Lack characteristic features of lipoblast and plexiform capillary network ♦♦ Angiolipoma −− Monomorphic univacuolated adipocytes with uniform nuclei −− Branching vascular pattern −− Lack lipoblasts ♦♦ Pleomorphic lipoma −− Pleomorphic single and multinucleated giant cells −− Peripheral circular arrangement of nuclei (floret cells) −− Mature adipose tissue −− No necrosis, mitotic figures, or true lipoblasts −− Complete excision for histologic examination is necessary due to sampling variation in order to avoid underdiagnosis ♦♦ Lipoblastomatosis −− Occurs in children <3 years −− Identical cytologic findings as myxoid liposarcoma ♦♦ Hibernoma −− Small round centrally located nuclei without scalloping −− Multiple small uniform cytoplasmic vacuoles ♦♦ Signet-ring cell carcinoma −− Mucin positive −− Lack lipoblasts and plexiform capillary network

Fibrous and Fibrohistiocytic Lesions Nodular Fasciitis (Fig. 1.111) ♦♦ Hypocellular smear of spindle to ovoid cells in a mucoid or metachromatic stroma ♦♦ Discohesive large plump myofibroblasts ♦♦ Oval nuclei with evenly distributed granular chromatin and inconspicuous nucleoli ♦♦ Tissue fragments containing fibrin and metachromatic mucoid substances may be observed ♦♦ Inflammatory background (lymphocytes, mast cells, and lipophages)

Fibromatosis ♦♦ Low to moderate cellularity with isolated cells or in loose clusters

Cytopathology

Fig.  1.111. Nodular fasciitis, anterior chest wall, FNA. Large plump myofibroblasts appearing admixed with lightly straining eosinophilic stroma. Papanicolaou stain, high power view.

♦♦ Spindled to oval uniform nuclei with finely granular chromatin, smooth nuclear contours, and inconspicuous nucleoli ♦♦ Pale, delicate cyanophilic cytoplasm with tapered ends ♦♦ Stripped nuclei can be numerous ♦♦ Fragments of collagenous metachromatic stroma with mucoid ground substance ♦♦ Atrophic skeletal muscle cells may be present ♦♦ Scattered lymphocytes and variable number of histiocytes may be observed

Dermatofibroma (Benign Fibrous Histiocytoma) ♦♦ Numerous oval to spindle cells arranged in a vague storiform pattern ♦♦ Lack significant cytologic atypia ♦♦ Occasional inflammatory cells (lymphocytes, lipophages, and hemosiderin-laden macrophages) ♦♦ Foreign body-type giant cells and Touton cells may be seen

Dermatofibrosarcoma Protuberans ♦♦ Individual or loose clusters of spindle cells with storiform pattern (best appreciated in tissue fragments) ♦♦ Uniform oval to elongated nuclei with smooth nuclear contour and finely granular chromatin ♦♦ Finely fibrillar metachromatic stroma, best appreciated on Romanowsky

Fibrosarcoma ♦♦ Single or loose clusters of oval to spindle cells ♦♦ Nuclear pleomorphism dependent on tumor grade, but generally, unlike malignant fibrous histiocytoma (MFH), bizarre giant cells are not observed ♦♦ Coarsely granular chromatin and indistinct nucleoli, variable mitotic figures ♦♦ Tapered scant cytoplasm ♦♦ Scant metachromatic collagenous stroma

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Fig. 1.112. Malignant fibrous histiocytoma. Large bizarre cells with irregular nuclei and coarsely granular chromatin. Papanicolaou stain, high power view.

Malignant Fibrous Histiocytoma (Fig. 1.112) Cytologic Findings ♦♦ Hypercellular smear of dimorphic population of histiocytes and spindle cells ♦♦ Storiform growth pattern in myxoid or inflammatory background ♦♦ Multinucleated giant cells with irregular nuclei and coarsely granular chromatin ♦♦ Bizarre pleomorphic cells often clustered around vessels ♦♦ Frequent atypical mitotic figures

Differential Diagnosis ♦♦ Liposarcoma −− Isolated or discohesive sheets of pleomorphic cells in a metachromatic background −− Lipoblasts and fine vasculature −− Well defined (discrete) lipid vacuoles with nuclear scalloping

Neural Tumors Neurofibroma ♦♦ Variable cellularity ♦♦ Cells isolated or in small aggregates in the background of abundant myxoid stroma ♦♦ Elongated spindle cells with wavy serpentine nuclei ♦♦ Finely granular chromatin, scant pale cytoplasm with indistinct cell borders ♦♦ Lack prominent nucleoli ♦♦ Naked nuclei with blunt or tapered ends are common

Schwannoma (Neurilemmoma) (Fig. 1.113) ♦♦ Cellular smear of uniform spindle cells with elongated wavy nuclei in a fibrillar (or metachromatic) background ♦♦ Ancient schwannoma may show cytologic atypia with large pleomorphic hyperchromatic or multilobulated nuclei

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♦♦ Uniform small centrally located nuclei with prominent nucleoli ♦♦ S-100 protein positive

Malignant Peripheral Nerve Sheath Tumors Cytologic Findings ♦♦ Cellular smear composed of single and loose clusters of cells with irregular contours ♦♦ Irregular nuclei are wavy, buckled or comma shaped ♦♦ Atypical mitotic figures ♦♦ Pale cytoplasm with indistinct cell borders and long cytoplasmic processes ♦♦ Metachromatic fibrillary matrix Fig.  1.113. Neurilemmoma (schwannoma). Cellular smear of uniform spindle cells with elongated, wavy nuclei. Papanicolaou stain, medium power view.

Differential Diagnosis ♦♦ Fibrosarcoma or monophasic synovial sarcoma −− May be cytologically indistinguishable, consider clinical presentation and relation to major nerves −− More regular cell contours with tapered nuclei rather than wavy nuclei −− S-100 protein negative

Primitive Neuroectodermal Tumors ♦♦ See discussion for Ewing sarcoma

Neuroblastoma

Fig. 1.114. Granular cell tumor, neck mass, FNA. Cellular smear of loosely cohesive large polygonal cells. The cytoplasm is abundant and eosinophilic, with obvious granularity that blurs with the background. Papanicolaou stain, medium power view.

displaying intranuclear cytoplasmic inclusions and smudgy chromatin ♦♦ Lack prominent nucleoli and mitotic figures ♦♦ Antoni A: Anastomosing and intervening fascicles of spindle cells with nuclear palisading ♦♦ Antoni B: Poorly cellular area with myxoid degeneration and scattered spindle cells with indistinct cell borders and vacuolated cytoplasm

Granular Cell Tumor (Fig. 1.114) ♦♦ Cellular smear composed of single and loose clusters of large polygonal, elongated, or rounded cells ♦♦ Dirty granular background ♦♦ Cells have abundant eosinophilic or granular cytoplasm and indistinct cell border

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♦♦ Cellular smear of discohesive cell clusters and isolated single cells ♦♦ Cells with high N/C ratio, finely granular chromatin, and inconspicuous nucleoli ♦♦ Nuclear molding may be seen ♦♦ Polygonal ganglion cells with clear cytoplasm may be noted ♦♦ Bi- or multinucleation, eccentric nuclei, and prominent nucleoli ♦♦ Neuropils (tangles of neuritic processes) and occasional Homer-Wright rosettes

Ganglioneuroma ♦♦ Large polygonal ganglion cells with abundant amphophilic cytoplasm and eccentric nuclei ♦♦ Spindle stromal cells with wavy nuclei in a fibrillary background

Miscellaneous Giant Cell Tumor of Tendon Sheath ♦♦ Cellular smears composed of two cell populations with similar nuclear features ♦♦ Small round to oval or spindle mononuclear cells similar to synovial lining cells or osteoblasts ♦♦ Large multinucleated osteoclastic-type giant cells ♦♦ Moderate amount of distinct cytoplasm with hemosiderin deposition ♦♦ Uniform eccentrically located nuclei with fine granular chromatin and inconspicuous nucleoli ♦♦ Background of hemosiderin-laden macrophages, xanthoma cells, and inflammatory cells

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Synovial Sarcoma ♦♦ Hypercellular smear of single cells and cell clusters ♦♦ Uniform spindle cells predominate ♦♦ Scant cytoplasm with tapered ends and oval or elongate nuclei with inconspicuous nucleoli ♦♦ Difficult to differentiate monophasic synovial sarcoma from low grade fibrosarcoma ♦♦ Biphasic population of epithelioid cells and spindle cells in a metachromatic stromal background ♦♦ Occasional glandular arrangement of cuboidal or columnar cells in biphasic synovial sarcoma ♦♦ Increased mitotic figures ♦♦ Focal immunoreactivity for cytokeratin in the epithelial elements

Leiomyosarcoma ♦♦ Cellular smear composed of uniform spindle cells arranged as tightly woven fascicles ♦♦ Centrally located cigar-shaped nuclei with blunted ends ♦♦ Cytoplasmic vacuoles may result in blunt or concave nuclear contours ♦♦ Variable degree of nuclear pleomorphism and necrosis

Angiosarcoma ♦♦ Hemorrhagic cellular smear composed of branching papillary clusters of spindle, polygonal, or rounded cells ♦♦ Concentrically arranged whorls (pseudoacini or rosette-like) of endothelial cells may be observed ♦♦ Moderate amount of pale cytoplasm and occasional nuclear groove ♦♦ Nuclear pleomorphism and prominent nucleoli ♦♦ CD31 and CD34 positive

Kaposi Sarcoma ♦♦ Isolated single and loosely cohesive clusters of spindle cells with well defined borders ♦♦ Elongate nuclei with finely granular chromatin and inconspicuous nuclei ♦♦ Pale delicate cytoplasm that may contain hemosiderin pigments ♦♦ Cells may contain characteristic diastase-resistant PASpositive hyaline globules ♦♦ Inflammatory background

Rhabdomyosarcoma ♦♦ Cellular smear of isolated or loose aggregates of round or spindle cells ♦♦ Scant cytoplasm that taper from nucleus as a “tadpole-shape” or as a broad bands (strap cell) ♦♦ Cytoplasmic cross striation is rarely observed ♦♦ Oval to round eccentric nuclei with variable nuclear pleomorphism, frequently eccentric ♦♦ Concentrically arranged fibrillary materials around the nucleus ♦♦ Variable mitotic figures and tumor diathesis ♦♦ Desmin +, muscle-specific actin +, and MyoD1+

Fig. 1.115. Low grade cartilagenous neoplasm, FNA. Fragments of cartilage with good preservation of the lacunae. Note the small uniform chondrocytes within lacunae and lack of mitotic figures or significant pleomorphism. Curettings yielded a chondroma. Papanicolaou stain, high power view.

Bone and Cartilage Chondroma (Fig. 1.115) ♦♦ FNA is rarely used in the diagnosis of chondroid neoplasms. Chondroid neoplasms may mimic metastatic epithelial malignancies clinically or radiologically, and may be aspirated in this context. Cytology cannot differentiate chondroma from low grade chondrosarcoma. Clinical and radiologic correlation is essential ♦♦ Smears from a chondroma are usually paucicellular and consist of fragments of cartilage. Cartilage appears intensely metachromatic on Diff-Quik stain. Chondrocytes are small and uniform and are present within lacunae. There is no nuclear pleomorphism. Binucleated forms may be present. No mitoses are seen

Chondroblastoma ♦♦ Aspirates from chondroblastoma show variable cellularity with single cells and discohesive clusters of mononuclear cells with uniform round to oval nuclei. There is typically a moderate amount of dense eosinophilic cytoplasm. Binucleated cells and multinucleated osteoclast-like giant cells are frequently noted ♦♦ Chondroblast nuclei are often grooved, indented, or lobulated with evenly distributed fine granular chromatin and inconspicuous nucleoli. Intranuclear cytoplasmic inclusions may be observed ♦♦ The chondroid matrix appears as metachromatic amorphous or fibrillar stroma which may invest individual tumor cells ♦♦ Chondrosarcomas generally show higher cellularity with atypia, mitoses, and more abundant matrix

Giant Cell Tumor ♦♦ FNA smears from conventional giant cell tumor of bone are usually highly cellular and show a dimorphic cell population. Large multinucleated osteoclastic-type giant cells are admixed with smaller oval mononuclear stromal cells.

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Cells occur in sheets and large aggregates and the dual cell population imparts a “checkerboard” appearance ♦♦ The mononuclear cells have oval nuclei with hyperchromatic, finely granular chromatin, and prominent nucleoli. The giant cells have identical nuclear features and may show >40 nuclei ♦♦ The background of the smears is clean and mitoses are not seen. Chondroid or osteoid matrix is not seen

Chondrosarcoma ♦♦ Chondrosarcomas are not routinely aspirated. This diagnosis is made radiographically and confirmed histologically. Aspirates may not be representative. Lytic areas should be sampled to exclude dedifferentiated chondrosarcoma ♦♦ Chondrosarcomas generally yield cellular smears with single isolated cells and discohesive cell clusters. The tumor cells are oval to polygonal with abundant, dense, vacuolated cytoplasm and a plasmacytoid appearance. Signet-ring cells may be seen. Mononuclear or binucleate tumor cells are present in lacunae and embedded in metachromatic stromal matrix. There is variable degree of atypia and mitoses seen

Osteosarcoma ♦♦ Diagnosis rests with finding malignant cells associated with osteoid matrix in the context of the appropriate radiological features. Numerous discohesive cells with marked nuclear pleomorphism and bizarre cells ♦♦ Multinucleated tumor cells and occasional osteoclast-like cells are observed ♦♦ Nucleoli may be prominent ♦♦ Cells with moderate to abundant eosinophilic granular cytoplasm ♦♦ Increased mitotic figures and abnormal mitotic figures may be seen ♦♦ Eosinophilic metachromatic osteoid matrix is best seen on Romanowsky

Ewing Sarcoma and PNET (Fig. 1.116) ♦♦ Ewing/PNET is a small round cell malignancy yielding highly cellular aspirate smears with cells arranged in tight clusters and isolated single monotonous cells. The tumor cells are approximately 2–3× size of mature lymphocytes.

Fig. 1.116. Metastatic Ewing sarcoma, lung, FNA. Isolated single monotonous cells with round nuclei. The chromatin is finely granular. Variable amount of cytoplasm is present with vacuoles. Diff-Quik, high power view. The cells have uniform round to oval nuclei with finely granular chromatin and inconspicuous/absent nucleoli. The cells are fragile and nuclear smearing/crush artifact may be seen. Stripped nuclei are common. Occasional Homer-Wright rosettes are seen. Mitoses are frequent ♦♦ Tumor cells may have cytoplasmic vacuoles containing glycogen (PAS positive). A “tigroid background” may be seen (also seen in seminoma) ♦♦ Ancillary studies are required for diagnosis. Specific chromosomal translocations can be detected by FISH or cytogenetics

Langerhans Cell Histiocytosis (Eosinophilic Granuloma) ♦♦ Aspirate samples from Langerhans cell histiocytosis are cellular and composed of numerous isolated large histiocytes admixed with eosinophils. Histiocyte nuclei are characteristically clefted and grooved or reniform. Nuclear chromatin is finely granular ♦♦ Cytoplasm is abundant and may be vacuolated. Variable numbers of eosinophils are seen. Multinucleated osteoclastlike giant cells are occasionally present

ESOPHAGUS, STOMACH, COLON, LIVER, AND PANCREAS Esophagus Normal Components ♦♦ Cellular smears that contain sheets of benign superficial and intermediate squamous cells. Parabasal cells may be seen in ulcer or vigorous brushing. Gastric cells may be noted in samples from gastroesophageal junction

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Infection ♦♦ Microscopic findings similar to those described in respiratory tract (Figs. 1.117 and 1.118) ♦♦ Squamous cells demonstrating reactive and reparative changes. Infectious organisms such as C. albicans embedded within the reactive sheets or HSV cytopathic effect may be detected in infectious esophagitis

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or single cells that are cytomegalic with normal N/C ratio. The nuclei are enlarged, hypochromatic, and have prominent nucleoli (may be irregular). Degenerative change with nuclear pyknosis, smudging, and karyorrhexis is not uncommon. Nuclear and cytoplasmic vacuoles can be prominent especially in the acute phase where numerous ingested neutrophils can be seen within the vacuoles. Multinucleation is common. The cells may have fragile cytoplasm in the acute phase and dense amphophilic cytoplasm in the chronic phase ♦♦ Granulation tissue formation with spindle fibroblasts and endothelial cells may also be present

Differential Diagnosis Fig.  1.117. Herpes simplex virus effect, esophageal brush. Single and multinucleated cells showing nuclear molding and ground-glass nuclei with a small intranuclear inclusion. Papanicolaou stain, high power view.

♦♦ Adenocarcinoma −− The cytologic atypia in therapy changes may mimic carcinoma. However, the normal N/C ratio and prominent degenerative changes resulting in lack of chromatin detail and large vacuoles point to therapy. In contrast, carcinoma cells should have well-preserved chromatin and more finely vacuolated cytoplasm

Barrett Esophagus Clinical ♦♦ The brushing should be taken several centimeters above the gastroesophageal junction

Microscopic ♦♦ Smear contains isolated single cells and small clusters of columnar mucin-producing cells with interspersed goblet cells. Distinctly, there is lack of significant cytologic atypia. Suspect dysplasia when cytologic atypia is observed

Differential Diagnosis

Fig. 1.118. Candida albicans. A cohesive sheet of squamous cells admixed with thin, uniform candidal pseudohyphae. Such pseudohyphae can frequently be seen at the edges of the affected clustered epithelial cells. Papanicolaou stain, medium power view.

Reflux Esophagitis ♦♦ The smears contain sheets of loosely cohesive squamous cells with reactive/regenerative atypia. The cells retain their normal polarity and N/C ratio. The cytoplasm is abundant and cyanophilic. The nuclei are slightly enlarged with regular nuclear membranes and uniformly distributed chromatin. Isolated single cells are rare and lack pleomorphism ♦♦ Inflammatory cells (lymphocytes, eosinophils, and histiocytes) may be observed

Radiation Change Microscopic ♦♦ The findings are similar to those seen in other body sites. Characteristically, the smear may contain syncytial sheets

♦♦ Gastroesophageal junction −− It is not possible to separate these two entities based on morphology alone. Barrett mucosa can only be suggested if the clinician indicates a brushing a few centimeters above the junction

Dysplasia ♦♦ Smears contain loosely cohesive sheets of hyperplastic epithelial cells with cytologic atypia. The nuclei are enlarged with nuclear hyperchromasia and irregular nuclear contours ♦♦ Low grade dysplasia may be indistinguishable from reactive atypia. The following features have been described in high grade dysplasia: Increased N/C ratio, hyperchromasia, nuclear membrane irregularity, nuclear pleomorphism, and prominent nucleoli. Contrary to frank carcinoma, there is lack of tumor diathesis or numerous isolated single cells

Squamous Cell Carcinoma Microscopic ♦♦ Cellular smears contain discohesive clusters, syncytial sheets and isolated cells with orangeophilic waxy cytoplasm in well-differentiated carcinoma. Keratinizing cells

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exhibit marked variation in size and shape and bizarre cells. Poorly differentiated tumors present as cohesive geographic sheets of pleomorphic cells with cyanophilic cytoplasm. Features that suggest squamous differentiation include ­keratin pearls, intercellular bridges, and distinctive cell borders ♦♦ Common features of carcinoma including nuclear pleomorphism, hyperchromasia, irregular nuclear membrane, and coarse clumped chromatin are all observed. Nuclear pyknosis, karyorrhexis, and apoptosis are also noted

Differential Diagnosis ♦♦ Atypical squamous cells of oral origin −− The atypical cells are usually small in number and do not exhibit all the malignant features or the background necrosis encountered in carcinoma. The presence of other oral contaminants such as Candida can be helpful in confirming their origin

Adenocarcinoma (Fig. 1.119) ♦♦ Cellular smears that contain discohesive sheets, acini, papillae, and isolated single columnar cells. The cohesive sheets

Essentials of Anatomic Pathology, 3rd Ed.

have blurred cell borders and loss of polarity within the sheets with obvious cellular crowding and irregular distribution of nuclei. Discohesion can be prominent with numerous abnormal single cells. The cytoplasm tends to be lacy and may contain vacuoles (mucin)

Stomach Normal Cytology ♦♦ Gastric mucosa presents as columnar cells in orderly arranged sheets with honeycomb pattern. The nuclei are basally located, round to oval with finely granular and evenly distributed chromatin. The cytoplasm is granular or vacuolated and mucus-filled

Gastric Ulcer Microscopic ♦♦ The smear contains sheets and clusters of epithelial cells with a spectrum of reactive and reparative changes in a background of fibrinous exudate. There are also plump spindle fibroblasts and endothelial cells indicating granulation tissue formation. Degenerative changes may also be present ♦♦ Reactive atypia can be very pronounced and mistaken for adenocarcinoma and therefore knowledge of clinical findings is essential for proper interpretation

Differential Diagnosis ♦♦ Adenocarcinoma −− The diagnosis of gastric adenocarcinoma should only be rendered on well-preserved cells with good nuclear detail. In addition to nuclear enlargement and prominent nucleoli, there are usually irregular nuclear membranes and nuclear overcrowding within sheets with disorderly arrangement. In contrast, in cases with reactive changes the cells are orderly arranged and frequently in a monolayer sheet reminiscent of repair

Chronic Gastritis ♦♦ The smears contain sheets with maintained cellular polarity and relatively normal N/C ratio. The nuclei may be slightly enlarged but the chromatin is vesicular, evenly distributed and the nuclear membrane is smooth. Inflammatory background and cellular debris may be present ♦♦ Helicobacter pylori may be seen in Pap-stained smears of gastric brushings, especially in mucus and are better appreciated on Diff-Quik stain

Hyperplastic or Regenerative Polyp ♦♦ These entities have no specific cytologic features. Generally, the smears contain microtissue fragments of normal gastric epithelium arranged as honeycomb sheets with no cytologic atypia

Adenocarcinoma (Fig. 1.120) Fig.  1.119. Mucinous carcinoma arising from Barrett mucosa, esophageal brush. (A) Signet-ring cells with highly vacuolated abundant cytoplasm and mild nuclear atypia. The disordered orientation of these atypical cells distinguish them from simple goblet cells. Papanicolaou stain. (B) Diff-Quik stain, high power view.

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♦♦ The smears from gastric carcinoma are hypercellular and contain numerous discohesive sheets, three-dimensional clusters, and isolated single cells. The cells within these sheets are disorderly arranged and exhibit obvious nuclear pleomorphism, irregularly distributed chromatin (clumping and clearing), and prominent nucleoli. The cytoplasm may

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The nuclei are elongated with regular outline and finely granular chromatin

Adenomatous Polyp ♦♦ No specific cytologic appearance however the smears tend to be cellular and contain microtissue fragments and strips of columnar cells with peripheral feathering. Nuclear polarity and cell cohesion are retained ♦♦ The nuclei have even chromatin distribution, regular smooth nuclear membrane, and macronucleoli. Contrary to adenocarcinoma there is lack of prominent nucleoli, significant nuclear pleomorphism, or tumor diathesis

Adenocarcinoma Fig. 1.120. Adenocarcinoma, gastric brush. Sheet of irregularly arranged cells with depth of focus. Note the cellular crowding and attempt to form glands within the sheet. Papanicolaou stain, high power view.

be granular or vacuolated. A background of necrosis and tumor diathesis is usually present ♦♦ Signet-ring cells appear as small cells with eccentrically located crescentic elongated nuclei with small but prominent nucleoli. The nuclear membranes are irregularly indented by the cytoplasmic vacuoles

Differential Diagnosis ♦♦ Repair −− Monolayer sheets with orderly arrangement. The nuclei are enlarged but vesicular and have a smooth nuclear membrane and prominent nucleoli. Irregular repair may have less organized groups and more cytologic atypia but evidence of true repair is usually found in the smear ♦♦ Vacuolated histiocytes −− Vacuolated histiocytes (muciphages) have an eccentric reniform nucleus similar to signet-ring cells. However, the nuclear membranes are irregular and smoothly indented by the vacuoles. The nuclei are small and lack prominent nucleoli. Mucin stains may not be helpful since they can be positive in both

Lymphoma ♦♦ The smears are highly cellular and contain a monotonous population of small or large cleaved or noncleaved lymphocytes. The background is relatively clean ♦♦ Negative reaction to mucin and immunostaining for keratin and leukocyte common antigen are extremely helpful in the differential diagnosis from poorly differentiated adenocarcinoma

Colon Normal Cytology ♦♦ Sheets with honeycomb or picket-fence arrangement lined by tall columnar cells with brush borders and goblet cells

♦♦ Hypercellular smear containing discohesive geographic sheets, clusters, and isolated single columnar cells. There is loss of nuclear polarity with nuclear pleomorphism, uneven chromatin distribution, and prominent nucleoli. The cytoplasm is granular and/or vacuolated. The background is dirty with tumor diathesis and mucin is observed in a large number of cases ♦♦ Signet-ring cells should be distinguished from vacuolated histiocytes (muciphages)

Liver Normal Components ♦♦ Normal hepatocytes −− Appear as sheets of polygonal cells with orderly arrangement. Hepatocytes may also be seen as clusters or as single cells. The polygonal cells have eosinophilic or basophilic cytoplasm that may show vacuoles or pigment (hemosiderin, lipofuscin or bile). The nuclei are round, central or slightly eccentrically located, have smooth nuclear contours, and evenly distributed finely granular chromatin. Nucleoli are usually present, and may be prominent. Anisonucleosis, bi- or multinucleation, and intranuclear pseudo-inclusions are all common findings ♦♦ Bile duct cells −− Honeycomb sheets or tightly packed glandular clusters in a clean background. The cells are low columnar or cuboidal in shape with basophilic well defined cytoplasm. The nuclei are round to oval often eccentric, with evenly distributed finely granular chromatin and inconspicuous or macronucleoli ♦♦ Kupffer cells −− Single, bare, comma-shaped nuclei between hepatocytes

Benign Lesions Cysts ♦♦ Congenital cyst −− The aspirated fluid is usually clear and contains few uniform cuboidal cells and some macrophages ♦♦ Ciliated hepatic foregut cyst −− These are located beneath the falciform ligament and the aspirated material will contain clusters of ciliated columnar cells and macrophages

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♦♦ Hydatid cyst −− Aspiration results in a thick turbid fluid. The smears contain fragments of laminated cyst wall and dirty background containing scolices and/or hooklets that are best demonstrated with Pap stain. The hooklets will appear as refractile material and do not pick up the stain color by the Diff-Quik stain

Reactive/Regenerative Changes ♦♦ Smears contain sheets of hepatocytes admixed with sheets of ductal cells. The cell cohesion and nuclear polarity are retained. There is normal N/C ratio and lack of significant nuclear pleomorphism. Occasional binucleation and prominent nucleoli are observed. In general, significant variation between cells and the presence of bile duct epithelium, lipofuscin, and hemosiderin usually indicate benignity

Steatosis ♦♦ Sheets of benign hepatocytes with large cytoplasmic (fat) vacuoles

Hepatocellular Adenoma Clinical ♦♦ Clearly defined focal mass

Microscopic ♦♦ The smears contain sheets and clusters of monotonous polygonal normal hepatocytes or hepatocytes with slight nuclear enlargement. There is lack of nuclear pleomorphism. The cell cytoplasm may contain glycogen, hemosiderin, or demonstrate fatty change. No cells of bile duct origin are observed

Differential Diagnosis ♦♦ Well-differentiated hepatocellular carcinoma −− The difference between these two entities can be very subtle. Generally, the cells have a low N/C ratio and the cytoplasm is less fragile and has more distinct borders in adenoma. Bare nuclei in the background are much fewer in adenoma ♦♦ Regenerative nodule and cirrhosis −− The smears are cellular and demonstrate marked anisokaryosis. There are also scattered single cells with nuclear pleomorphism and high N/C ratio

Focal Nodular Hyperplasia ♦♦ The smears are cellular and contain an admixture of benign liver elements including fragments of bile ducts, fibrous stromal tissue, and hepatocytes ♦♦ The cytologic findings are not specific, however, the presence of an admixture of hepatocytes and bile duct cells in the proper clinical setting support the diagnosis of focal nodular hyperplasia

Hemangioma ♦♦ Bloody smears containing few fibrovascular tissue fragments, vascular walls, and occasional fibrin. Few scattered endothelial cells with elongated normo-chromatic nuclei are observed

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Fig. 1.121. Hepatocellular carcinoma, liver, FNA. Monotonous population of atypical cells with slight increase of N/C ratio growing as clusters and trabeculae surrounded by endothelial cells. The polygonal shape and granular cytoplasm indicate the hepatocellular origin. Papanicolaou stain, medium power view.

Bile Duct Hamartoma ♦♦ Smears contain an admixture of benign bile ductal cells and strands of fibrous stroma

Malignant Lesions Hepatocellular Carcinoma (Fig. 1.121) Microscopic ♦♦ The cytologic findings are dependent on the degree of differentiation ♦♦ Well-differentiated tumors present as cellular smears with a monotonous population of cells predominantly arranged in trabecular pattern (>3–4 cell layers in thickness). Sinusoidal endothelial cell lining surrounds and/or traverses the trabeculae. Numerous single discohesive polygonal cells with abundant granular cytoplasm, round central nuclei, high N/C ratio, binucleation, smooth nuclear membrane, and prominent nucleoli are also observed. Intranuclear cytoplasmic inclusions and intracytoplasmic bile are commonly seen. Other findings include: cytoplasmic eosinophilic hyaline globules (alpha-fetoprotein, AFP), Mallory hyaline, small nuclear fragments, satellite nuclei, and atypical naked nuclei. Bile duct epithelium is characteristically absent ♦♦ The diagnosis can be confirmed by the canalicular polyclonal CEA and CD10 staining pattern

Variants ♦♦ Fibrolamellar hepatocellular carcinoma −− Smears contain very large polygonal cells with abundant eosinophilic granular cytoplasm. The nuclei are enlarged and contain single prominent nucleoli and intranuclear cytoplasmic inclusions. Pale bodies (fibrinogen) and PAS-positive hyaline globules can be detected. Fragments of fibrocollagenous tissue may be observed

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Differential Diagnosis

Differential Diagnosis

♦♦ Metastatic adenocarcinoma and cholangiocarcinoma −− These aspirates lack the sinusoidal endothelial cell lining, AFP, alpha-1-antitrypsin, intracytoplasmic Mallory hyaline, and bile production. The trabecular growth pattern and intranuclear inclusions are uncommon −− Mucin production and diffuse cytoplasmic CEA staining pattern are diagnostic of adenocarcinoma

♦♦ Reactive/regenerative atypia −− The smears contain cohesive monolayer sheets of cells with normal N/C ratio, regular nuclear membranes, and evenly distributed chromatin. Cell polarity is maintained and they lack significant nuclear pleomorphism. There may be an inflammatory background with cellular debris that should not be confused with tumor diathesis ♦♦ Hepatocellular carcinoma −− Present as cell balls and trabeculae with peripheral endothelium. The cells may show evidence of bile production. In contrast cholangiocarcinoma cells may be vacuolated and show evidence of mucin secretion. Sinusoidal (hepatocellular) versus diffuse CEA (adenocarcinoma) staining can be helpful

Hepatoblastoma Microscopic ♦♦ The smears are hypercellular and contain trabecula, cords, tubular, acinar, and papillary arrangement of cells covered by sinusoidal lining cells ♦♦ The cells are comprised of a mixture of fetal/embryonal type primitive cells and mesenchymal elements similar to other small round cell tumors of childhood. The cells have high N/C ratio and the nuclei are usually smaller than normal hepatocytes ♦♦ The nuclei are round, centrally located, and normochromatic or slightly hyperchromatic. The nuclear membrane is smooth and the nucleoli are inconspicuous ♦♦ The cytoplasm is scant to moderate and finely granular. Small cytoplasmic vacuoles may be noted but bile is rare ♦♦ The cells are positive for low molecular weight keratin and negative for vimentin, high molecular weight cytokeratin, and epithelial membrane antigen (EMA) ♦♦ Additional findings may include extramedullary hematopoiesis (very rare) and cartilaginous or osseous metaplasia

Differential Diagnosis ♦♦ Hepatocellular carcinoma −− The trabecula are broader than those seen in hepatoblastoma and the individual cells are larger and more pleomorphic ♦♦ Hepatocellular adenoma −− Aspirates tend to be less cellular than hepatocellular carcinoma or hepatoblastoma. The hepatocytes are benign appearing

Cholangiocarcinoma Cytologic Findings ♦♦ Well-differentiated tumors present as sheets and clusters of atypical cells that resemble bile duct epithelium. However, closer examination reveals more cellular crowding and slight nuclear atypia ♦♦ The findings in less differentiated tumors are similar to other adenocarcinomas. The smears are hypercellular and contain discohesive sheets, three-dimensional clusters and isolated single glandular cells with loss of nuclear polarity, nuclear pleomorphism, irregular nuclear membranes, coarse chromatin, atypical mitotic figures, and prominent nucleoli. Cellular borders within the aggregates are indistinct. The cytoplasm may be vacuolated. Tumor diathesis is present

Metastatic Adenocarcinoma ♦♦ Findings in metastatic adenocarcinoma from lung, stomach or pancreas are indistinguishable from cholangiocarcinoma ♦♦ Metastatic colon adenocarcinoma typically shows tall columnar cells with luminal borders and elongated or spindled hyperchromatic stratified nuclei in a background of extensive necrosis

Metastatic Carcinoid ♦♦ The smears are cellular and contain loosely arranged round monotonous plasmacytoid cells. The cytological features and immunohistochemical staining pattern are similar to those described in the lung

Pancreas ♦♦ Sampling of the pancreas is most commonly done through endoscopic ultrasound-guided FNA (EUS-FNA) or pancreatic duct brushing. This method of FNA sampling introduces gastric or intestinal mucosa in the sample that has to be ­recognized and distinguished from lesional cells

Normal Components ♦♦ Acinar cells −− Present as small clusters of cells with dense granular cytoplasm. The nucleus is small, round, and peripherally located. The chromatin is evenly distributed and the nuclear membrane is regular. Small nucleoli may be detected ♦♦ Ductal cells −− Sheets of columnar or cuboidal cells arranged in a honeycomb pattern. The cells have pale cytoplasm and round to oval uniform nuclei with fine granular chromatin and small nucleoli ♦♦ Islet cells −− Present as isolated and loose clusters of cells with round to oval uniform nuclei with finely granular chromatin (salt and pepper). Only few cells are observed in normal conditions and may not be distinguishable from acinar cells

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Acute Pancreatitis ♦♦ The smears are hypocellular with admixtures of ductal/­acinar cells, neutrophils, and histiocytes in a dirty necrotic background. Sheets of epithelial cells demonstrating degenerative/regenerative changes and reactive atypia (may mimic adenocarcinoma) may be present ♦♦ In cases with fat necrosis, lipophages and amorphous basophilic material are detected

Chronic Pancreatitis ♦♦ Smears are hypocellular and contain cohesive honeycomb sheets of ductal cells with reactive/reparative changes admixed with stromal fragments, myofibroblasts, and variable chronic inflammatory background (granulation tissue). The epithelial component is usually cohesive (no single intact cells) and lacks nuclear pleomorphism. An acinar component is less conspicuous. Degenerative changes may be seen in ductal and acinar cells

Cystic Mass Lesions ♦♦ Cystic pancreatic masses are best diagnosed based on a multimodal approach of clinical, radiologic, and cytologic findings in conjunction with chemical analysis of the aspirated fluid primarily to distinguish mucinous neoplasms from pseudocysts and serous cystadenoma. The latter two are managed clinically while the former is managed surgically

Pseudocyst Clinical ♦♦ Result from damage of the pancreatic parenchyma that results in autodigestion and release of pancreatic enzymes. It is most commonly a result of pancreatic injury such as alcoholic pancreatitis ♦♦ By definition, a pseudocyst is a simple nonseptated pancreatic cyst that can vary in size. Its fluid content is rich in amylase. The cyst has no epithelial lining

Microscopic ♦♦ The smears are hypocellular and clear or bloody and contain neutrophils, plasma cells, and lymphocytes in a dirty background. Epithelial elements are absent or rare ♦♦ Lipid-laden histiocytes, flecks of calcification, and necrotic fat cells may be seen in cases with fat necrosis. Occasional atypical mesenchymal cells and myofibroblasts represent granulation tissue formation ♦♦ Aspirated fluid is usually thin and nonmucinous. It may be clear or brown depending on the amount of blood. In complicated cysts, the fluid may be thick and appears mucoid. Purulent fluid should be cultured ♦♦ Fluid content positive for amylase (>250 U/ml) and negative for CEA (<5 ng/ml)

Serous Cystadenoma Clinical ♦♦ The majority of these cysts are benign neoplasms and surgical resection is curative, although not all cases have to be

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resected. These cysts are more common in women than men, can be unilocular, oligocystic, and commonly microcystic ♦♦ Microcystic neoplasms show proliferation of small cuboidal cells rich in glycogen lining the small cysts. They have a very characteristic radiologic picture described as “soap bubble” appearance due to the small cysts. These tumors frequently have a central scar imparting a “star burst pattern”

Microscopic ♦♦ The aspirated fluid is clear and thin. Some cases may be bloody. Most cases are acellular and considered inadequate for diagnosis. The presence of few clusters of bland cuboidal cells in the correct radiological setting can be helpful in confirming the diagnosis ♦♦ In cases with more cellularity, the cells appear as few clusters or sheets consisting of cuboidal cells with small rounded and slightly eccentric bland nuclei and inconspicuous nucleoli. The cytoplasm is usually scant and intracytoplasmic glycogen can be confirmed by PAS stain with and without diastase. Characteristically, mucin is absent ♦♦ Some reports describe a considerable number of hemosiderinladen macrophages, a finding that is not prominent in mucinous cysts or pseudocysts ♦♦ Cyst fluid is low in amylase and CEA is <5 ng/ml. A CEA >200 ng/ml would exclude serous cystadenoma

Neoplastic Mucinous Cysts: Mucinous Cystic Neoplasm and Intraductal Papillary Mucinous Neoplasm Clinical ♦♦ Mucinous cystic neoplasms (MCN) occur predominantly in women around 40–50 years old, in the body and tail of the pancreas with rare exceptions and therefore tend to be reached by transgastric approach. The subepithelial ovarian stromal component histologically characteristic of this cyst is not detected on cytology. Prognosis relies on evidence of stromal invasion and therefore is best evaluated on surgical resection with proper sampling. However, cytological atypia may be detected in these cases and should be reported ♦♦ Intraductal papillary mucinous neoplasms (IPMN) arise from the pancreatic duct or its side branches much more commonly in the head of the pancreas and therefore tend to be reached by a transduodenal approach. The cysts are lined by papillary proliferations with variable epithelial atypia. IPMN occurs in an elderly population with slightly male predilection. Prognosis depends on stromal invasion and degree of epithelial atypia

Microscopic ♦♦ The most characteristic feature in neoplastic mucinous cyst aspirates is thick colloid-like mucin that is usually difficult to aspirate and difficult to express from the needle. In half the cases, this mucin will be copious and covers the slide. In the other half, the extracellular mucin may not be as abundant and may appear as few thick and stringy clumps or wispy mucus. The presence of cellular debris and histiocytes aid in distinguishing this lesional mucin from intestinal mucin

Cytopathology

♦♦ The smears vary in cellularity but tend to be low cellular particularly in benign cases and those with low grade dysplasia. Muciphages may be the only cells present ♦♦ In cases with moderate dysplasia or higher, epithelial atypia is detected. Findings ranged from cohesive sheets and papillary clusters of cells resembling benign endocervical cells to cells clearly derived from mucinous adenocarcinoma ♦♦ CEA elevated in the cyst fluid (>200 ng/ml) and very high levels were found to correlate with malignancy. Amylase levels have not yet been characterized; however, some suggest that very high levels of amylase would favor IPMN over CMN

Differential Diagnosis ♦♦ Gastric/foveolar cells −− Foveolar cells are retrieved in aspirates performed with the transgastric approach. In rare occasions foveolar cells may be encountered in transduodenal approach when there is foveolar metaplasia −− The foveolar cells tend to have the mucus confined in the upper third of the cytoplasm giving the appearance of “mucin cap” rather than the diffuse distention of the cytoplasm of the mucinous lesional cells in CMN or IPMN. Also bear in mind that CMN which are aspirated via transgastric approach are not lined by foveolar type cells. On the other hand, IPMN can be lined by foveolar type cells but are aspirated transduodenally

Solid Masses Ductal Adenocarcinoma Microscopic ♦♦ Poorly differentiated ductal carcinoma can be easily recognized as they produce cellular smears with sheets, clusters, and discohesive cells with usual malignant features ♦♦ Well-differentiated ductal carcinoma can be more challenging due to the subtle atypia. The following features can be recognized on closer examination and help to establish the diagnosis −− A monotonous population of nonintestinal cells and absence of other cells such as acinar component or marked inflammation; findings seen in pancreatitis −− Background of coagulative necrosis and the presence of intact abnormal single cells even if few −− A disorderly arrangement of the cells within the sheets “drunken honeycomb” with uneven distribution, crowding, and overlapping of cells −− Nuclei while bland have pale chromatin due to parachromatin clearing and frequently have nuclear indentation or grooves −− Positive cytoplasmic staining to monoclonal CEA, CA124, B72.3, CA19-9, and MUC-1 and more than 20% of nuclei positive to P53. Cytokeratin 19 may also be helpful and it depicts ductal differentiation but can also be positive in a subset of pancreatic neuroendocrine neoplasms. Loss of cytoplasmic and nuclear reactivity to Smad4 (dpc4) is also supportive

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Differential Diagnosis ♦♦ Chronic pancreatitis −− Low cellular aspirates containing a mixture of reactive ductal cells and groups of acinar cells. In cases of pancreatitis with expansive fibrosis, fragments of fibrocollagenous tissue or scattered fibroblasts may also be seen

Solid Cellular Neoplasms Clinical ♦♦ These present as well-circumscribed masses radiologically and tend to produce very cellular aspirates with polygonal cells and are not easily distinguished from each other on cytology ♦♦ All occur with equal frequency in the pancreatic head and tail ♦♦ Solid-pseudopapillary neoplasm occurs nine times more frequently in females, while acinar cell carcinoma tends to occur four times more frequently in males ♦♦ Pancreatoblastoma occurs mostly in young children (below age 5)

Microscopic ♦♦ Pancreatoblastoma −− Cellular smears of polygonal cells. Acinar differentiation is the most common line of differentiation and those aspirates may be impossible to differentiate from acinar cell carcinoma −− Squamoid corpuscles are a diagnostic feature and are best recognized on cell block −− Cells with acinar differentiation will be positive to enzyme markers: trypsin, chymotrypsin, and alpha-1-antichy­ motrypsin ♦♦ Acinar cell carcinoma −− Cellular smears with clusters and isolated monotonous acinar cells that is predominantly cohesive. The nuclei are uniformly hyperchromatic, centrally placed enlarged nuclei with irregular nuclear membrane and prominent nucleoli (cherry red macronuclei). The cytoplasm is moderate in amount and when intact intense granularity can be detected. Because of the fragility of the cytoplasm, many stripped nuclei are usually seen in granular background. Benign ductal epithelium is absent −− Positive to enzyme markers: trypsin, chymotrypsin, and alpha-1-antichymotrypsin ♦♦ Pancreatic endocrine neoplasms (Fig. 1.122) −− The smears are hypercellular and contain loose clusters, rosettes, and isolated round uniform cells. The nuclei are eccentrically located imparting a plasmacytoid appearance. The chromatin is uniform with salt and pepper appearance and small inconspicuous nucleoli. The cytoplasm is moderate, pale, and basophilic. Cytoplasmic granularity is common −− Cells are positive for neuroendocrine markers including CD56, chromogranin, and synaptophysin. Neurosecretory granules can also be demonstrated by electron microscopy

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♦♦ Solid-pseudopapillary tumor (solid and papillary epithelial neoplasm) −− Cellular smears containing branching papillae with delicate fibrovascular cores, myxoid stroma and one to several layers of cells −− The nuclei are uniform, oval, and have the characteristic nuclear grooves. The chromatin is finely distributed and the nucleoli are small. The cytoplasm is scant and may contain a small perinuclear vacuole or a hyaline globule best detected on Diff-Quik stain −− Cells are negative for cytokeratin, positive for CD10, and show strong nuclear staining with beta-catenin

Fig. 1.122. Islet cell tumor, pancreas, FNA. A monotonous population of plasmacytoid cells with eccentric nuclei and moderate amount of cytoplasm. The nuclei have fine chromatin and very small nucleoli.

OVARY Overview Sampling Method ♦♦ Transvaginal sonographically guided aspiration (most common route) ♦♦ Transabdominal ♦♦ Transrectal ♦♦ Laproscopic visualization and aspiration Contaminants that may be observed in FNA of ovaries ♦♦ Squamous cells from skin or vaginal mucosa ♦♦ Colonic epithelium −− May be seen in transrectal and transabdominal aspirates. They are usually few cells and do not indicate perforation of bowel ♦♦ Mesothelial cells ♦♦ Mesenchymal cells −− Adipose tissue −− Smooth and skeletal muscle −− Collagen ♦♦ Note: it is important to ascertain the route of the needle and which form of possible contaminants may be present

Selected Lesions Follicular Cyst ♦♦ Aspirates are low in cellularity and contain isolated single cells and tight clusters of granulosa cells of variable size ♦♦ Granulosa cells have round to oval nuclei with nuclear grooves and coarse granular chromatin. Luteinized cells appear as large polygonal luteinized granulosa cells with abundant granular or vacuolated cytoplasm, eccentric nuclei

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with finely granular chromatin, and prominent nucleoli. Ciliated cells are absent ♦♦ Estradiol level in fluid >20 nmol/l in 90% of follicular cysts

Corpus Luteum Cyst ♦♦ Smears can be cellular and contain numerous luteinized granulosa cells with abundant granular cytoplasm with indistinct cell borders and large nuclei with nucleoli ♦♦ The background may be bloody and contain, fibrin, hemosiderin-laden macrophages, and fibroblasts. The presence of abundant fibroblasts and hematoidin-laden macrophages suggest a regressing corpus luteum ♦♦ Aspirates performed in the postpartum period may exhibit cytologic atypia that mimics carcinoma

Endometriotic Cyst ♦♦ The smears are low in cellularity and have a dirty and bloody background with numerous hemosiderin-laden macrophages, rare isolated or clusters of endometrial cells. Marked degenerative changes may be observed

Mature Cystic Teratoma ♦♦ The aspirated fluid is thick and turbid. The smears are dirty and contain abundant anucleated squames, mesenchymal cells, and columnar cells. Viscous amorphous debris representing sebaceous secretion may also be present. Depending on the type of differentiation, other elements such as bronchial, gastrointestinal mucosa, glial tissue, etc. may be present

Cystic Granulosa Cell Tumor ♦♦ Aspirates may be indistinguishable from follicular cyst. In more cellular aspirates, follicular or trabecular arrangement of uniform granulosa cells occasionally forming Call-Exner bodies may be seen

Cytopathology

Serous Cystadenoma ♦♦ The aspirates are more cellular than follicular cysts and contain clusters and groups with sheet-like (honeycomb) and papillary configurations. The cells are uniform and columnar in appearance and lack cytologic atypia. Ciliated cells or ciliary bodies (tufts of cilia) may be observed

Mucinous Cystadenoma ♦♦ Mildly cellular aspirates containing primarily mucinous background best appreciated on Diff-Quik stain. Floating within this mucin there may be only muciphages or few small honeycomb sheets of columnar mucin-producing cells. The cells have uniform nuclei with finely granular evenly distributed chromatin

Papillary Serous Cystadenocarcinoma Cytologic Findings ♦♦ The smears are hypercellular and composed of isolated cells and branching papillary groups of columnar or cuboidal cells with eosinophilic cytoplasm. The nuclei are eccentrically located and hyperchromatic with irregularly distributed chromatin. The nuclei are pleomorphic and contain prominent nucleoli. Psammoma bodies are commonly observed ♦♦ Cytologic features of borderline tumors (low malignant potential) vary from completely bland cells to highly atypical and almost indistinguishable from those of carcinoma

Differential Diagnosis ♦♦ Serous cystadenoma −− The aspirate is less cellular and contains clusters and groups of uniform columnar epithelial cells that lack cytologic atypia ♦♦ Atypical luteinized cells −− Luteinized cells particularly postpartum have been mistaken for carcinoma. Note however, that the smears are less cellular and the history of pregnancy or recent labor can be confirmatory ♦♦ Endometriosis −− Endometriosis presents with tight clusters with degenerative changes in a bloody background that can be mistaken for malignancy, particularly endometriosis in the secretory phase where the cytoplasm is more abundant and the smears may be more cellular. The presence of old blood and degenerative changes are helpful in the differential

Mucinous Cystadenocarcinoma Cytologic Findings ♦♦ Smears with abundant mucin and numerous clusters of columnar cells with picket-fence configuration and cell balls. The cells have vacuolated cytoplasm and eccentrically located nuclei with prominent nucleoli

Differential Diagnosis ♦♦ Colonic cell contaminants from transrectal aspirates −− These will appear as few single columnar cells or flat cohesive sheets with honeycomb appearance and lack cytologic atypia

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♦♦ Mucinous cystadenoma −− The aspirate is less cellular and the clusters and honeycomb sheets are regularly arranged with no cytologic atypia

Endometrioid Carcinoma ♦♦ The smears are cellular and contain clusters, sheets, and syncytial groups of cells with acinar configuration that may be indistinguishable from serous adenocarcinoma although psammoma bodies are not as common. The cells are cuboidal to polygonal in shape with low N/C ratio, abundant granular eosinophilic cytoplasm, fine cytoplasmic vacuoles, and prominent nucleoli

Clear Cell Carcinoma ♦♦ The smears are moderate in cellularity and contain sheets and clusters of large cells with abundant pale cytoplasm. The cells are highly atypical with pronounced nuclear pleomorphism and irregularity and characteristic hobnailing around the clusters. The nuclei are hyperchromatic and contain cherry red macronucleoli. The cytoplasm is abundant, clear, and fragile resulting in many stripped nuclei

Granulosa Cell Tumor ♦♦ Cellular smear with solid, follicular, and trabecular arrangements of cells. The cells are small, uniform with indistinct cell borders, nuclear grooves, evenly distributed chromatin, and small nucleoli. Occasional Call-Exner bodies (acinarlike structure with central amorphous reddish material) are observed

Brenner Tumor ♦♦ Smears contain a biphasic population of epithelial and mesenchymal cells. The epithelial component presents as sheets of polygonal to cuboidal epithelial cells with oval nuclei, nuclear grooves, and cytoplasmic eosinophilic globules

Fibrothecoma ♦♦ Hypocellular smear of spindle cells with elongated nuclei and distributed chromatin

Carcinoid ♦♦ Smears are cellular and contain discohesive cells with eccentric nuclei and plasmacytoid appearance. The chromatin is granular and evenly distributed “salt and pepper.” Bilateral ovarian involvement represents metastasis to the ovaries

Dysgerminoma ♦♦ The smears contain discohesive isolated large cells with abundant amphophilic cytoplasm (glycogen rich). The nuclei are enlarged with clumped chromatin and macronucleoli. Numerous lymphocytes and occasional histiocytes and giant cells may be observed. Diff-Quik stain demonstrates the “Tigroid background” resulting from the stripped glycogen rich cytoplasm, composed of interwoven lacy and PAS+ material

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KIDNEY Simple Cyst

Angiomyolipoma

Clinical

♦♦ The smears are moderate in cellularity and contain microtissue fragments with few single or isolated cells in a bloody background. A diagnostic sample would contain a triphasic population of smooth muscle cells (spindle cells with cigarshaped nuclei), adipocytes, and blood vessels ♦♦ The smooth muscle cells may have epithelioid appearance mimicking sarcoma and positively react to HMB 45 staining

♦♦ More than 50% of men over the age of 50 may have cysts and 1–5% of cysts may harbor cancer

Microscopic ♦♦ The smears are hypocellular with scant epithelial cells that are frequently pyknotic with degenerative nuclei. There are scattered macrophages with finely vacuolated cytoplasm (“foamy cells”), amorphous proteinaceous material, and inflammatory cells in the background

Oncocytoma (Fig. 1.123) Clinical ♦♦ These are benign tumors that have a characteristic radiological appearance. The mass is well defined and has a density similar to the surrounding parenchyma. A central scar and “spokewheel” pattern of feeding vessels are usually described ♦♦ The smears are cellular and contain sheets and isolated polygonal cells with abundant well defined eosinophilic cytoplasm (mitochondria rich). The cells have normal N/C ratio and resemble proximal tubular cells. The cells have single or multiple round nuclei with fine granular chromatin and inconspicuous or prominent nucleoli. Occasional degenerative bizarre nuclei, bi- and/or multinucleation are observed ♦♦ Mitotic activity and necrosis should not be seen in tumors diagnosed as oncocytoma ♦♦ Oncocytoma cells are positive with low molecular weight cytokeratin and negative to vimentin

Fig. 1.123. Oncocytoma, kidney, FNA. Cellular smear containing a monotonous population of cells with little cytologic atypia. The nuclei are round and small, and the cytoplasm is abundant and granular. Papanicolaou stain, high power view.

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Clear Cell Renal Cell Carcinoma (Figs. 1.124 and 1.125) Cytologic Findings ♦♦ Smears can vary widely in cellularity and bloody background due to the high vascularity of this tumor. Isolated cells, floral

Fig.  1.124. Renal cell carcinoma, kidney, FNA. (A) Sheet of cells with slight nuclear atypia, and abundant vacuolated cytoplasm mimicking histiocytes. The disorganization of these cells and the nuclear indentation by the vacuoles and nuclear irregularity distinguish this from a sheet of histiocytes. Papanicolaou stain. (B) Diff-Quik stain, high power view.

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Papillary Renal Cell Carcinoma

Fig.  1.125. Normal voided urine. Low cellular smear with urothelial cells that are single or binucleated with abundant cytoplasm. Papanicolaou stain, medium power view. grouping, and three-dimensional clusters of large columnar cells are usually seen in cellular aspirates ♦♦ Tumor cells are larger than adjacent proximal tubular cells and display variable nuclear pleomorphism depending on the tumor grade. Generally, the smear contains singly scattered cells, numerous stripped bare nuclei, and small clusters of cells aggregating around a thin blood vessel. The nuclei are enlarged with irregular nuclear membrane and coarsely ­granular chromatin and prominent nucleoli (grade 2 and above). Intranuclear vacuoles are common. The cytoplasm is abundant, ill defined, and vacuolated or granular (glycogen rich) and may contain hemosiderin. Metachromatic basement membrane-like material best demonstrated on DiffQuik stain is commonly seen. The cells are positive to PAS without digestion (glycogen) but negative for mucin ♦♦ Positive to low molecular weight cytokeratin, EMA, and vimentin; and negative to cytokeratin 18 and CEA. Also negative to Hale colloidal iron ♦♦ Genetic abnormalities include: 3p deletions, mutations of VHL gene, and deletions of 6q, 8p, 9p, and 14q

Variants ♦♦ Multilocular cystic renal cell carcinoma −− Cytologic features are similar to the solid variant. However, the cystic change may present a challenge in diagnosis as it may render a dirty background rich in histiocytes and few diagnostic cells

Chromophobe Renal Cell Carcinoma ♦♦ Cellular smear composed of isolated and tight clusters of large polygonal cells. The cells have distinct cell borders, pale granular or vacuolated cytoplasm, and a perinuclear halo. Nuclei are enlarged and irregular with coarsely granular chromatin and occasional nucleoli. Bi- and/or multinucleation are common. Cellular pleomorphism may be prominent ♦♦ The cells are positive to Hale colloidal iron and cytokeratin 18 but negative to vimentin ♦♦ Genetic abnormalities include monosomy of 1, 2, 6, 10, 13, 17, and 21. The DNA is hypodiploid

♦♦ Cellular smears containing papillae with true fibrovascular cores that present as feather like structures, complex fragments, and at times spherules or tubules ♦♦ Cells are cuboidal or columnar with high N/C ratio, variable amount of delicate basophilic cytoplasm with intracytoplasmic hemosiderin (prominent in some cases). The nuclei are relatively uniform with evenly distributed fine granular chromatin in most cases (depending on the grade) and frequently have nuclear grooves and pseudo-inclusions. The background tends to be bloody and may contain psammoma bodies, scattered foamy histiocytes, and hemosiderin-laden macrophages ♦♦ Distorted aspirated normal glomeruli may mimic papillary renal cell carcinoma ♦♦ The cells are positive to AE1/AE3 and EMA but negative to high molecular weight 34BE12. They are also nonreactive with Ulex europaeus and show variable staining with CK18 and vimentin ♦♦ Genetic abnormalities include trisomies 3q, 7, 8, 12, 16, 17, and 20 and loss of Y61

Collecting Duct Carcinoma Clinical ♦♦ This is an aggressive tumor that occurs in young population (around 30–45 years old). It is characterized by its hypovascularity and medullary location but may extend into the cortex ♦♦ The mass may be solid or cystic and may contain extensive hemorrhage or necrosis

Microscopic ♦♦ Cytologic presentation can vary from isolated cells to tubulopapillary groups ♦♦ The cells are pleomorphic with high N/C ratio and have more similarity to adenocarcinoma than renal cell carcinoma. The cytoplasm may be granular or vacuolated and some cells show evidence of mucin production. The nuclei are eccentrically located, hyperchromatic with coarsely granular chromatin, and prominent nucleoli ♦♦ Metachromatic stromal fragments and normal or dysplastic ductal cells may also be present ♦♦ Positive to high molecular weight cytokeratin, CEA, Ulex europaeus, peanut lectin agglutinin, and mucicarmine ♦♦ Genetic alterations include loss of chromosome 1, 6, 14, 15, 22, and deletions of 8p and 13q

Differential Diagnosis ♦♦ Benign hepatocytes −− It is not unusual to aspirate the liver while performing an aspirate of the right kidney and therefore it is very important to recognize them as benign cells. Hepatocytes present as cohesive sheets of polygonal cells with central nuclei and low N/C ratio. The cytoplasm is moderate to abundant and granular and may contain lipofuscin or bile pigment. Nuclear pseudo-inclusions are usually identified and can be frequent

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♦♦ Normal adrenal cortical cells −− Adrenal cells may be aspirated in the path of the needle to the kidney. They present as small cohesive groups of cells with uniform nuclei and abundant vacuolated cytoplasm ♦♦ Vacuolated macrophages −− These may be aspirated as a component of a benign cyst or part of cystic renal cell carcinoma. Histiocytes present as single isolated cells with eccentric reniform nuclei and inconspicuous nucleoli. However, histiocytes when abundant may form sheet like aggregates that mimic epithelial cells ♦♦ Adrenocortical neoplasm −− Cells from adrenocortical neoplasms present as vacuolated cytoplasm and many background stripped nuclei mimicking clear cell carcinoma. However, they lack metachromatic basement membrane-like material. Nuclear pleomorphism is usually more prominent −− Adrenocortical tissue, both benign and neoplastic are positive to Melan-A and a-Inhibin but negative to EMA ♦♦ Pheochromocytoma −− The smears contain isolated single cells and loose clusters of variable sized cells with nuclear pleomorphism and saltpepper chromatin. The cytoplasm is abundant and contains numerous red granules best seen on Diff-Quik stain. The cells are positive to vimentin and synaptophysin ♦♦ Retroperitoneal seminoma −− This differential while rare should be kept in mind since the neoplastic cells exhibit some features that overlap with renal neoplasms. The smears contain numerous discohesive cells admixed with lymphocytes. The cells have enlarged nuclei with thick irregular nuclear membrane and prominent nucleoli and a moderate amount of ill-defined vacuolated cytoplasm (glycogen rich) that tends to break and result in numerous stripped nuclei. The ­fragile

c­ ytoplasm results in the characteristic tigroid background composed of irregular lacy PAS-positive material

Wilms Tumor Microscopic ♦♦ While Wilms tumor is characteristically a triphasic tumor with blastema, epithelial, and spindle stromal cell components, monomorphic tumors are not uncommon ♦♦ The blastemal component presents as microtissue fragments with tightly packed tubular structures surrounded by small blastemal cells. The cells are small with high N/C ratio and hyperchromatic nuclei ♦♦ The epithelial component may form glands, complex branching tubules and glomeruloid bodies intermixed with metachromatic material. The cells are small cuboidal or columnar with scant cytoplasm and may be arranged as palisaded rows ♦♦ The stromal component presents as a network of spindled cells embedded within myxoid and collagenous stroma and fine capillaries. Skeletal muscle, cartilage, and fat differentiation may be seen

Differential Diagnosis ♦♦ Neuroblastoma −− Smears consist of isolated cells, loose clusters, and frequent Homer-Wright rosettes. Neuropil appears as a wispy network in the background and occasional polygonal ganglion cells may be noted ♦♦ Rhabdoid tumor −− Smears contain numerous clusters and isolated large and highly pleomorphic cells with eccentric nuclei and chromatinic clearing around macronucleoli. The cytoplasm is abundant, eosinophilic, and well defined. Intracytoplasmic eosinophilic globular hyaline inclusions may be observed. The cells are reactive to both keratin and vimentin

URINARY BLADDER Overview Types of Cellular Specimens

Cellular Components of Urinary Cytology (Fig. 1.125)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Urothelial cells −− Superficial umbrella cells, large and often multinucleated (more frequent in washings and catheterized urine) −− Intermediate pyramidal cells −− Cuboidal basal cells ♦♦ Squamous cells −− May be due to contamination −− Normally found in women and would show cyclic changes −− In males their presence indicate squamous metaplasia ♦♦ Renal epithelial cells (indicates renal disease or injury) ♦♦ Intestinal epithelial cells in ileal conduit specimens ♦♦ Endometrial cells (endometriosis)

Spontaneous voided urine Instrumentation (catheterization/cystoscopy) Bladder washing Ureteral and pelvic brushing and washing Urethral brushing Ileal conduit urine

Specimen Preparation ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

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Direct smear Membrane filtration Cytocentrifugation Monolayer thin preparation (ThinPrep and SurePath) Paraffin cell block (rarely used mainly for tissue fragments)

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♦♦ Prostatic or seminal vesicle epithelial elements, spermatozoa (particularly following prostatic massage) ♦♦ Red cells and inflammatory cells

Reporting Terminology ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Unsatisfactory for evaluation Negative for malignancy Reactive urothelial cells Atypical urothelial cells, favor reactive Atypical urothelial cells of undetermined significance (including dysplastic cells) ♦♦ Atypical urothelial cells, suspicious for malignancy ♦♦ Malignant cells are present −− Derived from low grade urothelial carcinoma −− Derived from high grade urothelial carcinoma −− Derived from carcinoma in situ −− Derived from adenocarcinoma −− Others (e.g., small cell and squamous cell carcinoma)

Benign Lesions and Mimics of Malignancy Reactive Urothelial Cells ♦♦ The specimen may be more cellular than usual and the urothelial cells contain slightly enlarged nuclei that are relatively uniform with smooth contours, finely granular chromatin, and sometimes prominent nucleoli. The chromatin may show peripheral condensation. The cytoplasm is vacuolated ♦♦ Cytoplasmic vacuolization and prominent nucleoli are features not seen in low grade urothelial carcinoma

Instrument Artifact and Lithiasis ♦♦ The sample can have a marked increase in cellularity with numerous cohesive ball-shaped and papillary tight clusters with cytoplasmic collar and smooth border due to the flattened urothelial cell at periphery of cell balls. These clusters should not be confused with urothelial carcinoma. Numerous multinucleated superficial cells (umbrella cells) are also seen ♦♦ Cytoplasmic vacuolization usually occurs in reactive urothelium or high grade carcinoma, but rarely occur in low grade carcinoma which tends to have dense cytoplasm

Decoy Cells (Fig. 1.126) ♦♦ The presence of these cells is indicative of polyoma virus (papovavirus) infection which may be asymptomatic or associated with hematuria. Some patients are immunocompromised, e.g., AIDS, diabetes mellitus, cancer or posttransplantation, however; many patients have no known predisposing factor. The infection usually resolves spontaneously. Identification of these cells is particularly significant in patients with renal transplant as it may indicate rejection ♦♦ The decoy cells appear as discohesive isolated enlarged cells without clustering. The cells have high N/C ratio with enlarged eccentric nuclei with ground-glass chromatin due to a single intranuclear dense dark ink-black large smudgy inclusion.

Fig. 1.126. Polyoma virus effect, urine. Note the enlarged, eccentric nuclei with ground-glass appearance due to the intranuclear inclusion. Sometimes the nuclei appear hyperchromatic, but the smudged dark chromatin should be distinguished from that of the urothelial carcinoma. Papanicolaou stain, high power view.

A peripheral ring of chromatin usually surrounds the nuclear inclusion. Some may have a thin halo around the inclusion (not to be confused with the conspicuous halo of cytomegalovirus). Some cells have short cytoplasmic tails (comet cells) ♦♦ It is important to recognize that decoy cells may have aneuploid DNA pattern and therefore should not be misinterpreted as carcinoma

Ileal Conduit ♦♦ Columnar (colonic) degenerative epithelial cells without atypia. The exfoliated cells appear as small histiocyte-like cells and eosinophilic cytoplasmic inclusions may be seen. The background is dirty and mucoid

Treatment Effect ♦♦ Radiation −− The cytologic features are similar to those described in other sites. Urine samples present with singly scattered abnormal cells with cytomegaly and bizarre cells (may be spindled). Multinucleation is common. The cells have normal N/C ratio and nuclear degeneration with a smudged chromatin pattern and macronucleoli. Cytoplasmic polychromasia, vacuolization, and cytophagocytosis are also noted. Acute therapy will also exhibit large cytoplasmic vacuoles with ingested neutrophils ♦♦ Chemotherapeutic effect −− Features of chemotherapy effect are similar to those with chronic radiation effect including cytomegaly with normal N/C ratio, degenerative intranuclear and cytoplasmic vacuoles, and multinucleation ♦♦ Cyclophosphamide (Cytoxan) and Busulphan (Myleran) therapy −− Produce highly atypical cells that mimic high grade urothelial carcinoma. The cells are cytomegalic and may have box shaped configurations. The enlarged nuclei are smudged and may be markedly hyperchromatic with one or two large irregular nucleoli

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♦♦ Thiotepa and Mitomycin C −− Treatment results in increased cell turnover and exfoliation in the initial stage. Cytologically it is associated with reactive-like changes ♦♦ Cyclosporine A −− This drug is nephrotoxic and causes shedding of tubular cells, sometimes as papillary tissue fragments. The cytoplasm is vacuolated and contains cytoplasmic inclusions (giant mitochondria). Microcalcifications may occur ♦♦ Intravesical Bacilli Calmette–Guerin (BCG) effect −− This drug causes necrotizing granulomas in the urothelial surface. These granulomas tend to open at the surface shedding much of the necrotic content including mixed inflammatory cells. Neutrophils are more prominent in the first week while lymphocytes and macrophages are more predominant later. While it is rare to shed the epithelioid histiocytes, multinucleated giant cells and lymphohistiocytic aggregates may occasionally be noted ♦♦ Laser effect −− Similar to cryotherapy, laser effect results in markedly spindled cells occurring singly and in groups. The nuclei are elongated with uniform dense chromatin

Urothelial Neoplasm General Facts ♦♦ May detect urothelial carcinoma long before it is detected clinically or confirmed histologically ♦♦ False positive cytology is truly false positive after extensive workup of the patient ♦♦ Urine cytology is more predictive of carcinoma as the grade gets higher ♦♦ High false negative rate for low grade tumors ♦♦ Cannot distinguish between low grade intraepithelial lesions, papilloma, and low grade urothelial carcinoma ♦♦ Cannot distinguish between high grade intraepithelial lesions, CIS and high grade urothelial carcinoma ♦♦ Papillary clusters in voided urine are highly suspicious for carcinoma in the absence of infection or stone ♦♦ Classification −− The World Health Organization/International Society of Urological Pathology Consensus Classification of Urothelial (Transitional Cell) Neoplasms of the Urinary Bladder (Epstein et al. 1998) ♦♦ Flat lesions with atypia −− Reactive (inflammatory) atypia −− Atypia of unknown significance −− Dysplasia (low grade intraepithelial neoplasia) −− CIS (high grade intraepithelial neoplasia) ♦♦ Papillary neoplasms −− Papilloma −− Inverted papilloma −− Papillary neoplasm of low malignant potential (formerly WHO grade 1 urothelial carcinoma)

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−− Urothelial carcinoma, low grade (formerly WHO grade 2 urothelial carcinoma) −− Urothelial carcinoma, high grade (formerly WHO grade 3 carcinoma) ♦♦ Invasive neoplasm −− Lamina propria invasion −− Muscularis propria (detrusor muscle) invasion

Microscopic ♦♦ Urothelial papilloma −− Cytologically, papilloma is often indistinguishable from low grade papillary urothelial carcinoma and is difficult to diagnose. The urine tends to have lower cellularity than that of low grade carcinoma. The cells are small with hyperchromatic nuclei ♦♦ Urothelial carcinoma in situ −− Often indistinguishable from high grade urothelial carcinoma. The urine sample contains predominantly isolated highly atypical single cells with cytoplasmic vacuolization (usually have more monotony than invasive high grade carcinoma), enlarged nuclei with irregular nuclear contour, coarsely granular chromatin, and prominent nucleoli. Tumor diathesis is absent ♦♦ Papillary neoplasms (Figs. 1.127 and 1.128) −− Classification and grading of urothelial carcinoma is difficult based on cytology −− Low malignant potential (a) Cytologically, the features may be indistinguishable from benign reactive urothelial cells or papilloma. The cells lack cytoplasmic vacuolization and prominent nucleoli −− Papillary carcinoma, low grade (a) The urine sample contains papillary and three-­ dimensional clusters with ragged border. True papillary fronds with fibrovascular core are pathognomonic.

Fig.  1.127. Urothelial carcinoma, high grade, voided urine. Cellular preparation with numerous highly atypical cells containing eccentric hyperchromatic and irregular nuclei. Papanicolaou stain, medium power view.

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♦♦

♦♦

Fig. 1.128. Urothelial carcinoma, voided urine. Cluster of highly atypical cells with eccentric hyperchromatic enlarged nuclei. Papanicolaou stain, high power view.

♦♦

♦♦ It is worth noting that the presence of clusters in voided urine specimens is diagnostic of urothelial carcinoma provided that infection and lithiasis can be excluded (b) The cells have increased N/C ratio with slight irregular nuclear contours and finely granular chromatin and nucleoli are inconspicuous. The nuclei tend to be eccentric and encroaching on the cytoplasm border as if they are about to be expelled (loss of cytoplasmic collar). The cytoplasm is homogeneous and lacks vacuolization. Umbrella cells are still present −− Papillary carcinoma, high grade (a) High grade urothelial carcinoma and CIS are often indistinguishable cytologically. The urine contains discohesive clusters and isolated single cells. The cells are pleomorphic with high N/C ratio, nuclear pleomorphism, irregular nuclear contours, coarse chromatin, and prominent nucleoli. Within the clusters increased nuclear overlapping and crowding is prominent. The cytoplasm may be vacuolated. The background may be dirty containing nuclear debris and inflammatory cells

Ancillary Testing ♦♦ FISH is especially useful in patients with “atypical” or “equivocal” urine cytology to improve bladder cancer detection. The centromeric probes of chromosomes 3, 7, and 17 aim at detecting aneuploidy (gain) of these chromosomes, while the fourth probe aims at detecting the loss in chromosome 9 of the 9p21 locus

Differential Diagnosis ♦♦ Reactive urothelial cells −− The cells have cytoplasmic vacuolization, prominent nucleoli, and features that are incompatible with low grade urothelial carcinoma ♦♦ Instrument artifact and lithiasis −− The sample have increased cellularity and many multinucleated superficial cells. The clusters are bordered by flattened urothelial cells

♦♦

♦♦

♦♦

−− Cytoplasmic vacuoles (cytoplasmic vacuolization usually occurs in reactive urothelium or high grade carcinoma, but rarely in low grade carcinoma) Decoy cells −− The urine sample contains discohesive isolated enlarged cells with high N/C ratio. The cells exhibit peripheral condensation of chromatin, dense smudgy intranuclear inclusions, and occasionally a thin halo Treatment effect −− The cells have a normal N/C ratio, smudged chromatin, cytoplasmic vacuoles, and cytoplasmic polychromasia. Multinucleated giant cells and reactive urothelial cells are also present Seminal vesicles −− Rare enlarged cells with large nuclei and cytoplasmic lipofuscin pigment Malacoplakia −− Rarely encountered and presents as macrophages containing Michaelis–Gutmann bodies Reactive renal tubular epithelium −− The presence of tubular epithelium in urine samples usually indicates renal parenchymal ischemic necrosis. The cells appear as round oval cells with small eccentric nuclei and granular cytoplasm (oncocyte-like cells) Renal collecting duct epithelium −− Present as microtissue fragments or isolated small polygonal cells with scant cytoplasm. The nuclei are centrally located with dense chromatin Urothelial papilloma −− Often indistinguishable from low grade papillary urothelial carcinoma (see above)

Urothelial Adenocarcinoma Microscopic ♦♦ The urine contains three-dimensional grouping with nuclear palisading. The cells have high N/C ratio, eccentric nuclei, irregular nuclear contours, and prominent nucleoli. Intracellular and extracellular mucin production may be observed

Differential Diagnosis ♦♦ Prostatic adenocarcinoma −− Present as acinar structures and small syncytial groups of cells with nucleomegaly and prominent nucleoli. Mucin is absent ♦♦ Herpes simplex virus-induced changes −− Cytologic features similar to those of other sites including multinucleation, nuclear molding, accentuation of nuclear membranes, and ground-glass intranuclear inclusions ♦♦ Decoy cells (see above) ♦♦ Glandularis cystitis −− Present as small groups of benign appearing glandular cells with cytoplasmic vacuoles and lack of cytologic atypia

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♦♦ Renal cell carcinoma −− Exfoliated cells from renal cell carcinoma are rarely encountered in urine. They are frequently degenerated and present as single cells or small groups of abnormal cells with round to oval hyperchromatic nuclei and prominent nucleoli. The cytoplasm appears more granular than expected due to degeneration ♦♦ Nephrogenic adenoma

−− Present as single or few small groups of vacuolated cells. The cells are polygonal to columnar in shape with uniform nuclei and no cytologic atypia ♦♦ Renal rejection −− The urine sample contains numerous renal tubular cells and T-lymphocytes. The background contains casts with thick outer border and clear center and red blood cells

PLEURAL AND PERITONEAL FLUID Benign Quiescent Mesothelial Cells ♦♦ Benign effusions are usually low in cellularity and contain scattered mostly single mesothelial cells and very few clusters ♦♦ The mesothelial cells are small rounded cells with a centrally located rounded nucleus and small inconspicuous nucleoli. The cytoplasm has two-tone staining with endoectoplasmic demarcation. The perinuclear cytoplasm stains lighter than the peripheral cytoplasm. At the cytoplasmic membrane the border appears fuzzy as a result of the numerous slender villi normally seen by EM as well as the submembranous glycogen vacuoles (positive to PAS and digested by diastase) ♦♦ Mesothelial cells also appear in doublets or triplets (forming short rows) with windows between the cells. Other features of mesothelium include cellular clasping (cytoplasm of one cell extends and wraps around another cell) and the appearance of cell within cell. Cytoplasmic degeneration may result in a large vacuole pushing the nucleus to the side and mimicking a histiocyte or signet-ring cell

Fig. 1.129. Reactive mesothelial cells, pleural fluid. Tight cluster with scalloped borders and uniformly arranged monotonous nuclei. The cytoplasm has two-tone staining indicative of the endo-ectoplasmic differentiation and small windows are apparent between the cells. Diff-Quik stain, high power view.

Reactive Mesothelial Cells (Fig. 1.129) (See Tables 1.4 and 1.5)

Causes of Mesothelial Hyperplasia

♦♦ Reactive mesothelial cells exhibit features of mesothelial cells more clearly, and the smears could vary in cellularity from moderate to highly cellular. In addition to the numerous singly scattered mesothelial cells, there are also loose aggregates of cells with demarcation lines or “windows” between cells. These clusters frequently have scalloped borders created by the cytoplasmic surface of the surrounding cells ♦♦ The majority of cells have single centrally placed nuclei. Cells may have two or more similar sized nuclei, and multinucleation increases proportionally with the reactive changes. The nucleoli are visible and may become prominent ♦♦ Reactive mesothelium usually present as monotonous cells with a small range of size variability and a continuum or spectrum of changes ranging from normal to atypia ♦♦ Mitotic figures are few; however in florid reactive cases such as cases with liver cirrhosis, mitotic figures may become considerably high and overlap with those seen in mesothelioma. Psammoma bodies may be present though rare

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Heart failure Infection (pneumonia, lung abscess) Infarction Liver disease (hepatitis, cirrhosis) Collagen disease Renal disease (uremia, dialysis) Pancreatic disease Radiation Chemotherapy (Bleomycin, Cytoxan) Traumatic irritation (hemodialysis, surgery) Chronic inflammation (pleuritis) Underlying neoplasm (fibroid, hamartoma) Foreign substance (talc, asbestos)

Differential Diagnosis ♦♦ Malignant mesothelioma (see below) ♦♦ Adenocarcinoma (see below)

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Table 1.4. Features of quiescent and reactive mesothelial cells Cytologic feature

Quiescent

Reactive/hyperplastic

Pattern

•  Sheets, closely apposed to one another •  Break off in small groups

•  Doublets or triplets with windows between them •  May form papillary groups •  Connections by clasp like articulation

Shape and size

•  Round to oval •  15-20 mm

•  Round to oval •  20-40 mm

Nucleus

•  Monotonous •  Oval to round •  Mononuclear or binuclear •  Evenly distributed chromatin

•  Variable •  Oval to round •  Mutinucleation •  Variable

Nucleolus

•  Inconspicuous

•  Variable

Cytoplasm

•  Moderate amount •  Translucent •  Peripheral vacuoles containing glycogen

•  Abundant •  Endo-ectoplasmic demarcation •  Peripheral vacuoles containing glycogen

Cell border

•  Fuzzy border due to microvilli

•  Cytoplasmic protrusions distal to cellular connections

Table 1.5. Comparison between transudate and exudate Transduate

Exudate

Appearance

Clear

Turbid

Specific gravity

<1.015

>1.015

Protein

<3 gm/dl

>3 gm/dl

Fluid/serum protein ratio

<0.5

>0.5

Fluid/serum LOH ratio

<0.6

>0.6

Miscellaneous Findings ♦♦ Collagen ball −− Collagen covered by mesothelial cells may be detached from the serosal surface or the ovary. The balls appear as smoothly contoured green bodies, naked or covered by a layer of mesothelial cells. Most commonly encountered in pelvic washings (forceful removal), although they have been described in pleural and peritoneal fluids as well ♦♦ Ciliocytophthoria (ascites) −− These are detached ciliary tufts that are derived from fallopian tube lining cells. They are often seen in later half of menstrual cycle or after surgical manipulation ♦♦ LE cells −− These cells are seen in patients with systemic lupus erythematosus. LE cell is a neutrophil or sometimes a macrophage ingesting a denatured nucleus of a injured cell (appears as a blue droplet)

♦♦ Tart cells −− These cells are also seen in patients with systemic lupus erythematosus. Tart cell is a macrophage that ingested a nonhomogenized nucleus of a dead cell

Rheumatoid Pleuritis/Pericarditis ♦♦ The appearance of the smears and cell blocks is almost diagnostic for rheumatoid disease. The smears contain abundant amorphous or cheesy pink necrotic granular debris (key feature) ♦♦ Elongated spindle epithelioid histiocytes with dense granular eosinophilic cytoplasm may be encountered in some cases ♦♦ Multinucleated giant cells, neutrophils, lymphocytes, and scattered reactive mesothelial cells may be noted

Tuberculosis ♦♦ The smears are highly cellular and consist predominantly of lymphocytes with few mesothelial cells frequently entrapped within the fibrinous exudate. The lymphocytes comprise mainly of activated T-lymphocytes with increase in T helper cells (CD4) and an increased CD4:CD8 ratio that is higher than that of the peripheral blood of the patient

Malignant Mesothelioma (Fig. 1.130) ♦♦ Smears from mesothelioma effusions vary in cellularity depending on the degree of exfoliation of that tumor. In diagnostic cases, the smears are highly cellular and may contain predominantly large single mesothelial cells, predominantly clusters of mesothelial cells, or a mixture of single cells and cellular spheres. The latter is the most common presentation ♦♦ The smears comprise of a single population of large cells that manifest all the features described in mesothelium (no evidence of two-cell population). The cells have a wide range in

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Fig.  1.130. Malignant mesothelioma, pleural fluid. Highly c­ ellular smear with numerous cellular clusters (morules) in the background of single and multinucleated cells. Note the gigantic size of some of the single cells. Also notice the enlarged nuclei with prominent nucleoli. Papanicolaou stain, medium power view.

size (range from normal size to gigantic). Some of the large cells may approach the size of a small morule ♦♦ Grouping of cells −− They present as large cellular spheres with smooth borders also known as morules, as three-dimensional clusters with scalloped borders, or as small loose clusters. Generally these clusters comprise a large number of cells −− Doublets and triplets are still recognizable in the background with pronounced intercellular windows and cellular clasping ♦♦ Individual cells −− Manifest an exaggerated appearance of all the features associated with mesothelium such as ecto-endoplasmic demarcation (two-tone cytoplasmic staining with denser, more eosinophilic perinuclear staining), fuzzy border around entire perimeter, clasp-like articulation between two cells and the cytoplasmic protrusion from pinched member of the pair, window-like spaces between the cells, peripheral vacuolization, and bleb formation −− The cells vary widely in size, yet the nuclear morphology remains bland although the nucleoli become very prominent and sometimes macronucleoli are visible. The nuclei are central and surrounded by abundant cytoplasm. The key feature of mesothelioma is the gigantic size of some cells and the very prominent nucleoli

Differential Diagnosis ♦♦ Reactive mesothelium −− Although reactive effusions can be cellular they do not approach the cellularity of malignant effusions. Also, the reactive cells tend to be similar in size with little variation among them while those of malignant mesothelioma vary widely in size. Other key features of mesothelioma include the cell morules and very prominent nucleoli. Some litera-

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Fig.  1.131. Metastatic papillary serous carcinoma of ovary, ­peritoneal fluid. A cellular smear with highly atypical cells arranged in complex papillae. Psammoma bodies are frequent. Papanicolaou stain, low power view. ture suggests that desmin and EMA can help in the separation of benign from malignant mesothelium. It is known that benign mesothelium has desmin filament and that it is lost as the cells develop malignancy. Therefore, a positive desmin stain and negative EMA confirm a reactive process. Meanwhile, a positive EMA and negative desmin staining confirm a malignant process ♦♦ Adenocarcinoma −− Reactive mesothelium presents as one cell population while adenocarcinoma will have two cell populations, i.e., malignant cells and background reactive mesothelial cells. Adenocarcinoma also tends to have more pleomorphism and nuclear atypia compared to reactive or malignant mesothelium. The majority of adenocarcinoma also lacks the morphologic features of mesothelium −− Immunocytochemistry is helpful in separating mesothelium from adenocarcinoma. A panel of antibodies is usually recommended as no single stain is diagnostic and the diagnosis is based on the pattern of staining within the panel. Mesothelial cells react with HBME-1, Calretinin, WT-1, podoplanin, D2-40, and CK5/6. Adenocarcinoma may variably react with these antibodies (particularly HBME-1 and WT-1) and will also react with other epithelial markers such as MOC-31, BerEP4, CEA, B72.3, LeuM1 (CD15), etc. EMA stains both mesothelioma and adenocarcinoma but the staining pattern is different. In mesothelioma, there is cytoplasmic staining with accentuation at the periphery (cytoplasmic membrane) while in adenocarcinoma the staining is strong and diffuse within the cytoplasm

Metastatic Adenocarcinoma (See Table 1.2) (Figs. 1.131–1.137) Cytologic Findings ♦♦ The smears are usually cellular and their pattern will vary depending on the primary origin. In most cases, a two-cell

Cytopathology

Fig. 1.132. Metastatic clear cell carcinoma of the ovary, peritoneal wash. Highly atypical cells arranged in tight clusters with abundant clear cytoplasm. Papanicolaou stain, high power view.

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Fig. 1.135. Metastatic adenocarcinoma of breast (ductal or lobular), pleural fluid. Another common appearance of breast carcinoma presenting with small clusters, short cords (Indian filing) and as cell within cell arrangement. Papanicolaou stain, high power view.

Fig. 1.133. Metastatic mucinous carcinoma of ovary, peritoneal fluid. Malignant cells arranged in tight papillary clusters. Cells present as signet-ring cells with eccentric nuclei and abundantly vacuolated cytoplasm. Fig. 1.136. Metastatic adenocarcinoma of the lung, pleural fluid. Large atypical cells appearing as small clusters or singularly scattered cells. Papanicolaou stain, high power view.

Fig. 1.134. Metastatic adenocarcinoma of breast (ductal), pleural fluid. The clusters may show bridging and cribriform appearance. Papanicolaou stain, medium power view.

population is detected, i.e., carcinoma cells in the background of benign reactive mesothelium ♦♦ Some carcinomas such as ovary, breast, colon, and lung will manifest as numerous cohesive three-dimensional clusters, papillae, or cell balls with smooth community border. Within these clusters, the cells are crowded with obvious nuclear overlapping and nuclear molding but no intercellular windows (do not confuse vacuoles with windows) ♦♦ Large, well-defined, smooth edged and eccentrically placed vacuoles ♦♦ Some carcinomas such as lung, breast, and pancreas present as numerous single large cells. The cells are obviously pleomorphic with enlarged hyperchromatic nuclei, high N/C ratios, irregular nuclear contours, anisonucleosis, prominent

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nuclei that may be irregularly indented by the cytoplasmic vacuoles. These cells tend to be small and may be confused with histiocytes ♦♦ Intracytoplasmic mucin may be detected in about 50% of cases, and it will stain as diffusely positive with PAS (instead of peripheral) and is resistant to diastase. Mucin can also detected by mucicarmine and positive hyaluronidase-­resistant Alcian blue stains ♦♦ Intranuclear pseudoinclusions may be detected in certain carcinomas such as papillary thyroid or renal

Differential Diagnosis

Fig. 1.137. Metastatic gastric adenocarcinoma, poorly differentiated, pleural fluid. The cells appear as small atypical cells with eccentric, highly atypical nuclei. These cells could easily be dismissed if the smear is not screened meticulously at the higher magnification. Papanicolaou stain, high power view. nucleoli, and mitotic figures. Bizarre cells, multinucleation with atypia, and variable nuclear size are also present ♦♦ Some such as gastroesophageal and colon adenocarcinomas present as small signet-ring cells with eccentric enlarged

♦♦ Reactive mesothelial cells −− Look for the intercellular windows and other mesothelial features such as the two-tone cytoplasm staining. The cells are negative to mucin staining and most epithelial markers ♦♦ Malignant mesothelioma (see Tables 1.2 and 28.2) −− These hypercellular smears compris of a monotonous one cell population. Many cellular spheres and single cells appear generally bland except for the increased size and prominent nucleoli −− Positive for Alcian blue that is nonresistant to diastase (hyaluronic acid). These cells are also negative to most epithelial markers and positive to mesothelial markers (see above)

CEREBROSPINAL FLUID AND CENTRAL NERVOUS SYSTEM Specimen Preparation of CSF

Ependymal Cells (Fig. 1.138)

♦♦ Cytospin ♦♦ Monolayer preparation ♦♦ Filter preparation −− More cells retained, but less optimal preservation and staining

♦♦ The cells are cuboidal to columnar in shape with indistinct cell border, amphophilic cytoplasm, cytoplasmic vacuoles, and microcilia. They are difficult to differentiate from choroid plexus cell (diagnostically not important). When present in clusters, they are less cohesive than choroid plexus ­cellular groups. In reactive conditions, they may appear pleomorphic.

Normal Components of CSF ♦♦ Usually no more than 5 cells/mm3 ♦♦ Few lymphocytes and histiocytes ♦♦ Occasional neutrophils and eosinophils may be present after operative procedure involving subarachnoid space ♦♦ Contaminants include cutaneous squamous cells, adipose tissue, skeletal muscle, cartilage, and vessels ♦♦ Hematopoietic precursors from bone marrow contaminants ♦♦ Corpora amylacea ♦♦ Talc powder ♦♦ Ventricular lining cells ♦♦ Brain tissue: occurs when cerebrospinal fluid (CSF) is retrieved through a shunt or after surgical manipulation. It presents as neuropil with embedded astrocytes and oligodendrocytes. Neuropil is fibrillar in appearance and stains blue by Papanicolaou stain and purple by Diff-Quik stain

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Fig. 1.138. Benign ependymal cells, CSF. Cluster of cuboidal cells with distinct cell borders. Papanicolaou stain, high power view.

Cytopathology

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Acute Lymphocytic Leukemia/Malignant Lymphoma Microscopic ♦♦ The CSF Prep is cellular and contains a monotonous population of single malignant cells with high N/C ratio, irregular nuclear contours, open chromatin, and prominent nucleoli. Ancillary studies may be essential for diagnosis and classification

Differential Diagnosis Fig.  1.139. Choroid plexus cells, CSF. Cuboidal to columnar cells with sharp cell borders. Note how they appear in a cluster with somewhat acinar-like formation that could be mistaken for metastatic adenocarcinoma. Papanicolaou stain, high power view. Phosphotungstic acid hematoxylin (PTAH) stains basal bodies of cilia

Choroid Plexus Cells (Fig. 1.139) ♦♦ They often present as papillary or microacinar groups with dense eosinophilic cytoplasm. The cellular border is more defined than that of ependymal cells, and yellow pigment may be detected in the cytoplasm

Pia-Arachnoid (Leptomeningeal) Cells ♦♦ Small round to spindle cells with abundant foamy cytoplasm and less defined cell border. Leptomeningeal cells resemble mesothelial cells

Brain Parenchyma ♦♦ Often seen in patients with ventricular shunts, intracranial hemorrhage, and head injury

Primitive (Blast-Like) Cells of Neonates ♦♦ Primitive cells are thought to be derived from the subependymal germinal matrix. They are often seen in CSF of neonates with hydrocephalus or intraventricular hemorrhage. They present as cohesive clusters of cells with high N/C ratio. They react positively with neuron-specific enolase and negatively with leukocyte common antigen

Inflammatory Conditions ♦♦ Acute meningitis: Neutrophils are seen initially in the CSF followed later by mononuclear inflammatory cells ♦♦ Viral meningitis: CSF characteristically contains mild lymphocytosis and rarely viral inclusions are detected ♦♦ Tuberculous meningitis: Mixed inflammation with lymphocytes may be observed ♦♦ Mollaret meningitis: This is a recurrent self-limiting aseptic meningitis characterized by Mollaret cells (activated large monocytes with abundant vacuolated cytoplasm), and pleocytosis with increased neutrophils followed by lymphocytes that fade with time

♦♦ Reactive lymphocytes −− These are due to a variety of reasons including intrathecal chemotherapy, viral infection, multiple sclerosis, etc. The lymphocytes are slightly enlarged and increased in number. Immunophenotyping frequently reveals T-lymphocytosis ♦♦ Puncture of marrow space −− The prep comprises a variety of cells including nucleated red cells and megakaryocytes. Hematopoietic precursors at different stages of development are present ♦♦ Ventricular lining cells −− These cells could be numerous particularly in CSF collected from ventricular shunts ♦♦ Primitive cells of neonates −− These cells appear as cohesive clusters while lymphocytes appear mostly as single cells. They are negative to common leukocyte antigen and positive to neuronspecific enolase ♦♦ Medulloblastoma −− Tight clusters or single isolated small blue cells with markedly increased N/C ratio and nuclear molding, hyperchromasia and irregular nuclear membranes

Astrocytoma Cytologic Findings ♦♦ Low grade −− The smears are hypocellular and composed of dispersed small cells in a fibrillar background. The cells have round nuclei with finely granular chromatin and pale cyanophilic cytoplasm with indistinct cell borders. Long or blunt cytoplasmic processes may be seen in cells −− Fibrillary background with small blood vessels in close association with tumor cells is seen on specimens retrieved by FNA ♦♦ High grade −− The smears are hypercellular and composed of highly pleomorphic cells with nuclear hyperchromasia and nuclear pleomorphism. Tumor giant cells with bizarre nuclei and prominent nucleoli are frequently noted. Endothelial proliferation is best appreciated on Diff-Quik. Mitotic activity is high, and atypical mitotic figures may be present. Degenerative changes and necrosis may be prominent

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Differential Diagnosis ♦♦ Reactive gliosis −− May be indistinguishable from low grade astrocytoma. The smears are usually less cellular and contain a polymorphous population of cells comprising an admixture of lymphocytes, histiocytes, and gemistocytes. Endothelial proliferation and atypical mitotic figures are absent

Ependymomas Microscopic ♦♦ Cellular smears containing honeycomb sheets or cohesive three-dimensional aggregates of columnar and polygonal cells. The cells have distinct cell borders and abundant eosinophilic cytoplasm, low N/C ratio, and small polarized round nuclei with finely to coarsely granular chromatin. Flexner–Wintersteiner (true) rosette and perivascular pseudorosette are observed

Differential Diagnosis ♦♦ Normal ependymal cells −− Often occur as singly isolated cells without clustering

Choroid Plexus Papilloma Microscopic ♦♦ Cellular smears with papillary and cohesive aggregates of cuboidal cells with distinct cell borders. The cells have low N/C ratio, uniform nuclei, smooth nuclear contours and fine chromatin, and small or inconspicuous nucleoli

Differential Diagnosis ♦♦ Primitive neuroectodermal tumors −− The smears from these tumors are moderate to high in cellularity and comprise groups of small blue cells with hyperchromatic angulated nuclei and nuclear molding. The nuclei have coarse granular chromatin and irregular nuclear membrane ♦♦ Metastatic adenocarcinoma −− Smears are moderate to high in cellularity containing pleomorphic cells appearing in small groups or as single cells. Breast carcinoma is among the most commonly metastatic adenocarcinomas encountered in the CSF. Adenocarcinoma cells have high N/C ratio and enlarged nuclei with coarse chromatin and prominent nucleoli. A history of primary carcinoma is helpful

Essentials of Anatomic Pathology, 3rd Ed.

amount, delicate, and occasionally vacuolated. Granulomatous inflammation is frequent. Tigroid background is characteristic and occurs as a result of the fragile cytoplasm that breaks during manual preparation of the smears (particularly noted in Diff-Quik stain). The cells are positive for placental alkaline phosphatase (PLAP)

Meningioma ♦♦ The smears are moderate in cellularity and comprise cohesive clusters and syncytial arrangement of uniform spindle cells with abundant eosinophilic cytoplasm. The nuclei are small with smooth nuclear contour and fine granular chromatin. The identification of whorls arrangement within the fragments, psammoma bodies, and intranuclear cytoplasmic inclusions are helpful features in establishing the diagnosis. The cells are positive for EMA

Retinoblastoma ♦♦ The cytologic features are very similar to those of PNET. The smears contain tight clusters of small blue cells with irregular coarsely granular chromatin. Occasional rosette formation is present. Tumor diathesis and inflammatory background may be noted

Medulloblastoma (Fig. 1.140) Microscopic ♦♦ The smears are highly cellular and composed of a uniform population of small blue cells with nuclear molding. The cells are isolated or as tight clusters, and pseudorosettes may be detected. The N/C ratio is high and the nuclei are round, hyperchromatic, with inconspicuous nucleoli

Differential Diagnosis ♦♦ Normal cerebellum −− Uniform cells of granular layer with smooth nuclear contours

Craniopharyngioma ♦♦ Anucleated squamous cells, lipid-laden macrophages, keratin pearls, and cholesterol crystals are seen

Germinoma ♦♦ Smears are highly cellular and contain numerous isolated single cells and loosely cohesive sheets of large tumor cells admixed with lymphocytes. The cells contain large vesicular uniform nuclei with prominent nucleoli. The cells have a distinct cell border, and the cytoplasm is scant to moderate in

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Fig. 1.140. Medulloblastoma, CSF. A somewhat cohesive group of small blue cells with hyperchromatic angulated nuclei and nuclear molding. Papanicolaou stain, high power view.

Cytopathology

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Metastatic Carcinoma (Figs. 1.141 and 1.142) ♦♦ Smears may have a variable number of cells presenting as clusters of malignant cells with features that may be reminis-

Fig. 1.141. Metastatic gastric carcinoma, CSF. Signet-ring cells with eccentric hyperchromatic atypical nuclei and vacuolated abundant cytoplasm. Papanicolaou stain, high power view.

cent of primary cancer. Immunohistochemical staining is often helpful to establish the primary

Fig. 1.142. Metastatic adenocarcinoma of breast, CSF. Malignant cells appearing in cell clusters or as long cellular cords (Indian filing). Papanicolaou stain, high power view.

SUGGESTED READING Gynecologic Cytology American Society for Colposcopy and Cervical Pathology: Management guidelines, www.ASCCP.org American Cancer Society, http://www.cancer.org American Society of Cytopathology, www.cytopathology.org Atkinson BF. Atlas of Diagnostic Cytopathology. 2nd ed. Philadelphia, PA: W.B. Saunders Company, 2004.

Nongynecologic Cytology General Geisinger KR, Stanley MW, Raab SS, Silverman JF, Abati A. Modern Cytopathology. Bethesda, MD: Churchill Livingstone, 2003. Sidawy M, Ali S, Goldblum J (eds.) Fine Needle Aspiration Cytology.1st ed. Philadelphia, PA: Elsevier, 2007.

Bibbo M, Wilbur D (eds.) Comprehensive Cytopathology. 3rd ed. Philadelphia, PA: Elsevier, 2008.

Lung

Cibas E, Ducatman B (eds.) Cytology Diagnostic Principles and Clinical Correlates. 3rd ed. Philadelphia, PA: Saunders, 2009.

Crapanzano JP, Zakowski MF. Diagnostic dilemmas in pulmonary cytology. Cancer (Cancer Cytopathol) 2001;93:364–375.

DeMay R. The Pap Test. Chicago, IL: American Society for Clinical, 2005.

Garg S, Handa U, Mohan H, Janmeja AK. Comparative analysis of various cytohistological techniques in diagnosis of lung diseases. Diagn Cytopathol 2007;35:26–31.

Geisinger KR, Stanley MW, Raab SS, Silverman JF, Abati A. Modern Cytopathology. Bethesda, MD: Churchill Livingstone, 2003. NCI Bethesda 2001, www.Bethesda2001.cancer.gov, www.Cytopathology. org/NIH Solomon D, Nayar R (eds.) The Bethesda System for Reporting Cervical Cytology. 2nd ed. New York, NY: Springer, 2004.

Ohori NP, Santa Maria EL. Cytopathologic diagnosis of bronchoalveolar carcinoma: does it correlate with the 1999 World Health Organization definition? Am J Clin Pathol 2004;122:14–16.

The American College of Obstetricians and Gynecologists www.ACOG.org

Sturgis CD, Nassar DL, D’Antonio JA, Raab SS. Cytologic features useful for distinguishing small cell from non-small cell carcinoma in bronchial brush and wash specimens. Am J Clin Pathol 2000;114:197–202.

Wilbur D, Henry M (eds.) College of American Pathologists Practical Guide to Gynecologic Cytopathology Morphology, Management, and Molecular Methods. 1st ed. Northfield, IL: College of American Pathologist, 2008.

Wiatrowska BA, Krol J, Zakowski M. Large cell neuroendocrine carcinoma of the lung: proposed criteria for cytologic diagnosis. Diagn Cytopathol 2001;24:58–64

Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 2007;197:346–355.

Breast Krishnamurthy S, Ashfaq R, Shin HJC, Sneige N. Distinction of phyllodes tumor from fibroadenoma. Cancer Cytopathol 2000;90:342–349.

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Michael CW, Buschman B. Can true papillary neoplasms and their ­mimickers be accurately classified by cytology. Cancer Cytopathol 2002;96:92–100.

Politi E, Kandaraki C, Apostolopoulou C, et  al. Immunocytochemical panel for distinguishing between carcinoma and reactive mesothelial cells in body cavity fluids. Diagn Cytopathol 2005;32:151–155.

The uniform approach to breast fine-needle aspiration biopsy. National Cancer Institute sponsored conference. Diagn Cytopathol 1997;16: 295–311.

Saad RS, Lindner JL, Lin X, Liu YL, Silverman JF. The diagnostic utility of D2-40 for malignant mesothelioma versus pulmonary carcinoma with pleural involvement. Diagn Cytopathol 2006;34:801–806.

Thyroid Ali SZ, Cibas ES (eds.) The Bethesda System for Reporting Thyroid Cytopathology. New York: Springer; 2010 Baloch ZW, Cibas Edmund S, Clark DP, Layfield LJ, Ljung BM, Pitman MB, Abati A. The national cancer institute thyroid fine needle aspiration state of the science conference: a summation. Cytojournal 2008;5:6.

Silverman JF. Effusion cytology of metastatic malignancy of unknown primary. Pathol Case Rev 2001;6:154–160. Walts AE. Cerebrospinal fluid cytology: selected issues. Diagn Cytopathol 1992;8:394–408. Zhu W, Michael CW. WT1, monoclonal CEA, TTF1, and CA125 antibodies in the differential diagnosis of lung, breast, and ovarian adenocarcinomas in serous effusions. Diagn Cytopathol 2007;35:370–375.

Pancreas Urinary Cytology Bubendorf L, Grilli B, Sauter G, Mihatsch MJ, Gasser TC, Dalquen P. Multiprobe FISH for enhanced detection of bladder cancer in voided urine specimens and bladder washings. Am J Clin Pathol 2001;116: 79–86. Epstein JI, Amin Mahul B, Reuter VR, Mostofi FK. Bladder Consensus Conference Committee. The world health organization/international ­society of urological pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Am J Surg Pathol 1998;22:1435–1447. Kini S (ed.) Thyroid Cytopathology: an Atlas and Textbook. Philadelphia: J.B. Lippincott Company, 2008 Xin W, Raab S, Michael CW. Low grade urothelial carcinoma: Reappraisal of cytological criteria on ThinPrep. Diagn Cytopathol 2003;29:125–129.

Body Fluids Attanoos RL, Griffin A, Gibbs AR. The use of immunohistochemistry in distinguishing reactive from neoplastic mesothelium. A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2. Histopathology 2003;43:231–238. Attanoos RL, Webb R, Dojcinov SD, Gibbs AR. Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum. Histopathology 2002;40:237–244. Attanoos RL, Webb R, Dojcinov SD, Gibbs AR, Ng WK, Chow JC, Ng PK. Thyroid transcription factor-1 is highly sensitive and specific in differentiating metastatic pulmonary from extrapulmonary adenocarcinoma in effusion fluid cytology specimens. Cancer 2002;96:43–48. Chhieng DC, Ko EC, Yee HT, et  al. Malignant pleural effusions due to small-cell lung carcinoma: a cytologic and immunocytochemical study. Diagn Cytopathol 2001;25:356–360.

Pitman MB, Deshpande V. Endoscopic ultrasound-guided fine needle aspiration cytology of the pancreas: a morphological and multimodal approach to the diagnosis of solid and cystic mass lesions. Cytopathology 2007;18:331–347. Van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005;62:383–389.

Lymph Nodes Dong HY, Harris NL, Preffer FI, et al. Fine-needle aspiration biopsy in the diagnosis and classification of primary and recurrent lymphoma: a retrospective analysis of the utility of cytomorphology and flow cytometry. Mod Pathol 2001;14:472–481. Meda BA, Buss DH, Woodruff RD, et al. Diagnosis and subclassification of primary and recurrent lymphoma. The usefulness and limitations of combined fine-needle aspiration cytomorphology and flow cytometry. Am J Clin Pathol 2000;113:688–699. Mourad WA, Tulbah A, Shoukri M, et al. Primary diagnosis and REAL/ WHO classification of non-Hodgkin’s lymphoma by fine-needle aspiration: cytomorphologic and immunophenotypic approach. Diagn Cytopathol 2003;28:191–195. Saboorian MH, Ashfaq R. The use of fine needle aspiration biopsy in the evaluation of lymphadenopathy. Semin Diagn Pathol 2001;18: 110–123. Wakely PE, Jr. Fine-needle aspiration cytopathology in diagnosis and classification of malignant lymphoma: accurate and reliable? Diagn Cytopathol 2000;22:120–125.

Bone and Soft Tissue Geisenger KR, Abdul-Karim FW. Chapter 5: Fine needle aspiration of soft tissue tumors. In Enzinger and Weiss Soft Tissue Tumors, Weiss SW and Goldblum JR (5th ed.). Mosby: Elsevier, 2008

Galagan K, Blomberg D, Cornbleet P, and Glassy E (eds.) Color Atlas of Body Fluids. 1st ed. Northfield, IL: College of American Pathologists, 2006.

Kilpartrick SE, Bergman S, Pettenati MJ, Gulley ML. The usefulness of cytogenetic analysis in fine needle aspirates for the histologic subtyping of sarcomas. Mod Pathol 2006;19:815–819.

Ordonez Nelson G. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 2007;38:1–16.

Layfield JL. Cytologic diagnosis of osseous lesions: A review with emphasis on the diagnosis of primary neoplasms of bone. Diagn Cytopathol 2009;37:299–310.

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2 Immunohistochemical Diagnosis in Surgical Pathology Nancy Klipfel, md, Raul Simental-Pizarro, md, and Clive R. Taylor, md, phd

Contents

I. Introduction to Immunohistochemistry........................2-7 Principles.............................................................2-7 Methods...............................................................2-7 Applications........................................................2-9

II. Head and Neck..................................2-10 Upper Respiratory Tract.................................2-10 Infection...................................................2-10 Squamous Cell Carcinoma....................2-10 Small and Large Cell Neuroendocrine Carcinoma..........................................2-10 Mucosal Malignant Melanoma..............2-11 Rhabdomyosarcoma...............................2-11 Angiosarcoma.........................................2-11 Kaposi Sarcoma......................................2-12 Langerhans Cell Histiocytosis...............2-12 Lymphoma...............................................2-12 Nasopharynx.....................................................2-12 Nasopharyngeal Carcinoma..................2-12 Sinonasal Undifferentiated Carcinoma..........................................2-12 Sinonasal Adenocarcinoma, Intestinal Type...................................2-12 Olfactory Neuroblastoma (Esthesioneuroblastoma)...................2-13 Mesenchymal Chondrosarcoma............2-13 Other Mesenchymal Tumors.................2-13 Lymphoma...............................................2-13 Metastatic Disease..................................2-14 Oropharynx......................................................2-14 Granular Cell Tumor.............................2-14

Rhabdomyoma........................................2-14 Other Mesenchymal Tumors.................2-14 Lymphoma...............................................2-14 Metastatic Disease..................................2-14 Salivary Gland..................................................2-14 Adenoid Cystic Carcinoma....................2-14 Salivary Duct Carcinoma.......................2-14 Epithelial-Myoepithelial Carcinoma..........................................2-15 Myoepithelial Carcinoma.......................2-15 Mesenchymal Tumors............................2-15 Lymphoma...............................................2-15 Metastatic Disease..................................2-15 Thyroid Gland..................................................2-16 Papillary Thyroid Carcinoma...............2-16 Follicular Adenoma and Carcinoma.....2-16 Hürthle Cell Neoplasms.........................2-16 Medullary Thyroid Carcinoma.............2-16 Undifferentiated (Anaplastic) Thyroid Carcinoma...........................2-16 Poorly Differentiated Squamous Carcinoma..........................................2-17 Mesenchymal Tumors............................2-17 Lymphoma...............................................2-18 Metastatic Disease..................................2-18 Parathyroid Gland...........................................2-18 Eye and Ocular Adnexa...................................2-18 Malignant Melanoma.............................2-18 Retinoblastoma.......................................2-18 Mesenchymal Tumors............................2-18 Lymphoma...............................................2-18 Metastatic Disease..................................2-18

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_2, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Miscellaneous Tumors of the Head and Neck Region..........................................2-18 Pleomorphic and Spindle Cell Lipoma................................................2-18 Paraganglioma/Carotid Body Tumor..................................................2-18

III. Thorax................................................2-19 Lung...................................................................2-19 Squamous Cell Carcinoma....................2-19 Adenocarcinoma.....................................2-19 Pleomorphic, Spindle Cell, Giant Cell, and Sarcomatoid Carcinoma..........................................2-21 Carcinoid and Atypical Carcinoid Tumors..............................2-21 Small Cell and Large Cell Neuroendocrine Carcinoma..............2-22 Pulmonary Blastoma..............................2-22 Sclerosing Hemangioma.........................2-23 Clear Cell Tumor (Sugar Tumor).........2-23 Bronchial Salivary Gland Type Neoplasms...........................................2-23 Inflammatory Myofibroblastic Tumor..................................................2-23 Synovial Sarcoma...................................2-23 Other Mesenchymal Tumors.................2-23 Lymphoma...............................................2-23 Metastatic Disease..................................2-23 Pleura................................................................2-24 Mesothelioma..........................................2-24 Solitary Fibrous Tumor and Hemangiopericytoma........................2-25 Other Mesenchymal Tumors.................2-25 Metastatic Disease..................................2-25 Mediastinum.....................................................2-25 Thymoma.................................................2-25 Thymic Carcinoma.................................2-25 Thymic Carcinoid and Atypical Carcinoid Tumors..............................2-26 Thymic Small Cell Carcinoma..............2-26 Germ Cell Tumors..................................2-26 Ewing Sarcoma/Peripheral Neuroectodermal Tumor...................2-27 Other Mesenchymal Tumors.................2-27 Lymphoma...............................................2-27 Metastatic Disease..................................2-27 Heart..................................................................2-27 Myxoma...................................................2-27 Fibroma...................................................2-27 Rhabdomyoma, Rhabdomyosarcoma..........................2-27 Hemangioma, Epithelioid Hemangioendothelioma, and Angiosarcoma.............................2-27

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Mesothelioma..........................................2-27 Other Mesenchymal Tumors.................2-27 Lymphoma...............................................2-27 Metastatic Disease..................................2-27

IV. Digestive Tract...................................2-28 Esophagus.........................................................2-28 Infection...................................................2-28 Squamous Cell Carcinoma....................2-28 High Grade Dysplasia in Barrett Esophagus...........................................2-28 Adenocarcinoma.....................................2-28 Small Cell Carcinoma............................2-28 Malignant Melanoma.............................2-29 Leiomyoma/Leiomyosarcoma................2-29 Granular Cell Tumor.............................2-29 Other Mesenchymal Tumors.................2-29 Lymphoma...............................................2-29 Metastatic Disease..................................2-29 Stomach.............................................................2-30 Adenocarcinoma.....................................2-30 Hepatoid Adenocarcinoma....................2-30 Well Differentiated Endocrine Neoplasms...........................................2-30 Gastrointestinal Stromal Tumor (GIST).................................................2-30 Glomus Tumor........................................2-31 Other Mesenchymal Tumors.................2-31 Lymphoma...............................................2-31 Metastatic Disease..................................2-31 Small Intestine, Colon, and Rectum...............2-31 Infection...................................................2-31 Adenocarcinoma.....................................2-31 Well Differentiated Endocrine Neoplasms...........................................2-32 Small Cell Neuroendocrine Carcinoma..........................................2-32 Granular Cell Tumor.............................2-32 Gastrointestinal Stromal Tumor (GIST).................................................2-32 Fibromatosis............................................2-32 Inflammatory Myofibroblastic Tumor..................................................2-32 Other Mesenchymal Tumors.................2-32 Lymphoma...............................................2-33 Metastatic Disease..................................2-33 Anus...................................................................2-33 Infection...................................................2-33 High Grade Squamous Dysplasia/Carcinoma In Situ/Bowen Disease.......................2-33 Squamous Cell Carcinoma....................2-33 Paget Disease...........................................2-33 Anal Gland Adenocarcinoma................2-33 Malignant Melanoma.............................2-33

Immunohistochemical Diagnosis in Surgical Pathology

Leiomyoma/Leiomyosarcoma................2-33 Other Mesenchymal Tumors.................2-34 Lymphoma...............................................2-34 Metastatic Disease..................................2-34

V. Hepatobiliary.....................................2-34 Liver...................................................................2-34 Infection...................................................2-34 Hepatic Adenoma...................................2-34 Hepatocellular Carcinoma.....................2-34 Hepatoblastoma......................................2-36 Cholangiocarcinoma...............................2-36 Hemangioma, Infantile Hemangioendothelioma, Epithelioid Hemangioendothelioma, and Angiosarcoma.....................................2-36 Undifferentiated Sarcoma......................2-36 Embryonal Rhabdomyosarcoma...........2-36 Angiomyolipoma.....................................2-36 Other Mesenchymal Tumors.................2-36 Lymphoma...............................................2-36 Metastatic Disease..................................2-37 Pancreas............................................................2-37 Invasive Ductal Carcinoma....................2-37 Mucinous Cystic Neoplasms..................2-37 Intraductal Papillary Mucinous Neoplasms...........................................2-37 Serous Cystic Neoplasms.......................2-37 Acinar Cell Carcinoma..........................2-37 Neuroendocrine Neoplasms...................2-37 Solid Pseudopapillary Neoplasm...........2-38 Gallbladder and Extrahepatic Bile Ducts......2-39 Adenocarcinoma.....................................2-39

VI. Genitourinary System........................2-39 Kidney...............................................................2-39 Pediatric Tumors....................................2-39 Adult Epithelial Tumors........................2-40 Miscellaneous Tumors............................2-42 Leiomyoma/Leiomyosarcoma................2-43 Other Mesenchymal Tumors.................2-43 Lymphoma...............................................2-43 Adrenal Gland..................................................2-43 Cortical Adenoma and Carcinoma..........................................2-43 Pheochromocytoma................................2-44 Neuroblastoma........................................2-44 Metastatic Disease..................................2-44 Urinary Bladder...............................................2-44 Nephrogenic Adenoma...........................2-44 Endocervicosis and Endometriosis (Müllerianosis)...................................2-44 Urothelial Carcinoma.............................2-45 Adenocarcinoma of the Urinary Bladder.................................2-45

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Clear Cell Carcinoma (Urothelial Carcinoma, Clear Cell or Glycogen-rich Type).....................2-45 Clear Cell Adenocarcinoma...................2-45 Small Cell Carcinoma............................2-45 Sarcomatoid Carcinoma........................2-45 Postoperative Spindle Cell Nodule........2-45 Inflammatory Myofibroblastic Tumor..................................................2-46 Leiomyoma/Leiomyosarcoma................2-46 Rhabdomyosarcoma...............................2-46 Other Mesenchymal Tumors.................2-46 Lymphoma...............................................2-46 Metastatic Disease..................................2-46 Prostate Gland..................................................2-46 Benign Prostatic Hyperplasia................2-46 Basal Cell Hyperplasia...........................2-46 Sclerosing Adenosis................................2-46 Atypical Adenomatous Hyperplasia........................................2-47 Atypical Small Acinar Proliferation.....2-47 Androgen Deprivation and Radiation Therapy Changes.............2-47 Prostatic Adenocarcinoma.....................2-47 Adenoid Cystic/Basal Cell Carcinoma..........................................2-47 Urothelial Carcinoma.............................2-48 Mucinous (Urothelial Type) Adenocarcinoma Arising in the Prostate....................................2-48 Seminal Vesicle Adenocarcinoma..........2-48 Leiomyoma/Leiomyosarcoma................2-48 Phyllodes Tumor.....................................2-48 Other Mesenchymal Tumors.................2-48 Lymphoma...............................................2-48 Testis..................................................................2-48 Adenomatoid Tumor..............................2-48 Germ Cell Tumors..................................2-48 Sex Cord Stromal Tumors.....................2-51 Solitary Fibrous Tumor/ Hemangiopericytoma........................2-51 Other Mesenchymal Tumors.................2-51 Lymphoma...............................................2-51 Metastatic Disease..................................2-51

VII. Gynecological Tract...........................2-51 Vulva and Vagina..............................................2-51 Paget Disease of the Vulva.....................2-51 High Grade Squamous Dysplasia/ Carcinoma In Situ/Bowen Disease.................................................2-52 Squamous Cell Carcinoma....................2-52 Clear Cell Carcinoma of the Vagina.....2-52 Malignant Melanoma.............................2-52 Deep Aggressive Angiomyxoma............2-52

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Sarcoma Botryoides (Embryonal Rhabdomyosarcoma).........................2-52 Leiomyoma/Leiomyosarcoma................2-53 Postoperative Spindle Cell Nodule.........................................2-53 Other Mesenchymal Tumors.................2-53 Lymphoma...............................................2-53 Metastatic Disease..................................2-53 Cervix................................................................2-53 Mesonephric Remnants, Hyperplasia, and Carcinoma............2-53 High Grade Squamous Dysplasia/ Carcinoma In Situ..............................2-54 Squamous Cell Carcinoma....................2-54 Endocervical Adenocarcinoma (Nonintestinal Type)..........................2-54 Endocervical Intestinal-Type Adenocarcinoma................................2-55 Small Cell Carcinoma............................2-55 Mesenchymal Tumors............................2-56 Lymphoma...............................................2-56 Metastatic Disease..................................2-56 Uterus, Corpus..................................................2-56 Endometrial Intraepithelial Carcinoma..........................................2-56 Endometrioid Carcinoma......................2-56 Serous Carcinoma...................................2-56 Mucinous Carcinoma.............................2-56 Clear Cell Carcinoma.............................2-57 Small Cell Carcinoma............................2-57 Carcinosarcoma (Malignant Mixed Müllerian Tumor)..............................2-57 Placental Site Nodule and Placental Site Trophoblastic Tumor..................2-57 Choriocarcinoma....................................2-57 Adenomatoid Tumor..............................2-58 Leiomyoma/Leiomyosarcoma................2-58 Endometrial Stromal Nodule and Sarcoma.......................................2-58 Sex Cord Elements within an Endometrial Stromal Tumor..................................................2-59 Undifferentiated Endometrial Sarcoma..............................................2-60 Other Mesenchymal Tumors................................................2-60 Lymphoma...............................................2-60 Metastatic Disease..................................2-60 Ovary.................................................................2-60 Endometriosis.........................................2-60 Endometrioid Carcinoma......................2-60 Serous Carcinoma...................................2-61 Mucinous Carcinoma.............................2-61 Clear Cell Carcinoma.............................2-61 Carcinoid Tumor....................................2-63

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Small Cell Carcinoma (Pulmonary Type)..............................2-63 Small Cell Carcinoma, Hypercalcemic Type.....................................................2-63 Transitional Cell Carcinoma.................2-64 Carcinosarcoma (Malignant Mixed Müllerian Tumor)..............................2-64 Germ Cell Tumors..................................2-64 Struma Ovarii.........................................2-65 Sex Cord Stromal Tumors.....................2-65 Other Mesenchymal Tumors.................2-66 Lymphoma...............................................2-66 Metastatic Disease..................................2-66 Peritoneum........................................................2-66 Adenomatoid Tumor..............................2-66 Primary Serous Carcinoma of Peritoneum.........................................2-66 Mesothelioma..........................................2-66 Desmoplastic Small Round Cell Tumor..................................................2-67 Solitary Fibrous Tumor/ Hemangiopericytoma........................2-67 Fibromatosis............................................2-67 Inflammatory Myofibroblastic Tumor..................................................2-67

VIII. Breast.................................................2-67 Sclerosing Adenosis, Tubular Adenoma/ Adenosis Tumor, Nipple Duct Adenoma, Complex Sclerosing Lesion/Radial Scar......................................2-67 Adenomyoepithelioma.....................................2-68 Microglandular Adenosis................................2-68 Intraductal Papillary Tumors.........................2-68 Lobular In Situ Carcinoma.............................2-69 Infiltrating Lobular Carcinoma......................2-70 Infiltrating Ductal Carcinoma.........................2-70 Breast Carcinoma Micrometastasis in Sentinel Lymph Nodes............................2-70 Metaplastic Carcinoma....................................2-70 Adenoid Cystic Carcinoma..............................2-71 Paget Disease of the Nipple..............................2-71 Biphasic Tumors: Fibroadenoma, Phyllodes Tumors........................................2-71 Granular Cell Tumor.......................................2-71 Malignant Myoepithelioma (Myoepithelial Carcinoma)..................................................2-71 Fibromatosis.....................................................2-71 Myofibroblastoma............................................2-72 Pseudoangiomatous Stromal Hyperplasia..................................................2-72 Angiosarcoma...................................................2-72 Other Mesenchymal Tumors...........................2-72 Lymphoma........................................................2-72 Metastases.........................................................2-72

Immunohistochemical Diagnosis in Surgical Pathology

IX. Mesenchymal Tissue...........................2-72 Fibrous and Fibrohistiocytic Tissue...............2-72 Nodular, Proliferative, and Ischemic Fasciitis...............................2-72 Benign Fibrous Histiocytoma................2-73 Juvenile Xanthogranuloma....................2-73 Solitary Fibrous Tumor and Hemangiopericytoma........................2-73 Myofibromatosis/Myofibroma...............2-74 Inflammatory Myofibroblastic Tumor..................................................2-74 Atypical Fibroxanthoma........................2-74 Dermatofibrosarcoma Protuberans........................................2-74 Desmoplastic Small Round Cell Tumor..................................................2-74 Deep (Desmoid) Fibromatosis...............2-75 Fibrosarcoma..........................................2-75 Smooth Muscle.................................................2-75 Leiomyoma/Leiomyosarcoma................2-75 Skeletal Muscle.................................................2-75 Rhabdomyoma........................................2-75 Rhabdomyosarcoma...............................2-75 Vessels................................................................2-76 Angiosarcoma, Epithelioid Hemangioendothelioma, and Hemangioma...............................2-76 Kaposi Sarcoma......................................2-76 Glomus Tumor........................................2-76 Neural Tissue....................................................2-77 Schwannoma...........................................2-77 Neurofibroma..........................................2-77 Granular Cell Tumor.............................2-77 Malignant Peripheral Nerve Sheath Tumor.....................................2-77 Cartilage............................................................2-77 Mesenchymal Chondrosarcoma............2-77 Bone...................................................................2-78 Chordoma................................................2-78 Small Cell Osteosarcoma.......................2-78 Ewing Sarcoma/Peripheral Neuroectodermal Tumor...................2-79 Langerhans Cell Histiocytosis...............2-79 Plasma Cell Dyscrasia, Plasmacytoma, and Multiple Myeloma.............................................2-79 Metastatic Disease..................................2-80 Miscellaneous....................................................2-80 Pleomorphic and Spindle Cell Lipoma................................................2-80 Angiomyolipoma.....................................2-80 Gastrointestinal Stromal Tumor (GIST).................................................2-80 Synovial Sarcoma...................................2-80 Clear Cell Sarcoma of Soft Tissue.........2-80

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Alveolar Soft Part Sarcoma...................2-80 Epithelioid Sarcoma...............................2-80 Undifferentiated High Grade Pleomorphic Sarcoma (Malignant Fibrous Histiocytoma).......................2-81

X. Skin....................................................2-82 Squamous Cell Carcinoma..............................2-82 Basal Cell Carcinoma.......................................2-82 Merkel Cell Carcinoma...................................2-83 Melanoma..........................................................2-84 Melanoma Micrometastasis in Sentinel Lymph Nodes...............................................2-84 Granular Cell Tumor.......................................2-84 Glomus Tumor..................................................2-85 Angiosarcoma, Epithelioid Hemangioendothelioma, and Hemangioma........................................2-85 Kaposi Sarcoma................................................2-85 Other Mesenchymal Tumors...........................2-85 Lymphoma........................................................2-85 Metastatic Disease............................................2-85

XI. Central Nervous System.....................2-86 Glial Tissue.......................................................2-86 Astrocytoma, Anaplastic Astrocytoma, and Glioblastoma Multiforme..........................................2-86 Oligodendroglioma.................................2-86 Ependymoma..........................................2-86 Subependymoma.....................................2-87 Gliosarcoma............................................2-87 Choroid Plexus Tumors...................................2-87 Dura...................................................................2-87 Meningioma, Atypical Meningioma, Malignant Meningioma.....................2-87 Hemangiopericytoma.............................2-88 Neural Tissue....................................................2-88 Ganglioglioma and Gangliocytoma.......2-88 Central Neurocytoma.............................2-88 Pineocytoma............................................2-88 Pineoblastoma, Medulloblastoma, Retinoblastoma, and Supratentorial (Central) Primitive Neuroectodermal Tumor..................................................2-89 Dysembryoplastic Neuroepithelial Tumor..................................................2-89 Sella....................................................................2-90 Pituitary Adenoma.................................2-90 Craniophayngioma.................................2-90 Miscellaneous....................................................2-90 Atypical Teratoid/Rhabdoid Tumor..................................................2-90 Hemangioblastoma.................................2-90 Germ Cell Tumors..................................2-91

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Lymphoma...............................................2-91 Metastatic Disease..................................2-91 Infections.................................................2-91

XII. Hematolymphoid Neoplasms.............2-92 Precursor Lymphoid Neoplasms.....................2-92 B Lymphoblastic Leukemia/ Lymphoma..........................................2-92 T Lymphoblastic Leukemia/ Lymphoma..........................................2-92 Mature B-Cell Neoplasms................................2-92 Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma........2-92 B-Cell Prolymphocytic Leukemia.........2-92 Splenic Marginal Zone Lymphoma......2-92 Hairy Cell Leukemia..............................2-92 Lymphoplasmacytic Lymphoma...........2-93 Plasma Cell Neoplasms..........................2-93 Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)........................................2-93 Nodal Marginal Zone Lymphoma.........2-93 Follicular Lymphoma, Nodal.................2-93 Primary Cutaneous Follicle Center Lymphoma.............................2-93 Mantle Cell Lymphoma.........................2-93 Diffuse Large B-Cell Lymphoma, NOS.....................................................2-93 Primary Mediastinal (Thymic) Large B-Cell Lymphoma...................2-93 Plasmablastic Lymphoma......................2-93 Primary Effusion Lymphoma................2-94 Burkitt Lymphoma.................................2-94 Lymphomatoid Granulomatosis............2-94 Mature T- and NK-Cell Neoplasms................2-94 T-Cell Prolymphocytic Leukemia.........2-94 T-Cell Large Granular Lymphocytic Leukemia.....................2-94

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Aggressive NK-Cell Leukemia..............2-94 Adult T-Cell Leukemia/Lymphoma......2-94 Extranodal NK/T-Cell Lymphoma, Nasal Type..........................................2-94 Enteropathy-Associated T-Cell Lymphoma..........................................2-94 Hepatosplenic T-Cell Lymphoma..........2-94 Subcutaneous Panniculitis-Like T-Cell Lymphoma..............................2-95 Mycosis Fungoides/Sézary Syndrome............................................2-95 Angioimmunoblastic T-Cell Lymphoma..........................................2-95 Peripheral T-Cell Lymphoma, NOS......2-96 Anaplastic Large Cell Lymphoma, ALK Positive......................................2-96 Primary Cutaneous Anaplastic Large Cell Lymphoma.......................2-96 Hodgkin Lymphoma........................................2-96 Nodular Lymphocyte Predominant Hodgkin Lymphoma..........................2-96 Classic Hodgkin Lymphoma..................2-97 Histiocytic and Dendritic Cell Neoplasms............................................2-97 Histiocytic Sarcoma................................2-97 Langerhans Cell Histiocytosis and Sarcoma.......................................2-97 Interdigitating Dendritic Cell Sarcoma..............................................2-98 Follicular Dendritic Cell Sarcoma........2-98 Disseminated Juvenile Xanthogranuloma..............................2-98 Myeloid Tumors................................................2-98 Myeloid Sarcoma....................................2-98 Blastic Plasmacytoid Dendritic Cell Neoplasm (Formerly Blastic NK-Cell Lymphoma).........................2-98

XIII. Suggested Reading.............................2-98

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INTRODUCTION TO IMMUNOHISTOCHEMISTRY Principles Histochemistry ♦♦ Beginning more than 100 years ago special stains were developed to facilitate cell recognition ♦♦ Early special stains were based upon chemical reactions of cell and tissue components (histochemistry) ♦♦ The use is limited in fixed tissues due to inactivation of native enzymatic activity by fixation or storage

Immunohistochemistry ♦♦ Immunohistochemistry (IHC) technique exploits the specific binding between antibody and antigen (Fig. 2.1) ♦♦ The “primary” antibody binds to the test antigen in the tissue section; the “secondary” or labeling antibody binds to the site of localization of the primary antibody ♦♦ Antibody is labeled, directly or indirectly, with a visible marker, usually an enzyme that acts upon a chromogen or substrate to give a colored product at the site of localization ♦♦ Several enzymes are employed, most often peroxidase or alkaline phosphatase ♦♦ Common chromogens are diaminobenzidine (DAB) and hydrogen peroxide for peroxidase and fast red for alkaline phosphatase; other commercial products available are brown, red, blue, black, and green ♦♦ IHC techniques have one principal aim in common – to attach the maximum amount of label at the site of localization of the antigen within the tissue with a minimum degree of nonspecific (background) binding ♦♦ Amplification methods have been developed to increase the amount of label deposited, increasing the sensitivity of detection of antigen, and/or allowing use of antibody at higher dilutions ♦♦ The ABC (Avidin–Biotin Conjugate) method was one of the early amplification methods, now largely replaced by polymer-linked antibodies that carry numerous enzymatically active sites; these reagents are widely available commercially and are generally of high quality, giving good results when properly used

Fig. 2.1. Polymer-based detection system, providing amplification of the signal, with low background and excellent reproducibility. From Taylor CR, Cote RJ. Immunomicroscopy: A Diagnostic Tool for the Surgical Pathologist. Saunders, Elsevier, 2005.

♦♦ More than 30 years ago it was shown that IHC methods are able to “stain” many antigens in routinely processed formalin fixed paraffin embedded (FFPE) tissues ♦♦ Subsequently, the range of “stains” that could be performed has increased enormously, as a result of two major factors: (1) The availability of literally thousands of monoclonal antibodies; (2) The advent of the antigen aetrieval (AR) method [sometimes known as heat-induced epitope retrieval (HIER)] that to a large extent restores the antigenicity of many molecules after FFPE, permitting staining by IHC

Methods General ♦♦ Immunohistochemical and in situ hybridization (ISH) methods, which are similar in practical application, have added a new dimension to the practice of histopathology, facilitating the specific demonstration of tissue, cell, and molecular components while conserving the ability to assess traditional morphologic criteria ♦♦ IHC usually is applied to an FFPE section as an aid to cell type recognition and diagnosis by the surgical pathologist ♦♦ There is growing recognition that results of IHC stains may be inconsistent between laboratories, and even from day to day within a laboratory. The use of appropriate controls is therefore vital ♦♦ The recent extended use of IHC methods to detect prognostic and predictive markers has increased demands for standardization and for improved control systems

Staining Protocol ♦♦ In order to achieve optimal, reproducible results it is ­necessary to monitor closely and control every step of the protocol, from tissue collection to interpretation of the final stained slide ♦♦ This is termed the “Total Test Approach” (Table 2.1)

Indications for IHC ♦♦ Indications should be part of the practice of the institution and should be appropriately documented in the Laboratory Manual ♦♦ There are two broad approaches to selection of the stain(s), and neither one is exclusive of the other −− Where the differential is very broad, as with a “tumor of unknown origin”, the decision may be to follow an algorithm −− Or the surgical pathologist may formulate a “working” diagnosis, and then select a small number of stains from the “test menu” in an attempt to confirm one option or exclude another ♦♦ Issues to consider include the number of stains that will be performed in total, the cost of such stains, reimbursement limits, and turnaround time (which impacts total hospital costs)

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Table 2.1. Immunohistochemistry Total Test Approach Elements of testing process

Primary quality assurance issues

Indications for IHC

Selection of appropriate stain(s)

Specimen acquisition/ preparation

Control of fixation time; antigen retrieval

Staining protocol

Reagents: labeling method

Analytic issues

Automation; qualifications of staff; proficiency testing of methods

Results: validation, reporting

Controls; criteria for interpretation

Interpretation; significance; reporting

Experience of pathologist; proficiency testing of reported results

Modified from Taylor CR, Cote RJ. Immunomicroscopy: A Diagnostic Tool for the Surgical Pathologist. Saunders, Elsevier, 2005

Specimen Acquisition/Preparation ♦♦ The fixative employed is critical; usually it is formalin ♦♦ Ideally tissue should be placed in the fixative immediately upon removal; this is considered more important for RNA preservation than for proteins (IHC) ♦♦ The total time in the fixative including transport, wait time in pathology, and time of the “processor” should be considered ♦♦ Total fixation should not be less than 8  h, and ideally not more than 24 h (though longer periods may suffice with the use of antigen retrieval) ♦♦ Guidelines have been published that cover fixation/processing protocols ♦♦ The above applies to FFPE tissues; IHC generally is also effective on frozen tissue or cytopathology preparations with alcohol fixation, although diffusion or loss of some antigens can occur ♦♦ Antigen retrieval (AR–HIER) −− Has greatly broadened the utility of IHC on FFPE tissues −− Used routinely on all FFPE tissues in many labs −− Involves heating deparaffinized sections in buffer (usually citrate Ph6), usually for 20  min, usually in a microwave −− Other buffers, times, and heating methods may be used for a minority of antibody/antigen stains where the standard method is not satisfactory −− AR should be optimized and standardized “in house” for each antibody/antigen stain −− For further details, consult comprehensive IHC texts or the AR literature

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Staining Protocol ♦♦ Reagents −− There are many commercial sources for both primary antibodies and labeling reagents −− Basic rule for pathologists and technologists alike: “READ THE PACKAGE INSERT” −− Most primary antibodies are “monoclonal,” having certain advantages of specificity, but attention should be paid to clone designation (number) as well as to listed specificity (e.g., several antibody clones exist to ER, with very different performance characteristics) −− Polyclonal antibodies in some instances give better staining on FFPE, but require careful specificity control (they, in fact, contain many different antibodies) −− Two broad options (a) “Home brew” – to purchase separately the primary and secondary (labeled) antibodies and conduct ­optimal titration/incubation time studies “in house” to establish the protocol (b) “RTU” – to purchase kits containing ready-to-use reagents (RTU) optimized by the manufacturer for both primary antibody and labeling system (c) Option B is technically simpler, but still must be validated for performance with tissues fixed and ­processed “in house” −− All reagents should be validated “in house” vs. known positive and negative controls ♦♦ Protocols −− The labeling method should be selected and validated with each of the primary antibodies −− With kits, the labeling method is preselected but validation still is necessary −− Labeling methods vary in ability for amplification, reproducibility, and ease of use −− Currently, polymer-based reagents offer the best combination of ease of use, reliability, and cost −− In general, results will be more consistent when a lab evaluates, selects, and uses the minimum number of different labeling systems that is required for the primary antibody menu; mouse monoclonal; rabbit monoclonal; polyclonal. The more different the protocols, the less consistency −− Double stain techniques employing two (or more) different primary antibodies are growing in popularity for improved assessment of complex staining patterns (e.g., CD20+CD3, B- vs. T-cell)

Analytical Issues ♦♦ Automations −− There is a basic choice between manual protocols and automation −− Choice is based upon volume of IHC work and expertise of technologists −− In general, automated methods offer better consistency and control

Immunohistochemical Diagnosis in Surgical Pathology

−− Automated systems may be “closed” – that is the labeling system employed is defined by the instrument, or “open,” where the user has the option of selecting and optimizing the whole protocol. The latter approach requires considerable “in house” technical experience ♦♦ Sensitivity and specificity −− Sensitivity in IHC is applied as a descriptor of the extent to which the primary antibody can be diluted and still achieve target recognition −− This usage differs from that in Clinical Pathology where sensitivity describes the ability of a test to detect positive cases of a disease within a population having the disease −− Specificity is used to describe the extent to which an antibody binds only its intended target (monoclonal antibodies have good specificity; polyclonal antibodies less) −− Sensitivity and specificity are, however, sometimes used loosely to describe the extent to which an IHC stain identifies a particular cell/tumor type (e.g., an S-100 stain has a high specificity for melanoma, but low specificity; the S-100 antibody itself may be both sensitive and specific for S-100 protein; it is the distribution of the antigen that is addressed in this usage) ♦♦ Qualifications of staff −− This critically affects the ability to perform good IHC staining −− There is no substitute for relevant and proper experience −− In addition to the Histotechnology Certification process, the ASCP (American Society of Clinical Pathology, Chicago, IL, USA) operates an Immunohistochemistry Qualification Program −− Comparable qualification and training exists in the European Union and elsewhere, but presently there is no international reciprocity ♦♦ Intra- and interlaboratory proficiency testing of procedures −− Participation in an external proficiency program is highly recommended −− The CAP (College of American Pathologists) provides such a program in the USA, by subscription −− UK-NEQAS-ICC (http://www.ukneqas.org.uk, United Kingdom, National External Quality Assessment Scheme for IHC) offers a more extensive program in Europe and elsewhere that also evaluates interpretation by the pathologist −− Guidelines for running an IHC lab are provided by the CAP accreditation program and CLSI (http://www.clsi. org)

Results: Validation/Reporting ♦♦ Controls/criteria for interpretation −− For a comprehensive review of controls, consult a specialist IHC text or the bibliography −− As a minimum, each batch run for a particular stain should include an “in house” positive control and a negative control (if a panel is run, then with experience, different stains in the panel may serve as negative controls for other panel members stained by the same protocol)

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−− The control section should have been fixed and processed in a manner identical to the test section −− Tissue microarrays (or sausage blocks) are useful when a new antibody is being validated (allows rapid and identical testing of multiple cases), but are not necessary and are even wasteful of tissues, for batch controls −− The results in the control section provide the basis for interpreting the staining pattern observed in the test section −− Note that for many stains, internal controls exist within the tissue; for example, residual normal plasma cells serve as controls for Ig staining of lymphomas −− It has been proposed that such internal controls, when quantified, may provide the basis for quantitative IHC (Quantifiable Internal Reference Standards), analogous to the ELISA method, used to measure proteins in the clinical laboratory −− Turnaround time (TAT): overnight incubations may fit well into the usual workload patterns of histology labs. If needed, IHC staining protocols may be designed to be completed in 90 min or less with the availability of the cut FFPE section −− In search of short TAT for the total test, fixation should not be reduced below 8 h

Interpretation, Significance, and Reporting ♦♦ As with surgical pathology in general, the reliability of the IHC interpretation increases with the experience of the pathologist ♦♦ Image analysis techniques are increasingly employed to assist the pathologist in interpretation, especially in rare event detection (micrometastases) and in semi quantitative analysis of ER and PR scores or proliferation rates ♦♦ The report should include as a minimum the usual patient demographics, the type of specimen tested (e.g., frozen, FFPE), antibodies employed (with clone designations as appropriate), results for all of the antibodies used (both positive and negative), and significance of the findings ♦♦ Reagent sources, exact protocols, and AR methods need not be part of the report but should be recorded in the laboratory log, for reference if needed

Applications Tumor Diagnosis and Classification ♦♦ Historically IHC has usually been employed for cell type and tumor identification ♦♦ These remain the most common uses today, with several hundred antibodies in routine use ♦♦ In this context, antibodies are chosen that recognize structural proteins or cell products that have a distribution restricted to a particular cell (tumor) lineage ♦♦ All surgical pathology books today include discussion of IHC markers along with histopathology; this also is true of the present text where IHC features are briefly described for each tumor type ♦♦ In addition, the remainder of this chapter presents a concise review of the major diagnostic applications of IHC, with an emphasis on tumor diagnosis and classification

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Tumor of Unknown Origin: Anaplastic Malignancies ♦♦ A separate chapter is devoted to the use of IHC in unknown or anaplastic tumors ♦♦ The use of a “decision tree” approach is discussed, together with other aspects of the rationale for antibody selection ♦♦ The anticipated findings with commonly used panels are described

Prognostic and Predictive Markers ♦♦ More recently IHC methods also have been adapted for identification of the degree of expression by tumors of certain molecules of known prognostic significance (e.g., ER and PR in breast cancer; Ki-67 or MIB-1 as a marker of proliferation) ♦♦ The demonstration of HER2 expression in breast cancer is an example of a predictive marker, of value in selecting patients likely to respond to Herceptin therapy ♦♦ Interpretation of these markers requires rigorous adherence to test protocols (for reproducibility) and some form of quantitative assessment by reference to standard controls ♦♦ With other prognostic and predictive markers currently in development, accurate quantitative IHC methods are being explored using Quantifiable Reference Standards and image analysis

Identification of Focal Invasion ♦♦ IHC staining for intact layers of basal type cells, in breast and prostate, is of value in distinguishing in situ carcinoma or intraepithelial neoplasia from early and focal invasion

♦♦ Loss or disruption of the basal layer may be demonstrated with different antibodies, including high molecular weight keratins, smooth muscle myosin, or p63 nuclear staining ♦♦ This is an area where double or triple stains are especially useful for interpretation

Identification of Micrometastases ♦♦ Although still under study, many investigators feel that the identification of micrometastases (small numbers of cancer cells) in sentinel or draining lymph nodes has value for prognosis and therapeutic decisions ♦♦ It has clearly been shown that IHC allows recognition of tumor micrometastases that are not identified on H&E ♦♦ Automated image analysis systems are especially suited to this purpose (rare event detection) ♦♦ Keratin cocktails are used for detection of carcinoma cells, and cocktails of S-100 with HMB 45 or Melan-A for melanoma cells ♦♦ Similar methods also are applied to bone marrow and peripheral blood detection, where the data are less clear

Identification of Infectious Agents ♦♦ There is an extensive literature on detection of bacteria and viruses by IHC ♦♦ Current applications include HPV subtypes in dysplasia of the cervix and H. pylori in gastric biopsies

NOTE: Antibodies in italics are the most useful for differential diagnosis.

HEAD AND NECK Upper Respiratory Tract Infection ♦♦ IHC antibodies to Herpes simplex virus (HSV1 and HSV2) show nuclear and cytoplasmic staining of infected squamous cells

Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous carcinoma except when diffusely poorly differentiated

Verification Panel (Table 2.2) ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ Lymphoepithelial carcinoma shows scattered single cells or nests of HMWK positive cells admixed with CD45 positive tumor-associated lymphoid cells

Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma is positive for pankeratin and CEA and negative for HMWK and p63 (nuclear)

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♦♦ Pseudoepitheliomatous hyperplasia is a malignant-appearing reactive change overlying another lesion (including granular cell tumor and lymphoma). IHC is not helpful to differentiate reactive vs. neoplastic squamous cells, but it can identify the underlying lesion; granular cell tumor is positive for S-100 and lymphoma for CD45

Small and Large Cell Neuroendocrine Carcinoma Verification Panel (Table 2.2) ♦♦ Pankeratin shows dot-like or diffuse cytoplasmic staining ♦♦ Chromogranin, synaptophysin, and NSE show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining ♦♦ S-100 can be focally positive in the tumor cell nuclei and cytoplasm (19%)

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Table 2.2. Head and Neck Small Round Blue Cell Tumor Differential Diagnosis

Poorly differentiated squamous cell carcinoma

Synaptophysin

S-100

Pankeratin

Muscle Markers a

CD45

−

−

+

–

−b

Sinonasal undifferentiated carcinoma

−

−

+

−

−

Neuroendocrine carcinoma

+

−

+

−

−

Rhabdomyosarcoma

−

−

−

+

−

Lymphoma

−

−

−

−

+

Olfactory neuroblastoma

+

−

−

−

−

Melanoma

−

+

−

−

−

a

Muscle markers include desmin, myogenin (nuclear), and Myo-D1 (nuclear) Lymphoepithelial type contains CD45 tumor-associated lymphoid cells

b

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin, synaptophysin, and chromogranin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, synaptophysin, chromogranin, and CD56 ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear) and Myo-D1 (nuclear) and negative for keratin, synaptophysin, and chromogranin ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous); some cases are focally positive for pankeratin (9%) and CD56 (9%); and negative for synaptophysin and chromogranin ♦♦ Olfactory neuroblastoma is positive for CD56, chromogranin, synaptophysin and vimentin and negative for pankeratin

Mucosal Malignant Melanoma Verification Panel (Table 2.2) ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Melanocytic markers (HMB 45, Melan-A) stain the tumor cell cytoplasm ♦♦ Rare cases show focal pankeratin positive cytoplasm (3%)

Differential Diagnosis ♦♦ Carcinoma is diffusely positive for pankeratin; some cases are focally positive for S-100 (19%); and negative for HMB 45 and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, CD56, and S-100 (19%); and negative for HMB 45 and Melan-A ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear), focally positive for S-100 and negative for HMB 45 and Melan-A

Rhabdomyosarcoma Verification Panel (Table 2.2) ♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei ♦♦ S-100 can be focally positive in the tumor cell nuclei and cytoplasm (12%)

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous) and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Mucosal malignant melanoma is positive for S-100, HMB 45, and Melan-A and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Neuroblastoma and retinoblastoma are positive for CD56, chromogranin, and synaptophysin and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Undifferentiated carcinoma is positive for pankeratin and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Angiosarcoma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Pankeratin can be focally positive in the tumor cell cytoplasm (17%)

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Differential Diagnosis ♦♦ Poorly differentiated carcinoma is diffusely positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear). The acantholytic variant of squamous cell carcinoma is morphologically similar to angiosarcoma but will not contain blood within the tumor-lined spaces ♦♦ Fibrosarcoma is positive for vimentin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear)

Kaposi Sarcoma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 and HHV8 stain the tumor cell nuclei. Benign endothelial cells are also positive for Fli-1

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear) ♦♦ Angiosarcoma and lobular capillary hemangioma (pyogenic granuloma) are positive for CD31, CD34, Factor VIII, Fli-1 (nuclear) and negative for HHV8 (nuclear) ♦♦ Fibrosarcoma is negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear)

Langerhans Cell Histiocytosis Verification Panel ♦♦ CD1a and CD68 stain the tumor cell membranes and cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis ♦♦ Histiocytic reaction is positive for S-100 and CD68 and negative for CD1a ♦♦ Hodgkin lymphoma is positive for LeuM1 and CD30 and negative for CD1a

Lymphoma (Table 2.2) ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most are B-cells with CD20 membranous staining. Refer to the section and chapter on lymph node for further discussion

Nasopharynx ♦♦ Salivary gland and brain tumors (e.g., meningioma and pituitary adenoma) can involve the nasopharynx; see the appropriate sections for further discussion

Nasopharyngeal Carcinoma ♦♦ Differentiated and undifferentiated types are based on morphology ♦♦ IHC is unnecessary for the diagnosis of squamous carcinoma except when diffusely poorly differentiated

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm

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♦♦ p63 stains the tumor cell nuclei ♦♦ EBV LMP1 stains the membrane/cytoplasm, and EBV EBER (in situ hybridization) stains the nuclei in scattered tumor cells, more commonly in the undifferentiated tumors ♦♦ The undifferentiated lymphoepithelial type shows scattered single or nests of HMWK positive cells admixed with CD45 positive tumor-associated lymphoid cells

Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma is positive for CEA and negative for HMWK and p63 (nuclear) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin

Sinonasal Undifferentiated Carcinoma Verification Panel (Table 2.2) ♦♦ Pankeratin and CK7 stain the tumor cell cytoplasm ♦♦ NSE, synaptophysin, chromogranin, and S-100 show variable cytoplasmic staining

Differential Diagnosis ♦♦ Undifferentiated nasopharyngeal carcinoma is positive for HMWK, EBV EBER, EBV LMP1, and p63 (nuclear) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin ♦♦ Neuroendocrine carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for pankeratin ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous) and some cases are focally positive for pankeratin (30%) ♦♦ Olfactory neuroblastoma is positive for CD56, chromogranin, synaptophysin, and vimentin and negative for pankeratin

Sinonasal Adenocarcinoma, Intestinal Type Verification Panel ♦♦ CK7 (60%), CK20, villin, and CEA stain the tumor cell cytoplasm ♦♦ CDX2 stains the tumor cell nuclei

Differential Diagnosis ♦♦ Sinonasal adenocarcinoma, nonintestinal type, is positive for CK7 and negative for CK20, villin, and CDX2 (nuclear) ♦♦ Adenoid cystic carcinoma contains myoepithelial cells that are positive for calponin, SMA, and p63 (nuclear) ♦♦ Metastatic colon carcinoma is positive for CK20, CEA, and CDX2 (nuclear) and negative for CK7

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Olfactory Neuroblastoma (Esthesioneuroblastoma) Verification Panel (Table 2.2) ♦♦ Synaptophysin, chromogranin, NSE, and vimentin stain the tumor cell cytoplasm ♦♦ CD56 stains the tumor cell membranes and cytoplasm ♦♦ S-100 stains the cytoplasm and nuclei of the spindled sustentacular cells surrounding the tumor cells in the nested or paraganglioma variant ♦♦ Pankeratin can be focally positive (35%) ♦♦ EMA is negative

Differential Diagnosis ♦♦ Neuroendocrine carcinoma is positive for chromogranin, synaptophysin, CD56, EMA, and pankeratin and negative for vimentin ♦♦ Mucosal malignant melanoma is positive for S-100, HMB 45, Melan-A, and vimentin and negative for chromogranin and synaptophysin ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), Myo-D1 (nuclear), and vimentin and negative for synaptophysin and chromogranin ♦♦ Lymphoma is positive for CD45, vimentin, and CD3 or CD20 and negative for synaptophysin and chromogranin ♦♦ Sinonasal undifferentiated carcinoma is positive for pankeratin and negative for vimentin ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear), CD99 (membranous), and vimentin; some cases are focally positive for keratin and synaptophysin; and negative for chromogranin

Mesenchymal Chondrosarcoma Verification Panel (Fig. 2.2)

Fig. 2.2. (A, B) CD99 stains the membranes (specific finding) and cytoplasm (nonspecific) of a mesenchymal chondrosarcoma.

♦♦ CD99 stains the tumor cell membranes (specific) and cytoplasm (nonspecific) ♦♦ Desmin, CD56, CD57, and NSE show variable cytoplasmic staining ♦♦ S-100 stains the cytoplasm and nuclei of the cartilaginous component ♦♦ Keratins and EMA are negative

♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous) ♦♦ Synovial sarcoma is positive for pankeratin, EMA, CD99 (membranous), and S-100

Differential Diagnosis ♦♦ Neuroendocrine carcinoma is positive for chromogranin, synaptophysin, EMA, CD56 and pankeratin and negative for CD99 (membranous) ♦♦ Mucosal malignant melanoma is positive for S-100, HMB 45, and Melan-A and negative for CD99 (membranous) ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for CD99 (membranous) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for desmin. Some types are positive for CD56, CD57, or CD99 (membranous) ♦♦ Sinonasal undifferentiated carcinoma is positive for pankeratin and negative for vimentin and CD99 (membranous)

Other Mesenchymal Tumors ♦♦ Other nasopharyngeal mesenchymal tumors include nasal angiofibroma, solitary fibrous tumor/hemangiopericytoma, fibromatosis, osteosarcoma, chondrosarcoma, Ewing sarcoma, malignant peripheral nerve sheath tumor, fibrosarcoma, and Kaposi sarcoma. Spindle cell carcinoma and melanoma must be considered in the differential diagnosis. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common Western primary types are CD20 positive diffuse large B-cell, follicular cell, and extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma. NK/T-cell lymphoma is positive for CD2, CD56, and CD3e (cytoplasmic) and is the

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most common nasal lymphoma in China. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the nasopharynx are kidney, lung, breast, thyroid, and prostate. Refer to Chapter 3 for further discussion

Oropharynx ♦♦ The diagnosis of the numerous oral jaw tumors is based on morphology. These include odontogenic, mesenchymal, and salivary gland neoplasms

Granular Cell Tumor ♦♦ This tumor can provoke a marked pseudoepitheliomatous hyperplasia that simulates invasive squamous cell carcinoma. The granular cell tumor cells must be identified around and below the reactive squamous nests

Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ CD68 and inhibin stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Carcinoma is positive for pankeratin; some cases are positive for S-100 (19%); and negative for inhibin ♦♦ Histiocytic inflammation is positive for S-100 and CD68 and negative for inhibin ♦♦ Paraganglioma is positive for chromogranin and synaptophysin and negative for CD68 and inhibin. S-100 stains the spindled sustentacular cells surrounding the tumor cell nests

Rhabdomyoma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

MSA and desmin stain the tumor cell cytoplasm Myogenin and Myo-D1 stain the tumor cell nuclei S-100 focally stains the tumor cell nuclei and cytoplasm Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Granular cell tumor is diffusely positive for S-100 and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Paraganglioma is positive for chromogranin and synaptophysin and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear). S-100 stains the spindled sustentacular cells surrounding the tumor cell nests ♦♦ Histiocytic reaction is positive for S-100 and CD68 and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Carcinoma is positive for pankeratin and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear)

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Other Mesenchymal Tumors ♦♦ Other laryngeal mesenchymal tumors include osteosarcoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, Ewing sarcoma, and chondrosarcoma. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion. Spindle cell carcinoma and melanoma must be considered in the differential diagnosis

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common Western primaries are CD20 positive ­diffuse large B-cell, follicular cell, Burkitt lymphoma and extranodal marginal-zone B-cell lymphoma of mucosaassociated lymphoid tissue (MALT) lymphomas. NK/T-cell lymphoma occurs rarely in the oropharynx and is positive for CD2, CD56, and CD3e (cytoplasmic). Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the oropharynx are breast, lung, prostate, and kidney. Refer to Chapter 3 for further discussion

Salivary Gland ♦♦ IHC is usually unnecessary for the diagnosis of salivary gland tumors

Adenoid Cystic Carcinoma Verification Panel ♦♦ CEA, EMA and keratin stain the cytoplasm of the ductal component ♦♦ SMA, SMMHC, calponin, and keratin stain the cytoplasm of the myoepithelial cell component

Differential Diagnosis ♦♦ Polymorphous low grade carcinoma, mucoepidermoid carcinoma, and basaloid squamous carcinoma lack a myoepithelial component and are negative for SMA, SMMHC, and calponin ♦♦ Basal cell adenoma and epithelial-myoepithelial carcinoma show the same IHC pattern and must be differentiated by morphology

Salivary Duct Carcinoma Verification Panel (Fig. 2.3) ♦♦ GCDFP-15 stains the tumor cell cytoplasm ♦♦ HER2 stains the tumor cell membranes

Differential Diagnosis ♦♦ High grade mucoepidermoid carcinoma is positive for GCDFP-15 (17%) and HER2 (21%) in some cases and shows squamous differentiation ♦♦ Poorly differentiated squamous cell carcinoma is often positive for HER2 (60%) and negative for GCDFP-15 ♦♦ Acinic cell carcinoma is sometimes positive for GCDFP-15 (42%) and negative for HER2 ♦♦ Metastatic breast carcinoma must be identified by clinical history

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♦♦ SMA, SMMHC, calponin, vimentin, and pankeratin stain the cytoplasm and p63 the nuclei of the myoepithelial cell component. S-100 and GFAP show variable cytoplasmic staining

Differential Diagnosis ♦♦ Mucoepidermoid carcinoma, acinic cell carcinoma, sebaceous carcinoma, and metastatic renal cell carcinoma lack a myoepithelial component and are negative for SMA, SMMHC, and calponin

Myoepithelial Carcinoma Verification Panel ♦♦ Pankeratin, SMA, calponin, SMMHC, and vimentin stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ S-100 and GFAP show variable cytoplasmic staining

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin; some types (squamous carcinoma) are positive for p63 (nuclear); and negative for SMA, calponin, SMMHC, and vimentin ♦♦ Leiomyosarcoma is positive for SMA, MSA, desmin, and calponin, and some are focally positive for keratin (40%) and p63 (nuclear) (23%) ♦♦ Nerve sheath tumor is positive for S-100 and negative for SMA, calponin, SMMHC, and p63 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for SMA, calponin, SMMHC, and p63 (nuclear) ♦♦ Synovial sarcoma is positive for CD99, bcl-2, EMA, pankeratin, S-100, calponin, and calretinin and negative for p63 (nuclear)

Mesenchymal Tumors ♦♦ Salivary gland mesenchymal tumors include hemangioma, lipoma, neurofibroma, inflammatory myofibroblastic tumor, malignant peripheral nerve sheath tumor, and rhabdomyosarcoma. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion

Lymphoma

Fig.  2.3. (A–C) GCDFP-15 stains the cytoplasm and HER2 stains the membranes of a salivary duct carcinoma.

Epithelial-Myoepithelial Carcinoma Verification Panel ♦♦ EMA and keratin stain the cytoplasm of the ductal component. Vimentin is negative

♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most lymphomas involving the salivary glands are CD20 positive extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), diffuse large B-cell and follicular lymphoma. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the salivary glands are skin (squamous carcinoma and melanoma), nasopharynx, lung, breast, kidney, and colorectal. Refer to Chapter 3 for further discussion

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Thyroid Gland Papillary Thyroid Carcinoma Verification Panel

Differential Diagnosis

♦♦ Thyroglobulin stains the tumor cell cytoplasm and colloid ♦♦ TTF-1 stains the tumor cell nuclei; benign follicular and C-cells are also positive ♦♦ HMWK (CK34be12, CK5/6) stains the areas of squamous metaplasia within the tumor ♦♦ Pankeratin stains the tumor cell cytoplasm ♦♦ Follicular variant of papillary carcinoma is diffusely positive for CK19

Medullary Thyroid Carcinoma

♦♦ In addition, these tumors show CEA cytoplasmic staining

Differential Diagnosis (Table 2.3) ♦♦ Follicular adenoma and carcinoma are negative or weak/ focal for CK19. Various markers have been studied to differentiate papillary and follicular neoplasms, but none are sensitive or specific

Follicular Adenoma and Carcinoma ♦♦ Immunostains do not differentiate these tumors. Vascular markers (CD31, CD34) help identify lymphovascular invasion

Verification Panel ♦♦ Thyroglobulin stains the tumor cell cytoplasm and colloid ♦♦ TTF-1 stains the tumor cell nuclei; benign follicular and C-cells are also positive ♦♦ Pankeratin stains the tumor cell cytoplasm

Differential Diagnosis (Table 2.3) ♦♦ Follicular variant of papillary carcinoma can be diffusely positive with CK19 while follicular carcinoma is negative or weak/focal ♦♦ An intrathyroid parathyroid gland or adenoma is positive for parathyroid hormone and negative for TTF-1 (nuclear) and thyroglobulin

Hürthle Cell Neoplasms ♦♦ This morphologic subtype of follicular tumors behaves more aggressively; it should be considered in a patient with lung or bone metastases with a history of thyroid disease ♦♦ These tumors show weaker thyroglobulin expression than the other follicular neoplasms and similar TTF-1 (nuclear) and pankeratin staining

♦♦ The clear cell variant of Hürthle cell tumors must be distinguished from metastatic renal cell carcinoma (RCC). RCC is positive for RCC Ma and CD10 and negative for TTF-1 (nuclear) and thyroglobulin

♦♦ Medullary carcinoma can have spindled, epithelioid, plasmacytoid, nested, and follicular morphology

Verification Panel (Fig. 2.4) ♦♦ Calcitonin, CEA, chromogranin, and synaptophysin stain the tumor cell cytoplasm ♦♦ TTF-1 stains the tumor cell nuclei; benign follicular and C-cells are also positive

Differential Diagnosis (Table 2.3) ♦♦ Follicular and papillary neoplasms are positive for thyroglobulin and TTF-1 (nuclear) and negative for calcitonin, chromogranin, and synaptophysin ♦♦ Carotid body tumors or paraganglioma are positive for chromogranin and synaptophysin and negative for calcitonin and TTF-1 (nuclear)

Undifferentiated (Anaplastic) Thyroid Carcinoma ♦♦ This undifferentiated carcinoma stains poorly with IHC. Better differentiated areas are helpful for morphologic diagnosis and focal expression with IHC testing

Verification Panel (Fig. 2.5) ♦♦ Pankeratin and vimentin stain the tumor cell cytoplasm focally ♦♦ TTF-1 (nuclear, 25%) and thyroglobulin (cytoplasm, 27%) stain the tumor cells only focally; both should be used to increase sensitivity ♦♦ Monoclonal CEA and HMWK stain the tumor cell cytoplasm focally

Differential Diagnosis ♦♦ Because of the varied morphology (spindled, pleomorphic, giant cell, small cell, and lymphoepithelial) of anaplastic

Table 2.3. Thyroid and Parathyroid Gland Tumor Differential Diagnosis Thyroglobulin

TTF-1

Calcitonin, CEA

Chromogranin

Parathyroid hormone

Papillary carcinoma

+

+

−

−

−

Follicular neoplasms

+

+

−

−

−

Medullary carcinoma

−

+

+

+

−

Parathyroid neoplasms

−

−

−

+

+

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Fig. 2.5. (A, B) Thyroglobulin focally stains the cytoplasm of an anaplastic thyroid carcinoma.

Poorly Differentiated Squamous Carcinoma Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the nuclei Fig. 2.4. (A–C) Calcitonin stains the cytoplasm and TTF-1 stains the nuclei of a thyroid medullary carcinoma.

thyroid carcinoma, many other poorly differentiated tumors must be considered including sarcoma, lymphoma, and metastatic carcinoma. Thyroglobulin and TTF-1 are negative in these tumors. Refer to Chapter 3 for further discussion ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for keratin, thyroglobulin, and TTF-1 (nuclear)

Differential Diagnosis ♦♦ Medullary thyroid carcinoma is positive for TTF-1 (nuclear) and calcitonin and negative for p63 ♦♦ Anaplastic thyroid carcinoma is focally positive for thyroglobulin and/or TTF-1. It can show squamous differentiation and stain with HMWK and p63 (nuclear)

Mesenchymal Tumors ♦♦ Thyroid gland mesenchymal tumors include schwannoma, leiomyoma, solitary fibrous tumor/hemagiopericytoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, and angiosarcoma. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion

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Lymphoma

Differential Diagnosis

♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most lymphomas involving the thyroid gland are CD20 positive diffuse large B-cell, extranodal marginal-zone B-cell lymphoma of MALT and rarely follicular lymphoma. Refer to the section and chapter on lymphoma for further discussion

♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for synaptophysin and chromogranin ♦♦ Metastatic small cell carcinoma is positive for pankeratin, CD56, chromogranin, and synaptophysin and negative for vimentin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for CD56, chromogranin, and synaptophysin ♦♦ Rhabdomyosarcoma is positive for CD56, desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for synaptophysin and chromogranin ♦♦ Ewing sarcoma is positive for CD99 (membranous), Fli-1 (nuclear), and vimentin and negative for CD56, synaptophysin, and chromogranin

Metastatic Disease ♦♦ The most common tumors to metastasize to the thyroid gland are kidney, lung, uterus, skin (melanoma), breast, and ­stomach. Refer to Chapter 3 for further discussion

Parathyroid Gland ♦♦ Benign parathyroid gland, adenoma, and carcinoma are differentiated by morphology. Immunostains are not useful

Verification Panel ♦♦ Parathyroid hormone, chromogranin, and pankeratin stain the cytoplasm of parathyroid neoplasms and benign glands

Differential Diagnosis (Table 2.3) ♦♦ In a gland fragment, thyroid follicular tissue and tumor are in the differential diagnosis. These are positive for TTF-1 (nuclear) and thyroglobulin and negative for parathyroid hormone

Eye and Ocular Adnexa Malignant Melanoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ HMB 45 and Melan-A stain the tumor cell cytoplasm ♦♦ Rare cases show focal pankeratin positive cytoplasm (3%)

Differential Diagnosis ♦♦ Carcinoma is diffusely positive for pankeratin; some cases are positive for S-100 (19%); and negative for HMB 45 and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for S-100, HMB 45, and Melan-A ♦♦ Schwannoma and malignant peripheral nerve sheath tumors are positive for S-100 and negative for HMB 45 and Melan-A ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), Myo-D1 (nuclear); some cases are positive for S-100 (12%); and negative for HMB 45 and Melan-A ♦♦ Retinoblastoma is positive for synaptophysin, chromogranin, NSE, and CD56 and negative for S-100, HMB 45, and Melan-A

Retinoblastoma Verification Panel ♦♦ Synaptophysin, chromogranin, NSE, CD56, and vimentin stain the tumor cell cytoplasm ♦♦ GFAP stains the cytoplasm of rare cells that might be entrapped astrocytes or differentiated tumor cells

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Mesenchymal Tumors ♦♦ Ocular mesenchymal tumors include hemangioma, hemangioblastoma, leiomyoma, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most lymphomas involving the eye are CD20 positive extranodal marginal-zone B-cell lymphoma of MALT and diffuse large B-cell lymphoma. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the orbit are lung, breast, gastrointestinal, genitourinary, and skin (melanoma). Refer to Chapter 3 for further discussion

Miscellaneous Tumors of the Head and Neck Region Pleomorphic and Spindle Cell Lipoma Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm ♦♦ S-100 stains the adipocyte nuclei and cytoplasm

Differential Diagnosis ♦♦ Liposarcoma is positive for S-100 and negative for CD34

Paraganglioma/Carotid Body Tumor Verification Panel (Fig. 2.6) ♦♦ Chromogranin and synaptophysin stain the cytoplasm ♦♦ S-100 stains the nuclei and cytoplasm of the sustentacular cells surrounding the tumor cell nests ♦♦ Keratin stains the tumor cell cytoplasm focally in some case (7%)

Differential Diagnosis ♦♦ Medullary carcinoma of the thyroid is positive for keratin, TTF-1 (nuclear), calcitonin, synaptophysin, and chromogranin

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Fig. 2.6. (A–D) Chromogranin (focally) and synaptophysin (diffusely) stain the cytoplasm in a paraganglioma (carotid body tumor) and S-100 stains the nuclei and cytoplasm of the sustentacular cells surrounding the tumor cell nests.

THORAX Lung Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous carcinoma except when diffusely poorly differentiated

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm. CK7 focally stains some cases (25%) ♦♦ p63 stains the nuclei ♦♦ TTF-1 (nuclear, 10%) and calretinin (focal, 40%) stain some cases

Differential Diagnosis (Tables 2.4 and 2.5) ♦♦ Poorly differentiated adenocarcinoma is diffusely positive for CK7 and negative for CK5/6 and p63 (nuclear)

♦♦ Mesothelioma is positive for CK7, calretinin, CK34be12, CK5/6, and WT1 (nuclear) and negative for p63 (nuclear) ♦♦ Metastatic squamous carcinoma to the lung is unusual. IHC does not help identify metastasis except when the lung primary expresses TTF-1 (nuclear)

Adenocarcinoma ♦♦ Some pathologists perform IHC on all adenocarcinomas in the lung to confirm primary site (TTF-1, CK7, and CK20). Refer to Chapter 3 for further discussion

Verification Panel ♦♦ TTF-1 stains the tumor cell nuclei (85%) ♦♦ CK7 and CEA stain the tumor cell cytoplasm

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Table 2.4. Primary Lung Carcinoma Differential Diagnosis (% Positive Tumors) Squamous cell carcinoma

Small cell carcinoma

Adenocarcinoma

TTF-1 (nuclear)

0–15

85–100

40–85

p63

80–100

0–31

0–30

CK5/6

80–100

5–25

0–20

Neuroendocrine Markersa

0–10

80–100

0–10

a

Chromogranin, synaptophysin, and CD56; CD56 is the most sensitive but not specific

Table 2.5. Epithelioid Lung and Pleural Tumor Differential Diagnosis (% Positive Tumors) Calretinin/WT1a/CK5/6

CK7

Additional tumor markers

Mesothelioma

+/+/+

+

D2-40, h-caldesmon

Squamous cell carcinoma

40/11/+

25

p63a

Lung adenocarcinoma

10/28/5

+

TTF-1a

Mucinous lung adenocarcinoma

−/NA/−

+

CDX2a, CK20

Metastatic breast carcinoma

15/−/45

+

GCDFP-15, ER/PRa, HER2

Metastatic serous ovarian adenocarcinoma

31/+/22

+

ERa, MOC31, Ber-EP4

Metastatic renal cell carcinoma

−/8/25

11

RCC Ma, CD10

Metastatic pancreatobiliary adenocarcinoma

10/−/20

+

CA19-9, CK20

Metastatic colorectal adenocarcinoma

18/53/24

27

CDX2a, CK20

Metastatic prostatic carcinoma

−/−/−

10

PSA, PAP

Metastatic gastric adenocarcinoma

−/11/−

52

Shows variable CK7/CK20 pattern

Metastatic papillary thyroid carcinoma

−/−/14

+

TTF-1a, Thyroglobulin

Thymic carcinoma

37/−/+

80

CD5

Angiosarcoma, epithelioid hemangioendothelioma

−/29/−

4

CD31, CD34, Factor VIII, Fli-1a

Nuclear staining NA not available

a

♦♦ ER (nuclear, 61%), CA125 (62%), CA19-9 (38%), HER2 (membranous, 38%), and WT1 (nuclear, 28%) are positive in some cases ♦♦ CK7, CK20, and CA19-9 stain the cytoplasm and CDX2 the nuclei of mucinous lung adenocarcinomas ♦♦ GCDFP-15 and p63 (nuclear) are negative in lung adenocarcinoma ♦♦ CK20 and CDX2 are negative in nonmucinous lung adenocarcinoma

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Differential Diagnosis (Tables 2.4 and 2.5) ♦♦ Metastatic carcinoma: TTF-1 (nuclear) is negative in metastatic adenocarcinoma except for rare metastatic thyroid tumors −− CK20 positive and CK7 negative carcinomas include colorectal and gastric −− CK7 and CK20 positive carcinomas include urothelial, pancreatobiliary, and gastric

Immunohistochemical Diagnosis in Surgical Pathology

2-21

−− CK7 and CK20 negative carcinomas include prostate, clear cell renal cell and hepatocellular −− Breast carcinoma is positive for CK7, GCFDP-15, HER2, and ER/PR (nuclear) and negative for TTF-1 (nuclear) and CK20 −− Ovarian (nonmucinous) and endometrial adenocarcinomas are positive for CK7 and negative for TTF-1 (nuclear) and CK20 −− Gastric carcinoma shows variable CK7 and CK20 staining and is negative for TTF-1 (nuclear) ♦♦ Mesothelioma is positive for CK7, CK5/6, WT1, and calretinin and negative for TTF-1 (nuclear) ♦♦ Squamous cell carcinoma is positive for CK5/6, p63 (nuclear), and CEA; some cases are positive for CK7 (25%) and TTF-1 (nuclear, 10%)

Pleomorphic, Spindle Cell, Giant Cell, and Sarcomatoid Carcinoma ♦♦ These undifferentiated tumors show only focal IHC positivity ♦♦ Melanoma, poorly differentiated sarcomas, and metastatic poorly differentiated carcinomas should be considered. These tumors can show weak or absent antigen reactivity. Additional tumor sampling might demonstrate better differentiated areas

Verification Panel ♦♦ Pankeratin and vimentin stain the cytoplasm focally ♦♦ TTF-1 stain scattered nuclei in some cases

Differential Diagnosis ♦♦ Pulmonary blastoma is positive for pankeratin, b-catenin (nuclear), and vimentin ♦♦ Mesothelioma is positive for pankeratin, CK7, calretinin, h-caldesmon, D2-40, CK5/6, vimentin, and WT1 (nuclear) ♦♦ Malignant peripheral nerve sheath tumors (focal) and melanoma (diffuse) are positive for S-100 ♦♦ Leiomyosarcoma is positive for MSA, SMA, and desmin ♦♦ Synovial sarcoma is positive for bcl-2, CD99 (membranous), pankeratin, EMA, and S-100 ♦♦ Angiosarcoma is positive for CD31, CD34, Factor VIII, and Fli-1 (nuclear); some cases positive for pankeratin (17%); and negative for TTF-1 (nuclear) ♦♦ Undifferentiated high grade pleomorphic sarcoma (malignant fibrous histiocytoma) is positive for vimentin

Carcinoid and Atypical Carcinoid Tumors ♦♦ Neuroendocrine tumors must be graded based on morphology; they show similar IHC patterns

Verification Panel (Fig. 2.7) ♦♦ Chromogranin, synaptophysin, and CD56 show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology

Fig. 2.7. (A–C) Synaptophysin stains the cytoplasm and pankeratin shows dot-like and diffuse staining in the ­cytoplasm of a pulmonary carcinoid tumor.

♦♦ Pankeratin stains the tumor cell cytoplasm in most cases (80%) ♦♦ TTF-1 nuclear staining is variable (30%)

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Differential Diagnosis ♦♦ Paraganglioma is positive for chromogranin and contains S-100 positive spindled sustentacular cells surrounding the tumor cell nests

Small Cell and Large Cell Neuroendocrine Carcinoma Verification Panel (Fig. 2.8) ♦♦ Pankeratin and CK7 show dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology ♦♦ TTF-1 stains the tumor cell nuclei (90% of small cell ­carcinoma cases). TTF-1 cannot be used to confirm the lung as a primary site in small cell carcinoma; it is positive in many other primary sites including upper respiratory and gastrointestinal ♦♦ Calretinin stains some tumors (47%)

Differential Diagnosis (Tables 2.4 and 2.5) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 (some types positive for CD56) and negative for pankeratin, chromogranin, synaptophysin, and TTF-1 (nuclear) ♦♦ Mesothelioma is positive for pankeratin, CK7, calretinin, h-caldesmon, D2-40, CK5/6, and WT1 (nuclear) and some cases are positive for chromogranin (10%), synaptophysin (8%) and CD56 (13%) ♦♦ Small cell variant of squamous carcinoma is positive for CK5/6 and p63 (nuclear) and negative for chromogranin, synaptophysin, and CD56 ♦♦ Ewing sarcoma is positive for CD99 (membranous), Fli-1 (nuclear); some cases positive for pankeratin, synaptophysin, and CD56; and negative for chromogranin ♦♦ Rhabdomyosarcoma is positive for MSA, desmin, myogenin (nuclear), Myo-D1 (nuclear), and CD56 and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, chromogranin, synaptophysin, and CD56

Pulmonary Blastoma ♦♦ This biphasic tumor is composed of malignant glandular and mesenchymal components

Verification Panel ♦♦ Pankeratin, CEA, and EMA stain the cytoplasm of the epithelial component ♦♦ Chromogranin, synaptophysin, and various other endocrine markers stain the cytoplasm of the endocrine component ♦♦ Vimentin, MSA, desmin, and S-100 will stain the mesenchymal, smooth muscle, skeletal muscle and chondroid components, respectively

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Fig. 2.8. (A–C) TTF-1 stains the nuclei and pankeratin shows dot-like and diffuse staining in the cytoplasm of a pulmonary small cell carcinoma.

♦♦ b-catenin stains the nuclei and cytoplasm in both the epithelial and stromal components

Immunohistochemical Diagnosis in Surgical Pathology

Differential Diagnosis ♦♦ Adenocarcinoma does not contain the malignant stromal component ♦♦ Carcinosarcoma is negative for b-catenin

Sclerosing Hemangioma Verification Panel

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Inflammatory Myofibroblastic Tumor Verification Panel ♦♦ ALK is positive in the nuclei and cytoplasm of the tumor cells. This is the most specific marker, but stains only 57% of cases ♦♦ Actin, desmin, and pankeratin focally stain the tumor cell cytoplasm

Differential Diagnosis

♦♦ TTF-1 stains the nuclei and EMA the membranes of the round stromal cells and surface cells ♦♦ Various (CK7, CK20, CAM 5.2) keratins are strongly positive in the cytoplasm of the surface cells and focally positive in the round stromal cells ♦♦ Vimentin stains the cytoplasm of both cell types ♦♦ PR stains the nuclei of the round stromal cells

♦♦ Fibrosarcoma is focally positive for SMA and negative for ALK and pankeratin ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin and negative for ALK ♦♦ Synovial sarcoma is positive for CD99 (membranous), bcl-2, pankeratin, and EMA; some cases are positive for SMA; and negative for ALK

Differential Diagnosis

Synovial Sarcoma

♦♦ Adenocarcinoma is positive for CK7; some cases are positive for CK20 (mucinous type) and PR (21%); and negative for vimentin ♦♦ Carcinoid tumors are positive for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Angiosarcoma is positive for CD31, CD34, Factor VIII, and Fli-1 (nuclear) and some cases are positive for pankeratin

Clear Cell Tumor (Sugar Tumor) ♦♦ Part of the perivascular epithelioid cell tumor group (PEComa). These tumors are cytologically bland

Verification Panel ♦♦ HMB 45, Melan-A, SMA, desmin, and vimentin stain the tumor cell cytoplasm ♦♦ Pankeratin is negative

Differential Diagnosis ♦♦ Clear cell variant of squamous cell carcinoma is positive for pankeratin, CK5/6, and p63 (nuclear) and negative for HMB 45, Melan-A, SMA, and desmin ♦♦ Adenocarcinoma is positive for pankeratin and TTF-1 (nuclear) and negative for HMB 45, Melan-A, SMA, and desmin ♦♦ Metastatic clear cell renal cell carcinoma is positive for vimentin, RCC Ma, and CD10 and negative for HMB 45, Melan-A, SMA, and desmin ♦♦ Melanoma is positive for S-100, vimentin, HMB 45, and Melan-A and negative for SMA and desmin ♦♦ Granular cell tumor is positive for S-100 and vimentin and negative for HMB 45, Melan-A, SMA, and desmin

Bronchial Salivary Gland Type Neoplasms ♦♦ The diagnosis of these tumors is based on morphology. These include adenoid cystic carcinoma, mucoepidermoid carcinoma, and epimyoepithelial carcinoma. Refer to the salivary gland section of this chapter

♦♦ IHC cannot differentiate a primary from a metastatic tumor

Verification Panel ♦♦ CD99, bcl-2, and EMA (77%) stain the tumor cell membranes and cytoplasm ♦♦ Pankeratin (67%) and SMA (15%) stain the tumor cell cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm in some cases (30%)

Differential Diagnosis ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin; some cases are positive for CD99 (37%) and bcl-2 (28%); and negative for S-100 ♦♦ Sarcomatoid carcinoma is focally positive for pankeratin and some cases are positive for CD99, bcl-2, and S-100 ♦♦ Inflammatory myofibroblastic tumor is positive for ALK (57%) and negative for CD99 (membranous)

Other Mesenchymal Tumors ♦♦ Other pulmonary mesenchymal tumors include chondroma, leiomyoma, schwannoma, solitary fibrous tumor/hemangiopericytoma, epithelioid hemangioendothelioma, primary or metastatic leiomyosarcoma, and angiosarcoma. Metastatic mesenchymal tumors cannot be differentiated from lung primary tumors by IHC or morphology. Refer to the mesenchymal tumor section of this chapter for further discussion

Lymphoma Verification Panel ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common types are CD20 positive B-cell MALT lymphoma and large cell lymphoma. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease (Table 2.5) ♦♦ The most common tumors to metastasize to the lung are breast, colon, stomach, pancreatobiliary, kidney, skin (melanoma), prostate, liver, thyroid, adrenal, male genital, and gynecolo­gical. Refer to Table 2.5 and Chapter 3 for further discussion

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Pleura Mesothelioma

♦♦ CEA, CA19-9, TTF-1 (nuclear), p63 (nuclear), and ER/PR (nuclear) are negative

♦♦ IHC markers are not completely specific or sensitive for mesothelioma, i.e., mesothelioma markers are focally positive in some carcinomas and vice versa. A panel of expected positive and negative markers (usually two of each) provides more definitive results ♦♦ Calretinin is positive in both epithelioid and sarcomatous types. CK5/6, WT1 (nuclear), and D2-40 are usually negative in sarcomatous mesothelioma

Differential Diagnosis (Table 2.5)

Verification Panel (Fig. 2.9) ♦♦ Calretinin stains the tumor cell nuclei and cytoplasm ♦♦ Pankeratin, CK5/6, h-caldesmon, CK7, D2-40 and vimentin stain the tumor cell cytoplasm ♦♦ WT1 (43–93%) stains the tumor cell nuclei ♦♦ Carcinoma markers are variably (usually focally) positive in mesothelioma: CA125 (48%), CD10 (48%), Ber-EP4 (13%), MOC-31 (8%), RCC Ma (focal, 8%), B72.3 (8%), and LeuM1 (5%) ♦♦ CD99 stains the tumor cell membranes in some cases (53%)

♦♦ Lung adenocarcinoma is positive for CK7, MOC-31, TTF-1 (nuclear), CEA, Ber-EP4, CA19-9 (68%), and LeuM1 (50%); some cases are positive for calretinin (10%) and CK5/6 (5%) and negative for h-caldesmon, D2-40, WT1 (nuclear), and vimentin ♦♦ Squamous carcinoma is positive for MOC-31, p63 (nuclear), CK5/6, CEA (77%), and vimentin (60%); some cases are focally positive for calretinin (40%), LeuM1 (30%), Ber-EP4 (40%), and D2-40 (50%); and negative for WT1 (nuclear) ♦♦ Serous carcinoma is positive for MOC-31, Ber-EP4, ER (nuclear), WT1 (nuclear), C19-9 (67%), and some cases are positive for calretinin (31%), CK5/6 (22%), D2-40 (15%), CEA (13%), and h-caldesmon (5%) ♦♦ Renal cell carcinoma is positive for RCC Ma, CD10, and LeuM1 (63%); some are positive for MOC-31 (50%), Ber-EP4 (42%), and calretinin (10%); and negative for CEA, B72.3, WT1 (nuclear), and CK5/6

Fig. 2.9. (A–D) CK7, vimentin, and calretinin stain the cytoplasm of an epithelioid and sarcomatoid mesothelioma.

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Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Synovial sarcoma is positive for CD99 (membranous), calretinin, bcl-2, and pankeratin; some cases are positive for CK5/6 (41%), S-100 (21%), and D2-40 (30%); and negative for h-caldesmon and WT1 (nuclear) ♦♦ Angiosarcoma is positive for CD31, CD34, Factor VIII, vimentin, and WT1 (nuclear); some cases are positive for pankeratin (17%) and D2-40 (43%); and negative for calretinin and CK5/6 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A; some cases are positive for calretinin (20%); and negative for pankeratin

Solitary Fibrous Tumor and Hemangiopericytoma ♦♦ These tumors are related by IHC and molecular studies

Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm; endothelial cells are also positive ♦♦ CD99 and bcl-2 stain the tumor cell membranes and cytoplasm ♦♦ Desmin, MSA, SMA, and S-100 focally stain some tumors (6–11%)

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Differential Diagnosis ♦♦ Lymphoblastic lymphoma is positive for CD3, TdT (nuclear), and CD1a and negative for pankeratin, HMWK, and CK7 ♦♦ Hodgkin lymphoma is positive for LeuM1 and CD30 and negative for pankeratin, HMWK, and CK7 ♦♦ Germinoma is positive for PLAP and CD117 and negative for pankeratin, HMWK, and CK7

Thymic Carcinoma ♦♦ The subtype should be identified as squamous, basaloid, mucoepidermoid, etc

Verification Panel (Fig. 2.10) ♦♦ Pankeratin, CK7, CK19, cam 5.2, HMWK (CK34be12, CK 5/6), and CD117 (65%) stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ CD5 stains the tumor cell membranes and cytoplasm (50%) ♦♦ Calretinin stains the tumor cell nuclei and cytoplasm in some cases (67%)

Differential Diagnosis ♦♦ Schwannoma is strongly positive for S-100; some are focally positive for EMA (35%) and CD34 (25%) ♦♦ Leiomyoma is diffusely positive for SMA, MSA, desmin, and bcl-2; some cases are positive for CD99 (27%); and negative for CD34 ♦♦ Synovial sarcoma is positive for CD99, bcl-2, pankeratin, and EMA; some cases are positive for SMA; and negative for CD34

Other Mesenchymal Tumors ♦♦ Other pleural mesenchymal tumors include epithelioid hemangioendothelioma, angiosarcoma, synovial sarcoma, and desmoplastic small round cell tumor. Refer to the mesenchymal tumor section for further discussion

Metastatic Disease (Table 2.5) ♦♦ The most common tumors to metastasize to the pleura are lung, breast, lymphoma/leukemia, ovary, pancreas, kidney, and gastrointestinal. Refer to Table  2.5 and Chapter 3 for further discussion

Mediastinum ♦♦ Thyroid and parathyroid tissue and tumors can occur in the mediastinum. Refer to the head and neck tumor section for further discussion

Thymoma Verification Panel ♦♦ Pankeratin, HMWK (CK34be12, CK5/6), and CK7 stain the tumor cell cytoplasm ♦♦ CD20 stains the cytoplasm of some spindle thymoma cells ♦♦ CD3, CD1a, CD99, and TdT (nuclear) stain the lymphoid population

Fig. 2.10. (A, B) CD5 stains the membranes and cytoplasm of a thymic carcinoma.

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Differential Diagnosis ♦♦ Lung adenocarcinoma is positive for pankeratin, CK7, and TTF-1 (nuclear); some cases are positive for CD5 (61%); and negative for calretinin and p63 (nuclear) ♦♦ Mesothelioma is positive for calretinin and WT1 (nuclear); some cases are positive for CD5 (69%); and negative for p63 (nuclear) ♦♦ Germinoma is positive for PLAP, OCT4 (nuclear), and CD117 and negative for keratins and calretinin ♦♦ Embryonal carcinoma is positive for pankeratin, CD30, and OCT4 (nuclear) and negative for CD5, HMWK, calretinin, and p63 (nuclear)

Thymic Carcinoid and Atypical Carcinoid Tumors Verification Panel ♦♦ Chromogranin, synaptophysin, and CD56 show variable tumor cell cytoplasmic staining. CD56 must be evaluated in the context of neuroendocrine morphology ♦♦ Pankeratin stains the tumor cell cytoplasm ♦♦ TTF-1 (nuclear) is negative

Differential Diagnosis ♦♦ Thymoma is positive for pankeratin and negative for CD56, chromogranin, and synaptophysin

Thymic Small Cell Carcinoma Verification Panel ♦♦ Pankeratin shows dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology ♦♦ TTF-1 (nuclear) is negative

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Scattered tumor-associated syncytiotrophoblastic giant cells are βhCG and pankeratin positive ♦♦ CD45 stains the tumor-associated lymphoid cells ♦♦ Pankeratin is negative or weak and focal (30%)

Differential Diagnosis ♦♦ Yolk sac tumor is positive for pankeratin, aFP, and a-1-antitrypsin; some cases are focally positive for PLAP (50%); and negative for CD117 and OCT4 (nuclear) ♦♦ Embryonal carcinoma is positive for OCT4 (nuclear), pankeratin, and CD30 and negative for CD117 ♦♦ Thymic carcinoma is positive for pankeratin; some cases are positive for CD117 (42%) and CD5 (55%); and negative for PLAP ♦♦ Lymphoblastic lymphoma is positive for CD3, TdT (nuclear), and CD1a and negative for PLAP ♦♦ Hodgkin lymphoma is positive for LeuM1 and CD30 and negative for PLAP

Yolk Sac Tumor (Endodermal Sinus Tumor) Verification Panel ♦♦ Pankeratin, aFP, and a-1-antitrypsin stain the tumor cell cytoplasm

Differential Diagnosis ♦♦ Embryonal carcinoma is positive for pankeratin, OCT4 (nuclear), and CD30 and negative for aFP and a-1-antitrypsin ♦♦ Thymic carcinoma is positive for pankeratin; some cases are positive for CD117 (42%) and CD5 (55%); and negative for aFP and a-1-antitrypsin

Embryonal Carcinoma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

Pankeratin stains the tumor cell cytoplasm CD30 and PLAP stain the tumor cell membranes and cytoplasm OCT4 stains the tumor cell nuclei aFP focally stains some tumors (22%)

♦♦ Lymphoblastic lymphoma is positive for CD3, TdT, and CD1a and negative for pankeratin, CD56, chromogranin, and synaptophysin ♦♦ Hodgkin lymphoma is positive for LeuM1 and CD30 and negative for pankeratin, CD56, chromogranin, and synaptophysin ♦♦ Lung small cell carcinoma is positive for TTF-1 (nuclear) ♦♦ Ewing sarcoma is positive for CD99 (membranous) and Fli-1 (nuclear); some cases positive for pankeratin, CD56, and synaptophysin; and negative for chromogranin

Differential Diagnosis

Germ Cell Tumors Germinoma Verification Panel

♦♦ Pankeratin and βhCG stain the tumor cell cytoplasm

♦♦ PLAP and CD117 stain the tumor cell membranes and cytoplasm ♦♦ OCT4 stains the tumor cell nuclei

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♦♦ Yolk sac tumor is positive for pankeratin and aFP and negative for OCT4 (nuclear) and CD30 ♦♦ Germinoma is positive for PLAP, CD117, and OCT4 (nuclear) and negative for CD30 and pankeratin ♦♦ Thymic carcinoma is positive for pankeratin and HMWK; some cases are positive for CD117 and CD5; and negative for CD30 and PLAP

Choriocarcinoma Verification Panel Differential Diagnosis ♦♦ Yolk sac tumors and other carcinomas are βhCG negative ♦♦ Germinoma is positive for PLAP, OCT4 (nuclear), and CD117 and negative for pankeratin and bhCG (positive in syncytiocytotrophoblasts)

Immunohistochemical Diagnosis in Surgical Pathology

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♦♦ Embryonal carcinoma is positive for pankeratin, βhCG (25%), CD30, and OCT4 (nuclear)

Differential Diagnosis

Ewing Sarcoma/Peripheral Neuroectodermal Tumor Verification Panel

Rhabdomyoma, Rhabdomyosarcoma Verification Panel

♦♦ CD99 stains the tumor cell membranes and cytoplasm (cytoplasmic staining alone is a nonspecific finding) ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Vimentin diffusely stains the tumor cell cytoplasm ♦♦ Pankeratin (30%), NSE (36%), synaptophysin (9%), and CD56 (9%) focally stain some tumors

Differential Diagnosis ♦♦ Lymphoblastic lymphoma is positive for CD99 (membranous), CD3, TdT, and CD1a and negative for pankeratin, HMWK, and CK7 ♦♦ Small cell carcinoma is positive for pankeratin, CD56, chromogranin, and synaptophysin and negative for CD99 and Fli-1 (nuclear). Lung tumors are positive for TTF-1 (nuclear)

Other Mesenchymal Tumors ♦♦ Other mediastinal mesenchymal tumors include lipoma, hemangioma, schwannoma, neurofibroma, paraganglioma, solitary fibrous tumor, synovial sarcoma, neuroblastoma, and malignant peripheral nerve sheath tumor. Refer to the soft tissue tumor section for further discussion

Lymphoma ♦♦ Mediastinal lymphomas include CD3 positive (CD45 negative) lymphoblastic lymphoma, LeuM1 and CD30 positive (CD45 negative) Hodgkin lymphoma, CD20 positive primary mediastinal B-cell lymphoma, and CD30 positive anaplastic large T-cell lymphoma. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the mediastinum are lung, thyroid, breast, and prostate. Refer to Chapter 3 for further discussion

Heart Myxoma Verification Panel ♦♦ Calretinin (75%), S-100, CD31, CD34, SMA, and MSA show variable staining ♦♦ Pankeratin is negative

Differential Diagnosis ♦♦ Metastatic carcinoma is positive for pankeratin

Fibroma Verification Panel ♦♦ Vimentin stains the tumor cell cytoplasm

♦♦ Leiomyoma is positive for SMA, MSA, and desmin

♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Carcinoma is positive for pankeratin and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Hemangioma, Epithelioid Hemangioendothelioma, and Angiosarcoma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Pankeratin can be focally positive in angiosarcoma (17%)

Differential Diagnosis (Table 2.5) ♦♦ Poorly differentiated carcinoma is diffusely positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, CD31, CD34, Factor VIII, and Fli-1 (nuclear)

Mesothelioma ♦♦ These cardiac tumors show the same IHC pattern and differential diagnosis as the pleural tumors (see discussion above)

Other Mesenchymal Tumors ♦♦ Other cardiac mesenchymal tumors include lipoma, inflammatory myofibroblastic tumor, leiomyosarcoma, synovial sarcoma, solitary fibrous tumor, and undifferentiated high grade pleomorphic sarcoma. Refer to the soft tissue tumor section for further discussion

Lymphoma ♦♦ Systemic disease commonly involves the heart and most show CD45 membranocytoplasmic staining. Rare primary lymphomas are CD20 positive large B-cell type. Refer to the lymphoma section for further discussion

Metastatic Disease (Table 2.5) ♦♦ The most common tumors to metastasize to the heart are lung, breast, stomach, skin (melanoma), hepatocellular, and colon. Refer to Table 2.5 and Chapter 3 for further discussion

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DIGESTIVE TRACT Esophagus Infection ♦♦ IHC antibodies to Herpes simplex virus (HSV1 and HSV2) show nuclear and cytoplasmic staining of infected squamous cells ♦♦ IHC antibody to cytomegalovirus shows nuclear and occasionally cytoplasmic staining of infected cells (endothelial, stromal, and occasionally glandular)

Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous carcinoma except when diffusely poorly differentiated

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei

Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma is positive for CEA and negative for CK5/6 and p63 (nuclear) ♦♦ Direct extension from a lung primary can be identified when it is positive for TTF-1 (nuclear, 23%)

High Grade Dysplasia in Barrett Esophagus Verification Panel (Fig. 2.11) ♦♦ p53 stains the dysplastic cell nuclei (70%) ♦♦ Ki-67 proliferation of the dysplastic cell nuclei extends to the surface epithelium ♦♦ Cyclin D1 nuclear expression is increased (45%)

Differential Diagnosis ♦♦ Low grade dysplasia and reactive/regenerative changes are negative for p53 (nuclear) and Cyclin D1 (nuclear) and do not show Ki-67 (nuclear) proliferation in the surface epithelium

Adenocarcinoma Verification Panel ♦♦ Pankeratin stains the tumor cell cytoplasm ♦♦ CDX2 stains the tumor cell nuclei ♦♦ No specific CK7/CK20 pattern is useful for this site

Differential Diagnosis ♦♦ Direct extension of a lung primary is usually positive for TTF-1 (nuclear) and negative for CDX2 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin

Small Cell Carcinoma Verification Panel ♦♦ Pankeratin shows dot-like or diffuse cytoplasmic staining

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Fig. 2.11. (A) Ki-67 shows increased proliferation in the central area of the glands of low grade dysplasia associated with Barrett esophagus. (B) Ki-67 shows proliferation extending into the surface in high grade dysplasia. (C) p53 expression in the nuclei of high grade dysplasia.

Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining ♦♦ TTF-1 stains the tumor cell nuclei (71%)

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin

Malignant Melanoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ HMB 45 and Melan-A stain the tumor cell cytoplasm ♦♦ Rare cases show focal pankeratin positive cytoplasm (3%)

Differential Diagnosis ♦♦ Carcinoma is diffusely positive for pankeratin; some cases are focally positive for S-100 (19%); and negative for HMB 45, and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for HMB 45 and Melan-A

Leiomyoma/Leiomyosarcoma Verification Panel

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Differential Diagnosis (Table 2.6) ♦♦ Gastrointestinal tumor is positive for CD117 and CD34 and can be focally positive for SMA

Granular Cell Tumor Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Inhibin and CD68 stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Adenocarcinoma is positive for pankeratin and negative for S-100 and inhibin ♦♦ Histiocytic inflammation is positive for S-100 and CD68 and negative for inhibin

Other Mesenchymal Tumors ♦♦ Other esophageal mesenchymal tumors include gastrointestinal stromal tumor, rhabdomyosarcoma and Kaposi sarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most lymphomas involving the esophagus are secondary from the mediastinum, nodes, and stomach. The most common primaries are CD20 positive diffuse large B-cell and extranodal marginal-zone B-cell lymphoma of MALT lymphoma. Refer to the lymphoma section and chapter for further discussion

Metastatic Disease

♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Some tumors are focally positive for pankeratin (40%)

♦♦ The most common tumors to metastasize to the esophagus are thyroid, lung, breast, skin (melanoma), kidney, prostate, and ovary. Refer to Chapter 3 for further discussion

Table 2.6. Gastrointestinal Spindle Cell Tumor Differential Diagnosisa (% Positive Tumors) CD117

CD34

ALK-1

SMA, MSA and Desmin

S-100

b-catenin (nuclear)

GIST

95

70

NA

48

−

5

IMFT

5

­6

57

+

−

−

Leiomyoma/ leiomyosarcoma

7

7

−

+

6

−

Schwannoma

−

−

18

−

+

−

Fibromatosis

30

−

−

81

−

92

Spindle cell carcinoma is pankeratin positive and negative for the markers in the table; spindle cell melanoma is positive for S-100 and CD117 (44%)

a

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Essentials of Anatomic Pathology, 3rd Ed.

Stomach Adenocarcinoma Verification Panel ♦♦ Pankeratin stains the tumor cell cytoplasm ♦♦ CDX2 stains the tumor cell nuclei (73%) ♦♦ No specific CK7/CK20 pattern is useful for this site

Differential Diagnosis ♦♦ Metastatic breast lobular adenocarcinoma is positive for ER/ PR (nuclear, 89%) and GCDFP-15 and negative for CK20 and CDX2 (nuclear) ♦♦ Epithelioid gastrointestinal stromal tumor is positive for CD117 and CD34 and negative for pankeratin

Hepatoid Adenocarcinoma Verification Panel ♦♦ Pankeratin, HepPar1, and alpha-fetoprotein stain the tumor cell cytoplasm focally

Differential Diagnosis ♦♦ Metastatic hepatocellular adenocarcinoma cannot be differentiated by IHC

Well Differentiated Endocrine Neoplasms Verification Panel ♦♦ Pankeratin stains the tumor cell cytoplasm (sometimes weakly) ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining

Differential Diagnosis ♦♦ Glomus tumor is positive for SMA and negative for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Well differentiated adenocarcinoma is positive for pankeratin and negative for chromogranin, synaptophysin, and CD56

Gastrointestinal Stromal Tumor (GIST) Verification Panel (Fig. 2.12) ♦♦ CD117 (95%) and CD34 (70%) stain the tumor cell membranes and cytoplasm; CD34 also stains endothelial cells ♦♦ SMA can be focally positive (25%)

Differential Diagnosis (Table 2.6) ♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin and negative for CD117 and CD34 ♦♦ Schwannoma (diffusely) and malignant peripheral nerve sheath tumor (focally) are positive for S-100 and negative for CD117 and CD34

132

Fig.  2.12. (A–C) CD117 and CD34 stain the cytoplasm and membranes of a gastrointestinal stromal tumor. CD34 also stains the endothelial cells of a benign small vessel (lower left).

Immunohistochemical Diagnosis in Surgical Pathology

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♦♦ Fibromatosis is positive for SMA (focally), b-catenin (nuclear) and CD117 (30%) and negative for CD34 ♦♦ Poorly differentiated carcinoma (vs. epithelioid GIST) is positive for pankeratin and negative for CD117 and CD34

Glomus Tumor Verification Panel ♦♦ SMA diffusely stains the tumor cell cytoplasm ♦♦ CD34 focally stains the tumor cell membranes and cytoplasm (53%)

Differential Diagnosis ♦♦ Carcinoid tumor is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for SMA and CD34 ♦♦ Epithelioid gastrointestinal tumor is positive for CD117 and CD34 and can be focally positive for SMA

Other Mesenchymal Tumors ♦♦ Other gastric mesenchymal tumors include gastrointestinal autonomic nerve tumor, schwannoma, lipoma, granular cell tumor, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, and Kaposi sarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common primaries are CD20 positive diffuse large B-cell and extranodal marginal-zone B-cell lymphoma of MALT lymphoma. Refer to the lymphoma section and chapter for further discussion

Metastatic Disease

Fig.  2.13. (A, B) CMV stains the nuclei and occasionally the cytoplasm of infected cells in cytomegalovirus colitis.

♦♦ The most common tumors to metastasize to the stomach are breast, skin (melanoma), lung, and other gastrointestinal carcinomas. Refer to Chapter 3 for further discussion

Small Intestine, Colon, and Rectum Infection (Fig. 2.13) ♦♦ IHC antibody to cytomegalovirus shows nuclear and occasionally cytoplasmic staining of infected cells (endothelial, stromal, and occasionally glandular)

Adenocarcinoma ♦♦ CDX2 (nuclear) stains most colorectal adenocarcinomas (90–100%) and many small intestinal adenocarcinomas (65%) ♦♦ Villin (membranocytoplasmic) stains most colorectal adenocarcinomas (90–100%) and many small intestinal adenocarcinomas (71%) ♦♦ Microsatellite instability IHC can be performed when clinically appropriate for evaluation of hereditary nonpolyposis colon cancer syndrome. The MLH1, MSH2, MSH6, and/or PMS2 nuclear staining is lost when abnormal (Fig. 2.14)

Fig. 2.14. PMS2 shows abnormal loss of nuclear staining in a colon cancer (upper left) indicating a loss of mismatch repair genes associated with nonpolyposis hereditary colon cancer. A fragment of benign mucinous colonic epithelium shows normal nuclear staining (lower right).

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Verification Panel ♦♦ Small intestinal adenocarcinoma expresses CK7 with variable strength and is frequently CK20 positive (56%) (normal small intestinal mucosa is CK20 positive and CK7 negative); AMACR (5%) is negative ♦♦ Colorectal adenocarcinoma is CK20 positive (94%), usually AMACR positive (60%); and occasionally CK7 positive (10%)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Histiocytic inflammation is positive for CD68 and S-100 and negative for inhibin

Gastrointestinal Stromal Tumor (GIST) Verification Panel ♦♦ CD117 (95%) and CD34 (70%) stain the tumor cell membranes and cytoplasm; CD34 also stains endothelial cells ♦♦ SMA (25%) can be focally positive

Differential Diagnosis

Differential Diagnosis (Table 2.6)

♦♦ Colorectal adenocarcinoma directly invading into or metastatic to small bowel is positive for CD20 and AMACR and negative for CK7 ♦♦ Epithelioid gastrointestinal tumor is positive for CD117 and CD34 and negative for pankeratin

♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin and negative for CD117 and CD34 ♦♦ Schwannoma (diffusely) and malignant peripheral nerve sheath tumor (focally) are positive for S-100; and negative for CD117 and CD34 ♦♦ Fibromatosis is positive for SMA (focally), b-catenin (nuclear); some are positive for CD117 (30%); and negative for CD34 ♦♦ Poorly differentiated carcinoma (vs. epithelioid GIST) is positive for pankeratin and negative for CD117 and CD34

Well Differentiated Endocrine Neoplasms Verification Panel ♦♦ Pankeratin stains the tumor cell cytoplasm (often weakly) ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining

Differential Diagnosis ♦♦ Well-differentiated adenocarcinoma is positive for pankeratin and negative for chromogranin, synaptophysin, and CD56

Small Cell Neuroendocrine Carcinoma Verification Panel ♦♦ Pankeratin shows punctuate or diffuse tumor cell cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for keratin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin

Granular Cell Tumor Verification Panel

Fibromatosis Verification Panel ♦♦ b-catenin stains the tumor cell nuclei ♦♦ CD117 stains some tumors (30%) ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm focally

Differential Diagnosis (Table 2.6) ♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin and negative for b-catenin (nuclear) and CD117 ♦♦ Inflammatory myofibroblastic tumor is positive for SMA, MSA, desmin, and ALK (57%) and negative for b-catenin (nuclear) and CD117 ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for b-catenin (nuclear)

Inflammatory Myofibroblastic Tumor Verification Panel ♦♦ ALK stains the tumor cell nuclei. This marker is the most specific for this tumor but stains only 57% of cases ♦♦ SMA, MSA, desmin, and keratin (30%) stain the tumor cell cytoplasm focally

Differential Diagnosis (Table 2.6)

♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Inhibin and CD68 stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

♦♦ Fibromatosis is positive for b-catenin (nuclear); focally positive for SMA and CD117; and negative for ALK ♦♦ Fibrosarcoma is negative for ALK, SMA, MSA, and desmin ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for ALK

Differential Diagnosis

Other Mesenchymal Tumors

♦♦ Adenocarcinoma is positive for pankeratin; some cases are positive for S-100; and negative for CD68 and inhibin

♦♦ Other small intestinal and colorectal mesenchymal tumors include lymphangioma, neurofibroma, ganglioneuroma, leiomyoma,

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Immunohistochemical Diagnosis in Surgical Pathology

lipoma, Kaposi sarcoma, leiomyosarcoma, and angiosarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma Verification Panel ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common types in the small intestine and colon are CD20 positive B-cell MALT, mantle cell, Burkitt, and diffuse large cell lymphoma. Small intestinal enteropathyrelated T-cell lymphoma is CD45 and CD3 positive. Refer to the section and chapter on lymphoma for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the small intestine and colon are skin (melanoma), lung, breast, kidney, and other gastrointestinal carcinomas. Refer to Chapter 3 for further discussion

Anus Infection ♦♦ IHC antibody to Herpes simplex virus (HSV1 and HSV2) shows nuclear and cytoplasmic staining of infected squamous cells

High Grade Squamous Dysplasia/Carcinoma In Situ/Bowen Disease Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ Ki-67 shows an increased proliferation rate into the upper one-third of the epithelium ♦♦ p16 stains the tumor cell nuclei and cytoplasm in HPVrelated lesions

Differential Diagnosis ♦♦ Melanoma in situ is positive for S-100, HMB 45, and Melan-A and negative for keratin ♦♦ Paget disease is positive for CEA, GCDFP-15, and HER2; some cases are positive for S-100; and negative for HMWK, HMB 45, and Melan-A ♦♦ Atrophy is negative for p16 and shows Ki-67 (nuclear) proliferation limited to the basal layers

Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous carcinoma except when diffusely poorly differentiated. This includes the basaloid variant

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p16 stains the tumor cell nuclei and cytoplasm in HPVrelated lesions

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Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma is strongly positive for CEA and negative for CK5/6 and p63 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin ♦♦ Basal cell carcinoma is positive for Ber-EP4 and negative for CEA and EMA

Paget Disease ♦♦ Two types have been demonstrated by IHC testing

Verification Panel ♦♦ CK20 positive, occasionally CK7 positive (13%) and GCDFP-15 negative tumors are often associated with colorectal adenocarcinoma (probable pagetoid spread into the epidermis) ♦♦ CK7 and GCDFP-15 positive and CK20 negative tumors are not associated with colorectal carcinoma, and possibly derive from the anal sweat glands

Differential Diagnosis ♦♦ Melanoma in situ is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, CK7, CK20, and GCDFP-15 ♦♦ Bowen disease is positive for CK5/6; focally positive for CK7; and negative for CK20 and GCDFP-15

Anal Gland Adenocarcinoma Verification Panel ♦♦ CK7 stains the tumor cell cytoplasm ♦♦ CDX2 (nuclear) is negative

Differential Diagnosis ♦♦ Rectal adenocarcinoma is positive for CK20 and CDX2 (nuclear) and negative for CK7

Malignant Melanoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ HMB 45 and Melan-A stain the tumor cell cytoplasm ♦♦ Rare cases show focal pankeratin positive cytoplasm (3%)

Differential Diagnosis ♦ ♦ Carcinoma is strongly positive for pankeratin; some cases are positive for S-100; and negative for HMB 45 and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin and chromogranin, synaptophysin and CD56 and negative for HMB 45 and Melan-A

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Some tumors are focally positive for pankeratin (40%)

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Differential Diagnosis (Table 2.6)

Lymphoma

♦♦ Gastrointestinal stromal tumor is positive for CD117 and CD34 and can be focally positive for SMA

♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common primary is CD20 positive large B-cell lymphoma. Refer to the section and chapter on lymphoma for further discussion

Other Mesenchymal Tumors ♦♦ Other anal mesenchymal tumors include hemangioma, lymphangioma, leiomyoma, schwannoma, neurofibroma, lipoma, hemangiopericytoma, aggressive angiomyxoma, rhabdomyosarcoma, fibrosarcoma, and Kaposi sarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the anus are colorectal, lung, breast, and pancreatic. Refer to Chapter 3 for further discussion

HEPATOBILIARY Liver ♦♦ Ubiquitin and pankeratin stain Mallory bodies ♦♦ A-1 antitrypsin stains the globules in livers with this enzyme deficiency

♦♦ Cholangiocarcinoma is positive for CK7, CK20, and CA199; does not have the CD10 and pCEA bile canalicular pattern staining; and is negative for HepPar1 ♦♦ Metastatic carcinoma is often positive for CK7 or CK 20; does not have the CD10 and pCEA bile canalicular pattern

Infection ♦♦ IHC antibodies to Hepatitis B show nuclear staining for HBV core and cytoplasmic staining for HBV surface (Fig. 2.15) ♦♦ IHC antibodies to Herpes simplex virus (HSV1 and HSV2) show nuclear and cytoplasmic staining of infected cells ♦♦ IHC antibody to cytomegalovirus shows nuclear and occasionally cytoplasmic staining of infected cells (endothelial, stromal, and epithelial)

Hepatic Adenoma Verification Panel ♦♦ HepPar1 stains the tumor cell cytoplasm; benign liver cells are also positive ♦♦ CD10 and polyclonal CEA stain the bile canaliculi ♦♦ CD34 is negative or patchy showing lack of capillarization

Differential Diagnosis ♦♦ Hepatocellular carcinoma shows diffuse CD34 positive neocapillarization around tumor nests and cords

Hepatocellular Carcinoma Verification Panel (Fig. 2.16) ♦♦ HepPar1 and a-FP (25%) stain the tumor cell cytoplasm. HepPar1 also stains benign liver cells ♦♦ CD10 and polyclonal CEA stain the bile canaliculi ♦♦ CD34 stains the neocapillarization around tumor cell nests and cords ♦♦ Pankeratin (10%), CK7 (24%), and CK20 (7%) are usually focal or negative

Differential Diagnosis (Table 2.7) ♦♦ Hepatic adenoma does not show the CD34 positive neocapillarization pattern

136

Fig. 2.15. HBV surface (A) stains the cytoplasm and HBV core (B) stains the nuclei in a Hepatitis B infected liver.

Immunohistochemical Diagnosis in Surgical Pathology

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Fig. 2.16. (A–D) HepPar1 stains the tumor cell cytoplasm, CD10 stains the bile canaliculi, and CD34 highlights the neocapillarization in a hepatocellular carcinoma.

Table 2.7. Hepatic Tumor Differential Diagnosis (% Positive Tumors) HepPar-1, pCEA a, CD10 a

CK7

CK20

CA19-9

CD31, CD34, Fli-1 (nuclear) b

CD45

7

−

−

−

Hepatocellular carcinoma

+

24

Cholangiocarcinoma

−

97

23

+

−

−

Metastatic carcinoma

0–15/−/−

Variesc

Varies

Varies

−

−

Angiosarcoma

−

25

−

−

+

−

Lymphoma

−

−

−

−

−

+

Canalicular pattern for pCEA and CD10 CD31, CD34, and Fli-1 (nuclear) highlight the neocapillarization in hepatocellular carcinoma and also stain the normal endothelial cells c Most carcinomas are predominantly CK7 and/or CK20 positive; urothelial, pancreatobiliary, gastric, and ovarian mucinous carcinomas are in the differential diagnosis with both markers positive. Refer to the chapter on tumor for further discussion a

b

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staining; and is negative for HepPar1. See Table 2.7 and the unknown chapter for further discussion ♦♦ Angiosarcoma is positive for CD31, CD34, Factor VIII, and Fli-1 (nuclear); some cases are positive for pankeratin (17%) and CD10; and negative for HepPar1

Hepatoblastoma Verification Panel ♦♦ HepPar1 stains the tumor cell cytoplasm ♦♦ a-FP (58%) and pankeratin (84%) stain many tumors ♦♦ CD99 stains the membranes (diagnostic) and cytoplasm of most tumors (75%) ♦♦ CD56 (33%), synaptophysin, and chromogranin stain some tumors focally

Differential Diagnosis ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for HepPar1 and a-FP ♦♦ Ewing sarcoma is positive for CD99 (membranous) and Fli1 (nuclear) and negative for HepPar1 and a-FP ♦♦ Neuroblastoma is positive for CD99, synaptophysin, chromogranin, and CD56 and negative for HepPar1 ♦♦ Wilms tumor is positive for WT1 (nuclear) and negative for HepPar1

Cholangiocarcinoma Verification Panel ♦♦ CK7, CK20 (23%), CA19-9 (84%), and monoclonal CEA stain the tumor cell cytoplasm CDX2 (21%) stains the tumor cell nuclei

Differential Diagnosis (Table 2.7) ♦♦ Hepatocellular carcinoma is positive for HepPar1; some cases are positive for CK7 (24%); and negative for CK20, mCEA, and CA19-9 ♦♦ Metastatic carcinoma shows variable staining patterns; most are CA19-9 negative. Refer to Table  2.7 and Chapter 3 for further discussion

Hemangioma, Infantile Hemangioendothelioma, Epithelioid Hemangioendothelioma, and Angiosarcoma ♦♦ These tumors are differentiated based on morphology; the IHC staining pattern is the same

Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Pankeratin can be focally positive in the tumor cell cytoplasm (17%)

Differential Diagnosis (Table 2.7) ♦♦ Hepatocellular carcinoma is positive for HepPar1 and the tumor cells are negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear); however, these demonstrate neocapillarization

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Poorly differentiated metastatic carcinoma is diffusely positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear)

Undifferentiated Sarcoma ♦♦ IHC is not diagnostic but is useful in the differential diagnosis. PAS with diastase highlights the distinctive tumor globules

Verification Panel ♦♦ Vimentin stains diffusely and keratin focally in the tumor cell cytoplasm

Differential Diagnosis ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), Myo-D1 (nuclear), and vimentin ♦♦ Hepatoblastoma is positive for HepPar1, a-FP, and vimentin

Embryonal Rhabdomyosarcoma Verification Panel ♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei

Differential Diagnosis ♦♦ Hepatoblastoma is positive for HepPar1 and a-FP and negative for desmin, MSA, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Undifferentiated sarcoma is negative for desmin, MSA, MyoD1 (nuclear), and myogenin (nuclear)

Angiomyolipoma Verification Panel ♦♦ HMB 45, Melan-A, SMA, MSA, and desmin are positive in the cytoplasm of the spindle and epithelioid tumor cells ♦♦ Keratins, EMA, and S-100 are negative (S-100 stains the adipose elements)

Differential Diagnosis ♦♦ Adipose tumors (e.g., liposarcoma) are positive for S-100 and negative for HMB 45, Melan-A, SMA, MSA, and desmin ♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for MSA, SMA, and desmin and negative for HMB 45 and Melan-A

Other Mesenchymal Tumors ♦♦ Other hepatic mesenchymal tumors include lymphangioma, solitary fibrous tumor/hemangiopericytoma, lipoma, inflammatory myofibroblastic tumor, and Kaposi sarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma (Table 2.7) ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. The most common type is CD20 positive diffuse large B-cell lymphoma. Less frequent are CD20 positive Burkitt and extranodal marginal-zone B-cell lymphoma of MALT lymphomas. Refer to the section and chapter on lymphoma for further discussion

Immunohistochemical Diagnosis in Surgical Pathology

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Metastatic Disease

Verification Panel

♦♦ The most common tumors to metastasize to the liver are colon, stomach, gallbladder, pancreas, lung, breast, eso­ phagus, and genitourinary. Refer to Chapter 3 for further discussion

♦♦ The intestinal type is positive for CDX2 (nuclear) and MUC1 and negative for MUC2 (8%) and is most frequently associated with colloid carcinoma ♦♦ The pancreatobiliary type is more frequently positive for MUC2 (44%) and negative for CDX2 (nuclear) and MUC1 and is associated with the typical pancreatic ductal adenocarcinoma

Pancreas Invasive Ductal Carcinoma ♦♦ IHC is unnecessary for the diagnosis of ductal carcinoma except when poorly differentiated ♦♦ Reactive changes must be differentiated by morphology; IHC is not diagnostic

Verification Panel ♦♦ CK7 (94%) diffusely and CK20 (52%) focally stain the tumor cell cytoplasm ♦♦ CA19-9 and mCEA stain the tumor cell membranes and cytoplasm

Differential Diagnosis ♦♦ Invasive ductal carcinoma must be identified by the lack of a predominantly cystic papillary mucinous component ♦♦ Mucinous cystic neoplasms have a distinct epidemiology and contain ovarian-type stroma that is positive for PR (nuclear), SMA, MSA, and desmin

Serous Cystic Neoplasms ♦♦ Diagnosis is based on morphology; IHC is usually unnecessary

Differential Diagnosis

Verification Panel

♦♦ Ampullary adenocarcinoma is positive for MUC2, more diffusely positive for CDX2 (nuclear), and negative for MUC1 and CK17; pancreatic ductal carcinoma is positive for MUC1 and CK17, heterogeneous for CDX2 (nuclear), and negative for MUC2 ♦♦ Acinar cell carcinoma is positive for pankeratin, a-1-anti­ trypsin, lipase, trypsin, and chymotrypsin and negative for CK7, CA19-9, and mCEA ♦♦ Neuroendocrine tumor is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for CA19-9

♦♦ CK7 diffusely and CA19-9 and B72.3 focally stain the tumor cell cytoplasm ♦♦ mCEA is negative

Mucinous Cystic Neoplasms ♦♦ Tumor location (tail, body), tumor unconnected to the ductal system, and female gender are characteristics of this tumor ♦♦ The glandular elements show the same IHC profile as invasive ductal adenocarcinoma (see above). The associated ovarian-type stroma shows distinctive IHC features

Verification Panel ♦♦ Progesterone receptor (PR) stains the nuclei of the ovariantype stroma ♦♦ Smooth muscle actin (SMA), muscle specific actin (MSA), desmin, inhibin, and calretinin stain the cytoplasm of the ovarian-type stroma

Differential Diagnosis ♦♦ Invasive ductal carcinoma lacks the PR (nuclear) and SMA/ MSA/desmin positive ovarian-type stroma ♦♦ Intraductal papillary mucinous neoplasms lack the PR (nuclear) and SMA/MSA/desmin positive ovarian-type stroma

Intraductal Papillary Mucinous Neoplasms ♦♦ Multiple morphological subtypes with corresponding IHC profiles have been identified. IHC is usually unnecessary

Differential Diagnosis ♦♦ Ductal carcinoma is positive for mCEA, CA19-9, B72.3, CK7, and CK20 (52%)

Acinar Cell Carcinoma ♦♦ Diastase PAS special stain demonstrates the cytoplasmic zymogen granules

Verification Panel ♦♦ Pankeratin, a-1-antitrypsin, lipase, trypsin, and chymotrypsin stain the tumor cell cytoplasm ♦♦ CK7, CA19-9, and mCEA are negative

Differential Diagnosis ♦♦ Ductal adenocarcinoma is positive for CK7, CA19-9, and mCEA and negative for a-1-antitrypsin, lipase, trypsin, and chymotrypsin ♦♦ Neuroendocrine tumor is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for a-1-anti­ trypsin, lipase, trypsin, and chymotrypsin ♦♦ Solid pseudopapillary neoplasm is positive for a-1-anti­ trypsin, PR (nuclear), b-catenin (nuclear), and CD56 and negative for pankeratin (weak, focal)

Neuroendocrine Neoplasms ♦♦ Pankeratin stains the tumor cell cytoplasm ♦♦ Synaptophysin, chromogranin (61%), and CD56 stain the cytoplasm focally or diffusely ♦♦ Chymotrypsin (30%) and a-1-antitrypsin (38%) are focally positive ♦♦ Hormone markers can identify the cell type; this is most useful for identifying insulinoma due to its better prognosis

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Differential Diagnosis ♦♦ Acinar cell carcinoma is positive for pankeratin, synaptophysin (67%), a-1-antitrypsin, lipase, trypsin, and chymotrypsin; some cases are positive for CD56 (17%); and negative for chromogranin ♦♦ Invasive ductal carcinoma is positive for pankeratin and negative for synaptophysin, chromogranin, and CD56 ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for pankeratin, synaptophysin, and chromogranin

Solid Pseudopapillary Neoplasm Verification Panel (Fig. 2.17) ♦♦ PR and b-catenin stain the tumor cell nuclei; PR also stains the benign islet cells ♦♦ CD10 stains the tumor cell membranes and cytoplasm ♦♦ Pankeratin shows focal weak or negative tumor cell cytoplasmic staining

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ a-1-antitrypsin, synaptophysin, vimentin, and CD56 stain the tumor cell cytoplasm ♦♦ Chromogranin is negative in the tumor cells

Differential Diagnosis ♦♦ Acinar cell carcinoma is positive for pankeratin, synaptophysin (67%), a-1-antitrypsin, lipase, trypsin, and chymotrypsin; some cases are positive for CD56 (17%); and negative for PR (nuclear) and b-catenin (nuclear) ♦♦ Invasive ductal carcinoma is diffusely positive for pankeratin and negative for PR (nuclear), b-catenin (nuclear), a-1-antitrypsin, synaptophysin, and CD56 ♦♦ Neuroendocrine tumor is positive for pankeratin, chromogranin, synaptophysin, a-1-antitrypsin, and CD56 and ­negative for PR (nuclear) and b-catenin (nuclear) ♦♦ Pancreatoblastoma is differentiated by morphology −− Immunostains are not necessary or useful for this tumor, which contains distinctive squamous corpuscles and is composed of ductal, acinar, and neuroendocrine elements

Fig. 2.17. (A–D) Pankeratin stains the cytoplasm (weakly) and trypsin stains the intracytoplasmic globules in a solid pseudopapillary neoplasm. PR stains the nuclei of tumor cells (left) and benign islets (right).

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Immunohistochemical Diagnosis in Surgical Pathology

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Gallbladder and Extrahepatic Bile Ducts

♦♦ Adenomyoma contains benign glands into or beyond the muscle layer; this is differentiated by morphology; IHC is not helpful ♦♦ Dysplasia in Rokitansky–Aschoff sinuses extends into or beyond the muscle layer; this is differentiated by morphology; IHC is not helpful

♦♦ These two tumors along with cholangiocarcinoma (intrahepatic bile duct carcinoma) show the same IHC staining pattern

Adenocarcinoma

Verification Panel

♦♦ IHC is usually unnecessary; diagnosis is made by location and associated dysplasia. IHC does not distinguish this neoplasm from others that arise from the biliary tree

♦♦ CK7, CK20 (23%), CA19-9, CDX2, and CEA are positive in the tumor cell cytoplasm

GENITOURINARY SYSTEM Kidney Pediatric Tumors Wilms Tumor (Nephroblastoma) Verification Panel

♦♦ Neuroblastoma is positive for CD56, synaptophysin, and chromogranin and negative for WT1 (nuclear)

Clear Cell Sarcoma of the Kidney ♦♦ IHC is not useful for identification, but can rule out other entities. Diagnosis is based on morphology

♦♦ WT1 stains the tumor cell nuclei ♦♦ Pankeratin, SMA, and vimentin focally stain the cytoplasm of the epithelial, smooth muscle, and mesenchymal components, respectively ♦♦ CD56 stains the tumor cell membranes and cytoplasm

Verification Panel ♦♦ Vimentin and bcl-2 stain tumor cell cytoplasm ♦♦ Tumor nuclei are negative for WT1 ♦♦ Tumor cells are negative for pankeratin and desmin

Differential Diagnosis (Table 2.8)

Differential Diagnosis (Table 2.8)

♦♦ Clear cell sarcoma of the kidney is negative for WT1 (nuclear) and positive for vimentin ♦♦ Metanephric adenoma is positive for WT1 (nuclear) and is differentiated by morphology (lack of blastemal element)

♦♦ Wilms tumor is positive for WT1 (nuclear) ♦♦ Conventional renal cell carcinoma is positive for pankeratin (focal), vimentin, RCC Ma, and CD10 and negative for bcl-2

Table 2.8. Pediatric Renal Neoplasms Differential Diagnosis (Bolded are Most Useful) INI1a

CD56

Synaptophysin, Chromogranin

WT1a

Vimentin

Fli-1a

Wilms tumor

+

+

+

+

−

−

Clear cell sarcoma

−

+

+

−

−

−

Rhabdoid tumor

−

+

−

NA

–

−

Neuroblastoma

−

−

+

+

+

−

PNET/Ewing sarcoma

−

−

+

−

−

+

Mesoblastic nephroma

+

+

NA

NA

NA

NA

Nuclear staining; INI1 is abnormal when staining is lost NA not available

a

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♦♦ Mesoblastic nephroma is positive for vimentin, MSA, SMA, and WT1 (nuclear)

Rhabdoid Tumor of the Kidney Verification Panel ♦♦ Vimentin (strongly and diffusely) and pankeratin (focally) stain the tumor cell cytoplasm ♦♦ EMA focally stains the membranes of the tumor cells ♦♦ INI1 is negative (loss of normal nuclear staining)

Differential Diagnosis (Table 2.8) ♦♦ Neuroblastoma is positive for synaptophysin, chromogranin, CD56, and INI1 (nuclear) ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear), CD99 (membranous), and INI1 (nuclear) ♦♦ Wilms tumor is positive for WT1 (nuclear) and INI1 (nuclear) ♦♦ Clear cell sarcoma is positive for INI1 (nuclear)

Neuroblastoma Verification Panel ♦♦ Synaptophysin, chromogranin, and S-100 are positive in the tumor cell cytoplasm ♦♦ CD56 stains the tumor cell membranes and cytoplasm

Differential Diagnosis (Table 2.8) ♦♦ Rhabdoid tumor of the kidney is negative for INI1 (loss of nuclear staining), synaptophysin, chromogranin, and S-100 and is positive focally for EMA ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous) and negative for synaptophysin and chromogranin

Differential Diagnosis (Table 2.8) ♦♦ Rhabdoid tumor of the kidney is negative for Fli-1 (nuclear), CD99 (membranous), and INI1 (loss of nuclear staining) ♦♦ Neuroblastoma is positive for CD56, synaptophysin, and chromogranin and negative for Fli-1 (nuclear) and CD99 (membranous)

Congenital Mesoblastic Nephroma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

WT1 stains the tumor cell nuclei Vimentin focally stains the tumor cell cytoplasm MSA and SMA focally stain the cytoplasm in most tumors Desmin focally stains the cytoplasm in rare tumors Tumor cells are negative for CD34, S-100, and keratins

Differential Diagnosis (Table 2.8) ♦♦ Clear cell sarcoma of the kidney is negative for MSA, SMA, desmin, and WT1 (nuclear) ♦♦ Wilms tumor is positive for WT1 (nuclear) and can be focally positive for actins. Pankeratin can identify the epithelial elements. Diagnosis is based on malignant and primitive morphology

Adult Epithelial Tumors Oncocytoma Verification Panel ♦♦ CK20 and CD117 stain the tumor cell and cytoplasm ♦♦ CD10 (29–58%) and LeuM1 (57%) stain tumor cell membranes and cytoplasm in some cases ♦♦ RCC Ma, vimentin, and CK7 are negative

Differential Diagnosis (Table 2.9)

Ewing Sarcoma/Peripheral Neuroectodermal Tumor Verification Panel ♦♦ Fli-1 is positive in the tumor and benign endothelial cell nuclei ♦♦ CD99 is positive in the membranes of the tumor cells (cytoplasmic staining is a nonspecific finding) ♦♦ CD56 stains rare tumors (9%)

♦♦ Chromophobe carcinoma is positive for CK7 and CD117 and negative for LeuM1, CK20, RCC Ma, CD10, and vimentin ♦♦ Conventional renal cell carcinoma is positive for RCC Ma, vimentin, CD10, and LeuM1 and negative for CD117 and CK7 ♦♦ Papillary carcinoma is positive for AMACR, RCC Ma, CD10, vimentin, and CK7 and negative for CD117

Table 2.9. Renal Epithelial Neoplasms Differential Diagnosis (% Positive Tumors, Bolded are Most Useful) RCC Ma

CD10

Vimentin

CK7

Conventional RCC

80–86

94–100

59–100

5–11

0

60

40

Papillary RCC

80–93

67–93

84

81

18

40

23

Chromophobe RCC

0–13

0–72

0

63–86

82–100

12

0

Oncocytoma

0

29–58

0

0–7

100

57

10

Urothelial carcinoma

0

0

0

100

43

34

100

142

CD117

LeuM1

CK 34be12

Immunohistochemical Diagnosis in Surgical Pathology

Conventional Type Renal Cell Carcinoma (Clear and Granular Cell) Verification Panel (Fig. 2.18) ♦♦ RCC Ma, EMA, and CD10 stain the tumor cell membranes and cytoplasm

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♦♦ Vimentin (diffusely) and pankeratin (focally) stain the tumor cell cytoplasm ♦♦ CK7 focally stains some cases (11%) ♦♦ CD117 is negative

Fig.  2.18. (A–E) CD10 and EMA stain the membranes and cytoplasm and vimentin stains the cytoplasm of a clear cell renal cell carcinoma. Pankeratin is usually weak and focal.

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Differential Diagnosis (Table 2.9) ♦♦ Chromophobe carcinoma is positive for CD117 and CK7 and negative for RCC Ma, CD10, and vimentin ♦♦ Oncocytoma is positive for CD117 and negative for RCC Ma, CD10, vimentin, and CK7 ♦♦ Xanthogranulomatous pyelonephritis is positive for CD68, CD10, and S-100 and negative for RCC Ma

Chromophobe Renal Cell Carcinoma Verification Panel ♦♦ CD117 stains the tumor cell membranes and cytoplasm ♦♦ CK7 (63–86%) and CD10 (0–72%) stain tumor cell membranes and cytoplasm in many cases ♦♦ RCC Ma, vimentin, and LeuM1 are negative

Differential Diagnosis (Table 2.9) ♦♦ Oncocytoma is positive for LeuM1, CK20, and CD117 and negative for CK7, RCC Ma, CD10, and vimentin ♦♦ Conventional renal cell carcinoma is positive for RCC Ma, vimentin, CD10, and LeuM1; some cases are focally positive for CK7 (11%); and negative for CD117 ♦♦ Papillary carcinoma is positive for AMACR, RCC Ma, CD10, vimentin and CK7 and negative for CD117

Papillary Renal Cell Carcinoma Verification Panel ♦♦ AMACR, RCC Ma, and CD10 stain the tumor cell ­membranes and cytoplasm ♦♦ CK7 and vimentin stain the tumor cell cytoplasm ♦♦ CD117 and WT1 (nuclear) are negative

Differential Diagnosis (Table 2.9) ♦♦ Chromophobe carcinoma is positive for CD117 and CK7 and negative for AMACR, RCC Ma, CD10, and vimentin ♦♦ Oncocytoma is positive for CD117 and CK20 and negative for CK7, AMACR, RCC Ma, CD10, and vimentin ♦♦ Conventional renal cell carcinoma is positive for RCC Ma, vimentin, and CD10; some cases are focally positive for CK7 (11%); and negative for AMACR ♦♦ Metanephric adenoma is positive for WT1 (nuclear)

Collecting Duct Carcinoma Verification Panel

Essentials of Anatomic Pathology, 3rd Ed.

Renal Medullary Carcinoma Verification Panel ♦♦ CK7, AE1/AE3, and vimentin stain the tumor cell cytoplasm ♦♦ mCEA stains the tumor cell membranes and cytoplasm ♦♦ INI1 is negative (loss of nuclear staining, 41%)

Differential Diagnosis ♦♦ Collecting duct carcinoma is negative for mCEA ♦♦ Conventional clear cell renal cell carcinoma is positive for INI1 (nuclear) and some cases are focally positive for CK7 (11%)

Mucinous Tubular and Spindle Cell Carcinoma Verification Panel ♦♦ AMACR and EMA stain the tumor cell membranes and cytoplasm ♦♦ CK7 stains the tumor cell cytoplasm ♦♦ RCC Ma, CD10, CD117, and WT1 (nuclear) are negative

Differential Diagnosis ♦♦ Metanephric adenoma is positive for WT1 and negative for EMA and CK7 ♦♦ Papillary carcinoma is positive for RCC Ma, CD10, EMA, AMACR, and CK7 and negative for CD117 ♦♦ Angiomyolipoma is positive for HMB 45 and negative for CK7

Urothelial Carcinoma Verification Panel ♦♦ CK7, CK20, and CK34be12 stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p53 stains the nuclei of high grade tumors

Differential Diagnosis (Table 2.9) ♦♦ Conventional clear cell renal cell carcinoma is positive for RCC Ma, CD10, vimentin, and pankeratin and negative for CK34be12 and p63 (nuclear)

Miscellaneous Tumors Metanephric Adenoma Verification Panel ♦♦ WT1 stains the tumor cell nuclei ♦♦ EMA and CK7 are negative

Differential Diagnosis

♦♦ Pankeratin and vimentin stain the tumor cell cytoplasm ♦♦ CK7 (58%) and RCC Ma (40%) stain some tumors ♦♦ CD10, CD117 and AMACR are negative

♦♦ Papillary carcinoma is positive for CK7 and negative for WT1 (nuclear) ♦♦ Wilms tumor is differentiated by the triphasic elements and malignant appearance; IHC is not useful

Differential Diagnosis

Renomedullary Interstitial Cell Tumor (Medullary Fibroma)

♦♦ Conventional renal cell carcinoma is positive for CD10, RCC Ma, and pankeratin and some cases are focally positive for CK7 (11%) ♦♦ Metastatic carcinoma is positive for pankeratin and negative for vimentin and RCC Ma

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♦♦ The diagnosis is based on morphology and clinical findings

Verification Panel ♦♦ COX-2 stains the tumor cell cytoplasm

Immunohistochemical Diagnosis in Surgical Pathology

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Angiomyolipoma Verification Panel (Fig. 2.19) ♦♦ HMB 45, Melan-A, SMA, MSA, and desmin are positive in the cytoplasm of the spindle and epithelioid tumor cells ♦♦ Keratins, EMA, and S-100 are negative (S-100 stains the adipose elements)

Differential Diagnosis ♦♦ Adipose tumors (e.g., liposarcoma) are positive for S-100 and negative for HMB 45, Melan-A, SMA, MSA, and desmin ♦♦ Leiomyoma and leiomyosarcoma are positive for MSA, SMA, and desmin and negative for HMB 45 and Melan-A

Juxtaglomerular Cell Tumor Verification Panel ♦♦ CD34, actin, renin, and vimentin stain the cytoplasm of the tumor cells

Differential Diagnosis ♦♦ Hemangiopericytoma is positive for CD34 and vimentin; some cases are positive for actin; and negative for renin

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Pankeratin can stain the tumor cell cytoplasm focally (40%)

Differential Diagnosis ♦♦ Sarcomatoid renal cell carcinoma is focally positive for CD10 and pankeratin and negative for SMA, MSA, and desmin ♦♦ Angiomyolipoma is positive for SMA, MSA, desmin, HMB 45, and Melan-A and negative for pankeratin ♦♦ Inflammatory myofibroblastic tumor is focally positive for SMA, MSA, desmin, pankeratin, and ALK (57%)

Other Mesenchymal Tumors ♦♦ Other renal mesenchymal tumors include solitary fibrous tumor/hemangiopericytoma, synovial sarcoma, Ewing sarcoma, and neuroblastoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Primary lymphoma of the kidney is extremely rare and is most commonly a CD20 positive B-cell posttransplant proliferative disorder. Refer to the lymphoma section and the lymph node chapter for further discussion

Adrenal Gland Cortical Adenoma and Carcinoma Verification Panel

Fig. 2.19. (A–C) HMB 45 and MSA stain the cytoplasm of an angiomyolipoma in a typical pattern swirling around the vessels.

♦♦ Inhibin, Melan-A, calretinin, and synaptophysin stain the tumor cell cytoplasm ♦♦ Chromogranin is negative

♦♦ Pankeratin focally stains the tumor cell cytoplasm in some cases (29%)

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Differential Diagnosis ♦♦ Pheochromocytoma is positive for synaptophysin and chromogranin and negative for inhibin, Melan-A, and calretinin ♦♦ Metastatic renal cell carcinoma is positive for RCC Ma and CD10 and negative for inhibin and Melan-A ♦♦ Metastatic carcinoma is strongly positive for pankeratin

Pheochromocytoma Verification Panel ♦♦ Chromogranin and synaptophysin stain the tumor cell cytoplasm ♦♦ Pankeratin focally stains the tumor cell cytoplasm in some cases (18%)

Differential Diagnosis ♦♦ Cortical nodules, adenoma, and carcinoma are negative for chromogranin and positive for synaptophysin, inhibin, Melan-A, and calretinin

Neuroblastoma Verification Panel ♦♦ Chromogranin, synaptophysin, and calretinin stain the tumor cell cytoplasm ♦♦ CD56 stains the tumor cell membranes and cytoplasm

Differential Diagnosis ♦♦ Pheochromocytoma is positive for chromogranin, synaptophysin and CD56 and negative for calretinin ♦♦ Metastatic carcinoma is positive for pankeratin

Metastatic Disease Verification Panel ♦♦ The most common tumors to metastasize to the adrenal gland are lung, breast, and kidney. Refer to Chapter 3 for further discussion

Urinary Bladder Nephrogenic Adenoma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CK7 stains the tumor cell cytoplasm PAX2 stains the tumor cell nuclei AMACR stains the tumor cell membranes and cytoplasm CD10, p63, and CK34be12 focally stain some tumors PSA, PAP, and CA125 are negative

Differential Diagnosis (Table 2.10) ♦♦ Clear cell adenocarcinoma is positive for CK20, CA125, CK7, and CK34be12 ♦♦ Urothelial adenocarcinoma is positive for CDX2 (nuclear), villin, CK20, AMACR, CK7, and CK34be12 ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR; some cases positive for CK7 (10%); and negative for CK34be12

Endocervicosis and Endometriosis (Müllerianosis) ♦♦ The infiltrating glands show a benign morphology lacking a desmoplastic response

Table 2.10. Urinary Bladder Epithelial Neoplasms Differential Diagnosis (% Positive Tumors, Bolded are Most Useful) PSA/PAP/ AMACR Urothelial carcinoma, usual and clear cell

0/0/0

CK7/CK20 86–100/40–66

CDX2a/ Villin 2/0

HMWK 65–100

CA125 0–35

p63a 83

Primary urothelial adenocarcinoma

0/0/65

62–80/53–80

22–50/74–100

100

0–60

NA

Urachal adenocarcinoma

NA

53/100

100/100

67

0

NA

Nephrogenic adenoma

0–36/0–50/100

100/0

NA/NA

25–55

0

0

Urothelial clear cell adenocarcinoma

0/0/83–100

90–100/25–50

0/NA

100

75–100

0

Prostatic adenocarcinoma

85–100/95/82–100

27/10

0/1

8

0

0

Colorectal carcinoma

0/NA/45–81

0–4/94–100

97–100/90–100

0

0–12

1

Seminal vesicle adenocarcinoma

0/0/0

75/0

0/NA

NA

75

NA

a

Nuclear stains

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Verification Panel

Differential Diagnosis (Table 2.10)

♦♦ ♦♦ ♦♦ ♦♦

♦♦ Nephrogenic adenoma is positive for AMACR, PAX2, and CK7 and negative for CK20 and p63 ♦♦ Clear cell urothelial adenocarcinoma is positive for AMACR, CK7, CK20, CK34be12, and CA125 and negative for p63

Endometriosis includes CD10 positive stromal cells ER and/or PR stain the glandular cell nuclei CA125 and CK7 stain the glandular cell cytoplasm Ki-67 shows a proliferation rate similar to normal ­endocervix (15%)

Differential Diagnosis

Clear Cell Adenocarcinoma Verification Panel

♦♦ Clear cell adenocarcinoma is positive for CK20, CA125, CK7, and CK34be12 and negative for ER and PR ♦♦ Urothelial adenocarcinoma is positive for CDX2 (nuclear), villin, CK20, AMACR, CK7, CA125 (60%), and CK34be12

♦♦ CK7, CK20 (25–50%), and CK34be12 stain the tumor cell cytoplasm ♦♦ AMACR, CD10 (42%), and CA125 stains the tumor cell membranes and cytoplasm

Urothelial Carcinoma Verification Panel

Differential Diagnosis (Table 2.10)

♦♦ CK7, CK20, and CK34be12 stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p53 stains the nuclei of high grade tumors

Differential Diagnosis (Table 2.10) ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 (nuclear) and CK34be12

Adenocarcinoma of the Urinary Bladder Verification Panel ♦♦ CK7, CK20, CA125, CK34be12, and villin stain the tumor cell cytoplasm ♦♦ CDX2 stains the tumor cell nuclei (50%) ♦♦ AMACR stains the tumor cell cytoplasm (65%)

Differential Diagnosis (Table 2.10) ♦♦ Nephrogenic adenoma is positive for AMACR and PAX2 and negative for CK20 and CA125 ♦♦ Clear cell adenocarcinoma is positive for AMACR, CK7, CK20, and CA125 and negative for CDX2 (nuclear) ♦♦ Colorectal adenocarcinoma is positive for AMACR, CD20, villin, and CDX2 (nuclear); some cases are focally positive for CK7 (27%); and negative for CA125 ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for CK34be12 and CA125 ♦♦ Cystitis glandularis is positive for CK7 and negative for CK20 and CDX2 (nuclear) ♦♦ Müllerianosis is positive for CK7, CA125, and ER/PR (nuclear) and negative for CK20

Clear Cell Carcinoma (Urothelial Carcinoma, Clear Cell or Glycogen-rich Type) Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

CK7, CK20, and CK34be12 stain the tumor cell cytoplasm p63 stains the tumor cell nuclei p53 stains the nuclei of high grade tumors CA125 is usually negative (0–35%)

♦♦ Nephrogenic adenoma is positive for AMACR, PAX2, and CK7 and negative for CK20 and CA125 ♦♦ Clear cell urothelial (glycogen-rich) carcinoma is positive for CK7, CK20, CK34be12, and p63 and negative for CA125

Small Cell Carcinoma Verification Panel ♦♦ Pankeratin shows punctuate or diffuse tumor cell cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 (membranocytoplasmic) is more sensitive for neuro­ endocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology and keratin staining

Differential Diagnosis ♦♦ Rhabdomyosarcoma is positive for CD56, desmin, myogenin, and Myo-D1 and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for pankeratin, chromogranin, and synaptophysin

Sarcomatoid Carcinoma Verification Panel ♦♦ HMWK (CK34be12, CK5/6) and pankeratin stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ SMA is focally positive in many tumors (40–73%)

Differential Diagnosis ♦♦ Inflammatory myofibroblastic tumor is focally positive for pankeratin, SMA, MSA, desmin, and ALK (57%) and negative for HMWK and p63 (nuclear) ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin; focally positive for pankeratin (58%) and p63 (nuclear); and negative for HMWK

Postoperative Spindle Cell Nodule ♦♦ Diagnosis is based on clinical history, tumor size, and lack of significant pleomorphism

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Verification Panel

Lymphoma

♦♦ SMA focally stains the tumor cell cytoplasm ♦♦ Pankeratin focally stains some tumors

♦♦ Most lymphomas show CD45 membranous staining; most are CD20 positive B-cell types. The most common primary type is CD20 positive extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). The most common secondary type is diffuse large B-cell lymphoma. Refer to the lymphoma section and the lymph node chapter for further discussion

Differential Diagnosis ♦♦ Leiomyosarcoma is strongly positive for SMA, MSA, and desmin ♦♦ Sarcomatoid carcinoma is more strongly positive for pankeratin and focally positive for SMA (40%)

Inflammatory Myofibroblastic Tumor Verification Panel ♦♦ ALK stains the tumor cell cytoplasm. This is the most specific marker, but stains only 57% of cases ♦♦ SMA, MSA, desmin, and keratin focally stain the tumor cell cytoplasm

Differential Diagnosis ♦♦ Leiomyosarcoma and fibrosarcoma are differentiated by infiltrative growth, increased atypia and atypical mitotic figures. Leiomyosarcoma is negative for ALK and strongly positive for SMA, MSA, and desmin. Fibrosarcoma stains only with vimentin ♦♦ Sarcomatoid carcinoma is positive for pankeratin, HMWK (CK34be12, CK5/6), and p63 (nuclear); positive for SMA in some cases (40%); and negative for ALK

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Pankeratin focally stains the cytoplasm (58%)

Differential Diagnosis ♦♦ Sarcomatoid carcinoma is positive for SMA, pankeratin, HMWK (CK34be12, CK5/6), and p63 (nuclear) and negative for MSA and desmin

Rhabdomyosarcoma Verification Panel ♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei ♦♦ CD56 stains the tumor cell membranes and cytoplasm

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Small cell carcinoma is positive for pankeratin (dot-like pattern) and chromogranin, synaptophysin, and CD56 and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Other Mesenchymal Tumors ♦♦ Other urinary bladder mesenchymal tumors include neurofiroma, granular cell tumor, hemangioma, solitary  fibrous tumor/hemangiopericytoma, Kaposi sarcoma, angiosarcoma, osteosarcoma, and malignant fibrous histiocytoma (undifferentiated high grade pleomorphic sarcoma). Refer to the mesenchymal section and Chapter 3 for further discussion

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Metastatic Disease (Table 2.10) ♦♦ The most common tumors to metastasize to the urinary bladder are colon (some by direct invasion), prostate, rectum, uterine cervix, and rarely stomach, skin (melanoma), breast, and lung. Refer to Chapter 3 for further discussion

Prostate Gland Benign Prostatic Hyperplasia Verification Panel ♦♦ CK34be12 stains the basal cell cytoplasm and p63 stains the basal cell nuclei ♦♦ PSA and PAP stain the glandular cell cytoplasm ♦♦ AMACR is negative in the hyperplastic glandular cells

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for AMACR and is negative for CK34be12 and p63 (due to the lack of basal cells) ♦♦ Prostatic intraepithelial neoplasia is positive for AMACR and is lined by CK34be12 and p63 positive basal cells (can be discontinuous)

Basal Cell Hyperplasia Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

CK34be12 stains the cell cytoplasm p63 stains the cell nuclei AMACR is usually negative PSA and PAP are negative

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 and CK34be12 (due to the lack of basal cells) ♦♦ Urothelial carcinoma is positive for CK34be12 and p63 and negative for AMACR

Sclerosing Adenosis Verification Panel ♦♦ CK34be12 stains the basal cell cytoplasm and p63 stains the basal cell nuclei ♦♦ PSA and PAP stain the glandular cell cytoplasm ♦♦ AMACR is negative

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 and CK34be12 (due to the lack of basal cells)

Immunohistochemical Diagnosis in Surgical Pathology

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Atypical Adenomatous Hyperplasia Verification Panel ♦♦ CK34be12 stains the basal cell cytoplasm and p63 stains the basal cell nuclei (can be discontinuous/patchy) ♦♦ AMACR stains some glands (25%)

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 and CK34be12 (due to the lack of basal cells)

Atypical Small Acinar Proliferation ♦♦ This lesion lacks the definitive morphology or IHC pattern of adenocarcinoma

Verification Panel ♦♦ CK34be12 is negative or equivocal in the basal cells ♦♦ p63 (nuclear) is negative or equivocal in the basal cells ♦♦ AMACR is negative or equivocal in the glandular cells

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for AMACR and negative for p63 (nuclear) and CK34be12 (due to the lack of basal cells) ♦♦ Prostatic glandular hyperplasia contains basal cells and is positive for p63 (nuclear) and CK34be12 and negative for AMACR

Androgen Deprivation and Radiation Therapy Changes Verification Panel ♦♦ CK34be12 stains the basal cell cytoplasm and p63 stains the basal cell nuclei (can be discontinuous/patchy) ♦♦ PSA and PAP stain the glandular cell cytoplasm ♦♦ AMACR is negative in the cells

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 and CK34be12 (due to the lack of basal cells)

Prostatic Adenocarcinoma Verification Panel (Fig. 2.20) ♦♦ AMACR stains the tumor cell membranes and cytoplasm ♦♦ PSA and PAP stain the tumor cell cytoplasm ♦♦ CK34be12 and p63 (nuclear) are negative due to the lack of basal cells

Differential Diagnosis ♦♦ Atrophy, basal cell hyperplasia, sclerosing adenosis, and atypical reactive changes contain basal cells that are positive for p63 (nuclear) and CK34be12. The glandular cells are negative for AMACR ♦♦ Atypical adenomatous hyperplasia can be focally positive for AMACR and equivocal for p63 (nuclear) and CK34be12

Fig.  2.20. (A) The CK34bE12-AMACR cocktail stains the basal cells (brown, CK34bE12) and the neoplastic glandular cells (red, AMACR) in high grade prostatic intraepithelial ­neoplasia. (B)  The CK34bE12-AMACR cocktail stains the basal cells (brown, CK34bE12) in benign glands (lower right) and the eoplastic glandular cells (red, AMACR) in carcinoma (upper left).

♦♦ Nephrogenic adenoma is positive for AMACR, CK7, and PAX2 (nuclear) and negative for PSA and PAP ♦♦ Urothelial adenocarcinoma is positive for p63 (nuclear) and CK34be12 and negative for PSA, PAP, and AMACR ♦♦ Mesonephric remnants are positive for CK34be12 and negative for PSA and PAP ♦♦ Seminal vesicle tissue is PSA, PAP, and AMACR negative

Adenoid Cystic/Basal Cell Carcinoma Verification Panel ♦♦ CK34be12 stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ PSA and PAP are negative

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Differential Diagnosis ♦♦ Basal cell adenoma is differentiated by morphology

Urothelial Carcinoma Verification Panel ♦♦ CK7, CK20, and CK34be12 stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p53 stains the nuclei of high grade tumors

Differential Diagnosis ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 (nuclear) and CK34be12

Mucinous (Urothelial Type) Adenocarcinoma Arising in the Prostate Verification Panel ♦♦ CK7, CK20, and CK34be12 stain the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ PSA and PAP are negative

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Pankeratin, PSA, and PAP stain the epithelial tumor cell cytoplasm

Differential Diagnosis ♦♦ Leiomyosarcoma lacks the PSA- and PAP positive ­epithelial component ♦♦ Prostatic stromal hyperplasia lacks the epithelial component

Other Mesenchymal Tumors ♦♦ Other prostatic mesenchymal tumors include fibroma, ­solitary fibrous tumor/hemangiopericytoma, granular cell tumor, hem‑ angioma, chondroma, stromal sarcoma, rhabdomyosarcoma, malignant peripheral nerve sheath tumor, ­osteosarcoma, chondrosarcoma, and synovial sarcoma. Refer to the ­mesen‑ chymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Primary lymphoma is rare and most lymphomas show CD45 membranous staining. Most are CD20 positive diffuse large B-cell lymphomas. Refer to the lymph node section of this chapter and the chapter on lymphoma for further discussion

♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR and negative for p63 and CK34be12 ♦♦ Colorectal adenocarcinoma is positive for CDX2 (nuclear) and CK20; some cases are focally positive for CK7 (27%); and negative for PSA, PAP, and p63 (nuclear) ♦♦ Cowper glands are focally positive for PSA and negative for PAP and CK34be12 (focally stains ducts and acinar lining cells, but not the mucinous glandular cells)

Testis Adenomatoid Tumor Verification Panel (Fig. 2.21)

Seminal Vesicle Adenocarcinoma Verification Panel

Differential Diagnosis

♦♦ CK7 and CA125 stain the tumor cell cytoplasm ♦♦ PSA, PAP, AMACR, and CK20 are negative

Differential Diagnosis (Table 2.10) ♦♦ Prostatic adenocarcinoma is positive for PSA, PAP, and AMACR; few cases are positive for CK7 (10%); and negative for CA125

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Pankeratin can focally stain the tumor cell cytoplasm (40%)

Differential Diagnosis ♦♦ Sarcomatoid carcinoma is more strongly positive for keratin and is usually negative for SMA, MSA, and desmin ♦♦ Postoperative spindle cell nodule is differentiated by clinical history, tumor size, and lack of significant pleomorphism

Phyllodes Tumor ♦♦ SMA, MSA, and desmin stain the stromal tumor cell cytoplasm

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♦♦ Calretinin, pankeratin, and CK5/6 stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei

♦♦ Adenocarcinoma is negative for calretinin and WT1 (nuclear) and positive for B72.3, CEA, and Ber-EP4 ♦♦ Mesothelioma is differentiated by malignant morphology

Germ Cell Tumors Seminoma Verification Panel (Fig. 2.22) ♦♦ PLAP and CD117 stain the tumor cell membranes and cytoplasm ♦♦ OCT4 stains the tumor cell nuclei ♦♦ Scattered syncytiotrophoblastic giant cells are βhCG and pankeratin positive ♦♦ CD45 stains the tumor-associated lymphoid cells ♦♦ Pankeratin is negative or weak and focal (30%)

Differential Diagnosis (Table 2.11) ♦♦ Yolk sac tumor is positive for keratin, aFP, and a-1-­ antitrypsin; some cases are positive for PLAP (50%); and negative for CD117 and OCT4 (nuclear) ♦♦ Embryonal carcinoma is positive for PLAP, OCT4 (nuclear), pankeratin, and CD30 and negative for CD117 ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for PLAP

Immunohistochemical Diagnosis in Surgical Pathology

Fig. 2.21. (A, B) Calretinin stains the nuclei and cytoplasm of a testicular adenomatoid tumor.

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Fig. 2.22. (A, B) PLAP stains the membranes and cytoplasm of a seminoma.

Table 2.11. Testicular Germ Cell Tumors Differential Diagnosis (% Positive Tumors) Pankeratin

PLAP

AFP

CD30

βhCG

Calretinin

Seminoma

−

+

−

−

−a

−

Yolk sac tumor

+

40

+

−

−a

−

Embryonal carcinoma

+

+

30

+

−

a

−

Choriocarcinoma

+

36

−

−

+

−

Sex cord/stromal tumors

−

−

−

−

−

+

a

βhCG stains syncytiocytotrophoblasts associated with the tumor

♦♦ Spermacytic seminoma is sometimes positive for CD117 (40%) and PLAP (20%) and negative for OCT4 (nuclear). It  does not contain the CD45 positive lymphoid component

Spermacytic Seminoma Verification Panel ♦♦ CD117 (40%) and PLAP (20%) focally stain the tumor cell membranes and cytoplasm in some cases

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♦♦ OCT4 (nuclear) is negative ♦♦ CAM 5.2 shows dot-like positivity is some cases (40%)

Differential Diagnosis ♦♦ Classic seminoma is positive for OCT4 (nuclear), PLAP, and CD117 ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 ♦♦ Metastatic carcinoma is positive for pankeratin and negative for CD117

Yolk Sac Tumor (Endodermal Sinus Tumor) Verification Panel ♦♦ Pankeratin, aFP, and a-1-antitrypsin stain the tumor cell cytoplasm ♦♦ PLAP shows membranous staining in 50% of tumors ♦♦ OCT4 (nuclear), CK117, and calretinin are negative

Differential Diagnosis (Table 2.11) ♦♦ Seminoma is positive for PLAP, OCT4 (nuclear), and CD117; some cases are focally positive for pankeratin (30%); and negative for aFP and a-1-antitrypsin

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Embryonal carcinoma is positive for PLAP, OCT4 (nuclear), pankeratin, and CD30; some cases are positive for aFP; and negative for a-1-antitrypsin ♦♦ Juvenile granulosa cell tumor is positive for calretinin and inhibin and negative for aFP and a-1-antitrypsin

Embryonal Carcinoma Verification Panel (Fig. 2.23) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Pankeratin stains the tumor cell cytoplasm CD30 and PLAP stain the tumor cell membranes and cytoplasm OCT4 stains the tumor cell nuclei aFP is focally positive in some tumors (22%) CD117 is negative

Differential Diagnosis (Table 2.11) ♦♦ Yolk sac tumor is focally positive for PLAP (50%), pankeratin, aFP, and a-1-antitrypsin and negative for OCT4 (nuclear) and CD30 ♦♦ Seminoma is positive for PLAP, OCT4 (nuclear), and CD117; some cases are focally positive for pankeratin (30%); and negative for CD30

Fig.  2.23. (A–D) Pankeratin stains the cytoplasm and CD30 and PLAP stain the membranes and cytoplasm of an embryonal carcinoma.

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Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Choriocarcinoma is positive for pankeratin, PLAP and βhCG and negative for OCT4 (nuclear) and CD30 ♦♦ Anaplastic large cell lymphoma is positive for CD30, TIA1, and ALK; variably positive for CD45; and negative for PLAP

Choriocarcinoma Verification Panel ♦♦ Pankeratin, βhCG, and PLAP stain the tumor cell cytoplasm

Differential Diagnosis (Table 2.11) ♦♦ Seminoma is positive for PLAP, OCT4 (nuclear), and CD117 and negative for pankeratin and βhCG (positive in syncytio­ cytotrophoblasts) ♦♦ Embryonal carcinoma is positive for pankeratin, βhCG (25%), CD30, and OCT4 (nuclear)

Sex Cord Stromal Tumors (Table 2.11) Sertoli Cell Tumor ♦♦ Sertoli cell nodules are differentiated by their small size and circumscription

Verification Panel ♦♦ Calretinin, SMA, and inhibin stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei ♦♦ Pankeratin stains some tumors (25%)

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is strongly positive for pankeratin and negative for calretinin, WT1 (nuclear), and inhibin ♦♦ Seminoma is positive for CD117, OCT4 (nuclear), and PLAP and negative for calretinin and inhibin ♦♦ Leydig cell tumor is positive for calretinin, inhibin, and Melan-A

Leydig Cell Tumor ♦♦ Hyperplastic, benign, and malignant tumors are ­differentiated by morphology

Verification Panel ♦♦ Calretinin, inhibin, and Melan-A stain the tumor cell cytoplasm ♦♦ Pankeratin is weak and focal

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Differential Diagnosis ♦♦ Yolk sac tumor is positive for pankeratin, AFP, and a-1-antitrypsin; some cases are focally positive for PLAP (50%); and negative for calretinin, inhibin, and Melan-A ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for calretinin, inhibin, and Melan-A ♦♦ Malakoplakia is positive for CD68 and S-100 and negative for calretinin, inhibin, and Melan-A

Solitary Fibrous Tumor/Hemangiopericytoma Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm; normal endothelial cells are also positive ♦♦ CD99 and bcl-2 stain the tumor cell membranes and cytoplasm ♦♦ Desmin, MSA, SMA, and S-100 are negative

Differential Diagnosis ♦♦ Schwannoma is strongly positive for S-100. Some tumors are focally positive for EMA (35%) and CD34 (25%) ♦♦ Fibromatosis is negative for CD34 and positive for b-catenin (nuclear) ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, desmin, and bcl-2; some cases are positive for CD34 (17%) and CD99 (27%)

Other Mesenchymal Tumors ♦♦ Other testicular mesenchymal tumors include lipoma, leiomyoma, neurofibroma, granular cell tumor, angiomyofibro‑ blastoma-like tumor, calcifying fibrous tumor, liposarcoma, desmoplastic small round cell tumor, leiomyosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most cases show CD45 membranous staining. Most are CD20 positive systemic large B-cell lymphomas. Rare primary lymphomas are B-cell follicular type. Refer to the section and chapter on lymph node for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the testis are from prostate, lung, skin (melanoma), colon, and kidney. Refer to Chapter 3 for further discussion

GYNECOLOGICAL TRACT Vulva and Vagina Paget Disease of the Vulva Verification Panel ♦♦ CK7, mCEA, and GCDFP-15 stain the tumor cell cytoplasm ♦♦ HER2 stains the tumor cell membranes ♦♦ S-100 focally stains some tumors (45%)

♦♦ HMWK (CK34be12, CK5/6) is negative in the tumor cell cytoplasm, and p63 is negative in the nuclei (background squamous cells are positive for these markers)

Differential Diagnosis ♦♦ High grade squamous dysplasia is positive for p63 (nuclear), CK5/6, and CK34be12 and negative for mCEA, GCDFP-15, and HER2

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♦♦ Melanoma in situ is positive for S-100, HMB 45, and Melan-A and negative for keratins and HER2 ♦♦ Mycosis fungoides is positive for CD3 and negative for CK7, mCEA, GCDFP-15, and HER2 ♦♦ Paget disease associated with colorectal carcinoma is positive for CK7, CK20, and CDX2 (nuclear) and negative for GCDFP-15 and HER2

High Grade Squamous Dysplasia/Carcinoma In Situ/Bowen Disease ♦♦ Diffuse staining with p16 is associated with high risk HPV. Negative or focal staining in the middle and upper cell layers can be seen with low risk HPV

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ Ki-67 shows an increased proliferation rate into the upper one-third of the epithelium ♦♦ p16 diffusely stains the tumor cell nuclei and cytoplasm in HPV-related lesions

Differential Diagnosis ♦♦ Melanoma in situ is positive for S-100, HMB 45, and Melan-A and negative for p63 (nuclear), keratins, mCEA, GCDFP-15, and HER2 ♦♦ Vulvar Paget disease is positive for CK7, mCEA, GCDFP15, and HER2; some are positive for S-100 (45%); and negative for HMWK, HMB 45, and Melan-A ♦♦ Atrophy, transitional metaplasia, and immature squamous metaplasia are negative for p16 and show Ki-67 proliferation limited to the basal layers

Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous ­carcinoma except when diffusely poorly differentiated

Verification Panel ♦♦ HMWK (CK5/6, CK34be12) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p16 is positive in the nuclei and cytoplasm of most HPVrelated carcinomas (vagina 67%, vulva 85%)

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

Differential Diagnosis ♦♦ Squamous cell carcinoma with clear cell change is negative for p53 (nuclear) ♦♦ Yolk sac tumor is positive for aFP and negative for p53 (nuclear) ♦♦ Microglandular hyperplasia is negative for p53 (nuclear) ♦♦ Metastatic renal cell carcinoma is positive for CD10 and RCC Ma ♦♦ Placental site nodule or placental site trophoblastic tumor is positive for pankeratin, βhCG, and hPL

Malignant Melanoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ HMB 45 and Melan-A stain the tumor cell cytoplasm (85%) ♦♦ Pankeratin focally stains the cytoplasm of rare cases (3%)

Differential Diagnosis ♦♦ Carcinoma is diffusely positive for pankeratin; some carcinomas are S-100 positive (19%); and negative for HMB 45 and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56; some cases are positive for S-100 (19%); and negative for HMB 45 and Melan-A ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for HMB 45 and Melan-A ♦♦ A blue nevus is positive for S-100, HMB 45, and Melan-A and must be differentiated based on morphology. A low Ki-67 (nuclear) proliferation rate can help identify a benign blue nevus

Deep Aggressive Angiomyxoma Verification Panel ♦♦ SMA and MSA stain the tumor cell cytoplasm ♦♦ ER and PR stain the tumor cell nuclei ♦♦ Some tumors are positive for desmin and CD34

Differential Diagnosis ♦♦ Angiomyofibroblastoma shows a similar staining pattern (though with less SMA and MSA staining) and must be differentiated based on morphology ♦♦ Superficial angiomyxoma is negative for ER (nuclear), PR (nuclear), and desmin

♦♦ Poorly differentiated adenocarcinoma is positive for mCEA and p16 and negative for CK5/6 and p63 (nuclear) ♦♦ Merkel cell carcinoma is positive for chromogranin, synaptophysin, CD56, and CK20 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for HMWK and p63 (nuclear)

Sarcoma Botryoides (Embryonal Rhabdomyosarcoma)

Clear Cell Carcinoma of the Vagina Verification Panel

♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for desmin, MSA, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for desmin, MSA, myogenin (nuclear), and MyoD1 (nuclear)

♦♦ p53 stains the tumor cell nuclei ♦♦ mCEA, vimentin, and ER/PR (nuclear) are negative

154

♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei

Differential Diagnosis

Immunohistochemical Diagnosis in Surgical Pathology

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tumor, angiomyofibroblastoma, angiofibroma, liposarcoma, low grade endometrial stromal sarcoma, undifferentiated vaginal sarcoma, rhabdomyosarcoma, synovial sarcoma, alveolar soft parts sarcoma, and malignant peripheral nerve sheath tumor. Refer to the mesenchymal section and Chapter 3 for further discussion

♦♦ Small cell carcinoma is positive for pankeratin, ­chromogranin, synaptophysin, and CD56 and negative for desmin, MSA, myogenin (nuclear) and Myo-D1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for desmin, MSA, myogenin (nuclear), and Myo-D1 (nuclear)

Lymphoma

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Pankeratin stains some tumors focally (40%)

Differential Diagnosis ♦♦ Sarcomatoid carcinoma is more strongly positive for keratin; some cases are focally positive for SMA (40%); and negative for MSA and desmin ♦♦ Postsurgical spindle cell nodule shows focal SMA, MSA, and desmin staining, and must be differentiated by clinical history, tumor size, and lack of significant pleomorphism

Postoperative Spindle Cell Nodule ♦♦ Diagnosis is based on clinical history, tumor size, and lack of significant pleomorphism

Verification Panel

♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Primary lymphoma of the vulva and vagina are extremely rare and are usually CD20 positive diffuse large B-cell type. Refer to the lymphoma section and lymph node chapter for further discussion

Metastatic Disease ♦♦ The most common tumors to spread to the vulva and vagina are from gynecological tumors of the cervix, uterus, and ovary. Direct spread or metastasis occur from colorectal and bladder carcinomas. Metastases also originate from the kidney and breast. Refer to Chapter 3 for further discussion

Cervix Mesonephric Remnants, Hyperplasia, and Carcinoma ♦♦ These three entities are differentiated by morphology

♦♦ SMA focally stains the tumor cell cytoplasm ♦♦ Pankeratin focally stains some tumors

Verification Panel

Differential Diagnosis ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin ♦♦ Sarcomatoid carcinoma is more strongly positive for pankeratin and focally positive for SMA (40%)

♦♦ CK34be12, CK7, calretinin, inhibin, and vimentin stain the cell cytoplasm ♦♦ EMA stains the cell membranes and cytoplasm ♦♦ CD10 stains the luminal surfaces ♦♦ p16 stains the cell nuclei ♦♦ ER/PR (nuclear) and CEA are negative

Other Mesenchymal Tumors

Differential Diagnosis (Table 2.12)

♦♦ Other vulvar and vaginal mesenchymal tumors include rhabdomyoma, superficial angiomyxoma, granular cell

♦♦ Cervical adenocarcinoma is positive for mCEA and p16 and negative for CD10, calretinin, and vimentin

Table 2.12. Endocervical Adenocarcinoma Differential Diagnosis CK7

p16

mCEA

CK20

Endocervical adenocarcinoma

+

+

+

−

Endocervical intestinal-type adenocarcinoma

+

−

+

Endometrioid adenocarcinoma

+

−

−

CDX2

Vimentin

Calretinin

CD10

−

−

−

−

+

+

−

−

−

−

−

+

−

−

Colorectal adenocarcinoma

−

−

+

+

+

−

−

−

Endometriosis

+

−

−

−

−

+

−

+a

Mesonephric lesions

+

+

−

NA

NA

+

+

+

Endometriosis shows adjacent CD10 positive stroma NA not available

a

155

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Endometrial adenocarcinoma is positive for ER/PR (nuclear), CK7, and EMA and rare cases are positive for calretinin (6%) ♦♦ Endometriosis is positive for CD10 in the stromal component

High Grade Squamous Dysplasia/Carcinoma In Situ ♦♦ Diffuse staining with p16 is associated with high risk HPV. Negative or focal staining in the middle and upper cell layers can be seen with low risk HPV

Verification Panel (Fig. 2.24) ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ Ki-67 shows an increased proliferation rate into the upper one-third of the epithelium ♦♦ p16 diffusely stains the tumor cell nuclei and cytoplasm in HPV-related lesions

Differential Diagnosis ♦♦ Melanoma in situ is positive for S-100, HMB 45, and Melan-A and negative for keratins, mCEA, GCDFP-15, and HER2 ♦♦ Atrophy, transitional metaplasia, and immature squamous metaplasia are negative for p16 and show Ki-67 proliferation limited to the basal layers

Squamous Cell Carcinoma ♦♦ IHC is unnecessary for the diagnosis of squamous ­carcinoma except when diffusely poorly differentiated

Verification Panel ♦♦ HMWK (CK34be12, CK5/6) stains the tumor cell cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ p16 is positive in the nuclei and cytoplasm of most HPVrelated carcinomas (cervix 77%)

Differential Diagnosis ♦♦ Poorly differentiated adenocarcinoma is positive for mCEA and negative for HMWK and p63 (nuclear) ♦♦ Small cell neuroendocrine carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for HMWK and p63 (nuclear)

Endocervical Adenocarcinoma (Nonintestinal Type) Verification Panel ♦♦ CK7 and mCEA stain the tumor cell cytoplasm ♦♦ p16 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis (Table 2.12) ♦♦ Intestinal-type endocervical adenocarcinoma is positive for CK7, CK20, mCEA, and CDX2 (nuclear) and negative for p16 ♦♦ Endometrioid adenocarcinoma is positive for ER/PR (nuclear), CK7, and vimentin; negative or weak and focal for p16; and negative for mCEA

156

Fig. 2.24. (A–C) High grade cervical intraepithelial neoplasia shows overexpression with diffuse p16 nuclear and ­cytoplasmic staining (left) and increased proliferation in the upper epithelium with Ki-67 nuclear staining (left). ♦♦ Colorectal carcinoma is positive for mCEA, CK20, and CDX2 (nuclear), and some cases are focally positive for CK7 (27%) ♦♦ Endometriosis is positive for CD10 in the stromal component; positive for vimentin in the glands and stroma; and negative for p16 ♦♦ Mesonephric remnants and carcinoma are positive for p16, vimentin, and CD10 (luminal surface) and negative for mCEA

Immunohistochemical Diagnosis in Surgical Pathology

Endocervical Intestinal-Type Adenocarcinoma Verification Panel (Fig. 2.25) ♦♦ CK7, CK20, and mCEA stain the tumor cell cytoplasm ♦♦ CDX2 stains the tumor cell nuclei

Differential Diagnosis (Table 2.12) ♦♦ Endocervical adenocarcinoma (nonintestinal type) is positive for CK7, mCEA, and p16 (nuclear) and negative for CK20 and CDX2 (nuclear) ♦♦ Endometrial adenocarcinoma is positive for CK7 and vimentin; negative or weak and focal for p16; and negative for mCEA, CK20, and CDX2 (nuclear) ♦♦ Endometriosis is positive for CD10 in the stromal ­component; positive for vimentin in the glands and stroma; and negative for mCEA, CK20, and CDX2 (nuclear) ♦♦ Mesonephric remnants and carcinoma are positive for p16, vimentin, and CD10 (luminal surface) and negative for mCEA and CK20

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Small Cell Carcinoma Verification Panel ♦♦ Pankeratin shows dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology ♦♦ p16 stains the tumor cell nuclei

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56 and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for chromogranin, synaptophysin, and CD56. Squamous cell carcinoma is positive for p63 (nuclear)

Fig. 2.25. (A–D) CK20 stains the cytoplasm, monoclonal CEA stains the membranes and cytoplasm, and CDX2 stains the nuclei in an intestinal-type endocervical adenocarcinoma.

157

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♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Rhabdomyosarcoma is positive for MSA, desmin, myogenin (nuclear), Myo-D1 (nuclear) and CD56 and negative for pankeratin, chromogranin, and synaptophysin

Mesenchymal Tumors ♦♦ Cervical mesenchymal tumors include leiomyoma, ­leio‑ myosarcoma, low grade endometrial stromal sarcoma, undifferentiated endocervical sarcoma, rhabdomyosarcoma, angiosarcoma, alveolar soft parts sarcoma, and malignant peripheral nerve sheath tumor. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Primary lymphoma of the cervix is extremely rare

Metastatic Disease (Table 2.12) ♦♦ The most common tumors to spread to the cervix are from uterus, ovary, and vagina. Direct spread or metastasis occurs from colorectal and bladder carcinomas. Metastases also originate from the breast and stomach. Refer to Chapter3 for further discussion

Uterus, Corpus Endometrial Intraepithelial Carcinoma Verification Panel ♦♦ p53 stains the tumor cell nuclei ♦♦ Ki-67 (nuclear) shows a very high proliferation rate

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

Differential Diagnosis ♦♦ Endocervical adenocarcinoma is positive for mCEA, PTEN (nuclear) and p16 (nuclear), and negative for vimentin and ER/PR (nuclear) ♦♦ Granulosa and Sertoli cell tumors and elements are positive for inhibin and calretinin and negative for EMA ♦♦ Atypical polypoid adenomyoma contains bundles of smooth muscle fibers positive for SMA, MSA, and desmin ♦♦ Serous carcinoma is positive for p53 (nuclear), WT1 (nuclear), PTEN (nuclear), and p16 (nuclear, >90% of tumor cells) and negative or focal for ER/PR (nuclear, 31%/12%). Ki-67 shows a high proliferative rate (>75%)

Serous Carcinoma Verification Panel ♦♦ CK7, pankeratin and B72.3 stain the tumor cell cytoplasm ♦♦ EMA, LeuM1, and CA125 stain the tumor cell membranes and cytoplasm ♦♦ Some cases are positive for CK5/6 (22%) and calretinin (25%) ♦♦ p53 shows overexpression in the tumor cell nuclei (87% of tumors, usually >75% of cells within the tumor) ♦♦ WT1 stains the tumor cell nuclei

Differential Diagnosis ♦♦ Endometrioid carcinoma is positive for ER/PR (nuclear); rare cases are positive for WT1 (nuclear, 6%) and p53 (nuclear, 7% positive); and negative for PTEN (loss of nuclear staining) ♦♦ Mesothelioma is positive for CK7, h-caldesmon, calretinin, CK5/6, CA125 (48%), and WT1 (nuclear); some cases are positive for B72.3 (8%), LeuM1 (5%), and p53 (nuclear 50%) ♦♦ Clear cell carcinoma is negative for WT1 (nuclear) and p53 (nuclear)

♦♦ Metaplastic endometrial glands are negative for p53 (nuclear) and show a lower Ki-67 rate ♦♦ Serous carcinoma is positive for p63 and shows confluent glands or stromal invasion. Immunostains are not helpful in differentiating these lesions

Mucinous Carcinoma

Endometrioid Carcinoma

♦♦ In the intestinal type, CK7 and CK20 stain the tumor cell cytoplasm and CDX2 the nuclei. CA125 is negative ♦♦ In the endocervical type, CK7 stains the tumor cell cytoplasm and CA125 the membranes in some cases. CK20 and CDX2 (nuclear) are negative

♦♦ Endometrial carcinoma extending into adenomyosis must be differentiated from invasive carcinoma by morphology. CD10 is unreliable for identifying a stromal component

Verification Panel ♦♦ ER, PR, and b-catenin (70%) stain the tumor cell nuclei. ER/ PR staining is decreased in FIGO 3 tumors ♦♦ CK7 and vimentin stain the tumor cell cytoplasm ♦♦ EMA and CA125 stain the tumor cell membranes and cytoplasm ♦♦ p16 nuclear and cytoplasmic staining is weak and focal, but is higher in FIGO 3 tumors ♦♦ Normal PTEN staining (nuclear and cytoplasmic) is lost ♦♦ p53 (nuclear) overexpression is uncommon (focal, 7%)

158

♦♦ The diagnosis is based on morphology. IHC shows a variable pattern based on tumor subtype and might be useful for the differentiation of primary vs. metastatic tumor

Verification Panel

Differential Diagnosis ♦♦ Endocervical adenocarcinoma is positive for CK7, mCEA, and p16 (nuclear); some cases are positive for CA125 (46%) and negative for CK20 ♦♦ Colorectal carcinoma is positive for CK20 and CDX2 (nuclear), and some cases are positive for CK7 (27%) ♦♦ Gastric carcinoma shows a variable CK7 (52%) and CK20 (62%) pattern and is positive for CDX2 (nuclear, 88%) ♦♦ Lung mucinous carcinoma is positive for CK7, CK20, and CDX2 and some cases for CA125 (15%)

Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Pancreatobiliary carcinoma is positive for CK7, CK20, CA125, and CDX2 (nuclear)

Clear Cell Carcinoma Verification Panel ♦♦ CK7, pankeratin, B72.3, and vimentin stain the tumor cell cytoplasm ♦♦ EMA, LeuM1, CA125 (73%), and CEA (38%) stain the tumor cell membranes and cytoplasm ♦♦ p16 is positive in some cases (50%) ♦♦ Ki-67 average proliferation rate is 11.5% ♦♦ WT1 (nuclear, 3%), p53 (nuclear, 10%), and ER (nuclear, 11%) are usually negative

Differential Diagnosis ♦♦ Metastatic renal cell carcinoma is positive for CD10 and RCC Ma and negative for CK7 ♦♦ Arias-Stella reaction shows a low proliferation rate with Ki-67 (<5%) ♦♦ High grade serous carcinoma is positive for WT1 (80%) and ER (nuclear 76%) and some cases show p53 overexpression (48%). Ki-67 proliferation is high (>75%)

Small Cell Carcinoma Verification Panel ♦♦ Pankeratin shows dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin, synaptophysin, and NSE show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for chromogranin, synaptophysin, and CD56. Squamous cell carcinoma is positive for p63 (nuclear) ♦♦ Granulosa and Sertoli cell tumors and elements are ­positive for calretinin and inhibin, and some cases are focally ­positive for pankeratin (12%), chromogranin, and synapto­ physin ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Mesothelioma is positive for pankeratin, CK7, calretinin, CK5/6, and WT1 (nuclear), and some cases are positive for chromogranin (10%), synaptophysin (8%), and CD56 (13%) ♦♦ Ewing sarcoma is positive for CD99 (membranous) and Fli-1 (nuclear); some cases are positive for pankeratin, synaptophysin, and CD56; and negative for chromogranin ♦♦ Rhabdomyoblastoma is positive for MSA, desmin, myogenin (nuclear), Myo-D1 (nuclear), and CD56 and negative for pankeratin, chromogranin, and synaptophysin

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♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, chromogranin, synaptophysin, and CD56

Carcinosarcoma (Malignant Mixed Müllerian Tumor) Verification Panel ♦♦ Pankeratin stains the tumor cell cytoplasm in the distinct epithelial components ♦♦ Smooth muscle markers (SMA, MSA, desmin), skeletal muscle markers [desmin, myogenin (nuclear), Myo-D1 (nuclear)], and cartilage marker (S-100) stain the mesenchymal elements ♦♦ Synaptophysin stains the neuroectodermal elements

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is diffusely positive for pankeratin and negative for the mesenchymal markers ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin ♦♦ Undifferentiated endometrial sarcoma is negative for pankeratin

Placental Site Nodule and Placental Site Trophoblastic Tumor Verification Panel ♦♦ Pankeratin, hPL, and inhibin diffusely stain the tumor cell cytoplasm ♦♦ βhCG focally stains the tumor cell cytoplasm ♦♦ Ki-67 shows a proliferation rate <15%

Differential Diagnosis ♦♦ Squamous cell carcinoma is positive for p16 and p63 (nuclear) and negative for hPL. Ki-67 proliferation rate is usually >60% ♦♦ Decidua is negative for pankeratin and hPL ♦♦ Choriocarcinoma is diffusely positive for pankeratin and βhCG and focally positive for hPL. Ki-67 proliferation rate is >60%

Choriocarcinoma Verification Panel ♦♦ Pankeratin, inhibin, and βhCG stain the tumor cell cytoplasm ♦♦ Ki-67 proliferation rate is >60%

Differential Diagnosis ♦♦ Placental site trophoblastic tumor is diffusely positive for pankeratin and hPL; focally positive for βhCG; and shows a Ki-67 proliferation rate <15% ♦♦ Other carcinomas are positive for pankeratin and negative for βhCG

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Adenomatoid Tumor Verification Panel ♦♦ Calretinin stains the tumor cell nuclei and cytoplasm ♦♦ Pankeratin and CK5/6 stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei

Differential Diagnosis ♦♦ Carcinoma is positive for B72.3, mCEA, and Ber-EP4; serous carcinoma is positive for WT1 (nuclear); and carcinoma is negative for calretinin and CK5/6

Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, calponin, h-caldesmon, and desmin stain the tumor cell cytoplasm ♦♦ Pankeratin (40%) and CD10 (20%) focally stain some cases

Differential Diagnosis ♦♦ Low grade endometrial stromal sarcoma is positive for CD10; some cases are focally positive for SMA (65%);

Essentials of Anatomic Pathology, 3rd Ed.

calponin (35%), and desmin (77%); and negative for h-caldesmon ♦♦ Sarcomatoid carcinoma is more strongly positive for keratin and is usually negative for SMA, MSA, and desmin ♦♦ Postsurgical spindle cell nodule shows similar (but focal) IHC results and must be differentiated by clinical history, tumor size, and lack of significant pleomorphism

Endometrial Stromal Nodule and Sarcoma ♦♦ These two tumors are differentiated by circumscription

Verification Panel (Fig. 2.26) ♦♦ CD10 stains the tumor cell cytoplasm ♦♦ SMA (50%), MSA, desmin (44%), and pankeratin (35%) show weak/focal tumor cell cytoplasmic staining ♦♦ ER and PR stain the tumor cell nuclei

Differential Diagnosis ♦♦ Leiomyoma/leiomyosarcoma is positive for h-caldesmon and more diffusely positive for SMA, MSA, calponin, and desmin; some cases are focally positive for ER (nuclear,

Fig. 2.26. (A–D) CD10 stains the membranes and cytoplasm and PR stains the nuclei of an endometrial stromal sarcoma. SMA stains the tumor cell cytoplasm focally and also stains the smooth muscle of a vessel in the lower left corner.

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57%) and PR (nuclear, 43%); and focal or negative for CD10 (leiomyoma, 20% positive) ♦♦ Solitary fibrous tumor/hemangiopericytoma is positive for CD34; some cases are focally positive for CD10; and negative for ER/PR (nuclear) ♦♦ PEComa is positive for HMB 45, Melan-A, SMA, MSA, and desmin, and some (usually epithelioid type) cases are positive for CD10 and ER/PR (nuclear)

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♦♦ Gastrointestinal stromal tumor is positive for CD117; some cases are positive for SMA (25%); and negative for CD10 and ER/PR (nuclear)

Sex Cord Elements within an Endometrial Stromal Tumor Verification Panel (Fig. 2.27) ♦♦ Calretinin and inhibin stain the tumor cell cytoplasm

Fig.  2.27. (A–E) Calretinin, pankeratin, and SMA stain the cytoplasm, and ER stains the nuclei of sex cord elements within an endometrial stromal tumor.

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♦♦ CD99 stains the tumor cell membranes ♦♦ ER and PR stain the tumor cell nuclei in some cases ♦♦ SMA and pankeratin are often positive

Ovary Endometriosis Verification Panel

Undifferentiated Endometrial Sarcoma Verification Panel

♦♦ CD10 stains the cytoplasm of the stromal elements

♦♦ This undifferentiated tumor expresses only vimentin

Differential Diagnosis ♦♦ Carcinosarcoma stains focally for pankeratin and ­appropriate markers for the mesenchymal elements [e.g., Myo-D1 (nuclear) for skeletal muscle differentiation] ♦♦ Leiomyosarcoma is positive for SMA, MSA, calponin, h-caldesmon, and desmin

Other Mesenchymal Tumors ♦♦ Other uterine mesenchymal tumors include hemangioma, lipoma, rhabdomyosarcoma, angiosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, alveolar soft parts sarcoma, and malignant peripheral nerve sheath tumor. Refer to the mesenchymal section and chapter for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Primary lymphoma of the uterus is extremely rare and is most commonly CD20 positive diffuse large B-cell type

Metastatic Disease ♦♦ The most common tumors to spread to the uterus are from cervix, ovary, and fallopian tube. Direct spread or metastasis occurs from colorectal and bladder carcinomas. Metastases also originate from the breast, stomach, pancreatobiliary tract, and lung. Refer to Chapter 3 for further discussion

Differential Diagnosis ♦♦ Adenocarcinoma does not contain the CD10 positive stromal elements

Endometrioid Carcinoma Verification Panel ♦♦ ER, PR, and b-catenin (70%) stain the tumor cell nuclei. ER/ PR staining is decreased in FIGO 3 tumors ♦♦ CK7 and vimentin stain the tumor cell cytoplasm ♦♦ EMA and CA125 stain the tumor cell membranes and cytoplasm ♦♦ p16 nuclear and cytoplasmic staining is weak and focal, but it is higher in FIGO 3 tumors ♦♦ Normal PTEN staining (nuclear and cytoplasmic) is lost ♦♦ p53 (nuclear) overexpression is uncommon (focal, 7%)

Differential Diagnosis (Tables 2.13 and 2.14) ♦♦ Endocervical adenocarcinoma is positive for mCEA, PTEN (nuclear), and p16 (nuclear) and negative for vimentin and ER/PR (nuclear) ♦♦ Granulosa and Sertoli call tumors are positive for inhibin and calretinin and negative for EMA ♦♦ Serous carcinoma is positive for p53 (nuclear), WT1 (nuclear), PTEN (nuclear), and p16 (nuclear, >90% of tumor cells) and negative or focal for ER/PR (nuclear, 31%/12%). Ki-67 shows a high proliferative rate (>75%)

Table 2.13. Ovarian Tubular Tumors Differential Diagnosisa (% Tumors Positive) EMA/CK7

ER/PRb

WT1b

Calretinin

Inhibin

Chromogranin/ synaptophysin

Endometrioid adenocarcinoma

+/+

+

15

13

−

−

Granulosa cell tumor

−/−

−

+

+

+

−

Carcinoid tumor

30/12

NA

−

−

−

+

Adenomatoid tumor

+/+

−

+

+

−

−

a Struma Ovarii is included in the differential diagnosis and is positive for CK7, TTF-1 (nuclear), and thyroglobulin b Nuclear staining NA not available

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Table 2.14. Ovarian Tumors Differential Diagnosis (% Tumors Positive) CK7/CK20/EMA

CA125/WT a

Additional tumor markers

Serous carcinoma

+/5/+

83/92

p53a

Endometrioid carcinoma

+/−/97

14/17

ER/PRa

Mucinous carcinoma

96/61/+

24/−

Clear cell carcinoma

+/−/+

80/14

mCEA, LEUM1, vimentin, CK34be12

Small cell carcinoma

+/−/86

NA/93

Chromogranin, synaptophysin

Granulosa cell tumor

13/−/−

−/96

Calretinin, inhibin

Metastatic colorectal adenocarcinoma

27/94/87

6/53

CDX2a, CK20

Metastatic endocervical adenocarcinoma

+/−/+

46/−

p16

Metastatic gastric adenocarcinoma

51/62/100

NA/0

Shows variable CK7/CK20 pattern

Metastatic breast carcinoma

99/4/100

17/−

GCDFP-15, ER/PRa, HER2

Metastatic lung Adenocarcinoma

97/7/98

26/−

TTF-1a

Metastatic renal cell carcinoma

11/3/73

−/8

RCC Ma, CD10

Metastatic pancreatobiliary adenocarcinoma

94/52/+

92/−

CA19-9

Mesothelioma

+/−/93

+/83

Calretinin, D2-40, h-caldesmon

Yolk sac tumor

−/−/−

−/−

Pankeratin, aFP

Embryonal carcinoma

78/−/−

NA/NA

CD30, PLAP, OCT4a

Nuclear staining NA not available

a

Serous Carcinoma Verification Panel (Fig. 2.28) ♦♦ CK7, pankeratin, and B72.3 stain the tumor cell cytoplasm ♦♦ EMA, LeuM1, and CA125 stain the tumor cell membranes and cytoplasm ♦♦ Some cases are positive for CK5/6 (22%) and calretinin (25%) ♦♦ p53 shows overexpression in the tumor cell nuclei (87% of tumors, usually >75% of cells) ♦♦ WT1 stains the tumor cell nuclei

Differential Diagnosis (Table 2.14) ♦♦ Endometrioid carcinoma is positive for ER/PR (nuclear); rare cases are positive for WT1 (nuclear, 6%) and p53 (nuclear, 7%); and negative for PTEN (loss of nuclear staining) ♦♦ Mesothelioma is positive for CK7, h-caldesmon, calretinin, CK5/6, CA125 (48%), and WT1 (nuclear); some cases are positive for B72.3 (8%), LeuM1 (5%), and p53 (nuclear 50%) ♦♦ Clear cell carcinoma is negative for WT1 (nuclear) and p53 (nuclear)

Mucinous Carcinoma ♦♦ The diagnosis is based on morphology. IHC shows a variable pattern based on tumor subtype and might be useful for the differentiation of primary vs. metastatic tumor

Verification Panel ♦♦ In the intestinal type, CK7 and CK20 stain the tumor cell cytoplasm and CDX2 the nuclei. CA125 is negative ♦♦ In the endocervical type, CK7 stains the tumor cell cytoplasm and CA125 the membranes in some cases. CK20 and CDX2 (nuclear) are negative

Differential Diagnosis (Table 2.14) ♦♦ Endocervical adenocarcinoma is positive for CK7, CEA, and p16 (nuclear); some cases are positive for CA125 (46%) and negative for CK20 ♦♦ Colorectal carcinoma is positive for CK20 and CDX2 (nuclear), and some cases are positive for CK7 (27%) ♦♦ Gastric carcinoma shows a variable CK7 (52%) and CK20 (62%) pattern and is positive for CDX2 (nuclear, 88%) ♦♦ Lung mucinous carcinoma is positive for CK7, CK20, and CDX2 and some cases for CA125 (15%) ♦♦ Pancreatobiliary carcinoma is positive for CK7, CK20, CA125, and CDX2 (nuclear)

Clear Cell Carcinoma Verification Panel (Fig. 2.29) ♦♦ CK7, pankeratin, B72.3, and vimentin stain the tumor cell cytoplasm

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Fig. 2.28. (A–C) CA125 stains the membranes and cytoplasm, and p53 stains the nuclei of an ovarian serous carcinoma.

♦♦ EMA, LeuM1, CA125 (73%), and CEA (38%) stain the tumor cell membranes and cytoplasm ♦♦ p16 is 50% positive ♦♦ Ki-67 proliferation rate average is 11.5%

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Fig. 2.29. (A–C) CK7 highlights the focal hobnail pattern, and CA125 stains the membranes, cytoplasm, and intracytoplasmic globules of an ovarian clear cell carcinoma. ♦♦ WT1 (nuclear, 3%), p53 (nuclear, 10%), and ER (nuclear, 11%) are usually negative

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Differential Diagnosis (Tables 2.14 and 2.15)

Differential Diagnosis

♦♦ Metastatic renal cell carcinoma is positive for CD10 and RCC Ma, and some cases are focally positive for CK7 (11%) ♦♦ Yolk sac tumor is positive for aFP and negative for EMA and CK7 ♦♦ Germinoma is positive for PLAP and negative for pankeratin ♦♦ Steroid cell tumor is positive for Melan-A, inhibin, and calretinin, and some cases are positive for CK7 (31%) ♦♦ High grade serous carcinoma is positive for WT1 (80%) and ER (nuclear 76%), and some cases show p53 overexpression (48%). Ki-67 proliferation is high (>75%)

♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for chromogranin and NSE. Squamous cell carcinoma is positive for p63 (nuclear) ♦♦ Granulosa and Sertoli cell tumors are positive for calretinin and inhibin, and some cases are focally positive for pankeratin (12%) and synaptophysin ♦♦ Desmoplastic small round cell tumor is positive for pankeratin, NSE, CD56 desmin (often dot-like), and vimentin; some cases are positive for chromogranin (5%) and synaptophysin (16%) ♦♦ Dysgerminoma is positive for PLAP, OCT4, and CD117, and some cases are focally positive for pankeratin (24%) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Ewing sarcoma is positive for CD99 (membranous), Fli-1 (nuclear); some cases are positive for pankeratin, synaptophysin, and CD56 and negative for chromogranin ♦♦ Rhabdomyoblastoma is positive for MSA, desmin, ­myogenin (nuclear), Myo-D1 (nuclear), and CD56 and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, chromogranin, synaptophysin, and CD56 ♦♦ Hypercalcemic type ovarian small cell carcinoma is positive for vimentin and occurs in young patients

Carcinoid Tumor Verification Panel ♦♦ Pankeratin shows dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin and synaptophysin show variable tumor cell cytoplasmic staining ♦♦ CD56 is more sensitive for neuroendocrine differentiation but less specific; it must be evaluated in the context of neuroendocrine morphology ♦♦ Calretinin focally stains some cases (21%)

Differential Diagnosis (Table 2.13) ♦♦ Granulosa and Sertoli cell tumors and elements are positive for CD56, calretinin, and inhibin, and some cases are focally positive for pankeratin (12%), chromogranin, and synaptophysin ♦♦ Brenner tumor is positive for pankeratin and negative for chromogranin and synaptophysin ♦♦ Metastatic carcinoid cannot be differentiated by IHC. Teratomatous elements suggest an ovarian primary ♦♦ Sertoli–Leydig cell tumor is positive for chromogranin, synaptophysin, Melan-A, calretinin, and inhibin and negative for pankeratin

Small Cell Carcinoma (Pulmonary Type) Verification Panel ♦♦ Pankeratin shows dot-like and diffuse cytoplasmic staining ♦♦ Chromogranin and NSE show variable tumor cell ­cytoplasmic staining

Table 2.15. Ovarian Clear Cell Tumors (% Tumors Positive) EMA

AFP

PLAP Inhibin

Clear cell carcinoma

+

−

−

−

Yolk sac tumor

−

+

40

−

Dysgerminoma

−

−

+

−

Steroid cell tumor

−

−

−

+

Small Cell Carcinoma, Hypercalcemic Type Verification Panel ♦♦ Pankeratin, calretinin, and vimentin (50%) stain the tumor cell cytoplasm ♦♦ EMA and CD10 stain the tumor cell membranes and cytoplasm ♦♦ WT1 and p53 stain the tumor cell nuclei ♦♦ CD56 (26%), BerEP4 (20%), and synaptophysin (13%) stain some tumors focally ♦♦ Chromogranin, CD99, desmin, and inhibin are negative

Differential Diagnosis ♦♦ Pulmonary-type ovarian small cell carcinoma is usually negative for EMA and vimentin, occurs in older patients, and is often associated with endometrioid carcinoma or Brenner tumors ♦♦ Granulosa and Sertoli cell tumors are positive for calretinin and inhibin, and some cases are focally positive for pankeratin (12%) and synaptophysin ♦♦ Desmoplastic small round cell tumor is positive for pankeratin, NSE, CD56, desmin (often dot-like), and vimentin; some cases are positive for chromogranin (5%) and synaptophysin (16%) ♦♦ Dysgerminoma is positive for PLAP, OCT4 (nuclear), and CD117, and some cases are focally positive for pankeratin (24%) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD56; and negative for pankeratin, chromogranin, and synaptophysin

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Ewing sarcoma is positive for CD99 (membranous), Fli-1 (nuclear); some cases are positive for pankeratin and synaptophysin; and negative for chromogranin ♦♦ Rhabdomyoblastoma is positive for MSA, desmin, myogenin (nuclear), Myo-D1 (nuclear), and CD56 and negative for pankeratin, chromogranin, and synaptophysin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, chromogranin, and synaptophysin

Transitional Cell Carcinoma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

Germ Cell Tumors Dysgerminoma Verification Panel ♦♦ PLAP and CD117 stain the cytoplasm of the neoplastic germ cells ♦♦ OCT4 stains the tumor cell nuclei ♦♦ Pankeratin is focally positive in some cases (24%) ♦♦ Scattered syncytiotrophoblastic giant cells are βhCG positive ♦♦ CD45 stains the tumor-associated lymphoid cells

Differential Diagnosis (Tables 2.15 and 2.16)

CK7 and vimentin stain the tumor cell cytoplasm CA125 stains the tumor cell cytoplasm p53, p16, and WT1 (82%) stain the tumor cell nuclei CK20 is negative

Differential Diagnosis ♦♦ Metastatic transitional cell carcinoma from the urinary bladder is positive for CK20, p53 (nuclear) and WT1 (nuclear), and usually CK7 (88%) and negative for vimentin and CA125 ♦♦ Malignant Brenner tumor is positive for cyclin D1 and EGFR and negative for p16 and p53 (nuclear)

Carcinosarcoma (Malignant Mixed Müllerian Tumor) Verification Panel

♦♦ Yolk sac tumor is focally positive for aFP and a-1-­ antitrypsin; some cases are positive for PLAP (50%); and negative for CD117 and OCT4 (nuclear) ♦♦ Embryonal carcinoma is positive for OCT4 (nuclear), pankeratin, and CD30 and negative for CD117 ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for PLAP ♦♦ Small cell carcinoma is positive for pankeratin and negative for PLAP

Yolk Sac Tumor (Endodermal Sinus Tumor) Verification Panel ♦♦ Pankeratin, aFP, and a-1-antitrypsin stain the tumor cell cytoplasm

♦♦ Pankeratin stains the tumor cell cytoplasm in the epithelial components ♦♦ Smooth muscle markers (SMA, MSA, desmin), skeletal muscle markers [desmin, myogenin (nuclear), Myo-D1 (nuclear], and cartilage marker (S-100) stain the m ­ esenchymal elements ♦♦ Synaptophysin stains the neuroectodermal elements

Differential Diagnosis ♦♦ Poorly differentiated endometrial carcinoma is diffusely positive for pankeratin ♦♦ Undifferentiated endometrial sarcoma is negative for pankeratin

Differential Diagnosis (Tables 2.15 and 2.16) ♦♦ Clear cell ovarian carcinoma is positive for pankeratin and negative for aFP and a-1-antitrypsin ♦♦ Embryonal carcinoma is positive for OCT4 (nuclear), pankeratin, and CD30; some are positive for aFP; and negative for a-1-antitrypsin ♦♦ Adenomatoid tumor is positive for pankeratin, calretinin, CK5/6, and WT1 (nuclear) and negative for aFP and a-1antitrypsin ♦♦ Metastatic renal cell carcinoma is positive for pankeratin (weak, focal), CD10, and RCC Ma and negative for aFP and a-1-antitrypsin

Table 2.16. Ovarian Germ Cell Tumors Pankeratin

PLAP

AFP

CD30

βhCG

Calretinin

Dysgerminoma

24

+

−

−

−a

−

Yolk sac tumor

+

40

+

−

−

−

Embryonal carcinoma

+

+

30

+

a

−

−

Choriocarcinoma

+

36

−

−

+

−

Sex cord/stromal tumors

−

−

−

−

−

+

βhCG stains syncytiocytotrophoblasts associated with the tumor

a

166

a

Immunohistochemical Diagnosis in Surgical Pathology

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Embryonal Carcinoma Verification Panel

Granulosa Cell Tumor Verification Panel (Fig. 2.30)

♦♦ Pankeratin and PLAP stain the tumor cell cytoplasm ♦♦ CD30 stains the tumor cell membranes and cytoplasm ♦♦ OCT4 stains the tumor cell nuclei

♦♦ Calretinin, SMA, inhibin, and CD56 stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei ♦♦ Pankeratin (25%), chromogranin and synaptophysin stain some tumors ♦♦ EMA is negative

Differential Diagnosis (Table 2.16) ♦♦ Yolk sac tumor is positive for pankeratin, AFP, and a-1-antitrypsin; some cases are positive for PLAP (50%); and negative for OCT4 ♦♦ Dysgerminoma is positive for PLAP, OCT4 (nuclear), and CD117; some cases are focally positive for pankeratin (24%) and negative for CD30 ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for PLAP, CD30, and OCT4 (nuclear)

Choriocarcinoma Verification Panel ♦♦ Pankeratin, inhibin, βhCG and PLAP stain the tumor cell cytoplasm

Differential Diagnosis (Tables 2.13 and 2.14) ♦♦ Carcinoid tumors are positive for chromogranin, synaptophysin, and CD56 and negative for calretinin and inhibin ♦♦ Endometrial stromal sarcoma is positive for CD10; some cases are positive for SMA (65%), calretinin (15%), and WT1 (nuclear); and negative for inhibin ♦♦ Endometrioid carcinoma is positive for pankeratin and EMA; some cases are positive for calretinin; and negative for inhibin ♦♦ Yolk sac tumor is positive for pankeratin, aFP, and a-1-anti­ trypsin and negative for calretinin, inhibin, and WT1 (nuclear)

Differential Diagnosis (Table 2.16) ♦♦ Dysgerminoma is positive for PLAP, OCT4 (nuclear), and CD117; some cases are focally positive for pankeratin (24%); and negative for βhCG (positive in tumor-associated syncytiocytotrophoblasts) ♦♦ Embryonal carcinoma is positive for pankeratin, CD30, PLAP, and OCT4 (nuclear), and some cases are focally positive for βhCG (25%)

Struma Ovarii Verification Panel ♦♦ Pankeratin and thyroglobulin stain the tumor cell cytoplasm ♦♦ TTF-1 stains the tumor cell nuclei ♦♦ Some cases are focally positive for calretinin (14%)

Differential Diagnosis ♦♦ Granulosa cell tumor is positive for calretinin and inhibin and negative for pankeratin, thyroglobulin, and TTF-1

Sex Cord Stromal Tumors Fibroma, Fibrothecoma, and Thecoma Verification Panel ♦♦ Calretinin and inhibin stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei (fibroma 80%, thecoma 20%) ♦♦ EMA, pankeratin, and CD10 are negative

Differential Diagnosis ♦♦ Endometrial stromal sarcoma is positive for CD10 and WT1 (nuclear) ♦♦ Carcinoma is positive for pankeratin and EMA; some cases are positive for calretinin (endometrioid carcinoma); and negative for inhibin and WT1 (nuclear)

Fig. 2.30. (A, B) Inhibin stains the cytoplasm of an ovarian granulosa cell tumor.

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♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, and synaptophysin; some cases are positive for calretinin; and negative for WT1 (nuclear) and inhibin

Sertoli Cell Tumor Verification Panel ♦♦ Calretinin, inhibin, and CD56 stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

sheath tumor. Refer to the mesenchymal section and chapter for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Primary lymphomas of the ovaries include CD20 positive B-cell diffuse large cell, Burkitt, and follicular types. Granulocytic sarcoma is positive for myeloperoxidase. Refer to the lymphoma section and lymph node chapter for further discussion

♦♦ Carcinoid tumors are positive for chromogranin, ­synaptophysin, and CD56 and negative for calretinin, inhibin, and WT1 (nuclear) ♦♦ Metastatic carcinoma is diffusely positive for ­pankeratin and negative for calretinin, inhibin, and WT1 (nuclear) ♦♦ Granulosa cell tumor shows the same IHC pattern as Sertoli cells ♦♦ Endometrioid carcinoma is positive for pankeratin and EMA; some cases are positive for calretinin; and negative for inhibin

Metastatic Disease

Sertoli–Leydig Cell Tumor Verification Panel

♦♦ Calretinin, pankeratin, and CK5/6 stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei

♦♦ The Sertoli cell component is positive for calretinin, desmin, inhibin, and WT1 (nuclear) ♦♦ The Leydig component is positive for Melan-A, calretinin, and inhibin

Differential Diagnosis ♦♦ Carcinoid tumors are positive for pankeratin, chromogranin, and synaptophysin and negative for Melan-A, calretinin, inhibin, and WT1 (nuclear) ♦♦ Carcinoma is diffusely positive for pankeratin and negative for calretinin, inhibin, and WT1 (nuclear) ♦♦ Yolk sac tumor is positive for pankeratin, aFP, and a-1-antitrypsin and negative for calretinin, inhibin, and WT1 (nuclear)

Steroid/Lipid Cell Tumor Verification Panel ♦♦ Melan-A and inhibin stain the tumor cell cytoplasm ♦♦ CK7, vimentin, S-100, and AE1/AE3 (50%) stain some cases

Differential Diagnosis (Table 2.15) ♦♦ Luteoma is differentiated based on clinical history ♦♦ Clear cell carcinoma is diffusely positive for pankeratin and negative for Melan-A ♦♦ Struma is positive for pankeratin, thyroglobulin, and TTF-1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for AE1/AE3

Other Mesenchymal Tumors ♦♦ Ovarian mesenchymal tumors include leiomyoma, lipoma, hemangioma, chondroma, leiomyosarcoma, low grade endometrial stromal sarcoma, undifferentiated ovarian sarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, osteosarcoma, chondrosarcoma, and malignant peripheral nerve

168

♦♦ The most common tumors to spread to the ovary are from the colon, stomach, breast, endometrium, cervix, appendix (mucinous tumors), and pancreatobiliary tract. Refer to Chapter 3 for further discussion

Peritoneum Adenomatoid Tumor Verification Panel

Differential Diagnosis (Table 2.13) ♦♦ Adenocarcinoma is positive for B72.3, CEA, and Ber-EP4 and negative for calretinin and WT1 (nuclear) ♦♦ Mesothelioma shows the same IHC pattern; it is ­differentiated by malignant morphology ♦♦ Yolk sac tumor is positive for aFP and pankeratin and negative for calretinin and WT1 (nuclear)

Primary Serous Carcinoma of Peritoneum Verification Panel ♦♦ MOC31 and Ber-EP4 stain the tumor cell cytoplasm ♦♦ ER stains the tumor cell nuclei

Differential Diagnosis ♦♦ Ovarian serous papillary carcinoma cannot be differentiated by IHC ♦♦ Mesothelioma is positive for calretinin, CK5/6, D2-40, and h-caldesmon and negative for MOC31 and Ber-EP4

Mesothelioma ♦♦ IHC markers are not completely specific or sensitive for mesothelioma. A panel of expected positive and negative markers (two each) provides more definitive results

Verification Panel ♦♦ Calretinin stains the tumor cell nuclei and cytoplasm ♦♦ Pankeratin, CK5/6, h-caldesmon, CK7, D2-40, and vimentin stain the tumor cell cytoplasm ♦♦ WT1 (43–93%) stains the tumor cell nuclei ♦♦ Carcinoma markers are variably (usually focally) positive in mesothelioma: CA125 (48%), CD10 (48%), Ber-EP4 (13%), MOC-31 (8%), RCC Ma (focal, 8%), B72.3 (8%), and LeuM1 (5%)

Immunohistochemical Diagnosis in Surgical Pathology

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♦♦ CD99 stains the tumor cell membranes in some cases (53%)

♦♦ CD99 and bcl-2 stain the membranes of the tumor cells ♦♦ Desmin, MSA, SMA, and S-100 are negative

Differential Diagnosis

Differential Diagnosis

♦♦ Adenocarcinoma is positive for CEA, Ber-Ep4, and LeuM1 and usually negative for WT1, calretinin, and vimentin ♦♦ Squamous carcinoma is positive for MOC-31, p63 (nuclear), CK5/6, CEA (77%), and vimentin (60%); some cases are focally positive for calretinin (40%), LeuM1 (30%), Ber-EP4 (40%), and D2-40 (50%); and negative for WT1 (nuclear) ♦♦ Serous carcinoma is positive for MOC-31, Ber-EP4, ER (nuclear), and WT1 (nuclear); and some cases are positive for calretinin (31%), CK5/6 (22%), D2-40 (15%), CEA (13%), and h-caldesmon (5%)

♦♦ Schwannoma is strongly positive for S-100. Some tumors are focally positive for EMA (35%) and CD34 (25%) ♦♦ Fibromatosis is positive for b-catenin (nuclear) and negative for CD34

Desmoplastic Small Round Cell Tumor Verification Panel

Differential Diagnosis

♦♦ Desmin shows dot-like staining in tumor cell cytoplasm ♦♦ Pankeratin, NSE, EMA, and vimentin stain the tumor cell cytoplasm ♦♦ WT1 stains the tumor cell nuclei ♦♦ Chromogranin (5%) and synaptophysin (16%) stain some cases

Differential Diagnosis ♦♦ Lymphoma is positive for CD45, CD3 or CD20, and vimentin and negative for desmin, WT1 (nuclear), ­pankeratin, chromogranin, and synaptophysin ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for pankeratin and WT1 (nuclear) ♦♦ Ewing sarcoma is positive for CD99 (membranous) and Fli-1 (nuclear); some cases are positive for pankeratin and synaptophysin; and negative for chromogranin

Solitary Fibrous Tumor/Hemangiopericytoma Verification Panel ♦♦ CD34 stains the cytoplasm of tumor cells; endothelial cells are also positive

Fibromatosis Verification Panel ♦♦ b-catenin stains the tumor cell nuclei ♦♦ CD117 stains some tumors (30%) ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm focally ♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin and negative for b-catenin (nuclear) and CD117 ♦♦ Inflammatory myofibroblastic tumor is focally positive for SMA, MSA, desmin, and ALK (nuclear) (57%) and negative for b-catenin (nuclear) and CD117 ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for b-catenin (nuclear)

Inflammatory Myofibroblastic Tumor Verification Panel ♦♦ ALK stains the tumor cell nuclei. This marker is the most specific for this tumor but stains only 50% of cases ♦♦ SMA, MSA, desmin, and keratin (30%) focally stain the tumor cell cytoplasm

Differential Diagnosis ♦♦ Fibromatosis is positive for b-catenin (nuclear), focally positive for SMA and CD117, and negative for ALK (nuclear) ♦♦ Fibrosarcoma is negative for ALK (nuclear), SMA, MSA, and desmin ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for ALK (nuclear)

BREAST ♦♦ The diagnosis of well-differentiated adenocarcinoma vs. benign lesions is more conclusive with two myoepithelial cell markers, preferably one cytoplasmic and one nuclear. The cytoplasmic stains are more sensitive and the nuclear marker is more specific ♦ ♦ ER and PR are used for prognostic and diagnostic purposes for in situ and invasive carcinomas. The percentage of positive tumor nuclei should be reported (Fig. 2.31)

Sclerosing Adenosis, Tubular Adenoma/ Adenosis Tumor, Nipple Duct Adenoma, Complex Sclerosing Lesion/Radial Scar Verification Panel ♦♦ Calponin, SMA, and SMMHC stain the cytoplasm of the myoepithelial cells surrounding the benign glandular component

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Table 2.17. Gland-forming Breast Lesions Differential Diagnosis Myoepithelial Basement membrane markers: Calponin, SMA, markers: SMMHC, and laminin and p63 (nuclear) collagen IV Sclerosing adenosis, tubular adenoma, radial scar, nipple duct adenoma

+

+

Microglandular adenosis

−

+

Tubular carcinoma

−

Discontinuous

Microglandular Adenosis ♦♦ This benign lesion does not contain myoepithelial cells

Verification Panel ♦♦ Laminin and collagen IV stain the thickened basement membrane around the small glands

Differential Diagnosis (Table 2.17) ♦♦ Well-differentiated (especially tubular) adenocarcinoma would lack continuous laminin and collagen IV positive basement membrane material around the glands Fig.  2.31. (A, B) ER stains the nuclei of a tubulolobular breast carcinoma; percent of positive cells is a prognostic and therapeutic indicator. ♦♦ p63 stains the nuclei of myoepithelial cells surrounding the benign glandular component

Differential Diagnosis (Table 2.17) ♦♦ Well-differentiated adenocarcinoma does not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC, and p63 (nuclear)

Adenomyoepithelioma ♦♦ Calponin, SMA, and SMMHC stain the cytoplasm of myoepithelial cells lining and proliferating between the benign glandular components ♦♦ p63 stains the nuclei of myoepithelial cells lining and proliferating between the benign glandular components

Differential Diagnosis (Table 2.17) ♦♦ Well-differentiated adenocarcinoma does not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC, and p63 (nuclear)

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Intraductal Papillary Tumors ♦♦ Papillary tumors are benign, atypical, or carcinoma based on the cellular and architectural atypia of the glandular epithelium and the presence of myoepithelial cells

Verification Panel (Fig. 2.32) ♦♦ Benign papilloma shows a simple glandular lining or simple hyperplasia with calponin, SMA, and SMMHC staining the cytoplasm and p63 staining the nuclei of myoepithelial cells lining the papillary fronds throughout the entire tumor ♦♦ Atypical papilloma shows an atypical intraductal proliferation with diminished myoepithelial cells focally, which would be negative for calponin, SMA, and SMMHC in the cytoplasm and p63 (nuclear) in those areas ♦♦ Intracystic/intraductal papillary carcinoma would not contain myoepithelial cells within the lesion and would be negative for calponin, SMA, and SMMHC in the cytoplasm and p63 (nuclear). Myoepithelial cells can be present lining the cyst wall

Differential Diagnosis ♦♦ Invasive papillary carcinoma does not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC, and p63 (nuclear) ♦♦ Pseudoinvasion is the presence of apparently infiltrating glands that is the result of infarction within a noninvasive

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Fig. 2.32. (A–E) Calponin stains the cytoplasm of the myoepithelial cells lining the papillary structures of a benign breast papilloma (B, C: low and high power). Calponin stains the cytoplasm of the myoepithelial cells lining the papillary structures of an atypical breast papilloma with a uniform rigid ductal cell proliferation (D, E: low and high power).

intracystic papillary carcinoma. This results in papillary fragments within a desmoplastic stroma. Myoepithelial cells positive for calponin, SMA, SMMHC, and p63 (nuclear) would be present lining and admixed with the pseudoinvasive papillary fragments

Lobular In Situ Carcinoma Verification Panel ♦♦ E-cadherin is negative in the tumor cell membranes and cytoplasm

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Differential Diagnosis

Infiltrating Ductal Carcinoma

♦♦ Ductal carcinoma in situ is positive for e-cadherin

♦♦ The diagnosis is usually based on morphology

Infiltrating Lobular Carcinoma

Verification Panel

Verification Panel (Fig. 2.33) ♦♦ Pankeratin is positive in the tumor cell cytoplasm ♦♦ E-cadherin is negative in the tumor cell membranes and cytoplasm

Differential Diagnosis ♦♦ Lymphocytic inflammation and lymphoma are negative for pankeratin and positive for CD45 ♦♦ Low grade infiltrating ductal carcinoma is positive for e-cadherin

♦♦ Well-differentiated adenocarcinoma (e.g., tubular carcinoma) does not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC in the cytoplasm, and p63 (nuclear) ♦♦ Poorly differentiated breast carcinoma can be confirmed as a primary tumor with GCDFP-15 staining the cytoplasm, HER2 staining the membranes and cytoplasm, and ER and PR staining the nuclei

Differential Diagnosis (Table 2.17) ♦♦ Benign lesions including sclerosing adenosis, tubular adenoma, and radial scar would contain myoepithelial cells positive for calponin, SMA, SMMHC, and p63 (nuclear) ♦♦ Microinvasive carcinoma (£1  mm) can be demonstrated showing malignant cells unassociated with myoepithelial cells, lacking calponin and p63 (nuclear) staining ♦♦ Fat necrosis is positive for CD68 in the foamy macrophages and negative for pankeratin. This differentiates this reactive process from the rare pankeratin positive histiocytoid/lipoid variant of ductal carcinoma ♦♦ Metastatic carcinoma or primary dermal carcinomas in the breast are rare. Cytoplasmic staining for GCDFP-15, membrane staining for HER2, and nuclear staining for ER and/or PR support a diagnosis of a breast primary. Refer to Chapter 3 for further discussion

Breast Carcinoma Micrometastasis in Sentinel Lymph Nodes ♦♦ The pankeratin positive cells must have the morphology of tumor cells (differentiated from mature squamous cells that can contaminate the slide) and are usually located in a subcapsular location

Verification Panel (Fig. 2.34) ♦♦ Pankeratin stains the cytoplasm of metastatic carcinoma cells

Metaplastic Carcinoma Verification Panel ♦♦ Pankeratin and CK7 stain the cytoplasm of the tumor ductal elements ♦♦ CK5/6 stains the cytoplasm of the tumor squamous elements ♦♦ Pankeratin and vimentin stain the spindled tumor cells ♦♦ Desmin, SMA, and muscle-specific actin stain the ­cytoplasm of muscle-derived elements ♦♦ S-100 stains the nuclei and cytoplasm of adipose and cartilage-derived elements Fig.  2.33. (A, B) Inflitrative lobular carcinoma (upper) and benign duct (lower). E-cadherin stains the membranes of the benign ductal cells (left) and is negative in the small infiltrative lobular carcinoma cells (right).

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Differential Diagnosis ♦♦ Malignant phyllodes tumor includes benign proliferative ductal elements within the malignant spindled areas ♦♦ Primary sarcomas are pankeratin negative

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Differential Diagnosis ♦♦ Melanoma in situ is positive for HMB 45, Melan-A, and S-100 and negative for pankeratin, mCEA, and GCDFP-15 ♦♦ Squamous cell carcinoma in situ is positive for pankeratin, CK5/6, and p63 (nuclear) and negative for S-100, HMB 45, GCDFP-15, and mCEA

Biphasic Tumors: Fibroadenoma, Phyllodes Tumors ♦♦ The diagnosis of these tumors is based on morphology

Verification Panel ♦♦ Calponin, SMA, and SMMHC stain the cytoplasm, and p63 stains the nuclei of myoepithelial cells

Differential Diagnosis Fig.  2.34. Pankeratin stains the cytoplasm of small clusters of micrometastatic breast ductal carcinoma in a sentinel lymph node.

♦♦ Leiomyosarcomas are strongly SMA, desmin, and MSA positive and can be focally pankeratin positive (40%)

Adenoid Cystic Carcinoma ♦♦ This carcinoma is composed of two cell types: glandular/epithelial and basal/myoepithelial

Verification Panel ♦♦ Pankeratin and EMA stain the cytoplasm of the glandular cells ♦♦ Calponin, pankeratin, SMA, and SMMHC stain the cytoplasm, and p63 stains the nuclei of myoepithelial cells

Differential Diagnosis ♦♦ Cribriform low grade DCIS would be morphologically similar but does not contain the myxoid or hyalinized basement membrane material within the glandular structures. It would contain the same type of cell components and thus, the same IHC pattern ♦♦ Cribriform adenocarcinoma would not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC, and p63 (nuclear) ♦♦ Collagenous spherulosis would contain the same type of cell components and thus, the same IHC pattern, but would lack atypia, desmoplasia, and the clefting collagen seen in adenoid cystic carcinoma

Paget Disease of the Nipple ♦♦ IHC verification is unnecessary when DCIS or invasive carcinoma is present in the subjacent tissue

Verification Panel ♦♦ Pankeratin, GCDFP-15, mCEA, and occasionally S-100 stain the tumor cell cytoplasm ♦♦ HER2 and EMA stain the tumor cell membranes and cytoplasm

♦♦ Well-differentiated adenocarcinoma would not contain myoepithelial cells and would be negative for calponin, SMA, SMMHC, and p63 (nuclear) ♦♦ Primary sarcomas do not have glandular elements and are negative for pankeratin ♦♦ Leiomyosarcoma is positive for SMA, desmin, and MSA and can be focally pankeratin positive (40%)

Granular Cell Tumor Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Inhibin and CD68 stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Breast adenocarcinoma is positive for pankeratin and S-100 (57%) and negative for inhibin ♦♦ Apocrine carcinoma is positive for pankeratin and androgen receptor (nuclear) and negative for S-100 ♦♦ Fat necrosis is positive for S-100 and CD68 and negative for inhibin

Malignant Myoepithelioma (Myoepithelial Carcinoma) Verification Panel ♦♦ Pankeratin, calponin, SMA, and SMMHC stain the cytoplasm, and p63 stains the nuclei of myoepithelial cells

Differential Diagnosis ♦♦ Mammary carcinoma is positive for pankeratin and negative for SMA, SMMHC, calponin, and p63 (nuclear) ♦♦ Leiomyoma and leiomyosarcoma are strongly positive for SMA and can be focally pankeratin positive (40%)

Fibromatosis ♦♦ This spindle cell tumor can entrap benign glandular breast elements

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Verification Panel ♦♦ b-catenin stains the tumor cell nuclei and cytoplasm ♦♦ SMA stains the cytoplasm focally of the most tumors (80%) ♦♦ CD117 stains the cytoplasm focally of some tumors (30%)

Differential Diagnosis ♦♦ Myofibroblastoma is positive for CD34 diffusely and desmin and actin focally

♦♦ Vascular neoplasms (hemangioma and angiosarcoma) are positive for CD34, CD31, Fli-1 (nuclear), and Factor VIII

Angiosarcoma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Pankeratin can be focally positive in the tumor cell cytoplasm (17%)

Myofibroblastoma

Differential Diagnosis

♦♦ This spindle cell tumor does not contain glandular elements

♦♦ Poorly differentiated carcinoma is diffusely positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear). The acantholytic variant of squamous cell carcinoma is morphologically similar to angiosarcoma but will not contain blood within the tumor-lined spaces

Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Desmin and SMA focally stain the tumor cell cytoplasm ER and PR stain the tumor cell nuclei

Differential Diagnosis ♦♦ Fibromatosis is positive for b-catenin; focally positive for SMA; and negative for CD34. It infiltrates around breast glandular elements ♦♦ Neurofibroma is positive for S-100 and negative for CD34, desmin, and actin

Pseudoangiomatous Stromal Hyperplasia Verification Panel ♦♦ Vimentin stains the cytoplasm of the spindle cells lining the slit-like spaces ♦♦ Progesterone receptor stains the nuclei of the spindle cells lining the slit-like spaces ♦♦ The spindle cells lining the slit-like spaces are negative for vascular markers including CD34, CD31, Fli-1 (nuclear), and Factor VIII

Differential Diagnosis ♦♦ Myofibroblastoma is positive for CD34

Other Mesenchymal Tumors ♦♦ Other breast mesenchymal tumors include hemangioma, inflammatory myofibroblastic tumor, lipoma, leiomyoma, schwannoma, liposarcoma, rhabdomyosarcoma, and leiomyosarcoma. Refer to the mesenchymal section and Chapter 3 for further discussion

Lymphoma ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most are CD20 positive B-cell types. The most common primary is diffuse large B-cell type. Less common are Burkitt lymphoma, extranodal marginal-zone B-cell lymphoma of MALT, follicular lymphoma, and lymphoblastic lymphoma (B- or T-cell). Refer to the section and chapter on lymph node for further discussion

Metastases ♦♦ The most common tumors to spread to the breast are skin (melanoma), rhabdomyosarcoma, and lung, ovary, kidney, thyroid, stomach, and prostate carcinomas. Refer to Chapter 3 for further discussion

MESENCHYMAL TISSUE Fibrous and Fibrohistiocytic Tissue ♦♦ Most fibrous tumors express only the mesenchymal marker vimentin. IHC testing is useful for excluding tumors derived from other cell types ♦♦ Reactive and proliferative fibrous lesions show variable pleomorphism and mitotic activity. IHC is not helpful for the differentiation of reactive processes vs. low grade neoplasms

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Nodular, Proliferative, and Ischemic Fasciitis Verification Panel ♦♦ SMA, SMA, and vimentin stain the cytoplasm of the myofibrocytes ♦♦ CD68 stains scattered cells, possibly intermixed histiocytic cells ♦♦ Desmin and S-100 are negative

Immunohistochemical Diagnosis in Surgical Pathology

Differential Diagnosis ♦♦ Benign fibrous histiocytoma shows negative or weak and focal SMA and MSA staining ♦♦ Fibromatosis is positive for b-catenin (nuclear) ♦♦ Sarcomas with myoid differentiation are differentiated by higher growth rate, deep location, and increased cellularity, pleomorphism, and mitotic activity

Benign Fibrous Histiocytoma Verification Panel ♦♦ Factor XIIIa stains the tumor cell membranes and cytoplasm ♦♦ SMA focally stains some cases (38%) ♦♦ Some deep lesions are positive for CD34 (40%)

Differential Diagnosis ♦♦ Neurofibroma is positive for S-100 ♦♦ Fasciitis is positive for SMA and MSA ♦♦ Dermatofibrosarcoma protuberans is positive for CD34 and negative for Factor XIIIa

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Juvenile Xanthogranuloma Verification Panel ♦♦ CD68 and fascin stain the tumor cell cytoplasm ♦♦ S-100 focally stains some cases (29%)

Differential Diagnosis ♦♦ Langerhans cell histiocytosis is positive for S-100, CD68, and CD1a

Solitary Fibrous Tumor and Hemangiopericytoma ♦♦ These tumors are related by IHC and molecular studies

Verification Panel (Fig. 2.35) ♦♦ CD34 stains the tumor cell cytoplasm; endothelial cells are also positive ♦♦ CD99 and bcl-2 stain the tumor cell membranes and cytoplasm ♦♦ Desmin, MSA, SMA, and S-100 focally stain some tumors (6–11%)

Fig. 2.35. (A–D) CD34 and bcl-2 stain the cytoplasm of a solitary fibrous tumor. A low proliferation rate is demonstrated with rare positive ki-67 nuclear staining.

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Differential Diagnosis ♦♦ Schwannoma is strongly positive for S-100; some are focally positive for EMA (35%) and CD34 (25%) ♦♦ Leiomyoma/leiomyosarcoma are diffusely positive for SMA, MSA, desmin, and bcl-2; some cases are positive for CD99 (27%); and negative for CD34 ♦♦ Synovial sarcoma is positive for CD99, bcl-2, pankeratin, and EMA; some cases are positive for SMA; and negative for CD34 ♦♦ Mesenchymal chondrosarcoma is positive for CD99 (membranous) and negative for CD34 ♦♦ Fibrous histiocytoma is positive for Factor XIIIa; some cases are positive for CD34; and negative for CD99 and bcl-2

Myofibromatosis/Myofibroma Verification Panel

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin ♦♦ Undifferentiated high grade pleomorphic sarcoma is usually negative for CD99 (membranous)

Dermatofibrosarcoma Protuberans Verification Panel ♦♦ CD34 stains the tumor cell membranes and cytoplasm; endothelial cells are also positive

Differential Diagnosis ♦♦ Neurofibroma is positive in the nuclei and cytoplasm for S-100 and negative for CD34 ♦♦ Fasciitis is negative for CD34 ♦♦ Benign fibrous histiocytoma is positive for Factor XIIIa, and some cases are positive for CD34 (40% of deep tumors)

♦♦ SMA and calponin stain the tumor cell cytoplasm ♦♦ Desmin and caldesmon are negative

Desmoplastic Small Round Cell Tumor Verification Panel (Fig. 2.36)

Differential Diagnosis

♦♦ Vimentin and pankeratin stain the tumor cell cytoplasm ♦♦ EMA and CD56 stain the tumor cell membranes and cytoplasm

♦♦ Fibrous histiocytoma is positive for Factor XIIIa, and some cases are positive for SMA ♦♦ Infantile fibrosarcoma and nodular fasciitis are ­differentiated by morphology

Inflammatory Myofibroblastic Tumor Verification Panel ♦♦ ALK is positive in the nuclei and cytoplasm of the tumor cells. This is the most specific marker, but stains only 57% of cases ♦♦ Actin, desmin, and pankeratin focally stain the tumor cell cytoplasm

Differential Diagnosis ♦♦ Leiomyosarcoma is diffusely positive for SMA, MSA, and desmin and negative for ALK ♦♦ Synovial sarcoma is positive for CD99, bcl-2, pankeratin, and EMA; some cases are positive for SMA; and negative for ALK ♦♦ Fibromatosis is positive for b-catenin (nuclear); focally positive for SMA and CD117; and negative for ALK ♦♦ Fibrosarcoma is focally positive for SMA and negative for ALK, MSA, and desmin ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for ALK ♦♦ Sarcomatoid carcinoma is negative for ALK and focally positive for pankeratin

Atypical Fibroxanthoma Verification Panel ♦♦ Vimentin, CD68 and lysozyme stain the tumor cell cytoplasm ♦♦ CD99 stains the tumor cell membranes

Differential Diagnosis ♦♦ Spindle cell squamous carcinoma is positive for pankeratin ♦♦ Melanoma is positive for S-100 and Melan-A, and some cases are positive for CD99 (membranous, 16%)

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Fig. 2.36. (A, B) Desmin shows dot-like cytoplasmic staining in a ­desmoplastic small round cell tumor.

Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Desmin stains the tumor cell cytoplasm diffusely or in a dotlike pattern ♦♦ WT1 and Fli-1 (67%) stain the tumor cell nuclei

Differential Diagnosis (Table 2.18) ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for keratin and WT1 (nuclear) ♦♦ Wilms tumor is positive for pankeratin, vimentin, desmin, and WT1 (nuclear) and negative for Fli-1 (nuclear) ♦♦ Synovial sarcoma is positive for pankeratin, EMA, and bcl-2 and negative for WT1 (nuclear) ♦♦ Neuroendocrine carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD56 and negative for desmin and WT1 (nuclear) ♦♦ Ewing sarcoma is positive for CD99 (membranous), pankeratin, and Fli-1 (nuclear) and negative for desmin and WT1 (nuclear) ♦♦ Seminoma (dysgerminoma) is positive for PLAP, CD117, and OCT4 (nuclear) and negative for desmin ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for pankeratin and desmin

Deep (Desmoid) Fibromatosis Verification Panel ♦♦ b-catenin stains the tumor cell nuclei ♦♦ CD117 stains some tumors (30%) ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm focally

Differential Diagnosis ♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin and negative for b-catenin (nuclear) and CD117 ♦♦ Inflammatory myofibroblastic tumor is focally positive for SMA, MSA, desmin, and ALK (57%) and negative for b-catenin (nuclear) and CD117 ♦♦ Gastrointestinal stromal tumor is positive for CD117, CD34, and SMA and negative for b-catenin (nuclear) ♦♦ Fibrosarcoma is diffusely positive for vimentin, focally positive for SMA; some cases are positive for CD117 (54%); and negative for MSA, desmin, and b-catenin ♦♦ Fasciitis is negative for b-catenin

Fibrosarcoma Verification Panel ♦♦ Vimentin diffusely and SMA focally stain the tumor cell cytoplasm

Differential Diagnosis ♦♦ Fibromatosis is positive for b-catenin (nuclear), vimentin and focally positive for SMA ♦♦ Inflammatory myofibroblastic tumor is positive for vimentin, SMA, ALK, MSA, and desmin ♦♦ Gastrointestinal stromal tumor is positive for vimentin, CD117, CD34, and SMA

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♦♦ Leiomyosarcoma is strongly positive for vimentin, SMA, MSA, and desmin ♦♦ Sarcomatoid carcinoma is positive for pankeratin and focally for vimentin and SMA

Smooth Muscle Leiomyoma/Leiomyosarcoma Verification Panel ♦♦ SMA, MSA, and desmin stain the tumor cell cytoplasm ♦♦ Some tumors are focally positive for pankeratin (40%)

Differential Diagnosis ♦♦ Gastrointestinal tumor is positive for CD117 and CD34 and can be focally positive for SMA

Skeletal Muscle Rhabdomyoma Verification Panel ♦♦ ♦♦ ♦♦ ♦♦

MSA and desmin stain the tumor cell cytoplasm Myogenin and Myo-D1 stain the tumor cell nuclei S-100 focally stains the tumor cell nuclei and cytoplasm Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Granular cell tumor is diffusely positive for S-100 and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Paraganglioma is positive for chromogranin and synaptophysin and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear). S-100 stains the spindled sustentacular cells surrounding the tumor cell nests ♦♦ Histiocytic reaction is positive for S-100 and CD68 and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Carcinoma is positive for pankeratin and negative for MSA, desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Rhabdomyosarcoma Verification Panel (Fig. 2.37) ♦♦ Desmin and MSA stain the tumor cell cytoplasm ♦♦ Myogenin and Myo-D1 stain the tumor cell nuclei ♦♦ S-100 can be focally positive in the tumor cell nuclei and cytoplasm (12%) ♦♦ CD56 and CD99 focally stain the tumor cell membranes and cytoplasm

Differential Diagnosis (Table 2.18) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is ­positive for Fli-1 (nuclear) and CD99 (membranous) and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear)

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♦♦ Undifferentiated carcinoma is positive for pankeratin and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Vessels Angiosarcoma, Epithelioid Hemangioendothelioma, and Hemangioma Verification Panel (Fig. 2.38) ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Pankeratin can be focally positive in angiosarcoma (17%)

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is diffusely positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Fibrosarcoma is negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Kaposi sarcoma is positive for CD31, CD34, Factor VIII, Fli-1 (nuclear) and HHV8 (nuclear)

Kaposi Sarcoma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 and HHV8 stain the tumor cell nuclei. Benign endothelial cells are also positive for Fli-1

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear) ♦♦ Angiosarcoma and lobular capillary hemangioma (pyogenic granuloma) are positive for CD31, CD34, Factor VIII, and Fli-1 (nuclear) and negative for HHV8 (nuclear) ♦♦ Fibrosarcoma is negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear)

Glomus Tumor Verification Panel Fig. 2.37. (A–C) Myo-D1 stains the nuclei, and MSA focally stains the cytoplasm of an embryonal rhabdomyosarcoma in the breast. ♦♦ Malignant melanoma is positive for S-100, HMB 45, and Melan-A and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Neuroblastoma is positive for CD56, chromogranin, and synaptophysin and negative for desmin, myogenin (nuclear), and Myo-D1 (nuclear)

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♦♦ SMA diffusely stains the tumor cell cytoplasm ♦♦ CD34 focally stains the tumor cell membranes and ­cytoplasm (53%)

Differential Diagnosis ♦♦ Carcinoid tumor is positive for pankeratin and ­chromogranin, synaptophysin, and CD56 and negative for SMA and CD34 ♦♦ Epithelioid gastrointestinal tumor is positive for CD117 and CD34 and can be focally positive for SMA ♦♦ Carcinoma is positive for pankeratin

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Table 2.18. Mesenchymal Small Round Blue Cells Tumor Differential Diagnosis Muscle markersa

Synaptophysin

S-100

Pankeratin

CD99/ Fli-1a

CD45

Rhabdomyosarcoma

+

−

−

−

11/−

−

Ewing sarcoma/PNET

−

−

0–21

30

+/+

−

Small cell osteosarcoma

–

−

−

−

+/NA

−

Synovial sarcoma, poorly differentiated

−

−

30

+

+/10

−

Desmoplastic small round cell tumor

Desmin dot-like pattern

−

−

+

35/+

−

Epithelioid sarcoma, proximal type

−

−

−

+

NA/−

−

Lymphoma

−

−

−

−

Varies

+

Metastatic small cell carcinoma

−

+

−

+

−/7

−

b

Neuroendocrine

Metastatic poorly differentiated carcinoma

−

Carcinoma

0–19

+

Varies/−

−

Metastatic Melanoma

−

−

+

−

11/+

−

Myo-D1 and myogenin show Nuclear staining. Desmin shows cytoplasmic staining Positive for SMA and MSA NA not available a

b

Neural Tissue Schwannoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis ♦♦ Gastrointestinal stromal tumor is positive for CD117 and CD34, and some cases are focally positive for S-100 (30%). Meningioma is positive for EMA and focally positive for S-100

Neurofibroma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis ♦♦ Schwannoma is positive for S-100 but does not contain the collagenous background

Granular Cell Tumor Verification Panel

♦♦ Histiocytic inflammation is positive for S-100 and CD68 and negative for inhibin ♦♦ Paraganglioma is positive for chromogranin and synaptophysin and negative for CD68 and inhibin. S-100 stains the spindled sustentacular cells surrounding the tumor cell nests

Malignant Peripheral Nerve Sheath Tumor Verification Panel ♦♦ S-100 stains scattered tumor cell nuclei and cytoplasm ♦♦ CD99 stains the tumor cell membranes and cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis ♦♦ Fibrosarcoma is negative for S-100 ♦♦ Synovial sarcoma is positive for pankeratin, EMA, and CD99 (membranous), and some cases are positive for S-100 (30%) ♦♦ Leiomyosarcoma is positive for SMA, MSA, and desmin ♦♦ Cellular neurofibroma is diffusely positive for S-100 ♦♦ Cellular schwannoma is diffusely positive for S-100

Cartilage

♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ CD68 and inhibin stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

♦♦ The diagnosis of most chondroid neoplasms is based on morphology ♦♦ S-100 stains the chondrocyte nuclei and cytoplasm

Differential Diagnosis

Mesenchymal Chondrosarcoma Verification Panel

♦♦ Carcinoma is positive for pankeratin and negative for S-100 and inhibin

♦♦ Vimentin stains the tumor cell cytoplasm

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Fig. 2.38. (A–D) CD34 stains the membranes and cytoplasm, pankeratin focally stains the cytoplasm, and Fli-1 stains the nuclei of an angiosarcoma. ♦♦ CD99 stains the tumor cell membranes (specific) and cytoplasm ♦♦ Desmin, CD57, and NSE show variable cytoplasmic staining ♦♦ Cytokeratins and epithelial membrane antigen are negative ♦♦ S-100 stains the cytoplasm and nuclei of the cartilaginous component

Bone

Differential Diagnosis

♦♦ S-100 stains the nuclei and cytoplasm ♦♦ Pankeratin, vimentin and EMA stain the cytoplasm

♦♦ Ewing sarcoma/peripheral neuroectodermal tumor is positive for Fli-1 (nuclear) and CD99 (membranous) ♦♦ Synovial sarcoma is positive for pankeratin, EMA, CD99 (membranous), and S-100 ♦♦ Hemangiopericytoma is positive for CD34 and CD99 (membranous) ♦♦ Melanoma is positive for S-100 and HMB 45 and Melan-A and some tumors are positive for CD99 (11%, mem‑ branous) ♦♦ Carcinoma is positive for pankeratin and negative for ­vimentin and CD99 (membranous)

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♦♦ The diagnosis of most bone neoplasms is based on mor‑ phology

Chordoma Verification Panel

Differential Diagnosis ♦♦ Carcinoma is positive for pankeratin and EMA and usually negative for S-100 and vimentin ♦♦ Chondrosarcoma is positive for S-100 and negative for pankeratin and EMA

Small Cell Osteosarcoma Verification Panel ♦♦ CD117 stains the tumor cell nuclei and cytoplasm ♦♦ SMA and MSA focally stain the tumor cell cytoplasm

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♦♦ S-100 (16%) and CD99 (membranous, 13%) focally stain some tumors

Differential Diagnosis (Table 2.18) ♦♦ Ewing sarcoma is diffusely positive for CD99 ­(membranous), CD117, and Fli-1 (nuclear) ♦♦ Metastatic small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, and CD117 and negative for SMA and MSA ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 ♦♦ Plasmacytoma is positive for CD138 and kappa or lambda

Ewing Sarcoma/Peripheral Neuroectodermal Tumor Verification Panel (Fig. 2.39) ♦♦ CD99 stains the tumor cell membranes and cytoplasm (cytoplasmic staining alone is a nonspecific finding) ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei ♦♦ Vimentin diffusely stains the tumor cell cytoplasm ♦♦ Pankeratin (30%), NSE (36%), synaptophysin (9%), and CD56 (9%) focally stain some tumors

Differential Diagnosis (Table 2.18) ♦♦ Small cell osteosarcoma is positive for CD117 and focally positive for CD99 (membranous), MSA, and SMA ♦♦ Mesenchymal chondrosarcoma is positive for CD99 (membranous) and negative for Fli-1 (nuclear) ♦♦ Metastatic small cell carcinoma is positive for pankeratin, chromogranin, and synaptophysin; some cases are positive for CD99 (membranous, 20%); and negative for Fli-1 (nuclear) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some types are positive for CD99 (membranous); and negative for Fli-1 (nuclear) ♦♦ Small cell carcinoma is positive for pankeratin, CD56, chromogranin, and synaptophysin and negative for CD99 and Fli-1 (nuclear). Lung tumors are positive for TTF-1 (nuclear)

Langerhans Cell Histiocytosis Verification Panel ♦♦ CD1a and CD68 stain the tumor cell membranes and cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis ♦♦ Histiocytic reaction is positive for S-100 and CD68 and negative for CD1a ♦♦ Hodgkin lymphoma is positive for LeuM1 and CD30 and negative for CD1a

Plasma Cell Dyscrasia, Plasmacytoma, and Multiple Myeloma Verification Panel ♦♦ CD138 stains the tumor cell membranes and cytoplasm ♦♦ Staining only for kappa or lambda identifies a monotypic population

Fig. 2.39. (A–C) CD99 stains the membranes (specific finding) and cytoplasm (nonspecific), and Fli-1 stains the cell nuclei of a Ewing sarcoma.

Differential Diagnosis ♦♦ Lymphoma is positive for CD45 and negative for CD138 ♦♦ Osteomyelitis does not show a monotypic population

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Metastatic Disease

Differential Diagnosis (Table 2.18)

♦♦ Metastatic disease is discussed in Chapter 3

♦♦ Liposarcoma is positive for S-100 and negative for CD34

♦♦ Ewing sarcoma is positive for CD99 and Fli-1 (nuclear); some cases are positive for pankeratin and NSE ♦♦ Leiomyosarcoma is ­diffusely positive for SMA, MSA, and desmin; some cases are positive for CD99; and negative for S-100 ♦♦ Sarcomatoid carcinoma is focally positive for pankeratin, and some cases are positive for CD99, bcl-2, and S-100 ♦♦ Inflammatory myofibroblastic tumor is positive for ALK (57%) and negative for CD99 ♦♦ Mesenchymal chondrosarcoma is positive for CD99 (membranous) and desmin; the chondroid areas are positive for S-100; and negative for pankeratin and EMA

Angiomyolipoma Verification Panel

Clear Cell Sarcoma of Soft Tissue Verification Panel

♦♦ HMB 45, Melan-A, SMA, MSA, and desmin are positive in the cytoplasm of the spindle and epithelioid tumor cells ♦♦ Keratins, EMA, and S-100 are negative (S-100 stains the adipose elements)

♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ HMB 45 stains the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

Differential Diagnosis

Differential Diagnosis

♦♦ Adipose tumors (e.g., liposarcoma) are positive for S-100 and negative for HMB 45, Melan-A, SMA, MSA, and desmin ♦♦ Leiomyoma and leiomyosarcoma are positive for MSA, SMA, and desmin and negative for HMB 45 and Melan-A

♦♦ Melanoma must be differentiated by clinical history and molecular genetics ♦♦ Fibrosarcoma is negative for S-100 and HMB 45 ♦♦ Metastatic renal cell carcinoma is positive for EMA, CD10, and RCC Ma and negative for S-100 and HMB 45 ♦♦ Alveolar soft parts sarcoma is positive for TFE3 (nuclear) and negative for S-100 and HMB 45

Miscellaneous Pleomorphic and Spindle Cell Lipoma Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm ♦♦ S-100 stains the tumor cell and adipocyte nuclei and cytoplasm

Differential Diagnosis

Gastrointestinal Stromal Tumor (GIST) Verification Panel ♦♦ CD117 (95%) and CD34 (70%) stain the tumor cell membranes and cytoplasm; endothelial cells are also positive for CD34 ♦♦ SMA can be focally positive (25%)

Alveolar Soft Part Sarcoma Verification Panel ♦♦ TFE3 stains the tumor cell nuclei and cytoplasm

Differential Diagnosis

Differential Diagnosis

♦♦ Leiomyoma and leiomyosarcoma are diffusely positive for SMA, MSA, and desmin; some cases are positive for CD34 (21%); and negative for CD117 ♦♦ Schwannoma (diffusely) and malignant peripheral nerve sheath tumor (focally) are positive for S-100; some cases are positive for CD34 (17–43%); and negative for CD117 ♦♦ Fibromatosis is positive for SMA (focally), b-catenin (nuclear), and CD117 (30%) and negative for CD34

♦♦ Metastatic clear cell renal cell carcinoma is positive for EMA, CD10, and RCC Ma and negative for TFE3 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A ♦♦ Paraganglioma is positive for chromogranin and syna‑ ptophysin ♦♦ Granular cell tumor is positive for S-100 ♦♦ Clear cell sarcoma is positive for S-100, HMB 45, and Melan-A

Synovial Sarcoma Verification Panel (Fig. 2.40)

Epithelioid Sarcoma Verification Panel (Fig. 2.41)

♦♦ CD99, bcl-2, and EMA (77%) stain the tumor cell ­membranes and cytoplasm ♦♦ Pankeratin (67%) and SMA (15%) stain the tumor cell cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm (30%) ♦♦ Fli-1 weakly stains the nuclei in some cases (30%)

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♦♦ Pankeratin and vimentin stain the tumor cell cytoplasm ♦♦ CD34 and EMA stain the tumor cell membranes and cytoplasm

Differential Diagnosis (Table 2.18) ♦♦ Granulomatous inflammation is positive for CD68 and negative for pankeratin, EMA, and CD34

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Fig. 2.40. (A–D) CD99 and EMA stain the cytoplasm, and bcl-2 stains the cytoplasm of a synovial sarcoma.

♦♦ Fibromatosis is positive for SMA (focally), b-catenin (nuclear), and CD117 (30%) and negative for CD34 and pankeratin ♦♦ Squamous cell carcinoma is positive for pankeratin; some cases are positive for vimentin; and negative for CD34 ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, EMA, and CD34 ♦♦ Synovial sarcoma is positive for pankeratin, EMA, ­vimentin, and CD99 (membranous) and negative for CD34

Differential Diagnosis

Undifferentiated High Grade Pleomorphic Sarcoma (Malignant Fibrous Histiocytoma) Verification Panel

♦♦ Synovial sarcoma is positive for bcl-2, CD99 (membranous), pankeratin, and EMA, and some cases are positive for S-100

♦♦ By definition, IHC testing is only positive for vimentin or shows only rare positive cells

♦♦ Rhabdomyosarcoma is positive for desmin, MSA, myogenin (nuclear), and Myo-D1 (nuclear) ♦♦ Malignant peripheral nerve sheath tumor shows scattered cells positive for S-100 ♦♦ Leiomyosarcoma is positive for MSA, SMA, and desmin ♦♦ Ewing sarcoma is positive for CD99 (membranous) and Fli1 (nuclear)

♦♦ Poorly differentiated carcinoma is positive for pankeratin ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A

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Fig. 2.41. (A–D) Pankeratin, vimentin, and CD34 stain the cytoplasm of an epithelioid sarcoma.

SKIN Squamous Cell Carcinoma Verification Panel

Basal Cell Carcinoma Verification Panel

♦♦ HMWK (34bE12, CK5/6) stains the tumor cell cytoplasm ♦♦ EMA stains the tumor cell membranes and cytoplasm ♦♦ p63 stains the tumor cell nuclei

♦♦ HMWK (34bE12, CK5/6) and bcl-2 stain the tumor cell cytoplasm ♦♦ Ber-EP4 stains the tumor cell membranes and cytoplasm ♦♦ p63 stains the tumor cell nuclei ♦♦ SMA stains many cases (76%)

Differential Diagnosis ♦♦ Basal cell carcinoma is positive for HMWK, p63 (nuclear), bcl-2, and Ber-EP4; many cases are positive for SMA (76%); and negative for EMA ♦♦ Merkel cell carcinoma is positive for CK20, chromogranin, and synaptophysin and negative for p63 (nuclear) and CK5/6 ♦♦ Sebaceous carcinoma is positive for CK5/6, EMA, and Ber-EP4 (80%)

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Differential Diagnosis ♦♦ Squamous cell carcinoma is positive for HMWK, p63 (nuclear), and EMA and negative for Ber-EP4, bcl-2, and SMA ♦♦ Trichoepithelioma shows bcl-2 expression only in the outer epithelial layer

Immunohistochemical Diagnosis in Surgical Pathology

Merkel Cell Carcinoma Verification Panel (Fig. 2.42) ♦♦ CK20 shows dot-like positivity in the tumor cell cytoplasm ♦♦ Chromogranin, synaptophysin, and CD56 variably stain the tumor cell cytoplasm ♦♦ S-100 and vimentin are negative

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Differential Diagnosis ♦♦ Malignant melanoma is positive for S-100, HMB 45, and Melan-A; some case are positive for CD56 (11%); and negative for chromogranin and synaptophysin ♦♦ Metastatic neuroendocrine carcinoma is positive for chromogranin, synaptophysin, and CD56 and negative for CK20

Fig. 2.42. (A–D) CK20 stains a dot-like and diffuse cytoplasmic pattern, and chromogranin (diffusely) and synaptophysin (focally) stain the cytoplasm of a dermal Merkel cell carcinoma.

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Melanoma Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Melanocytic markers (HMB 45, Melan-A) stain the tumor cell cytoplasm ♦♦ Rare cases show focal pankeratin positive cytoplasm (3%)

Differential Diagnosis ♦♦ Because of the varied morphology (epithelioid, spindled, pleomorphic, and small cell) of melanoma, many other poorly differentiated tumors must be considered including sarcoma, lymphoma, and metastatic carcinoma. Refer to Chapter 3 for further discussion ♦♦ Carcinoma is diffusely positive for pankeratin; some cases are focally positive for S-100 (19–44%); and negative for HMB 45 and Melan-A ♦♦ Small cell carcinoma is positive for pankeratin, chromogranin, synaptophysin, CD56, and S-100 (19%) and negative for HMB 45 and Melan-A ♦♦ Lymphoma is positive for CD45 and CD3 or CD20; some cases are positive for S-100; and negative for HMB 45 and Melan-A ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for HMB 45 and Melan-A

Melanoma Micrometastasis in Sentinel Lymph Nodes ♦♦ The S-100 and HMB 45 or Melan-A positive cells must have the morphology of tumor cells and are usually located in a subcapsular location. It is recommended that S-100 (most sensitive) and an additional melanoma marker (more specific) are used to identify micrometastases

Verification Panel (Fig. 2.43) ♦♦ S-100 stains the nuclei and cytoplasm of metastatic melanoma cells. S-100 also stains histiocytes and some lymphoid cells ♦♦ HMB 45 and Melan-A stain the cytoplasm of metastatic melanoma cells

Differential Diagnosis ♦♦ Capsular nevus is positive for S-100 and negative for HMB 45 and Melan-A. The cells are bland and located in the lymph node capsule ♦♦ Histocytes and some lymphoid cells are focally positive for S-100 and negative for HMB 45 and Melan-A; morphology is useful for differentiation

Granular Cell Tumor Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm ♦♦ Inhibin and CD68 stain the tumor cell cytoplasm ♦♦ Epithelial markers (various keratins and EMA) are negative

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Fig.  2.43. HMB 45 (A) and S-100 (B) stain small clusters of micrometastatic melanoma in a sentinel lymph node. S-100 (C) also stains histiocytes and some lymphocytes.

Differential Diagnosis ♦♦ Carcinoma is positive for pankeratin and negative for inhibin. Breast carcinoma can be positive for S-100 and renal cell carcinoma for CD68

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♦♦ Pankeratin can be focally positive in some cases (17%)

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Melanoma is positive for S-100, HMB 45, and Melan-A and negative for pankeratin, CD31, CD34, Factor VIII, and Fli-1 (nuclear) ♦♦ Fibrosarcoma is negative for CD31, CD34, Factor VIII, and Fli-1 (nuclear)

Kaposi Sarcoma Verification Panel (Fig. 2.45) ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 and HHV8 stain the tumor cell nuclei. Benign endothelial cells are also positive for Fli-1

Differential Diagnosis ♦♦ Poorly differentiated carcinoma is positive for pankeratin and negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear) ♦♦ Angiosarcoma and lobular capillary hemangioma (pyogenic granuloma) are positive for CD31, CD34, Factor VIII, and Fli-1 (nuclear) and negative for HHV8 (nuclear) ♦♦ Fibrosarcoma is negative for CD31, CD34, Factor VIII, Fli-1 (nuclear), and HHV8 (nuclear)

Other Mesenchymal Tumors Fig. 2.44. (A, B) SMA stains the cytoplasm of a glomus tumor in the skin.

Glomus Tumor Verification Panel (Fig. 2.44) ♦♦ SMA diffusely stains the tumor cell cytoplasm ♦♦ CD34 focally stains the tumor cell membranes and ­cytoplasm (53%)

Differential Diagnosis ♦♦ Carcinoid tumor is positive for pankeratin and chromogranin, synaptophysin, and CD56 and negative for SMA and CD34 ♦♦ Skin adnexal tumors are positive for pankeratin

Angiosarcoma, Epithelioid Hemangioendothelioma, and Hemangioma Verification Panel ♦♦ CD31, CD34, and Factor VIII stain the tumor cell cytoplasm; benign endothelial cells are also positive ♦♦ Fli-1 stains the tumor and benign endothelial cell nuclei

♦♦ Other dermal mesenchymal tumors include lipoma, lymphangioma, leiomyoma, neurofibroma, atypical fibroxanthoma, leiomyosarcoma, epithelioid sarcoma, and undifferentiated high grade pleomorphic sarcoma. Refer to the mesenchymal section of this chapter and Chapter 3 for further discussion

Lymphoma ♦♦ The most common primary lymphoma is CD3, CD4, and CD5 positive (CD7 and CD8 negative) mycosis fungoides. Other dermal lymphomas include CD4 positive primary cutaneous anaplastic large cell lymphoma, CD3 and CD4 positive lymphomatoid papulosis, and CD45 and CD20 diffuse large B-cell, follicular, marginal zone, and mantle cell lymphomas. Refer to the lymphoma section and chapter for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the skin in women are breast, colorectal, lung, ovarian, and melanoma and in men are lung, colorectal, melanoma, oropharyngeal, renal, and gastric. Refer to Chapter 3 for further discussion

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CENTRAL NERVOUS SYSTEM Glial Tissue Astrocytoma, Anaplastic Astrocytoma, and Glioblastoma Multiforme ♦♦ In low grade neoplasms, the principle of differential diagnosis is reactive changes; IHC does not discriminate between these lesions ♦♦ The IHC cytoplasmic GFAP staining pattern is seen in the various astrocytic neoplasms including the usual fibrillary type, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, and subependymal giant cell astrocytoma ♦♦ IHC can be useful in high grade, poorly differentiated tumors although the staining is usually focal and weak

Verification Panel ♦♦ GFAP stains the tumor cell cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm, but is not specific to astrocytic tumors

Differential Diagnosis ♦♦ Metastatic carcinoma is positive for pankeratin and negative for GFAP ♦♦ Metastatic melanoma is positive for S-100, HMB 45 and Melan-A and negative for GFAP

Oligodendroglioma ♦♦ The diagnosis of this tumor is based on morphology. IHC can help eliminate other tumors in the differential diagnosis

Verification Panel ♦♦ S-100 stains the tumor cell nuclei and cytoplasm, but is not specific to oligodendroglial tumors ♦♦ GFAP does not usually stain classic oligodendrocytes, but stains the cytoplasm of minigemistocytes and gliofibrillary oligodendrocytes

Differential Diagnosis

Fig. 2.45. (A–C) CD34 stains the cytoplasm of benign endothelial cells and Kaposi sarcoma tumor cells (slit-like vessels). HHV8 stains the nuclei of Kaposi sarcoma tumor cells, but not benign vessels (left).

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♦♦ Central neurocytoma is diffusely, strongly positive for synaptophysin and negative for GFAP ♦♦ Clear cell ependymoma is positive for GFAP and focally positive for EMA ♦♦ Clear cell meningioma is positive for EMA and negative for GFAP ♦♦ Metastatic clear cell carcinoma is positive for pankeratin and EMA and negative for GFAP ♦♦ Pineocytoma is strongly positive for synaptophysin. GFAP and S-100 stain background elements

Ependymoma Verification Panel ♦♦ GFAP stains the tumor cell cytoplasm

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♦♦ S-100 stains the tumor cell nuclei and cytoplasm, but is not specific to ependymal tumors ♦♦ EMA focally stains tumor cell membranes and cytoplasm (lumens of rosettes)

Differential Diagnosis ♦♦ Astrocytic tumors are positive for GFAP and negative for EMA ♦♦ Choroid plexus is diffusely positive for pankeratin and S-100 and focally positive for GFAP ♦♦ Metastatic adenocarcinoma is positive for pankeratin and negative for GFAP

Subependymoma Verification Panel ♦♦ GFAP focally stains the cytoplasm of the tumor cells

Differential Diagnosis ♦♦ Tanycytic ependymoma is positive with GFAP and is differentiated by morphology

Gliosarcoma Verification Panel (Fig. 2.46) ♦♦ GFAP focally stains the cytoplasm of the tumor cells in betterdifferentiated areas

Differential Diagnosis ♦♦ Metastatic sarcomatoid carcinoma is focally positive for pankeratin and negative for GFAP ♦♦ Sarcomas are negative for GFAP

Choroid Plexus Tumors ♦♦ Normal choroid plexus is positive for pankeratin and vimentin, focally positive for EMA. and negative for GFAP

Fig.  2.46. (A, B) GFAP stains the tumor cell cytoplasm of a gliosarcoma.

Verification Panel ♦♦ Pankeratin and vimentin stain papilloma tumor cell cytoplasm ♦♦ S-100 stains papilloma tumor cell nuclei and cytoplasm (90%) ♦♦ GFAP stains papilloma tumor cell cytoplasm (40%) ♦♦ Pankeratin and vimentin stain carcinoma tumor cell cytoplasm ♦♦ S-100 and GFAP (20%) are less frequent in choroid plexus carcinoma ♦♦ EMA, Ber-EP4, and CEA are usually negative in choroid plexus carcinoma

Differential Diagnosis ♦♦ Papillary ependymoma is positive for GFAP and negative for pankeratin ♦♦ Papillary meningioma is positive for EMA and negative for pankeratin and GFAP ♦♦ Metastatic carcinoma is positive for pankeratin; some cases are positive for S-100; and negative for vimentin

Dura Meningioma, Atypical Meningioma, Malignant Meningioma Verification Panel ♦♦ EMA stains the tumor cell membranes and cytoplasm ♦♦ S-100 stains the tumor cell nuclei and cytoplasm focally (20%) ♦♦ CD34 is negative in the tumor cells; endothelial cells are positive

Differential Diagnosis (Tables 2.19 and 2.20) ♦♦ Metastatic carcinoma is positive for pankeratin and EMA ♦♦ Melanoma is strongly positive for S-100 and negative for EMA ♦♦ Schwannoma is strongly positive for S-100 and usually negative for EMA

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Neural Tissue Ganglioglioma and Gangliocytoma

Table 2.19. Meningioma Differential Diagnosis (% Tumors Positive) EMA S-100 CD34 Keratin

♦♦ Diagnosis is based on location and morphology. Gang‑ liocytoma contains a benign glial component

Verification Panel

Meningioma

+

17

−

27

Schwannoma

−

+

−

−

♦♦ Synaptophysin stains the cytoplasm of the ganglion cells ♦♦ GFAP stains the cytoplasm of the glial elements

Solitary fibrous tumor hemangiopericytoma

−

−

+

−

Differential Diagnosis

Metastatic carcinoma

+

19

−

+

Table 2.20. CNS Clear Cell Neoplasms Differential Diagnosis (% Tumors Positive) RCC Inhibin S-100 EMA CD10 Ma Hemangioblastoma

+

+

−

−

−

Central Neurocytoma Verification Panel ♦♦ Synaptophysin stains the tumor cell cytoplasm. Synaptophysin will also stain background neuropil and must be interpreted carefully ♦♦ S-100 shows variable tumor cell nuclear and cytoplasmic staining ♦♦ GFAP is positive in rare tumor cells

Differential Diagnosis

Metastatic conventional clear cell renal cell carcinoma

−

21

+

+

+

Clear cell meningioma

−

17

+

−

−

Metastatic carcinoma (not RCC)

−

19

+

−

−

♦♦ Hemangiopericytoma is positive for CD34 and negative for EMA ♦♦ Metastatic renal cell carcinoma (vs. clear cell meningioma) is positive for CD10, RCC Ma, pankeratin (weakly), and EMA and negative for CD34 and S-100 ♦♦ Hemangioblastoma (vs. clear cell meningioma) is positive for inhibin and negative for EMA

Hemangiopericytoma Verification Panel ♦♦ CD34 stains the tumor cell cytoplasm; endothelial cells are also positive ♦♦ Most tumors are negative for EMA (10% positive) and S-100 (5% positive)

Differential Diagnosis (Table 2.19) ♦♦ Meningioma is positive for EMA and negative for CD34 ♦♦ Schwannoma is strongly positive for S-100. Some tumors are focally positive for EMA (35%) and CD34 (25%)

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♦♦ Pilocytic astrocytoma and pleomorphic xanthoastrocytoma are differentiated by morphology and lack of synaptophysin positive neoplastic neuronal elements

♦♦ Oligodendroglioma is negative for synaptophysin ♦♦ Clear cell ependymoma is positive for GFAP and S-100; focally positive for EMA; and negative for synaptophysin ♦♦ Clear cell meningioma is positive for EMA and negative for GFAP and synaptophysin ♦♦ Metastatic clear cell carcinoma is positive for EMA and negative for GFAP and synaptophysin ♦♦ Pineocytoma is also positive for synaptophysin. Morphology and tumor location differentiate these tumors

Pineocytoma ♦♦ Pineocytoma can be differentiated from benign pineal gland by the loss of GFAP staining around the normal lobules

Verification Panel ♦♦ Synaptophysin stains the tumor cell cytoplasm. Synaptophysin will also stain background neuropil and must be interpreted carefully

Differential Diagnosis ♦♦ Oligodendroglioma is negative for synaptophysin ♦♦ Clear cell ependymoma is positive for GFAP and S-100; some cases are focally positive for EMA; and negative for synaptophysin ♦♦ Clear cell meningioma is positive for EMA and negative for GFAP and synaptophysin ♦♦ Metastatic clear cell carcinoma is positive for EMA and negative for GFAP and synaptophysin

Immunohistochemical Diagnosis in Surgical Pathology

♦♦ Central neurocytoma is also positive for synaptophysin. Morphology and tumor location differentiate these tumors ♦♦ Germinoma is positive for PLAP, OCT4 (nuclear), and CD117 in the germ cells and CD45 in the lymphoid cells and negative for synaptophysin

Pineoblastoma, Medulloblastoma, Retinoblastoma, and Supratentorial (Central) Primitive Neuroectodermal Tumor ♦♦ Pineoblastoma, retinoblastoma, medulloblastoma (Fig. 2.47), and supratentorial (central) primitive neuroectodermal tumor are differentiated by tumor location

Verification Panel ♦♦ Synaptophysin, chromogranin, NSE, CD56, and vimentin stain the tumor cell cytoplasm ♦♦ GFAP stains the cytoplasm of rare cells that might be entrapped astrocytes or differentiated tumor cells

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Differential Diagnosis (Table 2.21) ♦♦ Lymphoma is positive for CD45 and CD3 or CD20 and negative for synaptophysin and chromogranin ♦♦ Metastatic small cell carcinoma is positive for pankeratin, CD56, chromogranin, and synaptophysin and negative for vimentin ♦♦ Melanoma is positive for S-100 and HMB 45 and/or Melan-A and negative for chromogranin and synaptophysin ♦♦ Rhabdomyosarcoma is positive for desmin, myogenin (nuclear), and Myo-D1 (nuclear) and negative for synaptophysin and chromogranin ♦♦ Ewing sarcoma is positive for CD99, Fli-1 (nuclear), and vimentin and negative for CD56, synaptophysin, and chromogranin ♦♦ In the pineal gland area, germinoma is positive for PLAP, CD117, and OCT4 (nuclear) in the germ cells and CD45 in the lymphoid cells and negative for synaptophysin and chromogranin

Dysembryoplastic Neuroepithelial Tumor ♦♦ Diagnosis is based on location and morphology

Fig. 2.47. (A–D) CD56, NSE, and synaptophysin stain the tumor cell cytoplasm of a medulloblastoma.

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Table 2.21. CNS Small Round Blue Cells Tumor Differential Diagnosis Synaptophysin

S-100

Pankeratin

+

0–21

−

Metastatic small cell carcinoma

+

−

Rhabdomyosarcoma

−

−

Lymphoma

−

Metastatic poorly differentiated carcinoma Metastatic melanoma

Nuclear TTF-1

Muscle markersa

CD45

−

−

−

+

+

−

−

−

−

+

−

−

−

−

−

+

Neuroendocrine Carcinoma

0–19

+

Lung Thyroid

−

−

−

+

−

−

−

−

Medulloblastoma Retinoblastoma Pineoblastoma Central PNET

a

Muscle markers include desmin, myogenin (nuclear), and Myo-D1 (nuclear)

Verification Panel

Verification Panel

♦♦ Synaptophysin stains the cytoplasm of the neural elements ♦♦ GFAP stains the cytoplasm of the glial elements

♦♦ INI1 shows loss of nuclear staining in the tumor cells ♦♦ Synaptophysin stains the cytoplasm of the PNET component ♦♦ Pankeratin and EMA stain the cytoplasm of the epithelial component ♦♦ GFAP stains the cytoplasm of tumor cells focally in some cases

Sella Pituitary Adenoma ♦♦ Diagnosis is based on location and morphology ♦♦ Pituitary adenoma can be differentiated from benign pituitary gland by the uniform staining for hormone markers (e.g., prolactin) ♦♦ IHC can identify tumor cell hormone type (e.g., growth hormone), but this is often evaluated with serological testing

Craniophayngioma ♦♦ Diagnosis is based on location and morphology

Verification Panel ♦♦ Pankeratin and CK5/6 stain the cytoplasm of the squamous elements

Miscellaneous Atypical Teratoid/Rhabdoid Tumor ♦♦ The diagnosis of this tumor in infants is primarily based on morphology

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Differential Diagnosis ♦♦ Medulloblastoma is positive for synaptophysin and INI1 (nuclear) and negative for pankeratin and EMA ♦♦ Ependymoma is positive for GFAP and INI1 (nuclear) and negative for synaptophysin

Hemangioblastoma Verification Panel (Fig. 2.48) ♦♦ ♦♦ ♦♦ ♦♦

Inhibin stains the tumor cell cytoplasm S-100 stains the tumor cell nuclei and cytoplasm (64%) EMA is negative in the tumor cells CD34 is negative in the tumor cells but highlights the tumor vasculature

Differential Diagnosis (Table 2.20) ♦♦ Metastatic conventional clear cell renal cell carcinoma is positive for EMA, RCC Ma, and CD10 and negative for inhibin

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♦♦ Clear cell or angiomatous meningioma is positive for EMA and S-100 and negative for inhibin

Germ Cell Tumors ♦♦ Germ cell tumors occur in the pineal gland region

Verification Panel ♦♦ Germinoma is PLAP, CD117, and OCT4 (nuclear) positive in the germ cells and CD45 positive in the tumor-associated lymphoid cells ♦♦ Yolk sac tumor is positive for aFP and pankeratin ♦♦ Embryonal carcinoma is positive for CD30, OCT4 (nuclear), and pankeratin

Differential Diagnosis ♦♦ Pinecytoma and pineoblastoma are positive for synaptophysin ­ and negative for PLAP, OCT4, and aFP ♦♦ Lymphoma is positive for CD45 and negative for PLAP, aFP, synaptophysin, and pankeratin

Lymphoma Verification Panel ♦♦ Most lymphomas show CD45 membranocytoplasmic staining. Most are CD20 positive large B-cell lymphomas. Refer to Table  2.21, the lymphoma section and the chapter on lymph node for further discussion

Metastatic Disease ♦♦ The most common tumors to metastasize to the brain are lung, breast, and skin (melanoma). Refer to Chapter 3 for further discussion

Infections ♦♦ IHC antibody to JC papova virus shows nuclear staining of infected cells in progressive multifocal leukoencephalopathy ♦♦ IHC antibody to Herpes simplex virus 1 and 2 show nuclear and cytoplasmic staining of infected cells ♦♦ IHC antibody to cytomegalovirus shows nuclear and occasionally cytoplasmic staining of infected cells ♦♦ IHC antibody to Toxoplasma gondii stains the bradyzoite organisms ♦♦ IHC antibody to Entamoeba histolytica stains the organisms

Fig.  2.48. (A–C) Inhibin stains the tumor cell cytoplasm of a hemangioblastoma. CD34 highlights the typical vascular pattern of this tumor.

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HEMATOLYMPHOID NEOPLASMS Introduction ♦♦ Diagnosis of most hematolymphoid neoplasms relies on a combination of morphologic and immunophenotypic data, with the integration of clinical and genetics information necessary in some. The central role of morphology cannot be overemphasized, not only through the routinely stained sections that initiate the workup but also through evaluation of immunohistochemical stains to establish the phenotype. The following notes describe the “characteristic” immunophenotypic profiles of hematolymphoid neoplasms for the major diagnostic categories as given in the 2008 WHO classification. It is important to recognize that although disease entities generally have a distinct immunophenotype, variations and exceptions occur. The reader is thus referred to the chapter on hematopoietic neoplasms in this book and to other reference material for in-depth discussion, and for contextual interpretation, which is essential for accurate diagnosis in many cases. While most immunophenotypic characteristics may be readily determined by immunohistochemistry, flow cytometry may be used to advantage, particularly for identifying light chain restriction in B-cell lymphomas, and surface heavy chains. Detection of Epstein-Barr virus infection may be accomplished by immunohistochemistry (EBV-LMP1) or by in-situ hybridization (EBER). Genetic studies to assess gene rearrangements as surrogates for clonality and – by extension – malignancy are more often necessary in the case of T-cell proliferations. ♦♦ Where several lineage (B- or T-cell) markers are given, in most instances one may be sufficient, resorting to others if findings are inconclusive or atypical.

Precursor Lymphoid Neoplasms B Lymphoblastic Leukemia/Lymphoma Immunophenotype Data ♦♦ PAX-5 (nuclear), CD19, CD22, CD79a are useful to establish B-lineage ♦♦ PAX-5 (nuclear) may be the most sensitive and specific B marker ♦♦ TdT (nuclear), CD10, CD24 usually positive ♦♦ CD45 may be absent ♦♦ CD20, CD34 variably expressed ♦♦ CD13, CD33 may be present ♦♦ Surface Ig typically absent ♦♦ MPO must be negative

T Lymphoblastic Leukemia/Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD3 establishes T-lineage CD1a, CD2, CD4, CD5, CD7, CD8 usually positive TdT (nuclear) usually positive CD10 may be positive

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♦♦ Coexpression of CD4 and CD8 in blasts may be seen ♦♦ TdT (nuclear), CD99, and CD34 expression favor precursor T vs. peripheral T-cell lymphoma ♦♦ CD13, CD33, CD117 may be present

Mature B-Cell Neoplasms Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Immunophenotype Data ♦♦ CD19, CD20, CD22, CD79a, PAX-5 (nuclear) establish B lineage ♦♦ CD5, CD23, CD43 coexpressed ♦♦ CD11c, IgM, IgD weakly expressed ♦♦ CD10, CD79b, FMC-7 negative or weak ♦♦ Cyclin D1 negative ♦♦ CD38, ZAP-70 expression associated with adverse prognosis

B-Cell Prolymphocytic Leukemia Immunophenotype Data ♦♦ CD19, CD20, CD22, PAX-5 (nuclear), CD79a, CD79b establish B lineage ♦♦ FMC-7, surface IgM positive ♦♦ CD5, CD23 expressed only in a minority of cases ♦♦ IgD may be expressed ♦♦ Cyclin D1 (nuclear) negative

Splenic Marginal Zone Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD20, CD79a, PAX-5 (nuclear) establish B lineage IgM positive, IgD often positive CD5, CD10, CD23, CD43 negative Annexin A1 and CD103 negative useful to exclude hairy cell leukemia ♦♦ bcl-6 negative useful to exclude follicular lymphoma ♦♦ Cyclin D1 (nuclear) negative useful to exclude mantle cell lymphoma

Hairy Cell Leukemia Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD20, PAX-5 (nuclear) establish B lineage CD22, CD11c, CD25, CD72, CD103, CD123 positive Annexin A1, T-bet, FMC-7, surface Ig positive Annexin A1 is most specific Cyclin D1 (nuclear) may be weakly positive CD5, CD10, CD23 usually negative

Immunohistochemical Diagnosis in Surgical Pathology

Lymphoplasmacytic Lymphoma Immunophenotype Data ♦♦ CD19, CD20, CD22, PAX-5 (nuclear), CD79a establish B lineage (lymphocytic component) ♦♦ Surface Ig positive (plasmacytic cells express cytoplasmic Ig) ♦♦ Positive for IgM most often, IgG sometimes,IgA rarely ♦♦ IgD negative ♦♦ CD5, CD10, CD23, CD103 negative ♦♦ CD25, CD38 may be positive ♦♦ CD138 positive (plasma cell component)

Plasma Cell Neoplasms Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD38, CD79a, CD138 establish B lineage CD38 may be weakly positive Surface Ig negative Kappa or lambda monotypic cytoplasmic staining CD19, CD20, PAX-5 (nuclear) typically negative CD56, CD117, CD20, CD52, CD10 may be positive Cyclin D1 (nuclear) may rarely be positive Background nonneoplastic plasma cells may be CD19 positive, CD38 positive, CD56 negative

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD20, CD79a, PAX-5 (nuclear) establish B lineage CD21, CD35, IgM positive CD43, CD11c, IgA, IgD variably expressed CD5, CD10, CD23 negative Cyclin D1 (nuclear) negative

Nodal Marginal Zone Lymphoma Immunophenotype Data ♦♦ CD19, CD20, CD22, CD79a, PAX-5 (nuclear) establish B lineage ♦♦ bcl-2 positive ♦♦ CD43 positive in half of cases ♦♦ CD5, CD10, CD23, bcl-6, cyclin D1 (nuclear) negative

Follicular Lymphoma, Nodal Immunophenotype Data ♦♦ CD19, CD20, CD22, CD79a, PAX-5 (nuclear) establish B lineage ♦♦ CD10, bcl-2, bcl-6 positive ♦♦ Surface Ig positive ♦♦ CD5, CD43, MUM1 (nuclear) negative ♦♦ CD21 and CD23 positive in follicular dendritic reticulum cells

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♦♦ bcl-2 may be negative in 10–15% of low grade tumors and in up to 50% of grade 3 cases ♦♦ bcl-2 may be positive in only 30% of pediatric cases ♦♦ bcl-2 must be positive for a diagnosis of follicular lymphoma in situ

Primary Cutaneous Follicle Center Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD20, PAX-5 (nuclear), CD79a establish B lineage CD10 positive if follicular pattern is present CD10 usually negative if the pattern is diffuse bcl-2 variable, usually weak if positive Ig usually negative CD5, CD43 negative

Mantle Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD20, CD79a, PAX-5 (nuclear) establish B lineage CD5, CD43, FMC-7, Cyclin D1 (nuclear) positive Surface IgM, IgD positive CD10, bcl-6 negative

Diffuse Large B-Cell Lymphoma, NOS Immunophenotype Data ♦♦ CD19, CD20, PAX-5 (nuclear), CD22, CD79a establish B lineage ♦♦ CD5, CD30 rarely positive ♦♦ CD10, bcl-6, MUM1 (nuclear) variably positive (may be used to subclassify for prognosis)

Primary Mediastinal (Thymic) Large B-Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD19, CD20, CD22, CD79a, PAX-5 establish B lineage CD30 weakly positive in majority of cases Ig negative CD10, CD23, bcl-2, bcl-6, MUM1 variably positive LeuM1 may occasionally be positive

Plasmablastic Lymphoma Immunophenotype Data ♦♦ CD38, CD138, MUM1 (nuclear) positive ♦♦ EBV EBER by in situ hybridization positive in majority of cases ♦♦ CD79a positive in a majority of cases ♦♦ CD30, EMA may be positive ♦♦ CD20, CD45, PAX-5 (nuclear), EBV LMP1 negative or weakly positive ♦♦ HHV8 (nuclear) negative

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Primary Effusion Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD45 usually positive HHV8 (nuclear) positive EBV EBER positive, EBV LMP1 negative B-cell markers CD19, CD20, PAX-5, CD79a usually negative T/NK cell markers CD3, CD2, CD7, CD4, CD8, CD16, CD56, TIA1, granzyme B usually negative ♦♦ Surface and cytoplasmic immunoglobulin negative ♦♦ CD30, CD138, EMA may be positive

Burkitt Lymphoma Immunophenotype Data ♦♦ CD19, CD20, PAX-5 (nuclear), CD22, CD79a establish B lineage ♦♦ CD10, bcl-6 positive ♦♦ bcl-2, MUM1 (nuclear) negative ♦♦ Ki-67 labeling index positive in nearly 100% of tumor cells ♦♦ Surface Ig positive

Lymphomatoid Granulomatosis Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD20 establishes B lineage for the large atypical cells EBV (LMP1, EBER) positive CD30 may be positive LeuM1 negative Reactive background contains CD3 positive T-lymphocytes and may contain CD68 positive histiocytes as well

Mature T- and NK-Cell Neoplasms (Table 2.22) T-Cell Prolymphocytic Leukemia Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD2, CD3, CD7 establish T lineage CD52 positive CD1a, TdT (nuclear) negative CD4, CD8 expression pattern variable (CD4+/CD8− most common) ♦♦ TCL1 overexpression

T-Cell Large Granular Lymphocytic Leukemia Immunophenotype Data ♦♦ CD2, CD3, CD8, TCRab establish T lineage ♦♦ CD16, CD57 positive in the majority of cases ♦♦ Cytotoxic molecules (TIA1, granzyme B, perforin) positive

Aggressive NK-Cell Leukemia Immunophenotype Data ♦♦ CD2, CD3e, CD56 positive

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♦♦ CD16 may be positive ♦♦ Cytotoxic molecules (TIA1, granzyme B, perforin) positive ♦♦ FAS ligand positive

Adult T-Cell Leukemia/ Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD2, CD3, CD5 positive CD4/CD8 variable (CD4+/CD8− most common) CD25 positive CD7 usually negative CD30 may be positive ALK negative Cytotoxic molecules negative

Extranodal NK/T-Cell Lymphoma, Nasal Type Immunophenotype Data ♦♦ CD2, CD56 positive ♦♦ Surface CD3 negative but CD3e positive ♦♦ Cytotoxic molecules (TIA1 (Fig. 2.49), granzyme B, perforin) positive ♦♦ EBV EBER positive, EBV LMP1 variable ♦♦ CD4, CD8, CD16, CD57, TCRd usually negative ♦♦ CD43, CD45RO, HLA-DR, CD25, CD95, FAS ligand may be positive

Enteropathy-Associated T-Cell Lymphoma Immunophenotype Data ♦♦ CD3, CD7 establish T lineage ♦♦ CD103 positive ♦♦ Cytotoxic molecules (TIA1, granzyme B, perforin) positive ♦♦ CD30 may be positive ♦♦ CD4, CD5 negative ♦♦ CD8, CD56 variable ♦♦ Enteropathy-associated T-cell lymphoma type II (monomorphic variant) shows the following immunophenotype ♦♦ CD3, CD8, CD56, TCRb positive ♦♦ CD4 negative

Hepatosplenic T-Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD2, CD3, TCRd1 establish T lineage TIA1, granzyme M positive CD56 variable Granzyme B and perforin negative CD4, CD5, TCRab negative CD8 variable

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Table 2.22. Typical Immunophenotypic Features of Common Mature T- and NK-Cell Neoplasms CD2

CD3

CD4

CD8

CD30

ALK

CD56

CM

EBV

Other

Leukemic/systemic T-PLL

+

+

+

−

TCL1+

T-LGLL

+

+

−

+

ANKCL

+

+C

−

−

ATCLL

+

+

+

−

HSTCL

+

+

−

+/−

PTCL, NOS

+

+

+

−

+/−

ALCL

+/−

+/−

+/−

+/−

+

+ +/−

+

+

+/−

+/−

+/−

+/−

−

CD16+,CD57+ +

−

FAS ligand+ CD25+

Nodal

AITCL

+

+

−

CD43 +/−, EMA+ CD10+, CXCL13+, CD21+FDC

+

+

+

−

MF

+

+

+

−

C-ALCL

+/–

+/–

+

–

+

Cutaneous –

−

CD7−

–

+

CLA+

+

+

Extranodal ENNKTCLNT

+

+C

−

−

−

EATCL

+

+

−

+/−

+/−

+

−

+

SPTCL

+

+ −

+

CD43+/− CD103+

−

CD43+

+C: Positive, cytoplasmic pattern; CM cytotoxic molecules (TIA-1, granzyme B, perforin); EMA epithelial ­membrane antigen; FDC follicular dendritic cells; T-PLL T-cell prolymphocytic leukemia; T-LGLL T-cell large g­ ranular ­lymphocytic leukemia; ANKCL aggressive NK-cell leukemia; ATCLL adult T-cell leukemia/lymphoma; HSTCL hepatosplenic T-cell lymphoma; PTCL, NOS peripheral T-cell lymphoma, not otherwise specified; ALCL anaplastic large cell lymphoma, ALK positive; AITCL angioimmunoblastic T-cell lymphoma; MF mycosis fungoides; C-ALCL primary cutaneous anaplastic large cell lymphoma; ENNKTCLNT extranodal NK/T-cell ­lymphoma, nasal type; EATCL enteropathy-associated T-cell lymphoma; SPTCL subcutaneous panniculitis-like T-cell lymphoma

Subcutaneous Panniculitis-Like T-Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD3 establishes T lineage CD8, CD43 positive Cytotoxic molecules (TIA1, granzyme B, perforin) positive CD4, CD56 negative

Mycosis Fungoides/Sézary Syndrome Immunophenotype Data ♦♦ CD2, CD3 establish T lineage

♦♦ CD4, CD5, TCRb positive ♦♦ CD7 negative ♦♦ Cytotoxic molecules (TIA1, granzyme B, perforin) usually negative

Angioimmunoblastic T-Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD2, CD3 establish T lineage CD4, CD5 positive CD10, bcl-6, CXCL 13, PD1 positive CD21, CD23 positive in proliferating follicular dendritic cell meshworks

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Peripheral T-Cell Lymphoma, NOS Immunophenotype Data

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ CD2, CD3 establish T lineage ♦♦ CD4, CD43, TCRab positive ♦♦ Aberrant T-cell antigen expression common

CD2, CD3, CD5, CD7 may be downregulated or negative CD4, CD8 coexpression or absence Loss of TCRs CD1a, CD99, TdT negative CD30 may be positive

Anaplastic Large Cell Lymphoma, ALK Positive Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD30, monoclonal ALK positive CD2, CD3, CD5, CD4, CD43 often positive Cytotoxic molecules (TIA1, granzyme B, perforin) positive EMA positive CD3, CD45 may be negative CD8 variable CLA negative EBV EBER and LMP1 negative ALK negative forms are now considered a provisional but distinct entity

Primary Cutaneous Anaplastic Large Cell Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦

CD4, CD30, CLA positive ALK, EMA negative CD2, CD3, CD5 variable Cytotoxic molecules (TIA1, granzyme B, perforin) often positive ♦♦ CD8, LeuM1 negative

Hodgkin Lymphoma (Table 2.23) Nodular Lymphocyte Predominant Hodgkin Lymphoma Immunophenotype Data Fig. 2.49. (A, B) The distinctly cytoplasmic granular pattern of the cytotoxic molecule TIA-1 is evident in this nasal-type extranodal NK/T-cell lymphoma.

♦♦ CD20, CD79a, CD75, CD45, PAX5 positive (B lineage markers) ♦♦ CD45, bcl-6 positive

Table 2.23. Typical Immunophenotypic Features of Hodgkin Lymphoma CD20

PAX-5

CD45

CD30

LeuM1

OCT2

BOB.1

MUM1

EMA

JC

bcl-6

NLPHL

+

+

+

−

−

+

+

−

+/−

+/−

+

CHL

−

+W

−

+

+

−

−

+

−

−

+/−

JC: J chain; +W: Positive, weak; LPHL nodular lymphocyte predominant Hodgkin lymphoma; CHL classic Hodgkin lymphoma

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

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OCT-2, BOB.1 positive EMA, J chain may be positive LeuM1, CD30, CD138 negative Ki-67 stains most neoplastic cells CD21, CD23 positive in follicular dendritic cell meshworks Background small lymphocytes are CD20 and CD3 positive B- and T-cells respectively

Classic Hodgkin Lymphoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD30, PAX5 (weak), MUM1 positive LeuM1 positive in majority of cases CD45, EMA, J chain, OCT-2, BOB.1, ALK negative CD20 rarely positive, typically weak and/or focal CD79a negative EBV EBER and LMP1 (Fig.  2.50) variably positive in the different subtypes

Histiocytic and Dendritic Cell Neoplasms (Table 2.24) Histiocytic Sarcoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD68, CD163, lyzozyme positive (one or more markers) CD45, CD45RO (UCHL-1), HLA-DR positive CD4, S-100 may be positive CD1a, CD207 (langerin) negative CD21, CD35 negative CD13, CD33, MPO negative

Fig. 2.50. (A, B) Immunoreactivity to EBV LMP-1 is often seen in Reed-Sternberg cells of classic Hodgkin lymphoma. The staining pattern is typically cytoplasmic and membranous and sometimes shows Golgi zone accentuation.

Langerhans Cell Histiocytosis and Sarcoma Immunophenotype Data ♦♦ CD1a, CD207, S-100 positive

Table 2.24. Typical Immunophenotypic Features of Histiocytic and Dendritic Cell Neoplasms CD1a

CD68

CD207

S-100

CD163

CD21

CD23 CD35 Fascin

Other

LCT

+

+

+

+

+/−

−

−

−

−

HS

−

+

−

+/−

+

−

−

−

−

IDCS

−

+W

−

+

−

−

−

−

+

FDCS

−

+/−

−

+/−

−

+

+

+

+

Clusterin, EBV(EBER)+

DJX

−

+

−

−

+

−

−

−

+

Factor XIIIa

Lyzozyme+

+W: Positive, weak; LCT Langerhans cell histiocytosis and langerhans cell sarcoma; HS histiocytic sarcoma; IDCS interdigitating dendritic cell sarcoma; FDCS follicular dendritic cell sarcoma; DJX disseminated juvenile xanthogranuloma

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♦♦ CD68, vimentin, HLA-DR positive ♦♦ CD4 may be positive ♦♦ CD21, CD23, CD35 negative

♦♦ Factor XIIIa, fascin may be positive ♦♦ CD1a, CD207 negative

Interdigitating Dendritic Cell Sarcoma Immunophenotype Data

Myeloid Tumors Myeloid Sarcoma Immunophenotype Data

♦♦ ♦♦ ♦♦ ♦♦

S-100, vimentin, fascin positive CD45, CD68, lyzozyme weakly positive CD1a, CD207, CD163 negative CD21, CD23, CD35 negative

♦♦ CD68, CD117, CD99, MPO, lyzozyme most often positive ♦♦ CD34, CD45, TdT may be positive

Follicular Dendritic Cell Sarcoma Immunophenotype Data ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD21, CD23, CD35 positive (one or more markers) Clusterin, vimentin, fascin, EGFR, HLA-DR positive EBV (EBER) positive CD68, S-100, EMA may be positive CD1a, CD163, lyzozyme negative

Disseminated Juvenile Xanthogranuloma Immunophenotype Data ♦♦ CD14, CD68, CD163, vimentin positive

Blastic Plasmacytoid Dendritic Cell Neoplasm (Formerly Blastic NK-Cell Lymphoma) Immunophenotype Data ♦♦ CD4, CD56, CD43, CD45, CD123, TCL1, CLA positive ♦♦ CD68, TdT (nuclear) may be positive ♦♦ Cytotoxic molecules (TIA1, granzyme B, perforin) negative ♦♦ CD34, CD117, EBV EBER negative ♦♦ CD3, CD20, lyzozyme and MPO negative

SUGGESTED READING General Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology 2002;40:403–439. Dabbs DJ. Diagnostic immunohistochemistry, 2nd ed. Edinburgh: Churchill Livingstone Elsevier; 2006. Nadji M, Nassiri M, Morales AR. American Society for Clinical Pathology. Efficient tumor immunohistochemistry: a differential diagnosis-driven approach Chicago: ASCP Press; 2006.

Taylor CR. Quantifiable internal reference standards for immunohistochemistry: the measurement of quantity by weight. Appl Immunohistochem Mol Morphol 2006;14:253–259. Taylor CR, Levenson RM. Quantification of immunohistochemistry – issues concerning methods, utility and semiquantitative assessment II. Histopathology 2006;49:411–424.

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Taylor CR, Cote RJ. Immunomicroscopy : a diagnostic tool for the surgical pathologist, 3rd ed. Philadelphia: Saunders/Elsevier; 2006.

Fischer S, Asa SL. Application of immunohistochemistry to thyroid ­neoplasms. Arch Pathol Lab Med 2008;132:359–372.

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Iezzoni JC, Mills SE. “Undifferentiated” small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 2005;124 Suppl:S110–S121.

Compton CC, Fielding LP, Burgart LJ, et  al. Prognostic factors in ­colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:979–994. Goldstein NS, Hewitt SM, Taylor CR, Yaziji H, Hicks DG. Recommendations for improved standardization of immunohistochemistry. Appl Immunohistochem Mol Morphol 2007;15:124–133. Shi SR, Cote RJ, Taylor CR. Antigen retrieval immunohistochemistry and molecular morphology in the year 2001. Appl Immunohistochem Mol Morphol 2001;9:107–116. Taylor CR. Quality assurance and standardization in immunohistochemistry. A proposal for the annual meeting of the Biological Stain Commission, June, 1991. Biotech Histochem 1992;67:110–117. Taylor CR. FDA issues final rule for classification and reclassification of immunochemistry reagents and kits. Am J Clin Pathol 1999;111: 443–444.

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Prasad AR, Savera AT, Gown AM, Zarbo RJ. The myoepithelial ­immunophenotype in 135 benign and malignant salivary gland tumors other than pleomorphic adenoma. Arch Pathol Lab Med 1999;123: 801–806.

Thorax, Lung Kargi A, Gurel D, Tuna B. The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. Appl Immunohistochem Mol Morphol 2007;15:415–420. Pomplun S, Wotherspoon AC, Shah G, Goldstraw P, Ladas G, Nicholson AG. Immunohistochemical markers in the differentiation of thymic and pulmonary neoplasms. Histopathology 2002;40:152–158. Rossi G, Murer B, Cavazza A, et al. Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical

Immunohistochemical Diagnosis in Surgical Pathology

study with special reference to CDX-2 homeobox gene and MUC2 expression. Am J Surg Pathol 2004;28:442–452.

Pleura Ordonez NG. What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 2007;38:1–16.

Gastrointestinal Tract Chen ZM, Ritter JH, Wang HL. Differential expression of alpha-­ methylacyl coenzyme A racemase in adenocarcinomas of the small and large intestines. Am J Surg Pathol 2005;29:890–896. Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol 1998;22:170–179. van Dekken H, Hop WC, Tilanus HW, et  al. Immunohistochemical ­evaluation of a panel of tumor cell markers during malignant progression in Barrett esophagus. Am J Clin Pathol 2008;130:745–753.

Hepatobiliary System Skacel M, Ormsby AH, Petras RE, McMahon JT, Henricks WH. Immunohistochemistry in the differential diagnosis of acinar and ­endocrine pancreatic neoplasms. Appl Immunohistochem Mol Morphol 2000;8:203–209.

Genitourinary Tract, Kidney Huang W, Kanehira K, Drew S, Pier T. Oncocytoma can be differentiated from its renal cell carcinoma mimics by a panel of markers: an automated tissue microarray study. Appl Immunohistochem Mol Morphol 2009;17:12–17. Liu L, Qian J, Singh H, Meiers I, Zhou X, Bostwick DG. Immunohisto­ chemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma: an optimal and practical panel for differential diagnosis. Arch Pathol Lab Med 2007;131:1290–1297. Pan CC, Chen PC, Ho DM. The diagnostic utility of MOC31, BerEP4, RCC marker and CD10 in the classification of renal cell carcinoma and renal oncocytoma: an immunohistochemical analysis of 328 cases. Histopathology 2004;45:452–459. Paner GP, Srigley JR, Radhakrishnan A, et al. Immunohistochemical analysis of mucinous tubular and spindle cell carcinoma and papillary renal cell carcinoma of the kidney: significant immunophenotypic overlap warrants diagnostic caution. Am J Surg Pathol 2006;30:13–19. Vasei M, Moch H, Mousavi A, Kajbafzadeh AM, Sauter G. Immunohistochemical profiling of Wilms tumor: a tissue microarray study. Appl Immunohistochem Mol Morphol 2008;16:128–134. Wang HY, Mills SE. KIT and RCC are useful in distinguishing chromophobe renal cell carcinoma from the granular variant of clear cell renal cell carcinoma. Am J Surg Pathol 2005;29:640–646.

Urinary Bladder Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006;37: 1371–1388. Westfall DE, Folpe AL, Paner GP, et al. Utility of a comprehensive immunohistochemical panel in the differential diagnosis of spindle

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Prostate Hameed O, Humphrey PA. Immunohistochemistry in diagnostic surgical pathology of the prostate. Semin Diagn Pathol 2005;22:88–104. Paner GP, Luthringer DJ, Amin MB. Best practice in diagnostic ­immunohistochemistry: prostate carcinoma and its mimics in needle core biopsies. Arch Pathol Lab Med 2008;132:1388–1396.

Testis Young RH. Testicular tumors – some new and a few perennial problems. Arch Pathol Lab Med 2008;132:548–564.

Gynecological System Dray M, Russell P, Dalrymple C, et al. p16(INK4a) as a complementary marker of high grade intraepithelial lesions of the uterine cervix. I: Experience with squamous lesions in 189 consecutive cervical biopsies. Pathology 2005;37:112–124. Mittal K, Soslow R, McCluggage WG. Application of immunohistochemistry to gynecologic pathology. Arch Pathol Lab Med 2008;132:402–423. Ulbright TM. Germ cell tumors of the gonads: a selective review ­emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol 2005;18 Suppl 2:S61–S79. Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R. Identification of the most sensitive and robust immunohistochemical markers in ­different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol 2009;33:354–366.

Mesenchymal Tissue Coindre JM. Immunohistochemistry in the diagnosis of soft tissue tumours. Histopathology 2003;43:1–16. Heim-Hall J, Yohe SL. Application of immunohistochemistry to soft tissue neoplasms. Arch Pathol Lab Med 2008;132:476–489.

Central Nervous System Edgar MA, Rosenblum MK. The differential diagnosis of central nervous system tumors: a critical examination of some recent immunohistochemical applications. Arch Pathol Lab Med 2008;132:500–509.

Hematolymphoid Neoplasms Dong HY, Browne P, Liu Z, Gangi M. PAX-5 is invariably expressed in B-cell lymphomas without plasma cell differentiation. Histopathology 2008;53:278–287. Jaffe ES. Pathobiology of peripheral T-cell lymphomas. Hematology Am Soc Hematol Educ Program 2006:317–322. Nathwani BN, Sasu SJ, Ahsanuddin AN, Hernandez AM, Drachenberg MR. The critical role of histology in an era of genomics and proteomics: a commentary and reflection. Adv Anat Pathol 2007; 14:375–400. Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 2007;38:1293–1304. Swerdlow SH. International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.

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3 Tumors of Unknown Primary Nancy Klipfel, md, Raul Simental-Pizarro, md, and Clive R. Taylor, md, p hd

contents

I. Introduction.........................................3-2

Definition.............................................................3-2 Organization.......................................................3-2 Approach.............................................................3-2 Notes....................................................................3-2 Limitations..........................................................3-3

II. The Undifferentiated Tumor.................3-3 Screening Panel..................................................3-3

Pleomorphic Tumors, CD45 Negative............3-10 Adult Small Round Blue Cell Tumors, CD45 Negative.............................................3-10 Pediatric Small Round Blue Cell Tumors, CD45 Negative.............................................3-10 Rhabdoid Tumors, CD45 Negative ................3-10 Tumors with Hemangiopericytomatous Vascular Pattern..........................................3-12

VI. Differential Diagnosis Based on the Second-Tier Testing Organ “Specific” and Other Markers..............3-4 Results...............................................3-12

III. Unknown Primary Cancer....................3-4

Pitfalls..................................................................3-5 Notes....................................................................3-5

IV. Differential Diagnosis Based on the Screening Panel Result..............3-6 Pankeratin-Positive, Vimentin-Negative Tumors............................................................3-6 Pankeratin- and Vimentin-Positive Tumors....3-6 Vimentin-Positive, Pankeratin-Negative Tumors............................................................3-6 CD45-Positive and CD45-Negative Hematolymphoid Neoplasms.......................3-6

V. Differential Diagnosis Based on Morphologic Features..........................3-9 Epithelioid Cell Tumors, CD45 Negative.........3-9 Spindle Cell Tumors, CD45 Negative ..............3-9 Biphasic Tumors (Epithelioid and Spindle), CD45 Negative...............................................3-9

S-100-Positive Tumors......................................3-12 CD117-Positive Tumors...................................3-12 CD99-Positive Tumors.....................................3-14 CD34-Positive Tumors.....................................3-14 Muscle Marker-Positive Tumors . ..................3-16 Neuroendocrine Marker-Positive Tumors..........................................................3-16

VII. Differential Diagnosis Based on the Site of Metastasis....................3-18 Pleural Tumors.................................................3-18 Lung Tumors....................................................3-18 Liver Tumors....................................................3-18 Bone Tumors.....................................................3-19 Lymph Node Tumors.......................................3-20 CNS Tumors......................................................3-21

VIII. Suggested Reading.............................3-43

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_3, © Springer Science+Business Media, LLC 2002, 2006, 2011

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INTRODUCTION Definition ♦♦ For this discussion, “unknown tumor” encompasses two situations, an undifferentiated tumor (assumed primary – unknown primary cancer (UPC)) that cannot be reliably diagnosed by light microscopy and a metastasis of unknown origin (MUO) ♦♦ Tumors of unknown primary account for about 3% of all cancer patients, which places them in the ten most common malignancies ♦♦ The goal is to correctly identify the tumor type or primary site while minimizing the number of markers (step-wise ­panels) and/or the testing time; usually the process is a ­compromise of these two systems ♦♦ Various studies have shown a success rate of 66–90%

♦♦

Organization ♦♦ The initial discussion is primarily about an undifferentiated primary tumor with the following sections concerning an MUO. However, there is extensive overlap between investigation of a UPC and an MUO ♦♦ The chapter is structured as several groups of tables of differential diagnoses −− By IHC screening panel −− By morphology −− By a positive reaction for a certain marker −− By metastatic site

Approach ♦♦ Information can guide and simplify the testing −− Is the lesion malignant? −− Is the lesion primary or metastatic? −− If metastatic, what is the primary site? −− Are there helpful morphologic or clinical features? (a) Distinctive morphology (dirty necrosis in colorectal carcinoma or signet ring cells in gastric, breast, or occasionally colorectal carcinoma) (b) Clinicoradiographic information (age, gender, location, pattern of spread, serology) ♦♦ The usual approach is that undifferentiated tumors are first screened to identify the type of cancer – carcinoma, lymphoma, melanoma, or sarcoma. The additional “second-tier” testing is performed to identify the specific type or primary site, as clinically required ♦♦ Differential diagnosis and additional test panels are based on the results of an initial screening panel, tumor primary or metastatic site, and morphology ♦♦ With appropriate, useful clinicoradiographic information, the process might be more for confirmation than investigation. This can reduce the test panel to a couple of expected

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♦♦

♦♦

♦♦

♦♦

positive and pertinent negative (tissue site) markers. For example, adenocarcinoma in the liver with the history of colon cancer; a panel of CK7, CK20, and CA19-9 can usually identify colon cancer (CK7−, CK20+, CA19-9−) and cholangiocarcinoma (CK7+, CK20±, CA19-9+). Hepatocellular carcinoma (HCC) is usually CK7−/CK20−, but the addition of a HepPar1 negative result would help rule-out HCC Ideal tumor markers are highly sensitive (positive in all cases of a particular tumor type) and highly specific (negative in all other tumors). However, less sensitive or specific markers are useful in some situations (e.g., with a limited differential diagnosis). For example, GCDFP-15 is expressed in 35–60% of breast metastases (low sensitivity), but is negative in most other tumors (high specificity). Thus, it is effective when positive but less useful when negative. A probabilistic approach is most appropriate (with an awareness of clinical information, tumor site, morphology, and expected percent positive tumors) Some markers are positive or negative throughout the tumor tissue (e.g., PSA), but many are typically focal (e.g., CK20, chromogranin). Whether a stain is considered positive depends on the marker, the external and internal controls, the tumor staining intensity and distribution, and the differential diagnosis. For example, a benign schwannoma stains strongly and diffusely for S-100 while a malignant peripheral nerve sheath tumor is weak and focal Undifferentiated tumor can be a carcinoma, sarcoma, lymphoma, or melanoma. Sarcomas often require IHC confirmation or subtyping UPC is predominantly adenocarcinoma, most commonly from lung, pancreas/bile duct, colon/rectum, kidney, breast, stomach, ovary, liver, esophagus and prostate. Less commonly, poorly differentiated carcinoma, neuroendocrine tumors, melanoma, lymphoma, and sarcoma (3%) are identified Testing panels and differential diagnosis can be based on morphology including epithelioid (carcinoma, melanoma), glandular (carcinoma), spindle (sarcoma, carcinoma, melanoma), small round blue cell (lymphoma, carcinoma, sarcoma, melanoma), and undifferentiated patterns

Notes ♦♦ The differential diagnosis of primary tumors is discussed in the immunohistochemistry chapter by organ system and tissue type, with further details included in chapters throughout the book ♦♦ A few benign and low malignant potential tumors are included when the morphology places them in the differential diagnosis ♦♦ Tumor genetics are listed in italics. In unknown tumors, molecular testing is most useful for confirming a ­suspected

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diagnosis of a sarcoma that has a known and consistent abnormality (e.g., synovial sarcoma). Some genetic results have a prognostic significance. The karyotypic complexity of many tumors limits the usefulness of genetic testing ♦♦ Molecular testing (cDNA microarrays or RT-PCR) of UPC yields accurate results of 61–89% in various studies. Difficulties occur in test strategy (e.g., microarray design), test performance (e.g., RNA contamination), and tissue availability (e.g., formalin fixed; DNA preservation). Presently, the cost of these studies is high ♦♦ RT-PCR can be performed on formalin fixed paraffin embedded tissue (FFPE) (e.g., c-kit and PDGFRA mutations in GIST) ♦♦ Using FFPE tissue, FISH probes (e.g., EWS, FKHR, SYT, ALK, and CHOP, etc.) can confirm an IHC suspected diagnosis

Limitations ♦♦ Refer to the introduction of the immunohistochemistry chapter for a discussion; errors occur in fixation, tissue sampling, processing, and interpretation ♦♦ Positive controls should be evaluated for every marker, preferably external and internal. The proper staining pattern (nuclear, cytoplasmic, or membranous) must be present ♦♦ Tumors of a certain cell lineage can lose expression of a typical marker or aberrantly express a marker not usually seen in that cell type. This situation is minimized by performing a panel of several expected positive and negative markers ♦♦ Necrosis and crush artifact can cause false-positive results ♦♦ Only very rare markers are nearly 100% sensitive and specific. Markers are listed as positive when a significant majority of tumors express the antigen. Low but significant expression is indicated with a percentage

THE UNDIFFERENTIATED TUMOR Screening Panel (Table 3.1) ♦♦ To determine cell lineage of an undifferentiated tumor, a typical screening panel includes pankeratin, vimentin, S-100, and ±CD45 (if indicated by morphology). This broadly identifies carcinomas, mesenchymal tumors, melanoma, and lymphomas. Germ cell tumors should be considered based on age and tumor site ♦♦ After the result of the screening panel is obtained, often a second testing panel is chosen to further characterize the tumor type or primary site. For example, lymphoma tested for specific subtype or a carcinoma for neuroendocrine, squamous differentiation or markers of a specific organ tissue type ♦♦ Tumors can stain with more than one screening antibody (e.g., lymphoma for vimentin and CD45); the strength and combination direct the final diagnosis or additional testing

♦♦ Rare tumors show no expression with the screening panel −− False negatives: Problems with fixation, test processing (check controls) −− True biological negatives: Undifferentiated tumors might not express antigens, such rare tumors are signed out as “malignant neoplasm, not otherwise specified” with a discussion of the IHC results. Additional molecular testing might be helpful −− Tumors that are negative with the initial screen include Hodgkin lymphoma (CD45−, CD15+, CD30+; suspected based on morphology), anaplastic large cell lymphoma (CD45−, CD30+, EMA+), and S-100-negative melanoma (4%) −− Expression of all markers or multiple conflicting markers could be due to processing problems or aberrant antigen expression

Table 3.1. Undifferentiated Tumor Screening Panela (Listed by Decreasing Expression; Rare Positivity in Parentheses) Pankeratin Carcinoma Nonseminomatous germ cell tumors Sarcoma (subset) (Adrenocortical tumors) (Melanoma)

EMA

Vimentin

S-100

CD45

Carcinoma (Sarcoma) (Lymphoma)

Sarcoma Lymphoma Germ cell tumors (Carcinoma)

Melanoma Sarcoma (Carcinoma) (Lymphoma)

Lymphomab

PLAP can be included in the screening panel for germ cell tumors in the appropriate clinical situation. CD45 positive nonneoplastic tumor-associated lymphoid cells are present in some tumors, including ­germinoma and lymphoepithelial carcinoma. a

b

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UNKNOWN PRIMARY CANCER ♦♦ UPC is primarily carcinoma, with a few percentages of melanoma, lymphoma, and sarcoma ♦♦ The majority (60%) are adenocarcinomas, 30% are undifferentiated carcinomas (mostly poorly differentiated adenocarcinomas), with 5–10% squamous carcinomas and 5% neuroendocrine carcinomas ♦♦ In autopsy studies, the most common unknown adenocarcinoma primary sites are lung, pancreas, bowel, kidney, biliary, stomach, ovary/uterus and prostate ♦♦ Morphology can be helpful, but by definition is not a defining feature: dirty necrosis (intraglandular cell debris) is associated with colorectal primaries and signet ring cells are seen in gastric, breast and occasionally colorectal primaries ♦♦ CK7 and CK20 staining pattern is very helpful in separating carcinomas into groups (Table 3.3). In some cases, combined with morphology and patient history, a diagnosis can be rendered. Alternatively, a third-tier test panel can be based on the CK7/CK20 results for a more definitive diagnosis. Again, the characterization is not absolute. CK7/CK20 testing is not diagnostic in gastric adenocarcinoma, which can show all four staining patterns (Table 3.3) ♦♦ Antigen expression in a metastasis can differ from the primary tumor. Tot (2002) reported patterns of CK7/CK20 expression in common tumor types (Table 3.2)

Organ “Specific” and Other Markers ♦♦ None are completely specific or sensitive ♦♦ TTF-1 (nuclear) is useful for identifying metastatic adenocarcinoma as a lung primary, other carcinomas being rarely positive −− However, it is not specific for small cell neuroendocrine tumors; up to 50% of small cell carcinomas from all other primary sites are positive for TTF-1 (lung 83%, extrapulmonary 42% (GI 53%, GYN 39%, bladder 33%)) −− Also positive in thyroid tumors ♦♦ CDX2 (nuclear) −− Typically expressed in GI and pancreatobiliary tract (colorectal, stomach, GEJ, pancreatobiliary tract, intestinal carcinoid tumors) −− Also positive in mucinous ovary, lung and urinary bladder adenocarcinoma ♦♦ GCDFP-15 −− Typically used to identify breast tumors −− Also positive in salivary gland, prostate, and skin adnexal tumors ♦♦ ER/PR (nuclear) −− Typically used to identify breast and endometrium −− Also positive in some ovary, lung, and neuroendocrine tumors −− Negative in colorectum and HCC

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Fig. 3.1. Poorly differentiated squamous cell carcinoma (A) of the lung is diffusely positive for CK5/6 (B) and focally positive for CK7 (C).

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Table 3.2. The Stability of CK7 and CK20 Expression in Primary and Metastatic Adenocarcinoma (Modified from Tot 2002, Tables 2–3, Reported as Primary and Metastasis (%)) CK7

CK20

Lung

98 and 73

9 and 20

Pancreatobiliary

93 and 93

50 and 42

Colon

16 and 15

91 and 93

Kidney

17 and 0

7 and 0

Stomach

55 and 42

71 and 48

Endometrium

96 and 92

19 and 13

Ovary

88 and 68

25 and 8

Urothelium

N/A

78 and 79

Prostate

11 and 13

19 and 25

Breast

90 and 78

7 and 8

♦♦

♦♦

♦♦

♦♦ ♦♦ CA125 −− Typically used to identify ovarian tumors −− Also positive in mesothelioma, pancreatobiliary tract, endocervix, and urinary bladder adenocarcinoma ♦♦ CA19-9 −− Typically used to identify pancreatobiliary tract tumors −− Also positive in ovary, colorectum, and lung tumors ♦♦ PSA −− Typically used for prostate tumors −− Also positive in rare salivary gland and breast tumors ♦♦ AMACR is useful for prostatic invasive versus in situ carcinoma, but not for identifying the prostate as a primary site −− Other carcinomas positive for AMACR: 92% Colorectum, 83% prostate, 44% breast, 14% lung, 10% melanoma, and 7% endometrium ♦♦ HepPar1 −− Typically used to identify HCC −− Positive in up to 50% of gastric carcinomas ♦♦ Thyroglobulin: specific to thyroid follicular cell tumors ♦♦ RCC Ma −− Used to identify conventional clear cell and papillary renal cell carcinoma −− Also positive in yolk sac tumor, embryonal carcinoma, and mesothelioma ♦♦ Monoclonal CEA −− Positive in lung, colon, stomach, pancreas, bladder, endocervix, breast, chordoma and urothelium

−− Negative in mesothelium, prostate, kidney, liver, adrenal, and endometrium −− Note: polyclonal CEA antibodies typically show much less specificity, but it can be used to demonstrate a canalicular pattern in HCC EMA −− Positive in most carcinomas and some sarcomas (synovial sarcoma, epithelioid sarcoma), also meningioma, choroid plexus tumors, chordoma, and ependymoma −− Negative in adrenocortex, HCC, seminoma, embryonal carcinoma, yolk sac tumor, granulosa cell tumor, and Sertoli cell tumor WT1 −− Typically used to identify Wilms tumor −− Also positive in mesothelioma, ovarian serous carcinoma, sex cord-stromal tumors, granulosa cell tumor, Sertoli cell tumor, metanephric adenoma and desmoplastic small round cell tumor (DSRCT) HMB45 −− Typically used to identify melanoma −− Also positive in perivascular epithelial cell tumors (PEComas) and clear cell sarcoma of soft parts Melan-A −− Typically used to identify melanoma −− Also positive in adrenocortical tumors, PEComas, and clear cell sarcoma of soft parts

Pitfalls ♦♦ EMA: Stains plasma cells, L&H cells (nodular lymphocyte predominant HL), and some neoplastic T-cells (anaplastic lymphoma) ♦♦ Pankeratin: Stains plasma cells occasionally ♦♦ CD117: Stains mast cells ♦♦ Mucinous tumors show variable staining for tissue associated markers within primary sites; CK7/CK20/CDX2 can show various patterns in lung, nasal cavity, ovary, cervix, etc. This could be due to varying degrees of intestinal differentiation

Notes ♦♦ Based on gender and tumor site, a panel for epithelioid cell tumors (cohesive groups of cells with moderate amounts of cytoplasm) could include HepPar1 for liver, RCC Ma or CD10 for kidney, p63 for bladder, inhibin for adrenocortex and CK5/6, CK7, CK20 ♦♦ Benign entrapped cells of the organ tissue (e.g., liver, lung, mesothelium) containing the metastasis must be differentiated from the tumor cells, e.g., benign hepatocytes admixed with cells of metastatic breast carcinoma. Immunohistochemistry must be interpreted in the context of the morphology ♦♦ Squamous cell carcinoma primary site usually cannot be identified by IHC except for the group of lung tumors that express TTF-1 (up to 25%)

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♦♦ There are no useful positive markers for gastric tumors; negative results for other markers can be helpful −− For example, in the differential diagnosis of primary gastric signet-ring cell carcinoma versus metastatic lobular breast carcinoma: CK20 and CDX2 (nuclear) are positive in stomach (both negative in breast), and ER/PR (nuclear) and GCDFP positive in breast (all negative in stomach). CK20 and CDX2 are also positive in colorectal carcinoma, and this might be more strongly considered in a different metastatic site

♦♦ CK7 negative tumors in the lung and ovary are usually metastases ♦♦ Dennis et al (2007), identified a ten-marker panel (CK7, CK20, TTF1, CDX2, CA125, ER, GCDFP-15, lysozyme, mesothelin, and PSA) that correctly classified 88% of UPC. Difficulties were identified when differentiating stomach and pancreas, stomach and colon, ovary and pancreas, and breast and ovary ♦♦ Lagendijk et al (1998) used a six-marker panel (CK7, CK20, CA125, CEA, ER, and GCDFP), which classified 80–90% of tumors

DIFFERENTIAL DIAGNOSIS BASED ON THE SCREENING PANEL RESULT ♦♦ The differential diagnoses discussed below are based on the results of the screening panel

Pankeratin-Positive, Vimentin-Negative Tumors (Table 3.3) ♦♦ This staining pattern is presumptive for carcinoma ♦♦ The subsequent test panel is based on patient history, tumor site, morphology, and extent and strength of keratin staining ♦♦ If vimentin is not tested, the diagnoses in Table  3.4 (keratin and vimentin-positive) should also be considered ♦♦ Note that some types of carcinoma are typically or occasionally positive for the mesenchymal marker, vimentin (Table  3.4). These include endometrium (endometrioid), salivary gland, kidney (conventional clear cell), thyroid (papillary and anaplastic), adrenocortex, ovary (endometrioid and serous) and squamous cell carcinoma (Figs. 3.2–3.3)

Pankeratin- and Vimentin-Positive Tumors (Table 3.4) ♦♦ The subsequent test panel is based on patient history, tumor site, morphology, and extent and strength of keratin staining ♦♦ This staining pattern is seen in some types of sarcoma and in the vimentin-positive subset of carcinoma

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Vimentin-Positive, Pankeratin-Negative Tumors (Table 3.5) ♦♦ These tumors are primarily sarcomas, but also include melanoma, with various morphologic expressions, including spindled, epithelioid and pleomorphic (Fig. 3.5) ♦♦ This table includes those tumors that are typically pankeratin negative (see Table 3.3 for the rarely positive tumors) ♦♦ The subsequent testing panel is based on patient history, tumor site, and morphology

CD45-Positive and CD45-Negative Hematolymphoid Neoplasms (Table 3.6) ♦♦ CD45 expression will identify 90–95% of hematolymphoid neoplasms in routine practice. See the IHC and lymph node chapters for further discussion ♦♦ Morphologic features direct appropriate testing strategy to arrive at a specific diagnosis in most instances ♦♦ Hematolymphoid neoplasms may be difficult to recognize in small biopsies, in cytologic material or when they present in unusual anatomic sites ♦♦ A CD45-negative result does not categorically exclude hematolymphoid neoplasms (Table 3.6). If lymphoma still is suspected, double stains for CD20 and CD3, or stains for CD79a, PAX5, or CD30, will identify most, but not all (Fig. 3.6)

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Table 3.3. Pankeratin-Positive, Vimentin-Negative Tumors CK7+ and CK20− Lung, nonmucinous adenocarcinoma   TTF-1 (nuclear) Lung, squamous cell carcinoma (22%) (Fig. 3.1)   CK5/6   p63 (nuclear) Lung, small cell carcinoma (24%)   TTF-1 (nuclear)   CD56   Chromogranin   Synaptophysin Breast, carcinoma   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Ovary, nonmucinous carcinoma   CA125   WT1 (nuclear)   ER/PR Pancreatobiliary, adenocarcinoma (28%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear) Endocervix, adenocarcinoma   mCEA

CK7+ and CK20+

CK7− and CK20+

CK7− and CK20−

Urothelium, carcinoma   CK5/6, k903   p63 (nuclear)

Colorectum, adenocarcinoma   CDX2 (nuclear)   Villin (membranous)

Pancreatobiliary, adenocarcinoma (64%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear)

Merkel cell carcinoma   CD56   Chromogranin   Synaptophysin

Hepatocellular carcinoma (78%)   HepPar1   pCEA (canalicular)   CD10 (canalicular)

Ovary, mucinous carcinoma   CA125   WT1 (40%, nuclear) Lung, mucinous adenocarcinoma   CDX2 (nuclear) Choriocarcinoma   bhCG Stomach, adenocarcinoma (32%)   CDX2 (nuclear, 73%)

Stomach, adenocarcinoma (35%)   CDX2 (nuclear, 73%)

Renal clear cell carcinoma (80%)   RCC Ma   CD10   3p deletion Prostate, adenocarcinoma   PSA, PAP Squamous cell carcinoma (70%)   CK5/6, k903   p63 (nuclear) Lung, small cell carcinoma (76%)   TTF-1 (nuclear)   CD56   Chromogranin   Synaptophysin Stomach, adenocarcinoma (14%)   CDX2 (nuclear, 73%)

Thymic carcinoma   CD5   CK5/6 Stomach, adenocarcinoma (19%)   CDX2 (nuclear, 73%) Renal clear cell carcinoma (17%)   RCC Ma   CD10   3p deletion Hepatocellular carcinoma (15%)   HepPar1   pCEA (canalicular)   CD10 (canalicular)

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Table 3.4. Pankeratin- and Vimentin-Positive Tumors Strong keratin Salivary and sweat gland carcinoma   CK7+/CK20−   GCDFP Endometrioid carcinoma (Fig. 3.2)   CK7+/CK20−   ER/PR (nuclear) Ovary, serous carcinoma   CK7+/CK20−   ER/PR (nuclear)   WT1 (nuclear)   p53 (nuclear) Thyroid, papillary and anaplastic carcinoma   CK7+/CK20−   TTF-1 (nuclear)   Thyroglobulin Squamous cell carcinoma   CK5/6   p63 Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear) Chordoma   S-100   EMA Epithelioid sarcoma   CD34   INI1 (nuclear, loss of staining) Myoepithelial carcinoma   SMA   SMMHC   Calponin   p63 Embryonal carcinoma   CK7+/CK20−   CD30   PLAP (membranous)   OCT4 (nuclear) Yolk sac tumor   CK7−/CK20−   AFP   a1AT   PLAP (membranous) Spindle cell carcinoma

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Focal keratin Renal clear cell carcinoma   CK7−/CK20− (80%)   CK7+/CK20− (17%)   RCC Ma   CD10   3p deletion Adrenocortical neoplasms (Fig. 3.3)   Inhibin   Melan-A   Synaptophysin Synovial sarcoma (Fig. 3.4)   bcl-2   CD99 (membranous)   S-100   t(X;18) Angiosarcoma (especially epithelioid variant), hemangioendothelioma   CD34   CD31   Fli-1 (nuclear) Desmoplastic small round cell tumor   Desmin (dot-like)   EMA   WT1 (nuclear)   CD99 (membranous)   t(11;22) (p13;q12) Ewing sarcoma   CD99 (membranous)   Fli-1 (nuclear)   t(11;22) (q24;q12) Extrarenal rhabdoid tumor   INI1 (nuclear, loss of staining)   EMA   CD99 (membranous)   Synaptophysin   MSA   Abnormalities 22q11.2 Sarcomatoid carcinoma

Rare keratin Leiomyosarcoma   SMA   MSA   Desmin Melanoma   S-100   HMB45   Melan-A Seminoma   CK7+/CK20− (28%)   PLAP (membranous)   CD117   OCT4 (nuclear) Rhabdomyosarcoma   Desmin   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

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Fig. 3.2. Endometrioid endometrial carcinoma (A) is positive with vimentin (cytoplasmic) (B) and ER (nuclear) (C).

DIFFERENTIAL DIAGNOSIS BASED ON MORPHOLOGIC FEATURES ♦♦ The differential diagnoses discussed below are based on morphologic features, where IHC stains are useful in separating different tumor types

Epithelioid Cell Tumors, CD45 Negative (Table 3.7) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ This category includes primarily carcinomas with moderate to abundant cytoplasm, as exemplified by adenocarcinoma, HCC and RCC; most of these will be keratin-positive (Tables 3.3 and 3.4) ♦♦ Pitfalls: A few large cell lymphomas might be considered in this category including diffuse large B-cell lymphoma (CD45+), anaplastic large cell lymphoma (CD45−, CD30+) and myeloid sarcoma (MPO+)

Spindle Cell Tumors, CD45 Negative (Table 3.8) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ Most of these tumors are of mesenchymal lineage ♦♦ Pitfalls: Spindle cell carcinoma, carcinosarcoma, melanoma, and mesothelioma must be considered in the differential diagnosis

Biphasic Tumors (Epithelioid and Spindle), CD45 Negative (Table 3.9) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ These tumors contain variable proportions of epithelioid and spindle cells

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Pleomorphic Tumors, CD45 Negative (Table 3.10) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology. These poorly differentiated tumors only rarely and weakly express other tumor antigens ♦♦ Most tumors are of mesenchymal lineage, but carcinoma and melanoma must be considered in the differential diagnosis

Adult Small Round Blue Cell Tumors, CD45 Negative (Table 3.11) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ CD45-positive lymphoma is discussed in the IHC and lymph node chapters ♦♦ Pitfalls −− Small cell osteosarcoma is positive only for vimentin; it must be recognized by osteoid production −− Lymphoblastic lymphoma and Hodgkin lymphoma are CD45 negative, but are not composed predominantly of small cells (Fig. 3.6)

Pediatric Small Round Blue Cell Tumors, CD45 Negative (Table 3.12) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology; note the differential diagnosis is age dependent, but significant overlap exists ♦♦ CD45-positive lymphoma is discussed in the IHC and lymph node chapters ♦♦ Pitfalls −− Small cell osteosarcoma is positive only for vimentin; it must be recognized by osteoid production −− Lymphoblastic lymphoma and Hodgkin lymphoma are CD45 negative, but are not usually composed of small cells (Fig. 3.6)

Rhabdoid Tumors, CD45 Negative (Table 3.13)

Fig.  3.3. Adrenocortical carcinoma (A) is positive for inhibin (B) and Melan-A (C).

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♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ Most tumors are of mesenchymal lineage ♦♦ Pitfalls: Spindle cell carcinoma, carcinosarcoma, melanoma, and mesothelioma must be considered in the differential diagnosis

Tumors of Unknown Primary

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Fig. 3.4. Synovial sarcoma (A) focally positive for pankeratin (B).

Table 3.5. Vimentin-Positive, Pankeratin-Negative Tumors S-100 Melanoma   HMB45 (Fig. 3.5)   Melan-A Langerhans cell histiocytosis   CD1a Clear cell sarcoma (soft tissue)   HMB45   Melan-A   t(12;22) Malignant peripheral nerve sheath tumor (focal) Granular cell tumor   Inhibin Adipose tumors Cartilage tumors

SMA, MSA Angiomyolipoma   HMB45 Fibromatosis   b-catenin Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Inflammatory myofibroblastic tumor   ALK   2p23 rearrangements Myofibroblastoma   CD34   Desmin   ER/PR (nuclear) Leiomyosarcoma   Desmin Glomus tumor   CD34 Rhabdomyosarcoma   Desmin   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

Miscellaneous Seminoma   PLAP (membranous)   CD117   OCT4 (nuclear) Angiosarcoma, epithelioid hemangioendothelioma   CD31   CD34   Fli-1 (nuclear)   Pankeratin (focal, weak) Kaposi sarcoma   CD31   CD34   Fli-1 (nuclear)   HHV8 (nuclear) Mesenchymal chondrosarcoma   CD99 (membranous)   S-100 (cartilage) Alveolar soft parts sarcoma   TFE3 (nuclear)   t(X;17) Osteosarcoma

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Fig. 3.5. This spindle cell melanoma (A) is positive for S-100 (B), HMB45 (C), and Melan-A (D); most desmoplastic and spindle cell melanomas are negative for HMB45 (0–19% positive) and Melan-A (0–15% positive).

Tumors with Hemangiopericytomatous Vascular Pattern (Table 3.14) ♦♦ The subsequent test panel is based on patient history, tumor site and morphology

♦♦ The hemagiopericytomatous vascular pattern consists of thin-walled, branching vessels. Typically, it is seen in hemangiopericytoma/solitary fibrous tumor, synovial sarcoma, mesenchymal chondrosarcoma, and leiomyosarcoma

DIFFERENTIAL DIAGNOSIS BASED ON THE SECOND-TIER TESTING RESULTS ♦♦ The differential diagnoses discussed below are based on positive results of a few common markers, where IHC stains are useful in separating different tumor types ♦♦ These markers are not part of the usual screening panels, but when used as second-tier stains, they give results that help identify certain categories of tumors

S-100-Positive Tumors (Table 3.15) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology

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♦♦ Pitfall: Nerves and adipose tissue are positive for S-100 (Figs. 3.10–3.12)

CD117-Positive Tumors (Table 3.16) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology (Figs. 3.13 and 3.14) ♦♦ Pitfall: Mast cells are positive for CD117 and often present in soft tissue tumors

Tumors of Unknown Primary

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Table 3.6. Hematolymphoid Tumors with Negative or Frequently Absent CD45 Expression Blastic or small round blue cell Lymphoblastic leukemia/ lymphoma (Fig. 3.6) B-cell   CD19, 22, 79a, 99   PAX-5 (nuclear)   CD10   TdT (nuclear)   CD5, 23, 43 coexpressed T-cell   CD3, 1a, 2, 4, 5, 7, 8, 99   TdT (nuclear) Myeloid sarcoma (subtype dependent)   CD34   MPO   CD13, 33, 99   HLA-DR

Plasmacytic (CD20 negative) Plasmacytoma, multiple myeloma   CD38   CD138   CD79a   Ig gene rearrangement Plasmablastic lymphoma   CD38   CD138   CD79a   EBER (EBV)   Ig gene rearrangement

Pleomorphic large cell Classical Hodgkin lymphoma   CD30   CD15   PAX-5 (nuclear)   MUM1 (nuclear) Anaplastic large cell lymphoma   CD30 (membranous, golgi)   ALK (60-85%)   EMA   Tia-1   t(2;5)

Spindle cell Interdigitating dendritic cell sarcoma   S-100   Fascin   CD45 (weak)   CD68 (weak)   Lysozyme (weak) Follicular dendritic cell sarcoma   CD21, CD23, and/or CD35   Clusterin   Fascin   EGFR   HLA-DR   EBV (EBER)   ±CD68, S-100, and EMA

Fig. 3.6. Lymphoblastic lymphoma (A) consists of neoplastic lymphoblasts positive for TdT (nuclear) (B). CD45 (C) stains reactive lymphocytes that serve as an internal control; note that the tumor cells are negative for CD45.

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Table 3.7. Epithelioid Cell Tumors, CD45 Negative Pankeratin Carcinoma (Tables 3.3–3.4) Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18) Desmoplastic small round cell tumor   Desmin (dot-like)   EMA   WT1 (nuclear)   CD99 (membranous)   t(11;22) (p13;q12) Leiomyosarcoma, epithelioid   SMA   MSA   Desmin   Pankeratin (focal) Ewing sarcoma   CD99 (membranous)   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12) Adrenocortical neoplasms   Inhibin   Melan-A   Synaptophysin   Pankeratin (focal, weak) Epithelioid sarcoma   CD34   INI1 (nuclear, loss of staining)

Miscellaneous Melanoma   HMB45   Melan-A Paraganglioma/pheochromocytoma   CD56   Chromogranin   Synaptophysin   S-100 (sustentacular cells) Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Granulosa cell tumor   Calretinin   Inhibin   WT1 (nuclear) Alveolar soft parts sarcoma   TFE3 (nuclear)   t(X;17) Clear cell sarcoma (soft tissue)   HMB45   Melan-A   t(12;22) Hemangioblastoma Glomus tumor   SMA   CD34 Hemangiopericytoma/solitary fibrous tumor   CD34   CD99   bcl-2   Inhibin Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

CD99-Positive Tumors (Table 3.17)

CD34-Positive Tumors (Table 3.18)

♦♦ The subsequent test panel is based on patient history, tumor site, and morphology (Figs. 3.15 and 3.16) ♦♦ Pitfall: Some hematolymphoid neoplasms are positive for CD99 (e.g., lymphoblastic lymphoma (CD45−) and myeloid sarcoma (MPO+))

♦♦ The subsequent test panel is based on patient history, tumor site, and morphology (Figs. 3.17 and 3.18) ♦♦ Pitfall: Endothelial cells are positive for CD34

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Table 3.8. Spindle Cell Tumors, CD45 Negative Pankeratin

Muscle marker expression

Carcinoma (Tables 3.3–3.4)   Especially squamous cell, breast,   and genitourinary Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18) Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)   Vimentin

Miscellaneous Melanoma   S-100   HMB45   Melan-A

Rhabdomyosarcoma   Desmin   MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

Paraganglioma/Pheochromocytoma   CD56   Chromogranin   Synaptophysin   S-100 (sustentacular cells)

Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities

Hemangiopericytoma/solitary fibrous tumor   CD34   CD99   bcl-2

Endometrial stromal sarcoma   CD10   ER/PR (nuclear)   SMA, MSA, desmin (focal)

Mesenchymal chondrosarcoma   CD99 (membranous)   S-100 (cartilage)

Angiomyolipoma/perivascular epithelial cell tumor (PEComa)   HMB45   Melan-A   MSA, desmin   S-100 stains the adipose Inflammatory myofibroblastic tumor   SMA, MSA, desmin (focal)   ALK   2p23 rearrangements Leiomyosarcoma   SMA   MSA   Desmin   Pankeratin (focal)

Malignant peripheral nerve sheath tumor   S-100 (focal) Dermatofibrosarcoma protuberans   CD34 Clear cell sarcoma (soft tissue)   S-100   HMB45   Melan-A   CD117   t(12;22) Fibromatosis   b-catenin   SMA (focal)   CD117 (30%) Fibrosarcoma

Myofibroblastoma   CD34   SMA, desmin (focal)

Table 3.9. Biphasic Tumors (Epithelioid and Spindle), CD45 Negative Pankeratin

Miscellaneous

Sarcomatoid carcinoma   Pankeratin (focal, weak)   Vimentin

Melanoma   S-100   HMB45   Melan-A

Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)   Vimentin Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18)

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Table 3.10. Pleomorphic Tumors, CD45 Negative Pankeratin Carcinoma (Tables 3.3–3.4)   Pankeratin (focal, weak)   Vimentin Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18) Leiomyosarcoma   SMA   MSA   Desmin   Pankeratin (focal)

Miscellaneous Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Melanoma   S-100   HMB45   Melan-A Liposarcoma   S-100 Malignant peripheral nerve sheath tumor   S-100, focal/weak Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Paraganglioma/pheochromocytoma   CD56   Chromogranin   Synaptophysin   S-100 (sustentacular cells) Atypical fibroxanthoma   CD68   Lysozyme   CD99 (membranous) High grade undifferentiated sarcoma

Muscle Marker-Positive Tumors (Table 3.19) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ Pitfalls −− SMA, MSA and sometimes desmin stain various myofibroblastic cells that are often present in a reactive process. These must be identified as morphologically separate from the tumor. A small biopsy might only sample tissue adjacent to the tumor that shows a myofibroblastic response −− Vessel walls and various other smooth muscle components will stain with SMA, MSA, and desmin

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−− The nuclear markers Myo D1 and myogenin are specific to skeletal muscle

Neuroendocrine Marker-Positive Tumors (Table 3.20) ♦♦ The subsequent test panel is based on patient history, tumor site, and morphology ♦♦ Pitfalls −− Neuroendocrine cells are present in many types of benign epithelia including respiratory and gastrointestinal −− Ganglion cells and other neural tissue are positive for neuroendocrine markers

Tumors of Unknown Primary

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Table 3.11. Adult Small Round Blue Cell Tumors, CD45 Negative CD56, chromogranin, synaptophysin

Pankeratin Small cell neuroendocrine carcinoma (Fig. 3.7)   Pankeratin (dot-like)   CD56   Chromogranin   Synaptophysin Merkel cell carcinoma   CK20 (dot-like)   CD56   Chromogranin   Synaptophysin

CD99 (membranous)

Small cell neuroendocrine carcinoma   Pankeratin (dot-like) Merkel cell carcinoma   CK20 (dot-like) Medulloblastoma, retinoblastoma, pineoblastoma, neuroblastoma

Ewing sarcoma   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12) Desmoplastic small round cell tumor   Desmin (dot-like)   Pankeratin   EMA   WT1 (nuclear)   t(11;22) (p13;q12) Mesenchymal chondrosarcoma   S-100 (cartilage)

Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18)

Rhabdomyosarcoma   Desmin   MSA   Myo D1   Myogenin (nuclear)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

Basaloid squamous cell carcinoma   CK5/6, k903   p63

Miscellaneous Rhabdomyosarcoma   Desmin   MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Melanoma (Fig. 3.8)   S-100   HMB45   Melan-A Malignant peripheral nerve sheath tumor   S-100 (focal, weak) Dedifferentiated liposarcoma   S-100

Synovial sarcoma   Pankeratin   EMA   bcl-2   S-100   t(X;18)

Table 3.12. Pediatric Small Round Blue Cell Tumors, CD45 Negative CD56 Medulloblastoma, retinoblastoma, pineoblastoma, neuroblastoma   Chromogranin   Synaptophysin

CD99 (membranous) Ewing sarcoma   CD99 (membranous)   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12) Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

MSA, desmin, myogenin (nuclear) Myo D1 (nuclear) Rhabdomyosarcoma   CD99 (membranous, focal)   Embryonal: LOH 11p15.5 (Fig. 3.9)   Alveolar: t(2;13), t(1;13)

WT1 (nuclear) Wilms tumor   Pankeratin (focal)   11p13 Desmoplastic small round cell tumor   Desmin (dot-like)   Pankeratin, EMA   CD99 (membranous)   t(11;22) (p13;q12)

Desmoplastic small round cell tumor   Desmin (dot-like)   Pankeratin, EMA   WT1 (nuclear)   t(11;22) (p13;q12)

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Table 3.13. Rhabdoid Tumors, CD45 Negative Pankeratin Carcinoma (Tables 3.3–3.4) Synovial sarcoma   EMA   bcl-2   CD99 (membranous)   S-100   t(X;18) Desmoplastic small round cell tumor   Desmin (dot-like)   EMA   WT1 (nuclear)   CD99 (membranous)   t(11;22) (p13;q12) Epithelioid sarcoma, proximal type   Pankeratin   EMA   CD34   INI1 (nuclear, loss of staining)   Vimentin

Miscellaneous Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Melanoma   S-100   HMB45   Melan-A Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5 Rhabdoid tumor of kidney   INI1 (nuclear, loss of staining)   Alveolar: t(2;13), t(1;13)

Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear) Leiomyosarcoma   SMA   MSA   Desmin   Pankeratin (focal) Extrarenal rhabdoid tumor   INI1 (nuclear, loss of staining)   EMA   Pankeratin (focal)

DIFFERENTIAL DIAGNOSIS BASED ON THE SITE OF METASTASIS ♦♦ The following categories of tumor are based on the site of metastatic disease, where IHC stains are useful in separating different tumor types

Pleural Tumors (Table 3.21) ♦♦ The subsequent test panel is based on patient history and tumor morphology ♦♦ Pitfall: Identify pleural lining associated with the metastatic tumor (shows the same staining pattern as mesothelioma)

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Lung Tumors (Table 3.22) ♦♦ The subsequent test panel is based on patient history and tumor morphology (Figs. 3.19 and 3.20) ♦♦ Pitfall: Identify lung parenchyma associated with the metastatic tumor (CK7+, CK20−, TTF-1 (nuclear)+)

Liver Tumors (Table 3.23) ♦♦ The subsequent test panel is based on patient history and tumor morphology (Figs. 3.21–3.23)

Tumors of Unknown Primary

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Table 3.14. Tumors with Hemagiopericytomatous Vascular Pattern CD99 (membranous)

Miscellaneous

Hemangiopericytoma/solitary fibrous tumor   CD34   bcl-2

Leiomyosarcoma   SMA, MSA, desmin   Pankeratin (focal)

Synovial sarcoma   Pankeratin   EMA   bcl-2   S-100   t(X;18)

Cellular mesoblastic nephroma and congenital fibrosarcoma   MSA (focal)   SMA (focal)   WT1 (nuclear)   t(12;15)

Mesenchymal chondrosarcoma   S-100 (cartilaginous areas)

Malignant peripheral nerve sheath tumor   S-100 (focal, weak) Endometrial stromal sarcoma   CD10   ER/PR (nuclear)   SMA, MSA, desmin (focal)

Fig. 3.7. Cervical small cell carcinoma (A) shows diffuse and dot-like cytoplasmic pankeratin (B), focal chromogranin (C), and diffuse CD56 staining (D).

♦♦ Pitfall: Identify benign liver parenchyma associated with the metastatic tumor

Bone Tumors (Table 3.24)

♦♦ CD45-positive lymphoma is discussed in the IHC and lymph node chapters ♦♦ Pitfall: Small cell osteosarcoma is positive only for vimentin; it must be recognized by osteoid production

♦♦ The subsequent test panel is based on patient history and tumor morphology (Figs. 3.24–3.26)

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Table 3.15. S-100-Positive Tumors Spindle

Epithelioid

Melanoma   HMB45 (0–19%)   Melan-A (0–15%)

Melanoma   HMB45   Melan-A

Synovial sarcoma   Pankeratin   EMA   CD99 (membranous)   bcl-2   S-100   t(X;18)

Granular cell tumor (Fig. 3.10)   Inhibin

Angiomyolipoma (perivascular epithelioid tumors–PEComa)   HMB45   Melan-A   MSA   Desmin   S-100 stains the adipose Malignant peripheral nerve sheath tumor   S-100 (focal, weak) Rhabdomyosarcoma   Desmin, MSA   Myo-D1 (nuclear)   Myogenin (nuclear)   S-100 (focal, weak)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Sex cord-stromal tumors   Inhibin   Calretinin   WT1 (nuclear)

Chordoma (Fig. 3.11)   Pankeratin   EMA

Miscellaneous Langerhans cell histiocytosis (Fig. 3.12)   CD1a   Langerin Liposarcoma Chondrosarcoma

Clear cell sarcoma (soft tissue)   HMB45   Melan-A   t(12;22) Renal clear cell carcinoma   CK7–/CK20–   RCC Ma   CD10   3p deletion Breast carcinoma (50%)   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Ovary, nonmucinous carcinoma   CA125   WT1 (nuclear)   ER/PR (nuclear) Sex cord-stromal tumors   Inhibin   Calretinin   WT1 (nuclear) Angiomyolipoma (perivascular epithelioid tumors–PEComa)   HMB45   Melan-A   MSA   Desmin   S-100 stains the adipose Salivary gland tumors Adenocarcinoma, NOS

Lymph Node Tumors (Tables 3.25 and 3.26) ♦♦ The subsequent test panel is based on patient history and tumor morphology (Figs. 3.27–3.29) ♦♦ Includes primary tumors of lymph nodes (mostly lymphomas, see IHC and hematolymphoid chapters) andmetastases ♦♦ Lymphoma must be ruled out with CD45 plus CD30 for anaplastic large cell and Hodgkin lymphomas

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♦♦ Depending on the lymph node site (drainage field), different primary site carcinomas will be suspected ♦♦ Sarcomas that spread to the lymph nodes include embryonal and alveolar rhabdomyosarcoma, angiosarcoma, epithelioid sarcoma, and synovial sarcoma (Tables 3.4, 3.5, and 3.8; Figs. 3.27–3.29)

Tumors of Unknown Primary

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Fig.  3.8. Vaginal melanoma (small round blue cell morphology) (A) is positive for HMB45 (B) and Melan-A (C).

CNS Tumors (Table 3.27) ♦♦ The subsequent test panel is based on patient history and tumor morphology ♦♦ The most common metastatic tumors are lung (Fig.  3.30), breast, melanoma, genitourinary, gastrointestinal, and leukemia/lymphoma. Choriocarcinoma is an uncommon tumor that commonly spreads to the CNS ♦♦ Pankeratin and EMA often stain astrocytes and astrocytic neoplasms, up to 96% of glioblastoma multiforme cases.

GFAP should be in the panel for a poorly differentiated epithelioid neoplasm to identify an astrocytic tumor ♦♦ S-100 stains normal, reactive, and neoplastic CNS cells. HMB45 and Melan-A are useful adjuncts to confirm the diagnosis of metastatic melanoma ♦♦ Recommended first-round panel for poorly differentiated neoplasm: GFAP, synaptophysin, CAM5.2, CK7, CK20, Melan-A, CD3, and CD20. Additional organ-specific or hematolymphoid markers can provide more specific diagnostic information

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Fig. 3.9. Embryonal rhabdomyosarcoma (A) is positive for Myo D1 (nuclear) (B).

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Fig. 3.10. Dermal granular cell tumor (A) is positive for S-100 (nuclear and cytoplasmic) (B).

Tumors of Unknown Primary

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Fig. 3.11. Chordoma (A) is positive for S-100 (B) and pankeratin (C).

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Fig. 3.12. Langerhans cell histiocytosis (A) cells are positive for CD1a (B).

Table 3.16. CD117-Positive Tumors, Showing Other Useful Markers Mesenchymal soft tissue Ewing sarcoma (45%)   CD99 (membranous)   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12) Synovial sarcoma   Pankeratin   EMA   bcl-2   CD99   S-100   t(X;18) Angiosarcoma (43%)   CD34   CD31   Fli-1 (nuclear)   Pankeratin (focal, weak) Clear cell sarcoma (soft tissue)   S-100   HMB45   Melan-A   t(12;22)

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Organ system   Gastrointestinal stromal   tumor (Fig. 3.13)    CD34    SMA (25%)   C-kit, PDGFRA abnormalities Fibromatosis   b-catenin Genitourinary   Angiomyolipoma    HMB45    Desmin, MSA, SMA   Seminoma/dysgerminoma/   germinoma (Fig. 3.14)    PLAP (membranous)    OCT4 (nuclear) Skin   Melanoma    S-100    HMB45    Melan-A   Mastocytosis

Fig.  3.13. Gastrointestinal stromal tumor (A) is positive for CD117 (B).

Fig. 3.14. Dysgerminoma (seminoma) (A) is positive for CD117 (B) and PLAP (membranous) (C).

Table 3.17. CD99-Positive Tumors (Membranous Pattern) Small round blue cell tumors Ewing sarcoma (Fig. 3.15)   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12) Angiomyolipoma (perivascular epithelioid tumors– PEComa)   HMB45   Melan-A   MSA, desmin   S-100 stains the adipose Synovial sarcoma   Pankeratin   EMA   bcl-2   S-100   t(X;18)

Spindle Synovial sarcoma   Pankeratin   EMA   bcl-2   S-100   t(X;18) Sex cord-stromal tumors   Inhibin   Calretinin   WT1 (nuclear) Hemangiopericytoma/solitary fibrous tumor   CD34 (Fig. 3.16)   bcl-2

Epithelioid Melanoma   S-100   HMB45   Melan-A Sex cord-stromal tumors   Inhibin   Calretinin   WT1 (nuclear) Carcinoma (Tables 3.3–3.4)  Various carcinomas including metaplastic breast, endometrioid, pleomorphic lung, and neuroendocrine

Mesenchymal chondrosarcoma   S-100 (cartilage) Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13)

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Table 3.17. (continued) Small round blue cell tumors

Spindle

Epithelioid

Lymphoblastic leukemia/lymphoma B-cell   CD19, 20, 22, 79a   PAX-5   CD5, 23, 43 co-expressed T-cell   CD3, 1a, 2, 4, 5, 7, 8   TdT (nuclear) Myeloid sarcoma (subtype dependent)   CD34   MPO   CD13, CD33   HLA-DR   Lysozyme

Fig.  3.15. Ewing sarcoma (A) is positive for CD99 (membranous) (B).

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Fig. 3.16. Hemangiopericytoma (A) is positive for CD34 (B).

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Table 3.18. CD34-Positive Tumors Vascular

Fibroblastic, myofibroblastic

Angiosarcoma, epithelioid hemangioendothelioma   CD31   Fli-1 (nuclear)   Pankeratin (focal, weak)

Hemangiopericytoma/solitary fibrous tumor (Fig. 3.17)   CD99   bcl-2

Kaposi sarcoma   CD31   Fli-1 (nuclear)   HHV8 (nuclear)

Myofibroblastoma   Desmin   MSA   SMA   ER/PR (nuclear)

Dermatofibrosarcoma protuberans (Fig. 3.18)   t(17;22)

Miscellaneous Epithelioid sarcoma   Pankeratin   EMA   INI1 (nuclear, loss of staining) Gastrointestinal stromal tumor   CD117   SMA (25%)   C-kit, PDGFRA abnormalities Pleomorphic/spindle cell lipoma   S-100

Glomus tumor   SMA

Fig. 3.17. Solitary fibrous tumor (A) is positive for CD34 (B); benign endothelial cells (lower right) are also positive.

Fig. 3.18. Dermatofibrosarcoma protuberans (A) is positive for CD34 (B).

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Table 3.19. Muscle Marker-Positive Tumors Skeletal muscle (nuclear stains) Myo D1 or myogenin (nuclear)

Smooth muscle SMA, MSA, desmin Leiomyosarcoma   Keratin (focal, weak)

Rhabdomyosarcoma   Desmin   MSA   CD99 (membranous, focal)   Embryonal LOH 11p15.5   Alveolar   t(2;13,) t(1;13)

Angiomyolipoma (perivascular epithelioid tumors–PEComa)   HMB45   Melan-A   S-100 stains the adipose Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Glomus tumor   SMA, MSA   CD34

Myofibroblastic MSA, desmin, SMA Myofibroblastoma   CD34   ER/PR (nuclear) Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Inflammatory myofibroblastic tumor   SMA, MSA   ALK   2p23 rearrangements Undifferentiated pleomorphic sarcoma   SMA, MSA (rare cells)

Table 3.20. Neuroendocrine Marker-Positive Tumors (CD56, Chromogranin, Synaptophysin) Carcinoma Small cell neuroendocrine carcinoma (various sites)   Pankeratin (dot-like) Merkel cell carcinoma   CK20 (dot-like)

Neuroblastic

Miscellaneous

Medulloblastoma, retinoblastoma, pineoblastoma, neuroblastoma   Pankeratin (−)

Paraganglioma, pheochromocytoma   S-100 (sustentacular cells)

Carcinoma (Tables 3.3–3.4)   Variable neuroendocrine expression:   Ovary, lung, pancreas, prostate, and breast

Table 3.21. Pleural Tumors Primary epithelioid

Primary spindle

Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)

Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)

Epithelioid hemangioendothelioma   CD34   CD31   Fli-1 (nuclear)

Melanoma   S-100   HMB45   Melan-A Solitary fibrous tumor/ hemangiopericytoma   CD34   bcl-2   CD99 (membranous)

Metastatic carcinoma Lung, nonmucinous   CK7+/CK20−   TTF-1 (nuclear) Lung, mucinous   CK7/CK20   CDX2 (nuclear) Breast   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Gastroesophageal/stomach   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Ovary, serous carcinoma   CA125   WT1 (nuclear)   p53 (nuclear)   ER, PR (nuclear)

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Metastatic miscellaneous Melanoma   S-100   HMB45   Melan-A

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Table 3.22. Lung Tumors Primary Adenocarcinoma, nonmucinous   CK7+/CK20−   TTF-1 (nuclear) Lung, mucinous   CK7+/CK20+   CDX2 (nuclear) Squamous cell carcinoma   CK5/6   k903   p63 (nuclear) Small cell carcinoma (3%)   CK7+/20− (24%)   CK7−/20− (76%)   TTF-1 (nuclear)   CD56   Chromogranin   Synaptophysin Adenocarcinoma, mucinous   CK7+/CK20+ Leiomyosarcoma   SMA, MSA, desmin Synovial sarcoma   bcl-2   CD99 (membranous)   S-100   t(X;18) Angiosarcoma and hemangioendothelioma   CD31   CD34   Fli-1 (nuclear)   Pankeratin (focal, weak)

Metastatic carcinoma Colorectal   CK7−/CK20+   CDX2 (nuclear)   Villin Pancreatobiliary tract (Fig. 3.19)   CK7+/CK20+ (64%)   CK7+/CK20− (28%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear) Breast   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Renal clear cell   CK7−/CK20−   RCC Ma   CD10   3p deletion Thyroid   CK7+/CK20−   Thyroglobulin   TTF-1 (nuclear) Choriocarcinoma   CK7+/CK20+   βhCG

Metastatic sarcoma Leiomyosarcoma (Fig. 3.20)   SMA, MSA, desmin Synovial sarcoma   bcl-2   CD99 (membranous)   S-100   t(X;18) Rhabdomyosarcoma   Desmin, MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Alveolar soft parts sarcoma   TFE3 (nuclear)   t(X;17) Malignant peripheral nerve sheath tumor   S-100 (focal) Angiosarcoma, epithelioid hemangioendothelioma   CD31   CD34   Fli-1 (nuclear)   Pankeratin (focal, weak) Liposarcoma   S-100 Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Undifferentiated pleomorphic sarcoma   SMA, MSA (rare cells) Fibrosarcoma Osteosarcoma

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Fig. 3.19. Metastatic pancreatic adenocarcinoma (A) to the lung is positive for CK20 (B) and CA19-9 (C).

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Fig. 3.20. Metastatic leiomyosarcoma (A) to the lung is positive for desmin (B) and MSA (C).

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Table 3.23. Liver Tumors Primary Hepatocellular carcinoma   CK7−/CK20−   HepPar1   pCEA (canalicular)   CD10 (canalicular) Cholangiocarcinoma   CK7+/CK20+ (64%)   CK7+/CK20− (28%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear) Angiosarcoma, epithelioid hemangioendothelioma   CD34   CD31   Fli-1 (nuclear)   Pankeratin (focal, weak)

Metastatic carcinoma Colorectum (Fig. 3.21)   CK7−/CK20+   CDX2 (nuclear)   Villin (membranous) Gastroesophageal/stomach   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Lung, adenocarcinoma, nonmucinous (Fig. 3.22)   CK7+/CK20−   TTF-1 (nuclear)

Metastatic miscellaneous Gastrointestinal stromal tumor   CD117   CD34   SMA (25%)   C-kit, PDGFRA abnormalities Melanoma   S-100   HMB45   Melan-A Lymphoma   CD45

Lung, adenocarcinoma, mucinous   CK7+/CK20+   CDX2 (nuclear) Pancreatobiliary, adenocarcinoma (Fig. 3.23)   CK7+/CK20+ (64%)   CK7+/CK20− (28%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear) Breast   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Renal clear cell carcinoma   CK7−/CK20−   RCC Ma   CD10   3p deletion

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Fig. 3.21. Metastatic colon carcinoma (A) to the liver is positive for CK20 (B) and CDX2 (nuclear) (C).

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Fig.  3.22. Metastatic small cell carcinoma (A) to the liver is positive for chromogranin (B) and TTF-1 (nuclear) (C). TTF-1 shows granular cytoplasmic staining in the background benign liver cells. TTF-1 is positive in small cell carcinomas from various sites (lung 83%, extrapulmonary 42%).

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Fig.  3.23. Metastatic pancreatobiliary adenocarcinoma (A) to the liver is positive for CK7 (B), CK20 (C), and CA19-9 (D). Intrahepatic cholangiocarcinoma cannot be differentiated by IHC (clinicoradiographic information is necessary for the diagnosis).

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Table 3.24. Bone Tumors Primary Lymphoma   CD45 B-cell   CD19, 20, 22, 79a T-cell   CD3, 2, 4, 5, 7, 8   TdT (nuclear) Myeloid sarcoma (subtype dependent)   CD34   MPO   CD13   CD33   HLA-DR   Lysozyme Plasmacytoma, multiple myeloma   CD38   CD138   CD79a   Ig gene rearrangement Langerhans cell histiocytosis   CD1a   Langerin   S-100 Chondrosarcoma   S-100 Osteosarcoma

Metastatic adult Breast carcinoma (Fig. 3.24)   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Prostate adenocarcinoma (Fig. 3.25)   CK7−/CK20−   PSA   PAP Lung, small cell carcinoma   CK7+/CK20−   TTF-1 (nuclear)   CD56   Chromogranin   Synaptophysin Lung, adenocarcinoma, nonmucinous   CK7+/CK20−   TTF-1 (nuclear) Lung, adenocarcinoma, mucinous CK7+/CK20+ CDX2 (nuclear) Colorectal adenocarcinoma   CK7−/CK20+   CDX2 (nuclear)   Villin Gastroesophageal/stomach adenocarcinoma   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Thyroid carcinoma   CK7+/CK20−   TTF-1 (nuclear)   Thyroglobulin Hepatocellular carcinoma   CK7−/CK20−   HepPar1   pCEA (canalicular)   CD10 (canalicular) Renal clear cell carcinoma   CK7−/CK20−   RCC Ma   CD10   3p deletion Urothelial carcinoma   CK5/6   k903   p63 (nuclear) Melanoma (Fig. 3.26)   S-100   HMB45   Melan-A

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Metastatic pediatric Neuroblastoma, retinoblastoma   CD56   Chromogranin   Synaptophysin Rhabdomyosarcoma   Desmin   MSA   Myo D1 (nuclear)   Myogenin (nuclear)   CD99 (membranous, focal)   Embryonal: LOH 11p15.5   Alveolar: t(2;13), t(1;13) Ewing sarcoma   CD99 (membranous)   Fli-1 (nuclear)   Pankeratin (focal)   t(11;22) (q24;q12)

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Fig. 3.24. Metastatic breast carcinoma (A) to bone is positive for GCDFP (B) and HER-2 (membranous) (C).

Fig. 3.25. Metastatic prostate carcinoma (A) to bone is positive for PSA (B).

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Fig.  3.26. Metastatic melanoma (A) to bone is positive for S-100 (B) and Melan-A (C).

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Table 3.25. Lymph Node Tumors, Cervical, Supraclavicular and Axillary Cervical

Supraclavicular

Axillary

Squamous cell carcinoma, upper respiratory and skin   CK5/6   k903   p63

Breast carcinoma   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear)

Breast carcinoma   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear)

Thyroid follicular cell neoplasms   CK7+/CK20−   TTF-1 (nuclear)   Thyroglobulin

Lung, adenocarcinoma, nonmucinous   CK7+/CK20−   TTF-1 (nuclear)

Melanoma   S-100   HMB45   Melan-A

Melanoma   S-100   HMB45   Melan-A Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)

Lung, adenocarcinoma, mucinous   CK7+/CK20+   CDX2 (nuclear) Lung, small cell carcinoma (Fig. 3.27)   CK7+/CK20−   TTF-1 (nuclear)   CD56 Gastroesophageal/stomach adenocarcinoma   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Endocervical adenocarcinoma   CK7+/CK20− Renal clear cell carcinoma   CK7−/CK20−   RCC Ma   CD10   3p deletion Prostate adenocarcinoma   CK7−/CK20−   PSA, PAP Thyroid follicular cell neoplasms   CK7+/CK20−   TTF-1 (nuclear)   Thyroglobulin

Lung, adenocarcinoma, nonmucinous   CK7+/CK20–   TTF-1 (nuclear) Lung, adenocarcinoma, mucinous   CK7+/CK20+   CDX2 (nuclear) Lung, small cell carcinoma   CK7+/CK20−   TTF-1 (nuclear)   CD56 Gastroesophageal/stomach adenocarcinoma   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Squamous cell carcinoma, esophagus and lung   CK5/6, k903   p63 Mesothelioma (Fig. 3.29)   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)

Hepatocellular carcinoma   CK7−/CK20−   HepPar1   pCEA (canalicular)   CD10 (canalicular) Ovary, serous carcinoma (Fig. 3.28)   CA125   WT1 (nuclear)   p53 (nuclear)   ER, PR (nuclear) Pancreatobiliary adenocarcinoma   CK7+/CK20+ (64%)   CK7+/CK20− (28%)   CA19-9   CA125 (50%)   CDX2 (70%, nuclear)

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Table 3.26. Lymph Node Tumors, Inguinal, Pelvic, and Retroperitoneal Inguinal

Pelvic

Retroperitoneal

Squamous cell carcinoma, anus, vulva, penis   CK5/6   k903   p63

Prostate adenocarcinoma   CK7−/CK20−   PSA   PAP

Ovary, nonmucinous   CA125   WT1 (nuclear)   ER/PR (nuclear)

Rectum adenocarcinoma   CK7−/CK20+   CDX2 (nuclear)   Villin

Urothelial carcinoma   CK5/6   k903   p63 (nuclear)

Endometrial carcinoma   CK7+/CK20−   ER/PR (nuclear)   Vimentin

Melanoma   S-100   HMB45   Melan-A

Endometrioid carcinoma   CK7+/CK20−   ER, PR   Vimentin   Endocervix   CK7+/CK20−

Seminoma/dysgerminoma   PLAP (membranous)   OCT4   CD117   OCT4 (nuclear)

Urothelial carcinoma   CK5/6   k903   p63 (nuclear) Mesothelioma   CK7+/CK20−   Calretinin   CK5/6   WT1 (nuclear)

Squamous cell carcinoma, cervix, penis, vulva   CK5/6   k903   p63

Embryonal carcinoma   CK7+/CK20−   CD30   PLAP (membranous)   OCT4 (nuclear) Yolk sac tumor   CK7−/CK20−   AFP   a1AT   PLAP (membranous) Choriocarcinoma   Pankeratin   bhCG Colon adenocarcinoma   CK7−/CK20+   CDX2 (nuclear)   Villin Urothelial carcinoma   CK5/6   k903   p63 (nuclear)

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Fig. 3.27. Metastatic small cell carcinoma (A) to a supraclavicular lymph node is positive for pankeratin (diffuse and dot-like) (B), synaptophysin (dot-like) (C), and TTF-1 (nuclear) (D); suggestive of a lung primary due to the TTF-1 result, but TTF-1 is not specific for primary site in small cell neuroendocrine carcinoma.

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Fig. 3.28. Metastatic ovarian serous carcinoma (A) to a supraclavicular lymph node is positive for CA125 (B), ER (nuclear) (C), WT1 (nuclear) (D), and p53 (nuclear) (E).

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Fig. 3.29. Metastatic mesothelioma (A) to an axillary lymph node is positive for calretinin (nuclear and cytoplasmic) (B).

Table 3.27. CNS Tumors Primary

Metastatic carcinoma

Neuronal tumors   GFAP   Synaptophysin

Lung, small cell   CK7+/CK20−   TTF-1 (nuclear)   CD56   Chromogranin   Synaptophysin

Meningioma   EMA   Pankeratin (−)

Lung, nonmucinous adenocarcinoma (Fig. 3.30)   CK7+/CK20−   TTF-1 (nuclear)

Hemangioblastoma   Inhibin

Lung, adenocarcinoma, mucinous   CK7+/CK20+   CDX2 (nuclear)

High grade glioma   GFAP   Pankeratin (focal)

Squamous cell   CK5/6   k903   p63 (nuclear)

Metastatic miscellaneous Melanoma   S-100   HMB45   Melan-A Lymphoma   CD45   CD3   CD20 Leukemia (subtype dependent)   CD34   MPO   CD13   CD33   HLA-DR   Lysozyme

Breast   CK7+/CK20−   GCDFP-15   Her2 (membranous)   ER/PR (nuclear) Endometrioid carcinoma   CK7+/CK20−   ER/PR (nuclear)   Vimentin Renal clear cell   CK7−/CK20−   RCC Ma   CD10   3p deletion

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Table 3.27. (continued) CNS Tumors Primary

Metastatic carcinoma

Metastatic miscellaneous

Colorectum   CK7−/CK20+   CDX2 (nuclear)   Villin (membranous) Gastroesophageal/stomach   CK7−/CK20+ (35%)   CK7+/CK20+ (32%)   CK7+/CK20− (19%)   CK7−/CK20− (14%)   CDX2 (nuclear, 73%) Choriocarcinoma   CK7+/CK20+   βhCG

Fig. 3.30. Metastatic lung adenocarcinoma (A) to the brain is positive for pankeratin and TTF-1 (nuclear) (B); in adenocarcinoma, TTF-1 is quite specific for lung (or thyroid) (C).

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SUGGESTED READING General Chu PG, Weiss LM. Keratin Expression in human tissues and neoplasms. Histopathol 2002;40:403–439. Dabbs, DJ (ed). Diagnostic immunohistochemistry. Philadelphia, Churchill Livingston, 2006. Nadji M, Nassiri M, Morales AR (eds). Efficient Tumor Immunohisto­ chemistry: A Differential Diagnosis-driven Approach. Chicago, ASCP Press, 2006. Taylor CR, Cote RJ (eds). Immunomicroscopy: A Diagnostic Tool for the Surgical Pathologist. 3rd ed., Philadelphia, Saunders, 2006.

Unknown Tumor Al-Nafussi A, Wong NA. Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis. Histopathol 2001;38:387–402. Anderson GG, Weiss LM. Determining tissue of origin for metastatic cancers: meta-analysis and literature review of immunohistochemistry performance. Appl Immunohistochem Mol Morphol 2010;18:3–8. Antonescu CR. The role of genetic testing in soft tissue sarcoma. Histopathol 2006;48:13–21. Bahrami A, Truong LD, Ro JY. Undifferentiated tumor: true identity by immunohistochemistry. Arch Pathol Lab Med 2008;132:326–348. Becher MW, Abel TW, Thompson RC, Weaver KD, Davis LE. Immunohistochemical analysis of metastatic neoplasms of the central nervous system. J Neuropathol Exp Neurol 2006;65:935–944. Bender RA, Erlander MG. Molecular classification of unknown primary cancer. Semin Oncol 2009;36:38–43. Cheng L. Establishing a germ cell origin for metastatic tumors using OCT4 immunohistochemistry. Cancer 2004;101:2006–2010. Cheng L, Sung MT, Cossu-Rocca P, et al. OCT4: Biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol 2007; 211:1–9. Cheuk W, Kwan MY, Suster S, Chan JK. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med 2001; 125:228–231.

Chu PG, Weiss LM. Keratin expression in human tissues and neoplasm. Histopathol 2002;40:403–439. Coindre JM. Immunohistochemistry in the diagnosis of soft tissue tumours. Histopathol 2003;43:1–16. Dennis JL, Hvidsten TR, Wit EC, Komorowski J, Bell AK, Downie I, Mooney J, Verbeke C, Bellamy C, Keith WN, Oien KA. Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm. Clin Cancer Res 2005;11:3766–3772. Gown AM, Yaziji H. Immunohistochemical analysis of ­carcinomas of unknown primary site. Pathol Case Rev 1999;4:250–259. Heim-Hall J, Yohe SL. Application of immunohistochemistry to soft tissue neoplasms. Arch Pathol Lab Med 2008;132:476–489. Krishnan C, George TI, Arber DA. Bone marrow metastases: a survey of nonhematologic metastases with immunohistochemical study of metastatic carcinomas. Appl Immunohistochem Mol Morphol 2007;15:1–7. Lagendijk JH, Mullink H, van Diest PJ, Meijer GA, Meijer CJ. Tracing the origin of adenocarcinomas with unknown primary using immunohistochemistry; differential diagnosis between colonic and ovarian carcinomas as primary sited. Hum Pathol 1998;29:491–497. Lagendijk JH, Mullink H, van Diest PJ, Meijer GA, Meijer CJ. Immunohistochemical differentiation between primary adenocarcinomas of the ovary and ovarian metastases of colonic and breast origin. Comparison between a statistical and an intuitive approach. J Clin Pathol 1999;52:283–290. Oien KA. Pathologic evaluation of unknown primary cancer. Semin Oncol 2009;36:8–37. Park SY, Kim KH, Kim JH, Lee S, Kang GH. Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma. Arch Pathol Lab Med 2007;131:1561–1567. Srivastava A, Hornick JL. Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. Am J Surg Pathol 2008;33:626–632. Tot T. Review: Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur J Cancer 2002;38: 758–763. Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic strategies for unknown primary cancer. Cancer 2004;100:1776–1785.

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4 Diagnostic Electron Microscopy Jean L. Olson, md

contents

I. Technical Background..........................4-2

Introduction and Principles..............................4-2 Specimen Requirements   and Preparation..............................................4-2 Pitfalls in Interpretation....................................4-2

II. Specific Features of Cellular Compartments.....................................4-2 The Nucleus.........................................................4-2 The Cytoplasm....................................................4-3

The Cell Surface (Plasmalemma)...................4-11 Extracellular Constituents...............................4-12

III. Diagnostically Useful Features of Entities . ........................................4-13 Neoplasms.........................................................4-13 Nonneoplastic Conditions................................4-18

IV. Suggested Reading.............................4-20

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_4, © Springer Science+Business Media, LLC 2002, 2006, 2011

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TECHNICAL BACKGROUND Introduction and Principles ♦♦ In 1986, Ernst Ruska was awarded the Nobel Prize in Physics for his pioneering work in the development of the electron microscope. Its diagnostic utility in anatomic pathology has been contested by advanced immunohistochemical and molecular genetic techniques in recent years. The electron microscope still remains a useful tool in selected instances of tumor diagnosis, some nonneoplastic conditions, and renal biopsy interpretation (see Chap. 34) ♦♦ The main contribution of the electron microscope has been and will continue to be to the understanding of the structure–function relationships at the subcellular level. Further understanding of the molecular processes can now be ascertained using ultrastructural localization techniques such as immunogold ♦♦ The transmission electron microscope uses a tungsten filament heated to 80,000–100,000 volts in order to emit an electron beam. The electron beam passes through a vacuum and is focused using electromagnetic lenses that act on the beam as glass lenses act on a beam of photons. As the beam passes through the specimen, some electrons are scattered but others are focused on the fluorescent screen where a real image is formed. Many laboratories now use a digital camera to record the image ♦♦ The resolving power of the electron microscope is approximately 10,000× greater than the light microscope due to the shorter wavelength of the electron and the better numerical aperture of the electromagnetic lenses. The resolution of the electron microscope is 0.3 nm

Specimen Requirements and Preparation ♦♦ For optimal viewing the specimen for electron microscopy should be fixed as rapidly as possible in strong

fixatives such as glutaraldehyde for proteins and postfixed with osmium tetroxide for lipids so that membranes are stabilized. Glutaraldehyde penetrates tissue very slowly so that it is necessary for the tissue to be minced into 1 × 1 × 1 mm cubes in order for proper and even fixation to occur ♦♦ Following dehydration and embedding in plastic, the tissue must be cut using a diamond knife on an ultramicrotome to a thickness of 80–100 nm. The thickness of the section can be estimated by the interference colors they generate by reflection. Modern ultramicrotomes have accurate settings for thickness. The sections are then picked up on copper grids and stained with uranyl acetate and lead citrate to add contrast

Pitfalls in Interpretation ♦♦ The major pitfalls in interpretation are due to the artifacts induced by poor fixation. Membranes and organelles may swell. Mitochondria may burst ♦♦ Specimen preparation may cause shrinkage of other structures so that measurements need to be carefully controlled ♦♦ Normal structures may be mistaken for pathology. For example, nuclear pores bear a resemblance to some viruses and have been interpreted as such by the unwary. Amyloid fibrils are similar in appearance to the microfibrils near the edges of elastin ♦♦ Sampling error is an ever present possibility. The sample is small as required for proper preservation. The lack of a feature does not mean that it is not present. It may be sufficiently sparse that it is not seen in the thin section that has been examined

SPECIFIC FEATURES OF CELLULAR COMPARTMENTS The Nucleus ♦♦ The chromatin pattern of the nucleus indicates the status of the DNA −− Euchromatin is finely and evenly dispersed (a) It indicates actively dividing immature cells (b) It is seen in such tumors as seminoma, Ewing sarcoma, and undifferentiated carcinomas −− Heterochromatin is condensed with clustering (a) It indicates resting, inactive cells (b) An increased number and size of condensed chromatin clumps in an enlarged nucleus are fairly common findings of various malignant neoplasms ♦♦ Nuclear configuration may also point toward a particular tumor

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−− Extreme cerebriform irregularity may be seen in Sézary syndrome and mycosis fungoides, dermatofibrosarcoma protuberans, and fibroadenoma of the breast −− Elongated and corrugated contour or saw-tooth configurations are typical of smooth muscle neoplasms −− Numerous nuclear pockets are typically seen in lymphoma and lymphocytic leukemia −− Cleaved or cleft nuclear envelopes are characteristic of lymphoma (Fig. 4.1) and lymphocytic leukemia, thyroid papillary carcinoma, Brenner tumor, granulosa cell tumor, and urothelial neoplasms ♦♦ Nuclear inclusions exist in various forms −− Viruses may be visualized by negative staining of whole particles or in thin sections. See section on nonneoplastic conditions for full discussion

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Fig.  4.2. Aldosteronoma (aldosterone-secreting adrenal cortical adenoma) demonstrating tubulovesicular cristae in mitochondria. Fig. 4.1. Lymphoma with convoluted nuclei.

−− It is important to differentiate virions from various other nuclear particulate inclusions that may occur (a) Intranuclear glycogen may be seen in liver cells in diabetes, glycogen storage disease, Wilson disease, and hepatocellular tumors (b) Other particulate structures seen in nuclei include nuclear bodies and perichromatin granules (c) Furthermore, nuclear pores simulate virions for the unwary ♦♦ Nucleolus −− Multiple pleomorphic enlarged nucleoli are frequently seen in various malignant tumors −− Anastomosing rope-like nucleolus is typical of seminoma (dysgerminoma)

The Cytoplasm ♦♦ Mitochondria may vary in cristal architecture, size, number, or may contain inclusions −− Tubulovesicular cristae are typically seen in steroid-producing cells, such as adrenal cortical adenoma (Fig. 4.2), Leydig cell tumor, ovarian hilus cell tumor, luteoma of pregnancy, thecoma, sex-cord stromal tumor, and granulosa cell tumor

−− Plate-like cristae are found in hepatocytes and tumors of same (Fig. 4.3) −− Giant mitochondria (megamitochondria) may be seen on occasion in any cell. They should only be considered significant when seen frequently in many cells (a) Certain adenomas of the pituitary, thyroid, or salivary glands may contain megamitochondria (b) Secretory endometrial glands are an example of normal cells that may have giant mitochondria (c) Such mitochondria may also be associated with drug toxicity such as alcohol or cyclosporine −− An increase in numbers of mitochondria is considered significant when the mitochondria push the other organelles to the side. Such cells are called oncocytes (a) Oncocytoma of thyroid gland (also called Hürthle cell neoplasm), salivary gland, parathyroid, kidney (Fig.  4.4) and bronchial gland as well as Warthin tumor are examples −− Mitochondria may contain various inclusions (a) Small granules are frequently seen and represent divalent cations. An increase in the number of such granules may represent irreversible injury (b) Crystalline inclusions may be seen with drug injury (e.g., halothane, rosiglitazone), mitochondrial myopathies, etc

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Fig.  4.3. Hepatocellular adenoma with plate-like cristae in mitochondria.

Fig. 4.4. Oncocytoma of kidney with numerous mitochondria.

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♦♦ Ribosomes and granular endoplasmic reticulum (GER) vary in amount depending on the state of the protein synthetic machinery −− Immature blastic or undifferentiated tumor cells show increased ribosomal rosettes. Examples include (a) Ewing sarcoma, seminoma, undifferentiated (lymphoepithelioma-like) carcinoma (b) Lymphoblastic lymphoma, Burkitt lymphoma −− Increased GER is noted in cells synthesizing proteins for export (a) Plasma cells, acinic cells, hepatocytes, fibroblasts, chondroblasts, and osteoblasts (b) And their neoplastic counterparts multiple myeloma, acinar cell carcinoma (salivary gland and pancreas), hepatocellular adenoma (Fig.  4.3) and carcinoma, fibroma, fibrosarcoma, chondroid tumors, and osteoblastic tumors −− Tubuloreticular inclusions represent modified endoplasmic reticulum (Fig. 4.5). (a) They are seen in vascular endothelial cells, lymphocytes, and monocytes of patients with increased alpha and beta interferon (b) Examples include human immunodeficiency virus or other viruses, systemic lupus erythematosus, and scleroderma

Fig.  4.5. Tubuloreticular inclusion in endothelial cell from glomerular capillary loop.

Diagnostic Electron Microscopy

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Fig. 4.6. Ewing sarcoma showing glycogen (arrow).

Fig. 4.7. Clear cell adenocarcinoma of ovary showing glycogen (arrows) filling cells.

♦♦ Increased smooth endoplasmic reticulum appears in steroidsecreting cells or as evidence of increased drug metabolism −− Steroid-secreting tumors include sex-cord stromal tumors, granulosa cell tumor, thecoma, Sertoli–Leydig cell tumor, hilus cell tumor of the ovary, Leydig cell tumor of the testis, and adrenal cortical tumors −− Hepatocytes associated with protracted use of barbiturate also show increased smooth endoplasmic reticulum ♦♦ Glycogen is particulate and resembles ribosomes, although glycogen is somewhat larger. It is often washed away in routine preparation but leaves behind a characteristic appearance. It comes in two-forms −− Beta glycogen; irregular shaped 15–30 nm particles −− Alpha glycogen; rosette-like aggregates (prominent in the liver) −− Glycogen is abundant in Ewing sarcoma (Fig.  4.6), seminoma, rhabdomyosarcoma, yolk sac tumor, clear cell adenocarcinoma of the breast, vagina, endometrium, ovary (Fig.  4.7), salivary gland and kidney; clear cell sarcoma, sugar tumor of the lung, and hepatocellular adenoma and carcinoma ♦♦ Lysosomes have varied appearances depending on whether they are primary or secondary and on what material is present within their membrane −− Primary lysosomes measure 0.25–0.5  mm and are membrane-limited dense bodies that may be mistaken for neurosecretory dense-coregranules. Lysosomes tend to be

more heterogeneous in size and shape than neurosecretory granules −− Secondary lysosomes are also known as autophagosomes, heterophagic vacuoles, or residual bodies and appear as lipofuscin pigment on light microscopy −− Secondary lysosomes may contain intracellular metabolic products or phagocytosed extracellular material −− Abundant lysosomes are seen in a variety of neoplasms or in lysosomal storage diseases (a) Granular cell tumor (Fig. 4.8), granular cell ameloblastoma, thyroid follicular neoplasm, prostatic adenocarcinoma, myelocytic, or monocytic leukemia (b) Genetically transmitted as autosomal recessive disease; for example, Tay-Sachs disease, Fabry disease (Fig. 4.9). See below for other examples of lysosomal storage diseases −− Michaelis–Guttmann bodies represent a specialized form of secondary lysosome seen in macrophages in malakoplakia. They are multilaminated, calcified spherules formed in secondary lysosomes, often containing calcium apatite crystals thought to represent bacterial remnants ♦♦ Neurosecretory, dense-core (or neuroendocrine) granules are membrane-limited dense-core granules that vary in size ­(50–400 nm), shape, and density depending on the protein contained in the granule but are uniform in appearance within a particular cell type. They usually have a halo between the core and the membrane

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Fig. 4.8. Granular cell tumor showing heterogeneity of lysosmal forms.

Fig. 4.10. Neuroblastoma showing more neurosecretory granules (arrow) in processes than in cell bodies.

Fig. 4.9. Fabry disease affecting glomerular podocyte with classic myelin-like appearance of storage material in lysosomes (arrow).

−− Neuroblastoma (Fig.  4.10), esthesioneuroblastoma, and ganglioneuroblastoma contain 100 nm round dense-core granules that are more concentrated in cell processes than in cell bodies −− Pheochromocytoma (Fig.  4.11) has two cell types, one with eccentric dense cores (norepinephrine) and the other (epinephrine) with centrally located spherical cores, resembling the granules of neuroblastoma −− Paraganglioma has spherical granules that measure 100–200 nm −− Carcinoid tumor (Fig.  4.12) contains serotonin-secreting pleomorphic granules −− Medullary thyroid carcinoma has two types of calcitonincontaining granules. Type 1 is large, medium-dense with no halo, and type 2 is small, very dense and has a halo −− Merkel cell tumor (cutaneous neuroendocrine carcinoma) contains small spherical granules (115–200 nm) −− Small (Fig.  4.13) and large cell neuroendocrine carcinoma contain sparse dense-core granules −− Renal juxtaglomerular cell tumor demonstrates spherical or rhomboid granules ♦♦ Secretory granules of normal and neoplastic exocrine glands are of two types −− Mucous granules (0.7−1.8  mm) are membrane-limited granular, reticulated, or flocculent material of various densities (Fig. 4.14)

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Fig. 4.11. Pheochromocytoma containing norepinephrine granules with eccentric cores (arrow) and epinephrine granules (all others).

Fig.  4.13. Small cell neuroendocrine carcinoma with sparse neurosecretory granules. Inset shows dense core with halo.

Fig. 4.12. Carcinoid tumor with pleomorphic granules.

Fig. 4.14. Adenocarcinoma of lungs, mucin cell type showing mucous granules (arrow).

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−− Electron microscopy does not differentiate various types of mucins; for this purpose, histochemical and immunohistochemical studies are needed −− Serous or zymogen granules (0.5–1.5 mm) are membranelimited, dense granular matrix that may or may not contain enzymes −− Serous or zymogen granules are seen in pancreatic acinar cells, serous acinic cells of salivary gland (Fig. 4.15) or of the upper respiratory tract, gastric chief cells, and Paneth cells ♦♦ Lipid droplets are not limited by a membrane and may be seen in virtually any kind of cell in small numbers. More abundant lipid droplets are seen in the following conditions −− Adipose tissue, normal and neoplastic, contains large droplets −− Hibernomas contain abundant lipid droplets and numerous mitochondria −− Steroid-secreting tumors – thecoma, ovarian hilus cell tumor, Leydig cell tumor, adrenal cortical tumors – contain numerous lipid droplets −− Numerous lipid droplets are also frequently observed in sebaceous gland tumor, renal clear cell carcinoma, xanthoma, and fibrohistiocytoma ♦♦ Microtubules and numerous types of cytoplasmic fibrils/filaments may be observed −− Microtubules are 25 nm wide and are seen in a variety of cells

Fig. 4.15. Acinic cell carcinoma with zymogen granules (arrow).

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(a) Axonemes of cilia are composed of 9+2 doublets in motile cilia (Fig. 4.16) and 9+0 in stereocilia (b) Neurotubules are noted in neuronal cell tumors (neuroblastoma, ganglioneuroma, primitive neuroectodermal tumor) particularly in their processes (c) Intracisternal microtubules have been described in melanoma and myxoid chondrosarcoma (d) Microtubules may also be seen in platelets in a circumferential band (e) Scattered microtubules have been described in many cell types −− Filaments or microfibrils are seen in different sizes (a) Thick filaments are usually skeletal muscle myosin and measure 15 nm wide (b) Intermediate filaments measure 10–12 nm wide and are composed of many different proteins including cytokeratin, vimentin, desmin, glial filaments, and neurofilaments * With the exception of tonofibrils (cytokeratin forming characteristic dense curvilinear bundles (Fig. 4.17)), they are not distinguishable by electron microscopy (c) Actin microfilaments measure 6–7 nm wide and are found in smooth and striated muscle cells, myofibroblasts, and myoepithelial cells −− Filamentous inclusions may be seen in certain conditions (a) Nemaline rod is a thread-like or oblong structure having a lattice-like appearance that may be found beneath the sarcolemma of skeletal muscle

Fig.  4.16. Cross-sections of respiratory cilia showing the 9+2 microtubular pattern. Note also dynein arms (arrows).

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Fig.  4.17. Squamous cell carcinoma showing typical curved tonofilaments. Fig. 4.18. Leydig cell tumor showing Reinke crystal. * They were first described in nemaline myopathy but have also been seen in muscular dystrophy and polymyositis (b) Mallory hyalin or body is an irregularly shaped accumulation of cytokeratin intermediate filaments in liver cells * They may be seen in alcoholic and nonalcoholic steatohepatitis, Wilson disease, and various cholestatic conditions * They have also been described in hepatocellular carcinoma ♦♦ Certain organelles are specific to particular cells or a group of cells −− Crystals of Reinke (Fig.  4.18) are hexagonal prism-like, highly ordered 10 nm thick filaments that are not limited by a membrane and are seen in Leydig cells and ovarian hilus cells. These crystals are found in 35% of Leydig cell tumors −− Charcot–Böttcher “crystalloids” are closely packed electron-dense, longitudinal arrays of fibrils or tubules lacking a geometric crystalline lattice in postpuberty Sertoli cells. They are described in an occasional Sertoli cell tumor −− Langerhans cell granule (Birbeck granule) (Fig. 4.19) is a 34 nm wide rod-shaped structure of variable length with a periodic or striated zipper-like core. The limiting membrane is often dilated at one end giving the granule a tennis racket-like appearance

Fig. 4.19. Langerhans histiocyte. Inset shows Birbeck granules.

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Fig. 4.20. Melanosomes are shown. The left panel shows a premelanosome prior to pigment accrual. The right panel shows a melanized melanosome.

(a) These structures are seen in Langerhans cell histiocytosis (eosinophilic granuloma, Letterer–Siwe disease, or Hand–Schüller–Christian disease) (b) They are absent in follicular dendritic and interdigitating dendritic cells −− Melanosomes (Fig.  4.20) are seen in cells that produce melanin (a) They mature stepwise in four stages with stage II–III premelanosomes most characteristic, consisting of ovoid or ellipsoidal vesicles with striated internal structures (b) They are seen in melanocytic neoplasms but stage II and III premelanosomes may also be seen in unpigmented variants of melanocytic neoplasms and may be aberrant −− Weibel–Palade body (Fig.  4.21) is a rod-shaped body with microtubular internal structures embedded in dense matrix seen in blood vessel endothelial cells but not in lymphatic endothelial cells (a) They are easily found in benign vasoformative tumors and epithelioid hemangioendothelioma (b) They are only rarely found in malignant vasoformative tumors, such as angiosarcoma or Kaposi sarcoma reflecting the lack of differentiation

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♦♦ Certain other organelles are uncommon and are not typical of any particular cell type although they are seen in particular disorders −− Ribosome–lamella complex consists of several layers of parallel cylindrical lamellae, separated by ribosome like granules (a) It is most commonly seen in patients with hairy cell leukemia (b) It is also described in various other neoplasms and disorders; for example, chronic lymphocytic leukemia, various lymphomas, reactive lymph node, adrenal cortical adenoma, insulinoma, Sertoli cell tumor, meningioma, and glioma −− Lamellar inclusion body (myelinosome) (Fig.  4.22) is a concentrically arranged, stacked electron-dense membrane and represents the surfactant in type II alveolar cells (a) This change is also seen as a metabolic product of many drugs including amiodarone and gentamycin (b) Similar structures are also seen in various lysosomal storage diseases (c) Spironolactone bodies resemble surfactant myelinosomes and are seen in zona granulosa cells of patients treated with the aldosterone antagonist, spironolactone

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The Cell Surface (Plasmalemma) ♦♦ Interdigitating complex cell membranes are common in glandular epithelial tumors (gastrointestinal adenocarcinomas, parathyroid adenomas, and sweat gland tumors), epithelioid sarcoma, meningothelial meningioma, and schwannoma ♦♦ Cilia may be motile (9+2 microtubular doublets) or may not move (stereocilia with 9+0 microtubular doublets) ♦♦ They are present on the luminal surfaces of many types of epithelial cells ♦♦ Cilia are lost in malignant tumors. Various abnormalities of the cilia are described in benign epithelial tumors. They are not useful in differential diagnosis ♦♦ Pinocytotic vesicles are seen in well-differentiated smooth muscle, vascular endothelial, and perineurial tumors ♦♦ Microvilli are a surface specialization that increases the surface area of an epithelial cell bordering a lumen. They characteristically contain anchoring rootlets and are covered by a glycocalyx −− Closely packed rigid microvilli (brush border) are seen in adenocarcinoma of gastrointestinal tract and intestinal-type adenocarcinoma of other sites −− Long, branching, shaggy microvilli are typical of mesothelial cells and mesothelioma (Fig.  4.23) (epithelial type) Fig. 4.21. Weibel–Palade bodies may be seen in endothelial cells.

Fig. 4.22. Lamellar inclusion bodies are noted in a type II alveolar lining cell and represent surfactant.

Fig. 4.23. Mesothelioma is characterized by long bushy microvilli.

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♦♦ Intracytoplasmic lumens are vacuolar-like structures lined by scattered microvilli −− They are a useful marker for adenocarcinoma −− They are particularly prominent in breast carcinoma (Fig. 4.24) (both ductal and lobular) ♦♦ Cell junctions occur in various types but the desmosome (Fig. 4.24, inset) is the most useful in tumor ultrastructure. −− In general, the number of intercellular junctions is reduced in tumor cells compared with their normal counterpart. They tend to be rudimentary especially in undifferentiated tumors −− Cell junctions of various types are found in all benign and malignant epithelial tumors, meningothelial meningiomas, thymomas, mesotheliomas, endocrine gland tumors, neuroendocrine tumors, germ cell tumors, sexcord stromal tumors, epithelioid sarcoma, epithelial component of synovial sarcoma, and vascular endothelial cell and its tumors − − In most other mesenchymal tumors, cell junctions are poorly developed, primitive or inconspicuous −− In leukemia, granulocytic sarcoma, and lymphoma, cell junctions are absent (one exception being follicular dendritic cell tumor)

Fig. 4.24. Ductal breast carcinoma shows two intracellular lumina with micovilli. (Inset) A desmosome seen at high magnification represents a “spot weld” between two cells.

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Extracellular Constituents ♦♦ Several special configurations of collagen fibers may be found in particular tumors ♦♦ Luse bodies are a fusiform collection of long-spaced collagen fibers with a periodicity of 100–150  nm that are seen most characteristically in schwannomas but may be seen in other tumors as well ♦♦ Amianthoid fibers are giant collagen fibers with diameter up to ten times of normal collagen fibrils (60  nm) that are detected in chondrosarcoma, synovial sarcoma, neurogenic sarcoma, and meningioma ♦♦ Skeinoid fibers are tangles of curvilinear fibrils with a periodicity of 41–48 nm that are described in neurogenic spindle cell tumors and gastrointestinal autonomic nerve tumors ♦♦ Amyloid fibrils are Congo-red positive and are birefringent under polarized light due to a beta-pleated sheet configuration ♦♦ These are haphazardly arranged, nonbranching fibrils (Fig. 4.25) with a diameter of 7–10 nm ♦♦ They are associated with numerous proteins but are commonly due to light chains of immunoglobulins and may accumulate in many different organs resulting in loss of function

Fig. 4.25. Amyloid fibrils.

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DIAGNOSTICALLY USEFUL FEATURES OF ENTITIES Neoplasms (See Tables 4.1 and 4.2 for General Features) ♦♦ Acinic cell carcinoma of the salivary gland and acinar cell carcinoma of the pancreas (Fig. 4.15) are characterized by −− Membrane-limited electron-dense round zymogen granules (0.3–1.5 mm) −− Stacked rough endoplasmic reticulum −− Well-developed Golgi apparatus −− Occasional small lumens lined by microvilli and juxtaluminal junction complexes −− Adenoid cystic carcinoma (salivary gland, breast, upper airway, skin) is characterized by clusters of polygonal cells forming microcystic spaces containing multilayered basal lamina with three types of cells −− Undifferentiated cells have a high nucleus/cytoplasm ratio and organelle-poor cytoplasm

−− Myoepithelial cells contain thin (actin) filaments condensed against the cell membrane facing the microcystic space that is lined by a basal lamina −− Ductular cells form true lumens lined by microvilli and held together by junctional complexes ♦♦ Adenoma and adenocarcinoma (tumors of exocrine glandular epithelium in general) are typified by a true glandular lumen or intracytoplasmic lumen lined by microvilli (Fig.  4.24). However, these may also be seen in epithelial mesothelioma, choroid plexus papilloma, glandular component of synovial sarcoma, and neuroendocrine neoplasms −− Other invariable features include various types of cell junctions and a distinct basement membrane along the stromal interface −− Other features depend on the tissue from which the tumor has arisen and the degree of differentiation. These include: a well-developed Golgi apparatus and exocrine

Table 4.1. Small Round Cell Tumors Neuroblas- Neuroendocrine Ewing Rhadomyotoma tumor sarcoma PNET sarcoma Lymphoma DRCTDD Glycogen Dense-core granules Cell junctions Cytoplasmic filaments Microtubules Basal lamina Others

± + +

± + +

+ − +

+ ± +

+ − +

± − −

± ± +

+ + − Neuropil

+ − ±

± − −

+ ± −

+Thick and thin − + Z-band

± − −

+ − +

PNET primitive neuroectodermal tumor, DRCTDD desmoplastic round cell tumor of divergent differentiation, + present, − absent, ± occasionally present

Table 4.2. Large Cell Tumors NeuroenSquamous Transitional cell Adenocar- docrine cell tumor Melanoma Lymphoma Sarcoma cinoma carcinoma carcinoma Cell junctions Microvilli with lumen Filaments Secretory granules Golgi RER Basal lamina

+ − +Tonofibrils − + +

+ − + − + +

+ + + + + +

+ ± + + + +

− − + − + −

− − ± – −

± ± + + ±

RER rough endoplasmic reticulum, + present, − absent, ± occasionally present

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♦♦

♦♦

♦♦

♦♦

secretory granules (mucous, serous, or zymogen), intermediate filaments (cytokeratin), interdigitation of cell membrane, and pools of glycogen particles, particularly in clear cell tumors (Fig. 4.7) −− Characteristic features of intestinal-type adenocarcinoma include rigid microvilli with prominent core rootlets, glycocalyx, junctional complex, and mucous granules Adipose neoplasms (lipomas and liposarcomas) are characterized by lipid droplets −− Commonly seen organelles include pinocytotic vesicles and basal lamina −− Varying amounts of rough endoplasmic reticulum, intermediate filaments, mitochondria, and glycogen particles may also be seen Adrenal cortical neoplasms (Fig. 4.2) show the characteristics of steroid-producing cells −− Typical organelles include abundant smooth endoplasmic reticulum and lipid droplets −− Mitochondria contain lamellar cristae (aldosteronoma) or tubulo-vesicular cristae (cortisol-secreting tumor) Black adenoma of the adrenal cortex contains abundant lipofuscin inclusions in zona reticularis type cells of a usually non-functioning adenoma Alveolar soft part sarcomas are characterized by Golgiassociated small dense granules (90 nm) and larger secretory granules (300 nm) that frequently contain rhomboid crystals (Fig. 4.26) −− Other features include stacked rough endoplasmic reticulum, clusters of mitochondria, variable glycogen particles, lipid droplets and rare rudimentary cell junctions

Essentials of Anatomic Pathology, 3rd Ed.

♦♦

♦♦

♦♦

♦♦

♦♦

♦♦ Fig. 4.26. Alveolar sarcoma of soft tissue showing typical crystals.

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−− Basal laminas are seen around groups of tumor cells Brenner tumors contain epithelial cells having the features listed below that are present in the fibroma–thecoma-like background −− Typical features include cleaved nuclei, varying numbers of glycogen particles, lipid droplets, lysosomes, and vesicles −− Intercellular spaces contain prominent microvilli with interdigitating cell membranes with the cells joined by numerous small desmosomes −− Basement membrane (basal lamina) encloses the epithelial clusters −− The borderline tumors have secretory (mucous) cells and ciliated cells along the cystic cavities Carcinoid (Fig.  4.12) islet cell tumors are the prototypical neuroendocrine tumor −− Numerous cytoplasmic neurosecretory dense-core granules are the characteristic finding −− Nests of oval or spindle cells are surrounded by a basal lamina −− Occasionally the nests have a lumen with microvilli −− Desmosomes join the cells and intermediate filaments are frequently found Chondroid tumors (chondroma and chondrosarcoma) are rare tumors with an appearance that can often be differentiated from other soft tissue neoplasms −− The scalloped cell surface (plasmalemma) is typical and not seen in other tumors of soft tissue −− The cytoplasm contains abundant rough endoplasmic reticulum, occasional clusters of glycogen, lipid, and intermediate filaments −− No basal lamina is present Cholangiocarcinoma can be differentiated from hepatocellular neoplasms −− The cells have intestinal-type microvilli on the luminal surface −− Mucous granules, abundant free ribosomes, and scanty rough endoplasmic reticulum are noted −− No glycogen is present unlike hepatocytes that have abundant glycogen −− A continuous basement membrane is often surrounded by a densely collagenous stroma Clear cell adenocarcinomas of the vagina, cervix, endometrium, and ovary (Fig. 4.7) have similar ultrastructure −− The cells form microcysts, tubules, and papillae lined by hobnail, cuboidal cells, or solid areas of polygonal cells −− The cytoplasm contains abundant cytoplasmic glycogen and stacks of rough endoplasmic reticulum −− The cell surface shows short and blunt microvilli −− The cells are joined by junctional complexes Clear cell renal carcinoma is similar to other adenocarcinomas by the presence of microlumen formation, sparse microvilli, primitive cell junctions, and basal lamina around groups of cells

Diagnostic Electron Microscopy

−− It differs from other renal cell neoplasms due to the abundance of cytoplasmic glycogen and lipid droplets −− In contrast, chromophobe cell renal carcinoma contains numerous cytoplasmic vesicles of unknown origin ♦♦ Clear cell sarcoma of soft tissue contains large pools of glycogen particles as well as melanosomes (Fig. 4.20) ♦♦ Desmoplastic small round cell tumor shows small groups of epithelial cells joined by primitive desmosome-like junctions −− The cytoplasm contains abundant ribosomes, a prominent Golgi apparatus and bundles of intermediate filaments in the paranuclear region −− Occasional cells may contain glycogen and neurosecretory granules −− The collagenous stroma shows fibroblasts and myofibroblasts ♦♦ Embryonal carcinomas have a high nuclear/cytoplasmic ratio, with large elongated or irregularly shaped nuclei having clumped chromatin and large, often multiple nucleoli −− The cytoplasm demonstrates abundant free ribosomes, mitochondria, aggregates of glycogen particles and intermediate filaments −− In better differentiated areas, smooth and rough endoplasmic reticulum, desmosomes, gland lumens, junction complexes, microvilli, and basal lamina are seen ♦♦ Epithelioid sarcomas have some features suggesting epithelial differentiation −− There are clusters of large polygonal cells having round or indented nuclei with coarse chromatin, multiple nucleoli, and abundant cytoplasm −− The cytoplasmic features suggesting epithelial differentiation include tonofibrils, cell junctions including desmosomes, and rare discontinuous basal lamina around groups of tumor cells −− Other cytoplasmic features include numerous intermediate filaments and a moderate amount of mitochondria, ribosomes, and endoplasmic reticulum ♦♦ Ewing sarcoma (Fig. 4.6) (peripheral neurectodermal tumor) shows sheets of uniform cells with large oval nuclei with smooth nuclear contour and finely dispersed chromatin −− The characteristic feature is abundant aggregates of glycogen particles −− Nucleoli are small or inconspicuous −− Numerous free ribosomes and occasional cytoplasmic filaments may be seen −− Primitive cell junctions are usually found ♦♦ Fibromas and fibrosarcoma consist of spindled cells with abundant rough endoplasmic reticulum, a small number of mitochondria and a few bundles of intermediate filaments, and are surrounded by collagen fibers ♦♦ Fibrous histiocytomas whether benign or malignant are tumors of fibroblastic cells and modified fibroblasts having histiocytic features, giant or multinucleate fibroblastic cells and histiocytic cells

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♦♦ Follicular dendritic cell neoplasms have oval or elongated nuclei with small amount of peripheral heterochromatin −− They contain scant cytoplasmic organelles −− Long cytoplasmic processes are held together by desmosomes −− No Birbeck granules are found ♦♦ Gastrointestinal autonomic nerve (GAN) tumor is considered a subgroup of gastrointestinal stromal tumors (GIST) −− Tightly arranged spindle and epithelioid cells have long, interdigitating cytoplasmic processes resembling axons −− The cells contain intermediate filaments, microtubules, and dense-core granules −− Bulbous synaptic vesicle-like structures are present −− Small primitive cell junctions are noted between the axonic processes −− Aggregates of curvilinear collagen fibrils (“skeinoid fibrils”) are typically found in the intercellular space ♦♦ GIST usually have features of smooth muscle −− It is a tumor consisting of spindle and epithelioid cells, tightly packed together, and displaying ultrastructural features of muscle cell, Schwann cell, fibroblast, autonomic nerve cell or primitive mesenchymal cell −− Skeinoid fibers may be seen between the cells ♦♦ Granular cell tumors (Fig. 4.8) are clusters of polygonal cells having abundant cytoplasm −− The characteristic finding is numerous pleomorphic phagolysosomes −− The cells may also show slender cytoplasmic processes joined by rare rudimentary junctions and with basal lamina around groups of tumor cells ♦♦ Granulosa cell tumors have nests of oval cells in part surrounded by basal lamina, and joined by primitive desmosome-like junctions −− In the adult form, nuclei tend to be deeply indented and the nucleus/cytoplasm ratio is high −− In the juvenile form, the nucleus/cytoplasm ratio is low and the nucleus is not indented −− In both types, cytoplasm is rich in lipid droplets and smooth endoplasmic reticulum; mitochondria have tubular or tubulovesicular cristae characteristic of steroidproducing cells ♦♦ Hemangiopericytomas contain spindle or polygonal cells arranged in a palisade around blood vessels −− Typically there is basal lamina around individual tumor cells −− The cells may be joined by primitive cell junctions and frequently have pinocytotic vesicles at the plasmalemmal surfaces −− Intermediate filaments may be noted in the cytoplasm ♦♦ Hepatocellular adenoma (Fig.  4.3) and carcinoma show differentiation typical of hepatocytes −− Intercellular canaliculi and intraluminal or cytoplasmic bile (homogeneous dense bodies, varying sized vesicles or membranous whorls) are often seen

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♦♦ ♦♦

♦♦

♦♦

♦♦

−− The cytoplasm often contains glycogen particles, lipid droplets, well-developed smooth endoplasmic reticulum and abundant mitochondria often with plate-like cristae −− Aggregates of intermediate filaments (Mallory bodies) or cytoplasmic dense, solid inclusions of alpha-1 antitrypsin may be seen in some cases Hilus cell tumor (of the ovary) has features identical to those of testicular Leydig cells (Fig. 4.18) Interdigitating dendritic cell neoplasm has large indented or pleomorphic nuclei with peripheral heterochromatin −− Cytoplasmic organelles are sparse and do not show Birbeck granules −− Interdigitating cytoplasmic processes do not show desmosomes Langerhans cell histiocytosis (Fig.  4.19) contains large mononuclear cells with filopodia −− The characteristic finding is the Birbeck or Langerhans granule which is a rod-shaped structure with striated core, sometimes with bulbous end giving a tennis racket-like appearance −− Primary lysosomes are present but secondary lysosomes (phagolysosomes) are usually absent Leukemias are characterized by an absence of cell junctions −− Myelocytic (granulocytic sarcoma) and myelomonocytic leukemias have typical primary cytoplasmic (azurophil) granules (a) Myeloperoxidase activity is present in the cytoplasmic granules (b) Auer rods (rod-shaped, membrane-limited structures with dense lamellar internal substructure) result from coalescence of the azurophilic granules −− Lymphocytic leukemias have peripherally condensed heterochromatin (a) These tumors have rare, myeloperoxidase-negative primary lysosomes (b) They do not have secretory granules in the cytoplasm −− Hairy cell leukemia is typified by small lymphoid cells with villus-like (hairy) cytoplasmic projections (a) In the spleen and lymph node, filopodia or cell processes are interdigitating (b) Ribosome–lamellar complexes, usually in the paranuclear location, are found in 50% of the cases Leydig cell tumor of testis and hilus cell tumor of ovary are identical in appearance −− Reinke crystals (Fig. 4.18) are diagnostic but are present in a minority of cases (35%) −− The nucleus is round with dispersed chromatin and a medium-sized nucleolus −− Cytoplasm contains the organelles associated with steroid production, namely, abundant vesicles of smooth endoplasmic reticulum, many lipid droplets, and mitochondria with tubulovesicular cristae −− Microvilli cover the cell surface with basal lamina covering the nonvillous surface

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♦♦ Lymphoepithelial (lymphoepithelioma-like) carcinoma or undifferentiated carcinoma of nasopharynx contain clusters of polygonal cells with small primitive desmosomes, tonofibrils, and prominent free ribosomes ♦♦ Lymphomas (Fig.  4.1) are characterized by an absence of intercellular junctions −− Various nuclear configurations may be seen including round to indented, multilobated, cleaved or cerebriform. Nuclear pockets may be seen. The nucleus may show peripheral heterochromatin −− Most lymphomas have abundant free ribosomes −− Certain types of lymphomas may be characterized by specialized organelles (a) Plasmacytoid and immunoblastic cells contain stacks of rough endoplasmic reticulum (b) The filliform or anemone cell is covered with microvilli (c) The signet-ring cell shows numerous vesicles in the cytoplasm ♦♦ Malignant melanoma (Fig. 4.20) is characterized by the presence of melanosomes even when the tumor does not show pigmentation by light microscopy −− Stage II and III melanosomes are elliptical membranelimited structures with striated lamellar core, without or with dense melanin deposition that are the most typically seen −− Stage I (vesicles) and stage IV (heavily pigmented) melanosomes, and atypical melanosomes are not as specific as stage II and III melanosomes for diagnosis ♦♦ Meningioma has features that may be seen in neural neoplasms −− These tumors have long, interdigitating cell processes with well-defined desmosomes and other forms of cell junctions −− The cytoplasm contains numerous intermediate filaments ♦♦ Merkel cell carcinoma is a cutaneous neuroendocrine carcinoma −− A peculiar feature of these tumors is aggregates of paranuclear intermediate filaments or tonofibrils −− The cytoplasm also contains dense-core granules −− Intercellular junctions are frequently seen ♦♦ Mesothelioma, epithelial cell type (Fig. 4.23) may be distinguished from adenocarcinomas −− Numerous, long slender microvilli with a height/width ratio of 10/1 or higher without anchoring actin rootlets or glycocalyx are characteristic −− Other features may be seen to varying extent in mesothelioma and adenocarcinoma including prominent intercellular junctions such as desmosomes, abundant intermediate filaments and tonofibrils −− Glycogen particles and intracytoplasmic lumens may also be seen in either tumor −− The cells generally sit on a basal lamina −− In spindle cell type or sarcomatous mesothelioma, a spectrum of cells including fibroblastic, myofibroblastic, mesothelial, and other hybrid cells are seen

Diagnostic Electron Microscopy

♦♦ Neuroblastoma (Fig.  4.10) is composed of oval cells with crowded cytoplasmic processes (neuropil) −− The characteristic finding is the presence of dense-core neurosecretory granules −− Microtubules and intermediate filaments are observed in cell processes −− Primitive intercellular junctions are noted and synaptic vesicles may be seen ♦♦ Neuroendocrine neoplasms as a group contain the organelles described below −− The tumor cells are oval or spindled often with polar processes −− The cells contain dense-core neurosecretory granules, which may be sparse especially in poorly differentiated tumors −− The cells are joined by intercellular junctions that may be poorly formed ♦♦ Oncocytomas (Fig.  4.4) occur in many different sites but always contain numerous mitochondria filling the cytoplasm ♦♦ Osteoblastic neoplasms (osteoma, osteoblastoma, osteosarcoma) show some similarities to chondroid tumors −− They are polygonal cells with scalloped cell surface containing abundant dilated rough endoplasmic reticulum −− They differ from chondroid tumors by the composition of the surrounding matrix that contains hydroxy-apatite deposits with woven type I collagen fibers ♦♦ Ovarian epithelial neoplasms show several different cytoplasmic features −− Serous tumors (benign, borderline, and malignant) contain glandular lumens and papillae, microvilli and cilia, junctional complexes, glycogen, and rare secretory granules. Groups of cells may be surrounded by a basal lamina −− Mucinous tumors differ from serous tumors by the presence of mucous granules (a) The endocervical type has uniform small secretory granules, fibrillogranular bodies, and basal nuclei (b) The intestinal-type has absorptive cells with microvilli, goblet cells with mucus, and neuroendocrine cells with neurosecretory granules −− Endometrioid tumors differ from the other two types by the presence of perinuclear filaments and abundant glycogen. Desmosomes and tonofibrils may be seen in squamous morules ♦♦ Paraganglioma and pheochromocytoma (Fig.  4.11) contain nests of polygonal cells surrounded by basal lamina −− Dense-core granules are round in paraganglioma and pleomorphic in pheochromocytoma −− Sustentacular (supporting Schwann-like) cells are seen in paraganglioma but not in pheochromocytoma ♦♦ Primitive neuroectodermal tumor and Ewing sarcoma are in the same family and have the same ultrastructural features ♦♦ Rhabdoid tumor (renal and extrarenal) are loosely arranged collections of oval cells with irregularly shaped nuclei and large nucleoli

4-17

−− They are characterized by large paranuclear whorls of intermediate filaments and occasional tonofibrils −− They may be joined by rudimentary cell junctions ♦♦ Rhabdomyosarcoma (alveolar and embryonal) show occasional sarcomeres but usually demonstrate only disorganized myofilaments (Fig. 4.27) −− Thick (15  nm) myosin filaments with or without thin (6 nm) actin filaments are present sometimes in association with Z-band formation −− Thick filament–ribosomal complexes may be seen. Glycogen is frequently present in the cytoplasm −− Basal lamina surrounds individual cells in alveolar but not embryonal type ♦♦ Schwannoma and malignant peripheral nerve sheath tumor are composed of cells with spindle nuclei with heterochromatin and numerous interwoven cell processes surrounded by basal lamina −− They contain no unique cytoplasmic organelles but may be joined by primitive cell junctions −− Luse bodies (long-spacing type I collagen fibers) may be found in the matrix ♦♦ Seminoma and dysgerminoma are closely apposed large polygonal cells, held together by various cell junctions, most often desmosome-like −− They are characterized by large rope-like nucleoli within large nuclei −− They also contain abundant glycogen particles and scant organelles

Fig. 4.27. Rhabdomyosarcoma showing incomplete sarcomeres (arrowhead) with Z-band material (arrow). Inset shows high magnification of thick and thin filaments.

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♦♦ Sertoli cell tumor is composed of tubules lined by basal lamina with the cells joined by junctional complexes −− Charcot–Böttcher filaments are the characteristic finding −− Well-developed Golgi and lipid droplets are common ♦♦ Small cell carcinomas usually contain sparse neurosecretory granules ♦♦ Small cell carcinoma, ovarian hypercalcemic type differs in that no dense-core granules and no glycogen are found ♦♦ Squamous cell carcinoma (Fig.  4.17) is characterized by numerous well-formed desmosomes and tonofibrils −− Keratohyalin granules are present in well-differentiated carcinoma −− Filopodia between cells, occasionally joined by desmosomes, are the result of shrinkage artifact ♦♦ Synovial sarcoma may be biphasic −− The epithelial components are surrounded by basal lamina with the luminal side having microvilli and junctional complexes −− The spindle cells are closely apposed and rudimentary junctions are present between them −− Sparse collagen fibrils and dense stromal matrix are in the background ♦♦ Thymoma is characterized by epithelial components with squamous differentiation admixed with varying numbers of lymphocytes ♦♦ Urothelial carcinoma may be differentiated from other epithelial tumors by the presence of small invaginations of luminal cell membrane, and the presence of apical vesicles and filaments −− The cells are joined by desmosomes −− Interdigitating, microvillus-like filopodia are present on the lateral cell borders

Nonneoplastic Conditions ♦♦ Storage diseases often have cellular inclusions that are distinctive and may be determined by ultrastructural study. Most of these are related to defects in lysosomal enzymes resulting in an aberrant product stored in secondary lysosomes. A few examples are described below −− Ceroid lipofuscinosis is a group of neurologic disorders characterized by seizures and progressive intellectual and motor decline. They are now grouped by enzyme defects (a) The storage products may be seen in lymphocytes, peripheral nerve, endothelial cells and smooth muscle cells (b) Appropriate tissues for study are blood buffy coat, skin, or rectal biopsy (c) Inclusions include curvilinear bodies, fingerprint profiles, and granular osmiophilic deposits −− The mucopolysaccharidoses include such diseases as Hunter and Hurler syndromes (a) The inclusions are similar to myelin figures and are called zebra bodies (Fig. 4.28) (b) The inclusions may be found on liver biopsy

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Fig. 4.28. Myelin figures called zebra bodies in liver of patient with Hurler syndrome. −− Glycogen storage disease results from enzymatic defects in glycogen metabolism (a) Large amounts of glycogen particles accumulate in the liver and skeletal muscle with some forms also affecting the heart (b) In all cases, the large amounts of glycogen displace the remaining organelles (c) In some of the forms, specific packeting of the glycogen allows differentiation from other forms ♦♦ Myopathies may be studied by ultrastructural features −− The mitochondrial myopathies demonstrate increased numbers of mitochondria that are often unusually large and abnormally shaped, having abnormal cristae, and crystalloid inclusion bodies −− Inflammatory myopathies are characterized by reduplication of the basement membrane with extruded dark bodies ♦♦ Ciliary dyskinesia results in chronic respiratory tract infection due to the inability of the ciliated cells to clear noxious substances −− Respiratory epithelial cilia on cross-section show a pair of centrally located microtubules and nine pairs of doublets at the periphery (9+2 pattern). Outer and inner dynein arms extend from each doublet (Fig. 4.16) −− In primary ciliary dyskinesia (or immotile cilia syndrome), outer and/or inner dynein arms are completely or almost completely absent. Those males with this defect are infertile, and other patients may have Kartagener syndrome

Diagnostic Electron Microscopy

4-19

Fig. 4.29. Small intestine biopsy shows intracellular lumina called microvillus inclusions in microvillus inclusion disease. The surface microvilli may also be blunted.

♦♦ Microvillus inclusion disease is an inherited, autosomal recessive condition, presenting with intractable diarrhea and steatorrhea. It is usually fatal in 2 years and may resemble celiac sprue −− Abnormal microvilli are noted at the luminal aspect of the enterocyte −− Apical intracytoplasmic inclusions are lined by microvilli (Fig. 4.29) ♦♦ Epidermolysis bullosa is a group of bullous skin diseases that can be distinguished from one another by characteristic ultrastructural features −− The bullae in epidermolysis bullosa dystrophica occur below the lamina densa, and the anchoring fibrils are totally absent or markedly reduced −− The bullae in junctional epidermolysis bullosa lie in the lamina lucida, and the anchoring fibrils are normal ♦♦ A variety of infections may also be recognized by their ultrastructural appearance −− Viruses have characteristic appearances. Immunoelec­ tron microscopy may provide definitive identification of the virus. More commonly immunohistochemical or molecular genetic study (such as in situ hybridization) is needed (a) The ultrastructural features of viruses useful in classification include symmetry of the capsid, presence or absence of an envelope and the diameter of the virion or nucleocapsid (b) Most viral particles or virions are characterized by round, elliptical or strand-like structures having a central dense core (nucleoid) and an outer shell (capsid)

Fig. 4.30. CMV virus particles in cytoplasm of infected cell.

(c) Examples: Papovavirus (45–53  nm), Adenovirus (70–90 nm), Herpes (100–150 nm; simplex, Varicellazoster, Cytomegalovirus (Fig.  4.30), Epstein–Barr virus), Poxvirus (220–450  nm), hepatitis B virus (42 nm), human immunodeficiency virus (HIV, 100– 130 nm) −− Parasites, particularly those found in the gastrointestinal tract, may be definitively identified by their characteristic ultrastructural appearance (a) Giardia lamblia may be identified on light microscopy but show very interesting ultrastructural features including a sucker plate. They sit on the luminal surface of enterocytes (b) Cryptosporidium is a tiny parasite that is difficult to ascertain with certainty on light microscopy. These organisms also attach to the luminal surface of enterocytes and attach the cell surface (c) Microsporidium is an intracellular parasite that sporulates within the enterocyte. It may also infect other organs such as the kidney The readers are further referred to Chap. 34, Nonneoplastic Renal Diseases Acknowledgments  The author would like to thank Dr. MooHahm Yum and Mr. Michael P. Goheen for their chapter in the previous edition of this book that served as a model for the current version

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SUGGESTED READING Banerjee SS, Eyden B. Divergent differentiation in malignant melanomas: a review. Histopathol 2008;52:119–129.

Ghadially FN. Ultrstructural Pathology of the Cell and Matrix. 4th ed. London: Butterworths; 1997.

Bergmann R. Immunohistopathologic diagnosis of epidermolysis bullosa. Am J Dermatopathol 1999;21:185–192.

Goebel HH, Wisniewski KE. Current state of clinical and morphological features of human NCL. Brain Pathol 2004;14: 61–69.

Dickersin GR. Diagnostic Electron Microscopy. A Text/Atlas. 2nd ed. New York, NY: Springer-Verlag; 2000. Doane FW, Anderson N. Electron Microscopy in Diagnostic Virology. New York, NY: Cambridge University Press; 1987. Erlandson RA. Diagnostic Transmission Electron Microscopy of Tumors. New York, NY: Raven Press; 1994. Ghadially FN. Diagnostic Electron Microscopy of Tumors. 2nd ed. London: Butterworths; 1985.

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Kuo J. Electron Microscopy:Methods and protocols (Methods in Molecular Biology). Totowa, NJ: Humana Press; 2007. Plesac TP, Ruiz A, McMahon JT, et al. Ultrastructural abnormalities of respiratory cilia. Arch Pathol Lab Med 2008;32:1786–1792. Uematsu Y. The role of electron microscopy in the diagnosis of surgical pathology in the central nervous system. Med Mol Morphol 2006; 39:127–135.

5 Transplantation Pathology Oscar W. Cummings, md

Contents

I. Introduction����������������������������������������5-3

General Considerations������������������������������������5-3 Transplant Recipient Candidate������������5-3 Organ Donor��������������������������������������������5-3 Simplified Transplantation Immunology��������5-4 Cellular or T-Cell-Mediated Rejection����������������������������������������������5-4 Immunosuppression��������������������������������5-4 Humoral or Antibody (B-Cell)Mediated Rejection�����������������������������5-4 Complications Common to All Transplants����������������������������������������������������5-5 Infection����������������������������������������������������5-5 Neoplasia��������������������������������������������������5-6 Posttransplant Lymphoproliferative Disease��������������������������������������������������5-6 Rejection���������������������������������������������������5-8 Disease Recurrence����������������������������������5-9 Drug Toxicity��������������������������������������������5-9

II. Kidney Transplantation������������������������5-9 Indications for Transplantation�����������������������5-9 Clinical Considerations�������������������������������������5-9 Rejection�������������������������������������������������������������5-9 Kidney Biopsy for Rejection�������������������5-9 Banff Criteria�������������������������������������������5-9 Recurrent Disease��������������������������������������������5-13 Glomerulonephritis�������������������������������5-13 De Novo GN��������������������������������������������5-14 Drug Toxicity���������������������������������������������������5-14 Viral Infections������������������������������������������������5-15 BK Virus�������������������������������������������������5-15 Cytomegalovirus������������������������������������5-15 Acute Tubular Necrosis�����������������������������������5-15

Ureter Obstruction/Pyelonephritis����������������5-15 Vein Thrombosis����������������������������������������������5-15 Posttransplant Lymphoproliferative Disorder�������������������������������������������������������5-15

III. Heart Transplantation�����������������������5-16 Indication for Transplantation�����������������������5-16 Clinical Considerations�����������������������������������5-16 Rejection�����������������������������������������������������������5-16 Acute Cellular Rejection�����������������������5-16 Humoral Rejection��������������������������������5-17 Transplant Coronary Artery Disease (Cardiac Transplant Vasculopathy/ Chronic Rejection)����������������������������5-18 Other Biopsy Findings��������������������������5-19

IV. Lung Transplantation�������������������������5-21 Indication for Transplantation�����������������������5-21 Clinical Considerations�����������������������������������5-21 Rejection�����������������������������������������������������������5-21 Acute Cellular Rejection�����������������������5-21 Chronic Rejection����������������������������������5-22 Early Posttransplant Changes������������������������5-24 Diffuse Alveolar Damage����������������������5-24 Cryptogenic Organizing Pneumonia (BOOP)����������������������������������������������5-24 Infection�����������������������������������������������������������5-25 Posttransplant Lymphoproliferative Disorder���������������������������������������������5-25 Recurrent Disease��������������������������������������������5-25

V. Liver Transplantation�������������������������5-25 Indication for Transplantation�����������������������5-25 Clinical Considerations�����������������������������������5-25

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_5, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Rejection�����������������������������������������������������������5-26 Acute Rejection��������������������������������������5-26 Banff Criteria�����������������������������������������5-28 Chronic Rejection����������������������������������5-28 Humoral Rejection��������������������������������5-28 Centrivenous Necrosis���������������������������5-29 Venous Outflow Tract Obstruction������5-29 Mechanical Bile Duct Obstruction����������������5-29 Hepatic Artery Thrombosis����������������������������5-29 Infection�����������������������������������������������������������5-30 Cytomegalovirus������������������������������������5-30 Adenovirus���������������������������������������������5-30 De Novo Autoimmune Hepatitis�����������5-30 Chronic Hepatitis of Transplantation���������������������������������5-30 Recurrent Disease��������������������������������������������5-31 Hepatitis B����������������������������������������������5-31 Hepatitis C����������������������������������������������5-31 Autoimmune Hepatitis��������������������������5-32 Primary Biliary Cirrhosis���������������������5-32 Primary Sclerosing Cholangitis������������5-32 Alcoholic Hepatitis and Nonalcoholic Steatohepatitis�����������������������������������5-33 Drug Effect�������������������������������������������������������5-33 Posttransplant Lymphoproliferative Disorder�������������������������������������������������������5-33

VI. Pancreas/Islet Cell Transplantation���5-33 Indication���������������������������������������������������������5-33 Clinical Considerations�����������������������������������5-33 Rejection�����������������������������������������������������������5-33 Other Disorders Seen in Allograft Pancreas Biopsies��������������������������������������������������������5-36

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Posttransplant Lymphoproliferative Disorder�������������������������������������������������������5-36

VII. Bone Marrow/Stem Cell Transplantation���������������������������������5-36 Indication for Transplantation�����������������������5-36 Clinical Considerations�����������������������������������5-36 Graft vs. Host Disease�������������������������������������5-36 Skin���������������������������������������������������������5-36 Gut����������������������������������������������������������5-37 Liver��������������������������������������������������������5-37 Lung��������������������������������������������������������5-39 Posttransplant Lymphoproliferative Disorder�������������������������������������������������������5-39

VIII. Small Bowel Transplantation�������������5-39 Indication for Transplantation�����������������������5-39 Clinical Considerations�����������������������������������5-39 Rejection�����������������������������������������������������������5-39 Chronic Rejection����������������������������������5-40 Infection�����������������������������������������������������������5-40 Preservation Injury�����������������������������������������5-44 Posttransplant Lymphoproliferative Disorder�������������������������������������������������������5-44

IX. Cornea Transplantation......................5-44 X. Other.................................................5-44 Face/Limb Transplantation����������������������������5-44 Xenotransplantation���������������������������������������5-44

XI. Suggested Reading.............................5-45

Transplantation Pathology

5-3

INTRODUCTION ♦♦ Organ failure is a common cause of death ♦♦ Prior to the modern era, organ transplantation failed because donor organs were quickly destroyed (rejected) by the recipient’s immune system – unless donor and recipient were identical twins ♦♦ With the advent of modern immune suppression, organ transplantation became feasible, creating a long waiting list for this life-saving procedure (Table 5.1)

General Considerations Transplant Recipient Candidate ♦♦ Waiting list for most organs is long and many patients die awaiting a suitable organ ♦♦ Good health except for the failed organ ♦♦ Rarely multiple organs can be transplanted together −− Heart and lung for congenital heart disease −− Pancreas and kidney together for type 1 diabetes −− Small intestine and other abdominal organs for functional short gut and subsequent total parenteral nutrition (TPN) induced liver injury ♦♦ Age is not a definite excluding factor in the USA −− However, it may be technically impossible to perform the surgery on small premature infants −− Older patients (>70 years old) often have multiple diseased organs that may exclude them from consideration ♦♦ Cardiac, pulmonary, liver, renal function assessed for adequacy

♦♦

♦♦ ♦♦

♦♦

♦♦

♦♦ ♦♦

♦♦

−− Significant multiorgan disease may disqualify someone from transplantation High grade malignancy, e.g., metastatic colon cancer, a general contraindication to transplantation because of cancer recurrence and death HIV infection is considered on a case by case basis – more feasible now with better HIV therapy Significant previous surgery at the allograft site may have induced adhesions or altered anatomy such that a transplant cannot be performed Primary amyloidosis is a general contraindication to transplant as it quickly recurs in the allograft −− Some exceptions for hereditary amyloid where liver/ cardiac transplant can be life prolonging Must be psychosocially appropriate – patient must be able to assist in one’s own care, take medications, return for followup visits, etc −− Family support is crucial to the success of the transplant −− Social workers and psychologists are integral members of the transplant team Suitable transplant candidates are placed on waiting list Factors affecting length of time on the waiting list may include availability of organ, tissue match, blood type, immune status, disease acuity, and the distance between the potential recipient and the donor Heart, liver, and intestine patients – sickest transplanted first

Organ Donor Table 5.1. Patients Awaiting Organs in the United States, from Indiana Organ Procurement Organization (IOPO, http:// www.iopo.org) Patients awaiting transplants in the USA 2009 Heart Heart/lung Lung Liver Kidney Kidney/pancreas Pancreas Intestine Total patientsa

2,821 84 1,902 15,780 79,901 2,222 1,495 216 102,031

The total may not sum correctly as some patients are in multiple categories

a

♦♦ Donor suitability – healthy (no viral infections, no rapid onset dementia, no high grade malignancy), “normal” organs ♦♦ Donations facilitated by United Network for Organ Sharing (UNOS, http://www.unos.org – transplant survival data by organ and transplantation center), which divides the USA into 11 regions −− The goal is to reduce organ preservation time, improve organ quality and survival outcomes, reduce costs incurred, and provide governance of the process at a local level ♦♦ Harvested organs distributed in region first ♦♦ If no suitable recipient in region, offered nationwide ♦♦ In general, organs are harvested from brain-dead donors and perfused with Wisconsin solution (proprietary) to prolong extracorporeal usefulness ♦♦ Heart and lung have short “shelf life” of 8−10 h; liver and kidney up to 24 h ♦♦ Organ and donor are assessed for blood group system (ABO), HLA and screened for antibody incompatibility, lymphocyte cross match (serum from the recipient)

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−− Depending on the organ and the clinical situation, some or all of these factors may not enter into a decision to use the organ in a particular patient −− Other criteria may also be important, i.e., size and weight depending on the organ

Simplified Transplantation Immunology Cellular or T-Cell-Mediated Rejection ♦♦ The major histocompatibility complex (MHC) of the immune system that governs “self vs. other” resides in three loci on chromosome 6 – the human leukocyte antigens (HLAs) ♦♦ These HLA loci are inherited in a Mendelian dominant fashion; each person with two haplotypes ♦♦ Class I MHC antigens are present on the surface of all nucleated cells ♦♦ The Class I antigen is composed of three alpha chains (coded by genes HLA-A, HLA-B, and HLA-C) noncovalently bound to beta2-microglobulin ♦♦ Class II antigens are found on activated T-cells, monocytes, macrophages, Langerhans cells, dendritic cells, endothelium – antigen-presenting cells (APCs) and certain other cells ♦♦ Class II antigens are a heterodimer composed of an alpha and a beta chain coded by the HLA-D region ♦♦ Both Class I and II molecules contain peptide-binding sites ♦♦ The allograft activates recipient T-cells via direct and indirect allorecognition ♦♦ Direct allorecognition – donor APC cells migrate to recipient lymphoid organs and interact with recipient T-cells ♦♦ Indirect allorecognition – recipient APC cells bind donor antigen and interact with the T-cells −− Natural killer (NK) cells also play a role in the process of allograft destruction but work through a somewhat different pathway ♦♦ T-cell activation steps −− Step 1: APC cell binds to the T-cell receptor on the T-cell −− Step 2: “Costimulation” by other cells surface antigens (CD28, CD40, CD40L, B71, B72) required for activation (a) Lack of costimulation results in anergy −− Step 3: Binding of the APC cell to the T-cell receptor with costimulation increases intracellular calcium via tyrosine kinase pathways in the T-cell −− Step 4: Increased intracytoplasmic calcium levels activate calcineurin −− Step 5: Activated calcineurin dephosphorylates nuclear factor for activated T-cells (NFATs), which is then transported into the nucleus −− Step 6: NFAT binds to the IL-2 promoter increasing the synthesis of IL-2 −− Step 7: Increased IL-2 causes increased DNA synthesis by binding to IL-2 receptors and recruits additional T-cells ♦♦ NK cells and activated T-cells destroy the allograft (cellular rejection)

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Immunosuppression ♦♦ Many immunosuppressive agents appear to interfere with T-cell activation or proliferation, thereby inducing temporary tolerance of the graft ♦♦ Common agents include −− OKT3, antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) (a) Interferes with step 1 (above) (b) Can induce serum sickness; induce antibodies −− Corticosteroids (a) Block step 6 (b) Numerous side effects (glucose intolerance, osteoporosis etc.) −− Calcineurin inhibitors: cyclosporin A, tacrolimus (FK506) (a) Blocks step 4 (b) Nephrotoxic −− Azathioprine (a) Blocks step 7 (adenosine synthesis) (b) Causes bone marrow suppression −− Mycophenolate mofetil (a) Blocks step 7 (guanine synthesis) (b) Causes bone marrow suppression (c) Can produce gastrointestinal (GI) symptoms including diarrhea (d) Colonic biopsies of mycophenolate toxicity may show inflammatory bowel disease-like inflammation or crypt apoptosis (graft vs. host disease (GVHD)-like changes) −− Rapamycin (Sirolimus) (a) Blocks step 7 (IL-2-driven cell cycle progression) (b) May induce bone marrow suppression −− Basiliximab, daclizumab, etc (a) Block late step 7 (b) Anti-IL-2 receptor antibodies −− Alemtuzumab (a) Binds to CD52 on both T-cells and B-cells leading to marked depletion of these cell types ♦♦ A combination of immunosuppressive agents is usually employed, idiosyncratic to the institution and the organ ♦♦ Immunosuppression is a careful balancing act – too little immunosuppression leads to graft destruction – too much immunosuppression leads to uncontrollable opportunistic infection or viral reactivation [cytomegalovirus (CMV), human papillomavirus (HPV), Epstein–Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), etc.] in infected individuals

Humoral or Antibody (B-Cell)-Mediated Rejection ♦♦ Contact with alloantigens (transfusion, pregnancy, transplantation) may produce alloantibodies leading to humoral rejection

Transplantation Pathology

♦♦ Hyperacute rejection −− In the case of strong preformed antibodies, such as an ABO incompatibility, there is almost immediate graft failure −− In this situation, the antigen–antibody complex deposits diffusely in the microvasculature triggering complement activation leading to thrombosis, recruitment of neutrophils, congestion, edema, and graft dysfunction ♦♦ Acute (subacute) rejection −− However, weaker antigen–antibody interactions can occur days to several months later −− The process is similar but tends to be patchier −− Small arterioles are also affected ♦♦ Chronic (late) rejection −− Most of the alloantibodies are directed against HLArelated antigens −− However, recently, there has been evidence to suggest that some chronic (late) humoral rejection may be related to non-HLA antigens such as vimentin and type V collagen −− The main endothelial damage tends to affect moderatesized arteries and arterioles −− As these vessels become occluded (so-called transplant vasculopathy) the graft becomes ischemic and dysfunctional ♦♦ Nonhyperacute rejection −− Detection of nonhyperacute humoral rejection can be difficult −− The histologic changes are often subtle with slight neutrophil margination and endothelial swelling −− Damage to larger vessels may not be detectable in small samples such as biopsies −− Circulating antibody–antigen complexes can be detected by a number of methods including lymphocytotoxicity assays, flow cytometry, ELISA assays, and a Luminex solid phase assay −− After the antibody–antigen complex binds to the endothelium, the complement cascade is triggered (Fig. 5.1) −− Two complement breakdown products, C4d and C3d, become covalently attached to the injury site −− Immunofluorescence studies on fresh tissue can identify immunoglobulin and complement in the vessels as a marker of humoral rejection (a) C4d can be detected by immunoperoxidase methods using formalin-fixed paraffin-embedded tissue as well as fresh tissue (b) It has been touted as a good marker of humoral rejection in the kidney and heart, in general practice ♦♦ Therapy for humoral rejection is evolving but suboptimal −− Usually the dosages of standard immunosuppressive drugs are increased and the patient under goes plasmapheresis −− The addition of rituximab to this regimen may be beneficial but further investigations are ongoing

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Fig. 5.1. Schematic of compliment activation after antibody binds to endothelium in humoral rejection. The dark lines indicate entities that mediate the reaction. § indicates tissue bond entity. Reprinted with permission from College of American Pathologists, Truong et al. 2007. ♦♦ There is hope that after an unknown period of time immunosuppression may no longer be needed because of graft tolerance or chimerism

Complications Common to All Transplants Infection Nonopportunistic ♦♦ Identical in clinical and histologic findings to those seen in the nontransplant patient; common sites and agents include −− Pneumonia: Pseudomonas, Staphylococcus, Streptococcus, Enterobacteriaceae −− Sepsis: Staphylococcus, Enterobacteriaceae, Pseudomonas, Enterococcus, anaerobes −− Wound infection: Staphylococcus, Pseudomonas, Entero­ coccus, Enterobacteriaceae, anaerobes, mixed flora −− Urinary tract: Enterococcus, Enterobacteriaceae, Pseudomonas

Opportunistic ♦♦ Virus −− Cytomegalovirus (a) Most common infection after transplantation (b) ~80% adult population exposed to and harbor latent virus * All transplant patients are given prophylactic antiviral therapy (c) Typically noted 30+ days after the transplant (d) Classic nuclear enlargement with intranuclear and cytoplasmic inclusions (Fig. 5.2) (e) Present with graft dysfunction, possibly fever

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Fig. 5.2. Cell with nuclear enlargement and classic CMV nuclear and cytoplasmic inclusions in gastric mucosa. Inflammatory reaction to the virus is variable with little inflammation seen here. Levels into the block are helpful. If only the nuclear inclusions are noted, it might be confused for Herpes or adenovirus. If only the cytoplasmic inclusions are found, may be confused with toxoplasma. (f) Culture, immunohistochemistry or molecular methods may aid diagnosis (g) Occurs in the graft itself or nontransplanted organs (h) Treated with Ganciclovir or other antiviral agents and lowered immunosuppression −− Adenovirus (a) Most common in children but can be seen in adults (b) Classic intranuclear inclusions (c) Usually seen in gut, liver, or lung −− Herpes viruses (a) Classic intranuclear inclusions (Fig. 5.3A, B) (b) Brain, skin, and liver are most commonly affected −− Epstein–Barr virus (a) Common virus, >50% of the adult population exposed and harbor latent virus (b) EBV-negative donor organ matched to negative recipient to prevent posttransplant lymphoproliferative disease (c) In situ hybridization (EBER) employed for detection ♦♦ Protozoan −− Pneumocystis (a) Classic pulmonary histology (Fig. 5.4A, B) treated in the usual fashion. Most transplant patients are given prophylactic treatment to prevent infection −− Toxoplasmosis (a) Inflammatory infiltrates may be seen in heart, lung, brain associated with classic cytoplasmic inclusions (Fig. 5.5) ♦♦ Fungi −− Candida (a) Can involve any site

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Fig. 5.3. (A) Liver with classic herpes hepatitis. Only ground-glass nuclear inclusions with little or no nuclear enlargement are seen with this virus. (B) Ultrastructural examination of the liver shows classic targetoid particles of herpes virus. This technique is useful is distinguishing Herpes inclusions from adenovirus inclusions. (b) Classic pseudohyphae well visualized with silver stain (GMS) or PAS −− Aspergillus (a) Angioinvasive hyphae often presents with infarction of involved organ

Neoplasia Condyloma ♦♦ Immunosuppression causes increased viral proliferation ♦♦ Condylomas very common – HPV

De Novo Carcinogenesis ♦♦ De novo carcinogenesis is also common ♦♦ Cutaneous squamous cell carcinoma most common ♦♦ Kaposi sarcoma

Posttransplant Lymphoproliferative Disease ♦♦ PTLD is a lymphoid and plasma cell proliferation that develops in immunosuppressed patients most commonly secondary to EBV infection

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Fig. 5.5. Toxoplasma cyst from the brain from a 7-year-old child status post bone marrow transplant for acute lymphocytic leukemia (ALL).

Early (Plasma Cell Hyperplasia and Mononucleosis-Like) Fig.  5.4. (A) Lung with classic foamy alveolar exudates and slight chronic inflammation of the interstitium consistent with Pneumocystis. (B) Gomori methenamine silver (GMS) stain of Fig. 5.4A showing classic Pneumocystis cysts.

♦♦ The disease incidence is difficult to quantitate because of variability due to organ type, patient age, and immunosuppression regimen ♦♦ The general incidence is between 1 and 5%, more common in children and patients on high immunosuppression regimens such as small bowel allografts ♦♦ The most important predisposing factor is seronegativity for EBV at the time of transplantation ♦♦ The majority of PTLD in solid organ transplant patients is donor derived; however, in bone marrow transplant (BMT) patients, the reverse is true ♦♦ The allograft itself may be involved although this is uncommon in heart transplant patients ♦♦ Nonallograft organ involvement may be seen including lung, liver, GI tract, spleen, lymph nodes, and central nervous system −− It may be multifocal −− Most commonly in BMT patients ♦♦ PTLD may be divided into three major types, early, polymorphous, and monoclonal

♦♦ Early type is seen largely in children and seronegative adults representing their first EBV infection ♦♦ It presents with fever, pharyngitis, and lymphadenopathy generally reflecting the location of the lesion ♦♦ The tonsils, adenoids, and nodes are enlarged but the underlying architecture is preserved ♦♦ Histology exhibits numerous plasma cells, lymphocytes, and occasional immunoblasts or paracortical expansion with numerous immunoblasts in a background of T-cells and plasma cells ♦♦ Usually EBV and a polyclonal B-cell immunophenotype can be demonstrated ♦♦ The lesion responds favorably to decreased immuno­ suppression

Polymorphous ♦♦ Polymorphous variant is usually seen within the first year after solid organ transplantation, 6 months for BMT ♦♦ Presentation is variable, sometimes with mass effect and or graft dysfunction −− Systemic symptoms may or may not be present ♦♦ It may occur in the graft itself or in nongrafted sites; bone marrow involvement is rare ♦♦ Polymorphous PTLD histology demonstrates a dense polymorphous mononuclear infiltrate with prominent immunoblasts often exhibiting easily found mitotic figures and plasma cells effacing the underlying architecture (Fig. 5.6) ♦♦ The infiltrate should not be characteristic of a classic lymphoma type

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Fig. 5.6. Enlarged lymph node showing a pleomorphic infiltrate including numerous plasma cells and large plasmacytoid cells with scattered immunoblasts consistent with polymorphous PTLD. Immunostaining for EBV was positive (not shown).

♦♦ EBV can be demonstrated by culture, immunohistochemistry, or molecular techniques in most cases (>70%) ♦♦ Flow cytometry, genomic analysis, or immunohistochemistry shows a predominantly polyclonal B-cell proliferation ♦♦ The large atypical cells may be CD30-positive but lack CD15 ♦♦ Late lesions (4+ years after transplantation) are more likely to be EBV-negative ♦♦ HHV-8 has been identified in some of these EBV-negative cases ♦♦ Polymorphous PTLD often responds to lowered immunosuppression; however, the mortality may still run 20–40%

Monoclonal ♦♦ Monoclonal variant of PTLD usually presents as a mass involving the graft itself or in a nongrafted site ♦♦ Histology of the lesion shows a dense monotonous mononuclear infiltrate that effaces the architecture reminiscent of typical B-cell lymphomas (Fig. 5.7) ♦♦ The B-cell tumors are usually diffuse high grade lesions but T-cell lymphomas can also be seen ♦♦ EBV is less easily demonstrated than in the above-mentioned types ♦♦ Flow cytometry and/or immunohistochemical studies typically show a monoclonal B-cell proliferation but gene rearrangement studies may be needed if it is a T-cell lesion ♦♦ Treatment consists of lowered immunosuppression and lymphoma chemotherapy but the mortality can be as high as 70–%

Variants ♦♦ Some authors include a rarely seen Hodgkin-like variant ♦♦ Non-EBV-driven lymphomas can also develop

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Fig. 5.7. Colon mass showing a diffuse, relatively monotonous infiltrate of large atypical lymphocytes of PTLD lymphoma. Immunostaining for EBV was negative (not shown). −− They have the typical presentation and histology of lymphoma occurring outside the transplant milieu −− Lymphomas derived from mucosa-associated lymphoid tissue (MALT) should be placed in this category −− Outcome depends on the lymphoma type

Rejection ♦♦ General patterns

Hyperacute Rejection ♦♦ Immediate graft failure secondary to preformed antibodies ♦♦ Marked congestion – may see fibrin platelet thrombi in capillaries

Acute Cellular Rejection ♦♦ Seen first 7–10 days after transplant ♦♦ Organ dysfunction often clinically evident ♦♦ Mixed mononuclear infiltrate of lymphocytes, lymphoblasts, eosinophils attacking epithelial structures ♦♦ Endotheliitis – lymphocytes associated with and disrupting endothelium (usually with enlarged chromatic nuclei) of small veins may be seen ♦♦ Usually responds to increased immunosuppression ♦♦ Precursor to chronic rejection

Chronic Cellular Rejection ♦♦ Later occurrence but can be seen as early as 2 months posttransplant but usually one or more years later ♦♦ Severe organ dysfunction ♦♦ Mononuclear infiltrate associated with marked destruction, loss or fibrosis of epithelial structures ♦♦ Often associated with transplant arteriopathy ♦♦ Not easily treated, often results in graft failure

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Acute Vascular Rejection

♦♦ Usually associated with chronic cellular rejection ♦♦ Not easily treated, often seen in failed grafts

♦♦ Necrotizing or cellular vasculitis ♦♦ Usually associated with severe cellular rejection ♦♦ Responds poorly to therapy

Disease Recurrence

Chronic Vascular Rejection (Transplant Vasculopathy)

Drug Toxicity

♦♦ Diffusely involves moderate-sized arterioles ♦♦ Foamy intimal change ♦♦ Concentric fibromuscular proliferation with an intact internal elastica

♦♦ Organ dependent – see below ♦♦ Probable common cause of morbidity in the transplant patient ♦♦ Poorly recognized, a diagnosis of exclusion ♦♦ Osteoporosis, hypertension, and glucose intolerance (type 2 diabetes) are common side effects of immunosuppression

KIDNEY TRANSPLANTATION Indications for Transplantation

Banff Criteria

♦♦ Indications for transplantation are generally chronic renal failure produced by sundry injuries including hypertension, diabetes, glomerulonephritis (GN), etc

♦♦ Banff consensus scheme for evaluating renal transplant biopsies has evolved over time, the latest iteration provided in Table 5.2 −− It is a complex system mainly divided into humoral rejection, cellular rejection, and other based on evaluation of a number of subparameters ♦♦ Category 2: antibody-mediated changes −− “C4d deposition without morphologic evidence of active rejection” is a new category of antibody-mediated rejection (ABMR) −− In this category, the patient has circulating antibodies and C4d deposition in the graft but no other signs of

Clinical Considerations ♦♦ Cadaveric and living related donors used −− Living related organs fair slightly better (95% 1-year graft survival compared to 88% graft survival for cadaveric grafts) ♦♦ Allograft usually placed ectopically in the pelvic fossa ♦♦ Renal artery and vein anastomosed to iliac vessels; ureter tunneled into urinary bladder ♦♦ Native kidneys are usually left in situ except in adult polycystic kidney disease −− Infection and neoplasia risk −− May develop renal cell carcinoma ♦♦ Donor organ sometimes biopsied for evaluation of arteriolonephrosclerosis (Fig. 5.8) −− We report number of sclerotic glomeruli vs. the total number of glomeruli

Rejection Kidney Biopsy for Rejection ♦♦ Presents with elevation of creatinine 7–10  days or longer after transplantation ♦♦ Diagnoses by cutting needle biopsy obtained often with ultrasound guidance ♦♦ Formalin fixation generally adequate but frozen (for immunofluorescence) and glutaraldehyde-fixed specimens (for ultrastructure) may be obtained if disease other than rejection is suspected ♦♦ Five or more glomeruli considered adequate for diagnosis ♦♦ At least two H&Es plus connective tissue stains and PAS are typically evaluated

Fig. 5.8. Wedge biopsy of kidney prior to transplantation to evaluate extent of underlying disease. Capsule is seen in lower right corner. There is patchy interstitial fibrosis, intact and occasional senescent glomeruli and hyaline arteriolosclerosis. The organ was used successfully for transplantation.

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Table 5.2. Banff 2007 Consensus Classification of Renal Allograft Pathology 1. Normal 2. Antibody-mediated changes (may coincide with categories 3–6) Due to documentation of circulating antidonor antibody, and C4d or allograft pathology   C4d deposition without morphologic evidence of active rejection   C4d+, presence of circulating antidonor antibodies, no signs of acute or chronic TCMR or ABMR (i.e., g0, cg0, ptc0, no ptc lamination). Cases with simultaneous borderline changes or ATN are considered as indeterminate   Acute antibody-mediated rejection    C4d+, presence of circulating antidonor antibodies, morphologic evidence of acute tissue injury, such as (type/grade):      I. ATN-like minimal inflammation      II. Capillary and or glomerular inflammation (ptc/g > 0) and/or thromboses     III. Arterial – v3   Chronic active antibody-mediated rejection   C4d+, presence of circulating antidonor antibodies, morphologic evidence of chronic tissue injury, such as glomerular double contours and/or peritubular capillary basement membrane multilayering and/or interstitial fibrosis/tubular atrophy and/or fibrous intimal thickening in arteries 3. B  orderline changes: “Suspicious” for acute T-cell-mediated rejection (may coincide with categories 2, 5 and 6) This category is used when no intimal arteritis is present, but there are foci of tubulitis (t1, t2 or t3) with minor interstitial infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis 4. T-cell-mediated rejection (TCMR) (may coincide with categories 2, 5, and 6)   Acute T-cell-mediated rejection (type/grade):    IA. Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2)    IB. Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of severe tubulitis (t3)    IIA. Cases with mild-to-moderate intimal arteritis (v1)    IIB. Cases with severe intimal arteritis comprising >25% of the luminal area (v2)    III. Cases with “transmural” arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3)   Chronic active T-cell-mediated rejection:    “Chronic allograft arteriopathy” (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neo-intima) 5. Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology (may include nonspecific vascular and glomerular sclerosis, but severity graded by tubulointerstitial features) Grade    I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical area)    II. Moderate interstitial fibrosis and tubular atrophy (26–50% of cortical area)   III. Severe interstitial fibrosis and tubular atrophy/loss (>50% of cortical area) 6. Other. Changes not considered to be due to rejection – acute and/or chronic; may include isolated g, cg, or cv lesions and coincide with categories 2–5)

g =glomerulitis, cg =double contour glomerular loops, ptc =peritubular capillary, v =vasculitis, t =tubulitis, i =interstitial inflammation, cv =chronic vascular lesions. Grading for some of these lesions is provided in the text

−−

−−

−− −−

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humoral (ABMR) or cellular (TCMR) allograft rejection or injury Some examples of injury are given including no glomerulitis (g0), no double contour glomerular basement membranes (cg0), no peritubular capillary inflammation (ptc0) or laminations C4d deposition is considered to be present when more than 50% of the peritubular capillaries show positive staining via the immunoperoxidase method Arterial and venous staining is not considered The clinical significance of this category is unclear but its presence should be an indication for careful clinical followup

♦♦ ABMR −− “Acute ABMR” has three required elements: circulating antibodies, C4d deposition in the graft and manifestation of acute tissue injury −− The injury is grade based on the compartment involved (a) I for mild tubular changes (b) II for capillary and glomerular changes (c) III for arteritis −− Clinically, this may be correlated with two syndromes (a) In hyperacute (immediate) rejection when the graft is revascularized on the operating room table, it becomes dusky and fails to make urine

Transplantation Pathology

* There is no useful therapy available and it results in immediate graft loss because of preformed antibodies * It is an uncommon problem in the modern era but when seen it may have been due to inadvertent ABO incompatibility * There are now protocols to pretreat patients such that ABO-incompatible grafts survive almost as well as matched grafts (b) Delayed hyperacute (accelerated acute) rejection can also be seen * It occurs several hours to several days after the transplant, presents with increased creatinine and decreased urine flow; it may be reversible with appropriate treatment ♦♦ Chronic active ABMR −− “Chronic active ABMR” again has three required elements (a) Circulating antibodies (b) C4d deposition in the graft (c) Manifestation of chronic tissue injury −− Two out of the following four are needed to support the diagnosis (d) Arterial intimal fibrosis without elastosis (e) Duplication of glomerular basement membrane (f) Multilaminated PTC basement membrane (g) Interstitial fibrosis with tubular atrophy −− Chronic active ABMR presents with progressive loss of graft function (rising creatinine) over months to years, often with proteinuria and hypertension ♦♦ Category 3 and 4, T-cell-mediated rejection (TCMR) −− The borderline category is relatively self evident but is based on evaluating the extent of tubulitis (Table 5.3) and interstitial inflammation (a) Significant interstitial inflammation is defined as >25% of the parenchyma being inflamed (b) Borderline cellular rejection is tubulitis with insignificant interstitial inflammation or t1 tubulitis with significant interstitial inflammation

Table 5.3. Grading of Tubulitis (Applies to Nonatrophic Tubules) t0 t1 t2 t3

No mononuclear cells in the tubules Foci with 1–4 cells/tubular cross-section (or 10 tubular cells) Foci with 5–10 cells/tubular cross-section >10 cells/tubular cross-section or, the presence of at least two areas of basement membrane destruction accompanied by significant interstitial inflammation and t2 tubulitis elsewhere in the biopsy

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Table 5.4. Vasculitis Grading Scheme v0

No vasculitis

v1

Mild-to-moderate intimal arteritis in at least one arterial cross-section Severe intimal arteritis with at least 25% of crosssectional area lost in at least one arterial cross-section Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle necrosis with lymphocytic infiltrate in the vessel

v2 v3

−− Acute TCMR is divided into five subgrades (a) Grade I rejection shows significant interstitial inflammation with t2 tubulitis (grade IA) or t3 tubulitis (grade IB) (b) If arteritis is present, grades IIA, IIB, or III are ­reported depending on the grade of the vasculitis (Table 5.4) −− Chronic active TCMR refers to the chronic vasculopathy that is common to all transplant sites (a) It may have a significant humoral component as well ♦♦ Category 5, interstitial fibrosis, tubular atrophy and category 6, other acute or chronic injuries refers to fibrosis and/or degenerative changes that do not appear to be due to rejection but may be related to hypertension, diabetes or other disorders −− The term chronic transplant nephropathy/glomerulopathy has been supplanted by more specific diagnoses such as chronic ABMR or others as the histology dictates ♦♦ The rejection grades themselves are somewhat difficult to illustrate in a limited space because of the many permutations of the main categories 2–5 −− Some features of classic cellular rejection are shown in Fig. 5.9A–F −− Figure 5.9A illustrates significant interstitial inflammation −− If coupled with t2 tubulitis (Fig. 5.9B), the patient would have T-cell-mediated acute cellular rejection IA −− If C4d were also present (Fig. 5.9C), it would be both cellular and humoral rejection −− If the interstitial inflammation and tubulitis were coupled with v1 arteritis, (Fig. 5.9D) the patient would have grade IIA cellular rejection −− Interstitial fibrosis and tubular atrophy can bee seen in Fig. 5.9E ♦♦ Other nonrejection related pathology −− Nonrejection mediated medial arterial changes can be seen in Fig. 5.9F −− The glomerulus is abnormal and needs to be evaluated further with specials stains, immunofluorescence, or ultrastructural examination

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Fig. 5.9. (A) Allograft kidney showing an interstitial edema and a mononuclear cell infiltrate occupying >25% of the parenchyma, a significant interstitial infiltrate. (B) Allograft kidney showing 5–10 mononuclear inflammatory cells infiltrating the tubular epithelium – t2 tubulitis. (C) Immunoperoxidase stain for C4d showing positive staining in peritubular capillaries consistent with antibody-mediated rejection. (D) An arteriole with endothelial and mural inflammation, a v1 vasculitis. (E) Kidney allograft with chronic interstitial inflammation and fibrosis. The glomeruli also appear to show loop abnormalities. Without additional information one cannot distinguish chronic rejection from recurrent or de novo glomerulonephritis. (F) Arteriosclerosis is seen here with a background of interstitial inflammation and fibrosis. This was a hypertension-related lesion.

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Fig. 5.10. (A) PAS stain highlighting the double contour glomerular capillary loops. (B) Silver stain (Jones) showing similar findings. −− Figure  5.10A, B shows glomerular double-contoured loops that must be interpreted in context of the rest of the biopsy

Recurrent Disease Glomerulonephritis ♦♦ Recurs in 5–20% of allografts, causing graft failure in −− <10% −− Variable timing, months to years after transplant −− Often present with proteinuria, hematuria, and renal insufficiency −− Requires immunofluorescence and ultrastructural examination to diagnose accurately – same criteria for diagnosis as in native kidney

IgA Nephropathy (Fig. 5.11A, B) ♦♦ Recurs 3 months and later after transplant ♦♦ 25–60% incidence of recurrence

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Fig. 5.11. (A) Allograft kidney with a glomerulopathy from a patient originally transplanted for IgA nephropathy. (B) Immuno­ fluorescence for IgA on kidney indicating recurrent IgA nephropathy.

Necrotizing Crescentic GN (Wegener Granulomatosis, Microscopic Polyangiitis) ♦♦ Clinical factors (cANCA, pANCA levels, disease subtype, type of transplant) are not useful for predicting recurrent disease ♦♦ Recurrence seen in up to 18%

Antiglomerular Basement Membrane (Anti-GBM) Disease ♦♦ 50% recurrence rate when anti-GBM antibodies in serum ♦♦ 5–15% recurrence rate when serum cleared of anti-GBM antibodies for more than 6 months

Hemolytic Uremic Syndrome ♦♦ Clinical presentation of recurrence gradual or abrupt ♦♦ Thrombocytopenia, hemolysis, progressive renal dysfunction ♦♦ 30% recurrence rate with poor graft survival after recurrence

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Focal Segmental Glomerulosclerosis ♦♦ Recurrence is typically early with a mean 14  days after transplant ♦♦ Proteinuria, hypertension, increased creatinine ♦♦ 20–30% recurrence in first transplant with 40–50% graft loss ♦♦ 75% recurrence in subsequent transplant, if initially lost to recurrent disease

Membranous GN ♦♦ ~30% recurrence rate

Essentials of Anatomic Pathology, 3rd Ed.

−− Presents with increased creatinine −− Minimal interstitial inflammation −− Nodular, new onset, arteriolar hyaline change is suggestive of toxicity (Fig. 5.12) −− Also vacuolization of smooth muscle cytoplasm in arteriole wall (Fig. 5.13) ♦♦ Antibiotics, etc −− Variable interstitial infiltrate often with eosinophils (Fig. 5.14)

Membranoproliferative GN ♦♦ Type I: underlying circulating immunocomplexes usually persist after transplant −− 20–30% recurrence with 40% graft loss, higher with subsequent grafts −− HLA-matched grafts said to be more susceptible to recurrence ♦♦ Type II: recurs in 50–100% of grafts −− Presents after 1 year posttransplant with hematuria and proteinuria

Lupus Nephritis ♦♦ ♦♦ ♦♦ ♦♦

<10 % recurrence rate, all pattern types recur Usually seen 3 or more years after transplantation Diabetic changes often recur, typically >1 year after transplant Present with progressive renal dysfunction typically without or only mild proteinuria

De Novo GN ♦♦ Uncommon, when seen, often membranous GN

Fig. 5.13. Small arteriole from an allograft kidney showing vacuolization of the smooth muscle cytoplasm within the wall of the vessel. This finding is suggestive of calcineurin inhibitor toxicity. Note the lack of an interstitial infiltrate.

Drug Toxicity ♦♦ Cyclosporine or FK506 toxicity

Fig.  5.12. Small arteriole from an allograft kidney showing intramural hyaline globule consistent with calcineurin inhibitor toxicity. Note the lack of an interstitial infiltrate.

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Fig. 5.14. Interstitium of a renal allograft expanded by a mononuclear infiltrate including numerous macrophages and eosinophils. Some tubular damage is present. The patient presented with creatinine elevation, which resolved with discontinuation of antibiotic therapy – a drug toxicity.

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Viral Infections BK Virus ♦♦ Small nonenveloped double-stranded DNA virus of the polyomavirus family ♦♦ Latent infection present in at least 50% of the population ♦♦ Usual onset within 3 months posttransplant but can be seen years later ♦♦ Present with graft dysfunction ♦♦ Histology shows polymorphous interstitial infiltrate associated with tubulitis mimicking rejection (Fig. 5.15) ♦♦ Characteristic ground glass to lavender intranuclear inclusions often associated with nuclear enlargement of the tubular epithelium ♦♦ Virus can be confirmed with immunohistochemistry (Fig. 5.16), or ultrastructural examination ♦♦ Treated with decreased immunosuppression

Cytomegalovirus

Fig. 5.16. Immunoperoxidase-type staining using antibodies to the BK virus on the same patient as seen in Fig. 5.15. The nuclear inclusions are nicely highlighted.

♦♦ Typically seen starting 30 days after transplant ♦♦ Presents with graft dysfunction ♦♦ Histology shows polymorphous interstitial infiltrate associated with tubulitis may mimic rejection ♦♦ Characteristic nuclear enlargement with prominent intranuclear and cytoplasmic inclusions ♦♦ Inclusions may be found in the tubular epithelium, endothelial cells in veins and glomerular capillaries and in stromal cells

Acute Tubular Necrosis ♦♦ Seen early after transplant, consistent with preservation effect (Fig. 5.17)

Fig.  5.17. A kidney allograft several days after implantation showing enlarged tubular nuclei with scattered mitotic figures consistent with recovering ATN. ♦♦ May be seen late as a manifestation of hypotension or drug effect

Ureter Obstruction/Pyelonephritis ♦♦ Common, variable timing ♦♦ Presents with fever, increased creatinine, pyuria ♦♦ Interstitial infiltrate of neutrophils with edema Fig. 5.15. An allograft kidney with a mild-to-moderate interstitial infiltrate. Two tubules exhibit enlarged nuclei with amphophilic nuclear inclusions very suggestive of BK virus infection. Some tubular damage is present which might be errantly diagnosed as rejection if the viral inclusions were not noted.

Vein Thrombosis ♦♦ Interstitial edema and marked congestion

Posttransplant Lymphoproliferative Disorder ♦♦ Patients with kidney transplants have the lowest incidence, <1%

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♦♦ In the allograft the atypical, interstitial, B-cell, mononuclear infiltrate with mitotic figures must be differentiated from rejection

♦♦ EBV often can be demonstrated (EBER) ♦♦ Treatment is typically decreased immunosuppression

HEART TRANSPLANTATION Indication for Transplantation ♦♦ Chronic severe heart failure due to multiple causes including coronary artery disease, myocardial infarction, myocarditis, congenital malformations, etc

Clinical Considerations ♦♦ Contraindications to transplantation −− Malignancy −− Active infection (HIV) −− Amyloidosis ♦♦ Cadaveric organs are ABO matched to donor ♦♦ Orthotropic transplant −− Recipient atria (with cavae and pulmonary veins) are anastomosed to donor atria creating slightly enlarged composite atria −− Donor aorta above the level of the coronaries anastomosed to recipient aorta −− Donor pulmonary artery to recipient pulmonary artery

Rejection Acute Cellular Rejection ♦♦ Acute cellular rejection first occurs 7–10  days after transplantation ♦♦ May present with elevated right side heart pressures and or malaise ♦♦ No clinical parameter correlates well with rejection, but right-sided pressures and EKG abnormalities may be an indication of rejection −− Usually right-sided myocardial biopsy are performed at regular intervals (protocol biopsies) to look for rejection ♦♦ A minimum of three formalin-fixed myocardial fragments are considered adequate for evaluation −− Three H&E-stained levels should be examined −− No special stains are required, but special stains may be used as needed, i.e., C4d ♦♦ Consensus criteria for diagnosis of rejection were initially developed by a multi-institutional panel of experts convened under the auspices of the International Society for Heart and Lung Transplantation (ISHLT) in 1990 −− After many years of use and followup, the system was revised (Table 5.5) to incorporate this experience ♦♦ The original cardiac rejection grading system from 1990 was more complex with multiple subgrades

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−− This system is still in use in some institutions, so Table 5.6 is provided to allow comparison with the old system −− It is immediately apparent that the current system has shrunken from four major grades to three and that all the subgrades have been eliminated −− The grading system is relatively easy to apply (a) Focal small infiltrates both perivascular or interstitial with or without minimal myocyte damage are 1R (Fig. 5.18) −− In the past a single focus of aggressive appearing mononuclear cells was difficult to classify (a) It may have represented rejection or penetrating Quilty effect (described below) (Fig. 5.19) (b) We cut multiple additional levels to see if there is a connection to a surface Quilty lesion; if not, 1R rejection

Table 5.5. Revised ISHLT Consensus Grading System for Cardiac Rejection 2005 Grade 0 R

No rejection

Grade 1 R, mild myocyte damage Grade 2 R, moderate damage Grade 3 R, severe

Interstitial and/or perivascular infiltrate with up to one focus Two or more foci of infiltrate with associated myocyte Diffuse infiltrate with multifocal myocyte damage, +/− edema, +/− hemorrhage, +/− vasculitis

The R denotes the revised system to avoid confusion with the old grading system.

Table 5.6. Comparison of the Current and Previous ISHLT Grading Systems Current classification

Description

Grade 0R

None

Grade 1R Grade 2R Grade 3R

Mild Moderate Severe

1990 Classification Grade 0 Grade 1A, Grade 1B, Grade 2 Grade 3A Grade 3B, 4

Transplantation Pathology

Fig. 5.18. Allograft heart showing two small perivascular infiltrates characteristic of grade IR acute cellular rejection.

Fig. 5.19. A single moderately dense lymphocytic infiltrate that was difficult to grade in the old system. One should examine multiple levels though a lesion like this to exclude the possibility of tangentially cut Quilty effect. If no Quilty can be identified, then a diagnosis of grade 1R cellular rejection is appropriate. −− Multifocal aggressive infiltrates with focal myocyte damage is grade 2R (Fig. 5.20) −− A diffuse inflammatory process with multifocal necrosis or arteritis is 3R (Fig. 5.21) −− Treatment for acute cellular rejection is institution specific (a) At our institution, in adults, grade 2R and above rejection is treated with increased immune suppression, grade 1R is generally not treated

Humoral Rejection ♦♦ The incidence and diagnosis of humoral rejection is somewhat controversial ♦♦ Hyperacute rejection has been well described but is uncommon

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Fig.  5.20. Diffuse lymphocytic interstitial infiltrate that was noted in all five fragments in the biopsy specimen consistent with moderate acute rejection, 2R.

Fig. 5.21. A diffuse interstitial infiltrate associated with extensive myocyte necrosis a feature of severe 3R rejection, grade 3B in the old grading system.

−− Graft becomes dusky and ceases pumping immediately after revascularization −− Due to preformed antibodies producing microvascular injury, i.e., ABO incompatibility −− Histology shows marked congestion, endothelial swelling (Fig. 5.22A), fibrin platelet thrombi may be present −− Immunofluorescence shows immunoglobulin and complement deposition in capillaries (a) C4d deposition may (Fig.  5.22B) or may not be seen (b) The criteria for a positive C4d are not well established but staining of more than 50% of the capillaries could be supported by the literature (c) Staining in veins and arterioles should not be interpreted as positive

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Table 5.7. Scheme for Evaluating Cardiac Antibody-Mediated Rejection (AMR) 1. Histologic evidence of acute capillary injury (a and b are required) (a) Capillary endothelial changes: swelling or denudation with congestion (b) Macrophages in capillaries (c) Neutrophils in capillaries (more severe cases) (d) Interstitial edema and/or hemorrhage (more severe cases) 2. Immunopathologic evidence for antibody-mediated injury (in the absence of OKT3 induction) a or b or c are required (a) Ig (G,M, and/or A) + C3d and/or C4d or C1q (equivalent staining diffusely in capillaries, 2–3+), demonstrated by immunofluorescence (b) CD68 positivity for macrophages in capillaries (identified using CD31 or CD34), and/or C4d staining of capillaries with 2–3+ intensity by paraffin immunohistochemistry (c) Fibrin in vessels (optional; if present, process is reported as more severe)

Fig. 5.22. (A) A protocol endomyocardial biopsy 2 months after transplantation showing dilation of small vessels with swollen endothelium and prominent nuclei suggesting humoral rejection. (B) An immunoperoxidase stain, employing anti-C4d, of the biopsy shown in A, exhibits diffuse capillary staining consistent with humoral rejection.

−− Acute humoral rejection, onset within days to months after transplantation, and chronic humoral rejection, with an onset 6 months to years after transplantation, have also been reported (a) Initial studies were poorly controlled and lacked precise definitions (b) A recent report employing strict definitions, serology and immunofluorescence found a 4% incidence of humoral rejection over a 10-year period (c) 65% of the cases of humoral rejection were late in onset (d) Criteria for the diagnosis of cardiac humoral rejection are shown in Table 5.7 ♦♦ If the changes noted in part 1 of Table  5.7 are seen in the biopsy, it is suggested that additional immunologic studies, elaborated in part 2, be performed to confirm the diagnosis

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−− It should be noted that although graft dysfunction is likely a late manifestation humoral rejection, it is usually present −− The clinical significance of humoral rejection without graft dysfunction is unclear ♦♦ Serologic evidence of anti-HLA class I and/or class II antibodies or other antidonor antibody (e.g., non-HLA antibody, ABO) at time of biopsy (supports clinical and/or morphologic findings) is also an important indicator of cardiac humoral rejection ♦♦ Mixed cellular and humoral rejection may also occur ♦♦ As noted in other systems, treatment is difficult including increased immunosuppression and plasmapheresis

Transplant Coronary Artery Disease (Cardiac Transplant Vasculopathy/Chronic Rejection) ♦♦ ~10% of heart transplant patients develop clinically significant vessel disease ♦♦ Risk factors include acute rejection, CMV infection, hyperlipidemia, and glucose intolerance ♦♦ The etiology of arteriopathy is not completely known, but combination of cellular and humoral injury seems likely ♦♦ Early: foamy endothelial changes ♦♦ Late: circumferential fibrointimal proliferation that obliterates the lumen leading to infarction −− As the lumen narrows predisposes to thrombosis (Fig. 5.23) ♦♦ Difficult to diagnose without angiogram −− No known treatment −− Usually leads to graft failure

Transplantation Pathology

Fig. 5.23. An epicardial coronary artery from an explanted cardiac allograft showing classic transplant vascular disease of chronic rejection. There is marked fibrointimal thickening of the wall in a concentric fashion with an acute thrombus in the lumen.

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Fig. 5.25. Fibrosis and granulation tissue consistent with a previous biopsy site in a cardiac allograft.

Fig.  5.26. Classic appearance of Quilty effect. The lesions can be quite variable in size. Small vessels often traverse the infiltrate. Fig. 5.24. Protocol endomyocardial biopsy 2 weeks after transplantation showing focal ischemic myocyte necrosis. These small, often subendothelial foci of necrosis are often noted in the first month after transplantation. If this pattern is seen in late biopsies, it is a marker of vascular injury or occlusion.

Other Biopsy Findings ♦♦ Focal subendocardial layer of myocyte necrosis in early biopsies consistent with preservation effect (Fig. 5.24) −− Goes on to fibrosis with time −− The thinner the necrotic layer the better ♦♦ Granulation tissue with or without chronic inflammatory cells is an old biopsy site, not rejection (Fig. 5.25) ♦♦ Quilty effect −− A nodular collection of lymphocytes involving the endocardium (Fig. 5.26) −− May extend into the endocardium with damage to adjacent myocytes (penetrating Quilty effect) (Fig. 5.27)

Fig. 5.27. High power view of the base of the infiltrate seen in Fig. 5.26. Note the myocyte damage at the interface. This is not an indication of rejection. Imagine how this focus would look if cut tangentially.

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−− Small vessels often seen in the infiltrate −− Mixture of T- and B-cells without prominent nucleoli, mitoses, or atypia −− Associated with calcineurin inhibitor-based immunosuppression but etiology is not known −− Not rejection −− Note: if tangentially cut, penetrating Quilty effect may be confused for rejection −− Differential diagnosis includes PTLD and rejection ♦♦ Myocytes with cytoplasmic contraction bands (without nuclear pyknosis) are present in every biopsy and are not significant (Fig. 5.28) ♦♦ Extensive adipose tissue (Fig.  5.29) or mesothelium (Fig. 5.30) suggests myocardial perforation −− Endocardial thrombi (Fig.  5.31) should be reported but are not usually clinically significant

Fig.  5.28. Artifactual contraction bands. Note that there is no pyknosis. This artifact is present in almost all cardiac biopsies.

Fig. 5.29. A large amount of adipose tissue in a cardiac biopsy raises the possibility of perforation.

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−− Chordae tendineae (Fig.  5.32) and portions of cardiac valve should also be mentioned in the report −− Chronic biopsy injury to the valve can result in insufficiency ♦♦ CMV or toxoplasma inclusions may be seen in patients without previous exposure, usually within the 1st year after transplantation (Fig. 5.33) ♦♦ Diffuse interstitial fibrosis suggests calcineurin inhibitor toxicity but is seldom seen with current immunosuppression regimens ♦♦ Giant cell myocarditis may recur in the allograft (Fig. 5.34)

Fig. 5.30. A strip of mesothelium from a right ventricular biopsy is a sure indicator of perforation. The patients usually do not feel the cardiac biopsies because the allograft is deinnervated. However, biopsy of an innervated structure may be felt. Tamponade is not a common complication because adhesions limit the accumulation of extracardiac fluid.

Fig. 5.31. Thrombi are often seen among the tissue fragments in protocol heart allograft biopsies.

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Fig. 5.32. Chordae tendineae or fragments of valve can be seen in cardiac biopsy material. They should be mentioned in the report. If the damage is significant, it can lead to valve insufficiency.

Fig. 5.34. Recurrent giant cell myocarditis in a failed allograft.

Fig.  5.33. Toxoplasmosis in the biopsy of a 19-year-old heart transplant patient. Note the lack of inflammation.

LUNG TRANSPLANTATION Indication for Transplantation ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Chronic pulmonary failure COPD/emphysema Cystic fibrosis Idiopathic pulmonary fibrosis (usual interstitial pneumonia) Pulmonary hypertension (often with heart transplant because of congenital heart disease)

Clinical Considerations ♦♦ Allograft is matched for size and side; one or both lungs may be transplanted

♦♦ If bilateral, done as two single lungs ♦♦ Donor mainstem bronchus, artery, and vein are anastomosed to recipient bronchus, artery, and vein

Rejection Acute Cellular Rejection ♦♦ Typically seen 7–10 days after transplant ♦♦ May present with malaise, fever, shortness of breath, and pulmonary infiltrates on chest radiographs ♦♦ Four, formalin-fixed transbronchial biopsy fragments are considered adequate for diagnosis

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♦♦ General recommendation is to review three H&E levels, a connective tissue stain (for bronchiolitis obliterans), and a silver stain for fungi and Pneumocystis ♦♦ Acute cellular rejection grading (Table 5.8)

Table 5.8. ISHLT Working Formulation for Grading Pulmonary Allograft Rejection 2007 A. Acute rejection [with/without (B)]   Grade A0, none   Grade A1, minimal   Grade A2, mild   Grade A3, moderate   Grade A4, severe B. Airway inflammation – lymphocytic bronchitis/bronchiolitis   B0, no airway inflammation   B1, minimal airway inflammation   B3, moderate airway inflammation   B4, severe airway inflammation  BX, unable to grade because of sampling problem, infection, tangential cutting, etc. C. Chronic airway rejection – bronchiolitis obliterans   a. Active   b. Inactive D. Chronic vascular rejection – accelerated graft vascular sclerosis

−− Grade A0: no perivascular infiltrates −− Grade A1, minimal rejection: rare perivascular mononuclear infiltrates that are not notable at low power but seen at high magnification −− Grade A2, mild rejection: perivascular mononuclear infiltrates that are easily seen at low power (Fig. 5.35) −− Grade A3, moderate rejection: perivascular mononuclear infiltrates that are easily seen at low power, often with endotheliitis, with extension into the surrounding interstitium (Fig. 5.36) −− Grade A4, severe rejection: changes seen in moderate rejection plus alveolar wall damage with hyaline membranes, eosinophils and neutrophils; necrosis and vasculitis may be present

Chronic Rejection ♦♦ A significant clinical problem that limits the overall 5-year survival of pulmonary allografts to 50% ♦♦ Presents with increasing shortness of breath, cough, and obstructive spirometry ♦♦ Often no pulmonary infiltrates on radiograph ♦♦ This clinical presentation is often termed bronchiolitis obliterans syndrome −− The bronchiolitis obliterans syndrome grade is based on the patient’s spirometry value, forced expiratory volume over 1 s (FEV1)

Fig. 5.35. Mild pulmonary rejection characterized by small perivascular infiltrates visible at low power without extension into the alveolar wall. Low power magnification on the left, higher power on the right.

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Fig. 5.36. Moderate pulmonary rejection showing a large perivascular infiltrate with extension into the surrounding alveolar walls

Fig. 5.37. Wedge biopsy showing obliterative bronchiolitis from a lung transplant patient 2 years out presenting with progressive shortness of breath. There is a fibroproliferative lesion between the smooth muscle in the bronchiole wall (right center) and the epithelium that is artifactually denuded in part of the specimen. There is mild activity.

−− Patients with grades 2 and 3 bronchiolitis obliterans syndrome have a poor outcome −− However, a biopsy is often necessary to exclude other factors that might decrease the FEV1 ♦♦ Histology shows bronchiolitis obliterans is also termed obliterative bronchiolitis (OB) to avoid confusion with bronchiolitis obliterans organizing pneumonia (BOOP) (see below) −− On H&E stain, one notes narrowing of the bronchiole lumen by a fibrous overgrowth between the muscle layer and the epithelium −− Usually occurs in membranous or higher bronchioles −− An elastic stain is useful to highlight the lesion

Fig. 5.38. (A) Elastic stain highlighting the diminution of the bronchial lumen in obliterative bronchiolitis. Note the absence of vasculopathy in the pulmonary artery in the lower right. (B) Trichrome stained section showing early Bronchiolitis obliterans. There is a mural fibrous proliferation obscuring the lumen of this small membranous bronchiole. The pulmonary artery branch is visible to the extreme left and is without arteriopathic changes. −− The grading scheme recognizes active and inactive forms, grade Ca or Cb, respectively (Table 5.8), based on whether or not inflammation is present with the fibroplasia (Figs. 5.37 and 5.38A, B) ♦♦ The etiology of OB is debated but recent evidence suggests that alloantibodies developed to protected epitopes may play a role in its development −− Unmasked type V collagen (normally tightly bound to type I collagen in the bronchial wall) has been proposed as one such antibody target leading to the development of OB ♦♦ Subacute humoral rejection has been reported and C4d may play a role in its diagnosis −− However, C4d has been little investigated in lung transplantation and is not generally considered useful in evaluating chronic lung allograft dysfunction ♦♦ Acute cellular rejection may or may not be present with OB

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Fig. 5.39. A pulmonary allograft with severe transplant vasculopathy consistent with chronic rejection. ♦♦ OB may be associated with chronic transplant vasculopathy, grade D rejection (Fig. 5.39) −− Chronic vasculopathy is uncommon, seen in <1.5% of biopsies, usually wedge biopsies −− It may not be a clinically significant lesion in and of itself, but when seen is usually a marker of OB ♦♦ OB generally does not respond well to treatment

Fig. 5.40. Moderate chronic bronchiolitis (B3) from a lung transplant patient.

Early Posttransplant Changes Diffuse Alveolar Damage ♦♦ Diffuse alveolar damage (DAD) may be seen in early posttransplant biopsies; must distinguish from grade A4 rejection −− In DAD, hyaline membranes present but no significant inflammatory infiltrate as noted in A4 rejection ♦♦ Lymphocytic bronchitis/bronchiolitis (grade B) may be seen with any of the above grades of rejection and the report should also include its absence or presence (Fig. 5.40) −− However, the significance of this lesion is unclear −− Some observers feel that lymphocytic bronchiolitis is a definite manifestation of cellular rejection and a precursor to obliterative bronchiolitis (see below) −− However, it is also a manifestation of chronic aspiration and bacterial infection −− Separating these inflammatory reactions from rejection is impossible on a histologic basis ♦♦ Increased immunosuppression usually improves acute rejection

Cryptogenic Organizing Pneumonia (BOOP) (Fig. 5.41) ♦♦ May be seen in early posttransplant biopsies ♦♦ Most likely related to the trauma of surgery −− When seen late after transplant must distinguish from bronchiolitis obliterans (Table 5.9) ♦♦ The significance of late organizing pneumonia is unclear

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Fig.  5.41. Organizing pneumonia also known as bronchiolitis obliterans organizing pneumonia (BOOP) that can sometimes be confused for obliterative bronchiolitis. It is a granulation tissuelike focus in the airspace itself, rather in the wall of a bronchiole.

Table 5.9. Illustrating Some Differences Between Obliterative Bronchiolitis and Cryptogenic Organizing Pneumonia Also Known as Bronchiolitis Obliterans Organizing Pneumonia (BOOP) Timing

Appearance

Location

Bronchiolitis obliterans

Late

Mural fibrosis, compressing lumen

Membranous bronchial and above

Cryptogenic organizing pneumonia

Early

Granulation tissue in Respiratory the airspace itself bronchiole and below

Transplantation Pathology

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Fig. 5.42. Cytomegalovirus pneumonitis in a lung transplant patient. ♦♦ Some authors have suggested a relationship with acute cellular rejection while in other settings it is a nonspecific manifestation of injury such as aspiration, infection, or hypoperfusion ♦♦ Usually, clinicopathologic correlation is required to determine its etiology ♦♦ Obliterative bronchiolitis may be diagnosed in transbronchial biopsies but it can be difficult or impossible in some cases −− A wedge biopsy may be needed

Infection ♦♦ Pneumonia: bacterial but also opportunistic pathogens including CMV (Fig. 5.42), Pneumocystis, Aspergillus, and Candida ♦♦ Pseudomonas: a common infection of the bronchi ♦♦ Foci of fibrosis and hemosiderin may be seen in biopsy material representing old biopsy sites −− Generalized hemosiderosis should be noted and a clinical investigation undertaken to determine its etiology −− There have been recent reports of de  novo interstitial fibrosis involving the upper lobes but the significance of this finding is unclear

Fig.  5.43. Explanted allograft lung showing early honeycomb change consistent with recurrent usual interstitial pneumonia. Other foci show fibrosis that is variable in time and place (not shown).

Posttransplant Lymphoproliferative Disorder ♦♦ Must be distinguished from rejection, lymphocytic bronchiolitis, and bronchial-associated lymphoid tissue ♦♦ A 5%+ incidence of PTLD has been noted in lung transplant patients ♦♦ Sections of the lesion usually contain atypical, large, B-cell lymphoid cells with mitotic figures, admixed with plasma cells ♦♦ EBER is diagnostic

Recurrent Disease ♦♦ Uncommon but leiomyomatosis, sarcoid, and usual interstitial pneumonia can be seen (Fig. 5.43) ♦♦ Smoking-related lung disease (respiratory bronchiolitis, COPD, eosinophilic granuloma) may recur if the patient resumes smoking after transplantation

LIVER TRANSPLANTATION Indication for Transplantation ♦♦ Acute or chronic liver failure ♦♦ Some acute causes include: drugs such acetaminophen (very common), toxins, fulminate viral hepatitis, HBV >> HBA, fulminate autoimmune hepatitis ♦♦ Chronic liver failure is usually cirrhosis of any etiology; viral infections, i.e., HCV, alcoholic liver disease, and chronic cholestatic disorders (primary biliary cirrhosis and primary sclerosing cholangitis) are common

♦♦ In children, the most frequent indications for transplant are biliary atresia and congenital disorders, i.e., hereditary hyperoxaluria

Clinical Considerations ♦♦ Small (under 4  cm) hepatomas [hepatocellular carcinoma (HCC)] are common in cirrhotic patients and are not a contraindication for transplantation ♦♦ Cadaveric brain-dead donors are generally used

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♦♦

♦♦

♦♦ ♦♦

♦♦

♦♦

♦♦

−− However, some facilities perform living related donor partial liver transplants, usually a lobe from an adult into a child Non-heart-beating donors have also been used but graft survival over time seems to be less than that for conventional donors Recipient and organ are size (usually by weight) are important considerations −− An oversized organ will often fail The organ and patient is typically ABO matched Recipients are stratified on the waiting list based on the model for end-stage liver disease (MELD) score −− It is based on the patient’s serum bilirubin and creatinine levels Donor livers are sometimes evaluated by frozen section prior to transplant −− Chronic liver disease including fibrosis or fatty liver >50% may not be suitable for transplant (surgeon’s discretion) (Fig. 5.44) Orthotropic transplants are performed with removal of the native liver −− The allograft is anastomosed to the vena cava, portal vein, and a systemic artery (a) The donor bile duct is usually sewn end-to-end of recipient, except with chronic cholestatic disease where the bile duct is sewn to a Roux-limb (hard to do ERCP) −− Donor cholecystectomy usually performed Explanted liver should be examined carefully for incidental HCC −− HCC gross examination shows soft, bulging mass above the cut surface, often a different color from surrounding nodules (Fig. 5.45)

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  5.45. Cut section of a native liver with end-stage liver disease secondary to HCV infection and alcohol toxicity. Note the nodule that is larger and a different color from its neighbors – it is an incidental hepatocellular carcinoma. −− HCC shows number, size, presence or absence of vascular invasion, lymph node status should be noted in the pathology report ♦♦ An explanted allograft liver should be carefully examined, especially the artery, for etiology of graft failure

Rejection ♦♦ Preservation effect is usually seen in the liver biopsies taken prior to day-7 after transplant ♦♦ The findings can be variable depending on how well the graft was preserved ♦♦ Centrilobular hepatocyte ballooning is often seen but if severe, central coagulative necrosis may be present ♦♦ When seen the report should indicate the extent of necrosis ♦♦ Canalicular cholestasis is often present ♦♦ The portal tracts may show ductular proliferation with neutrophils and edema (Fig. 5.46A, B) ♦♦ Usually resolves after 7 days but can persist for 30 days

Acute Rejection

Fig. 5.44. Approximately 50% macrovesicular fatty change in a potential liver allograft. Some would consider this liver unsuitable for transplantation.

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♦♦ First onset not usually until 7–10 days after transplantation (Table 5.10) ♦♦ Elevated liver function tests, primarily alkaline phosphatase, and gamma glutamyl transpeptidase (GGT), which is very useful to follow in children ♦♦ May have fever and or peripheral eosinophilia ♦♦ Formalin-fixed liver biopsy adequate if five or more portal tracts are present ♦♦ Characterized by −− Mixed but predominantly mononuclear portal infiltrate (Fig. 5.47) −− Manifestations of interlobular bile duct damage (Fig. 5.48) −− Endotheliitis (Fig. 5.49)

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Fig. 5.47. Portal tract expanded by a mixed infiltrate with bile duct damage and endotheliitis consistent with acute cellular rejection.

Fig.  5.46. (A) Liver biopsy 3 days after transplantation. The lobule shows numerous changes including cholestasis, slight centrilobular ballooning, moderate fatty change, and Kupffer cell prominence. Most of the changes are consistent with preservation effect. (B) The portal tracts have a sprinkling of neutrophils, lymphocytes, edema, and slight ductular proliferation.

Fig.  5.48. Interlobular bile duct damage consistent with acute cellular rejection. There is a duct-centric chronic inflammatory cell infiltrate, often with eosinophils.

Table 5.10. Banff Grading System for Hepatic Allograft Rejection Indeterminate Mild Moderate Severe

Portal infiltrates that fail to meet the criteria for rejection Infiltrates in a minority of tracts with little tract expansion Infiltrates expanding most or all the portal tracts At least moderate portal infiltrates plus central perivenular infiltrates with hepatocyte damage

Fig. 5.49. Hepatic allograft with classic endotheliitis of rejection involving a portal vein branch.

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Table 5.11. Rejection Activity Index for Scoring Rejection Activity in Hepatic Allografts Portal inflammation Lymphocytes involving but not noticeably expanding a minority of triads Most triads expanded with mixed infiltrate Marked expansion of most triads with spillover into lobule Bile duct changes Minority of ducts cuffed and infiltrated by inflammatory cells Most or all ducts infiltrated by inflammatory cells As in 2 with degenerative changes or focal luminal disruption Venous endothelial inflammation Endothelitis involving some portal or hepatic veins Endothelitis involving most or all portal or hepatic veins As in 2, with inflammation that extends into the parenchyma with necrosis

= 1 = 2 = 3 = 1 = 2 = 3 = 1 = 2 = 3

♦♦ Two of these three factors must be present to diagnose acute cellular rejection (Fig. 5.47) ♦♦ An unusual manifestation of rejection, especially among children, is a mononuclear infiltrate around the central veins often associated with endotheliitis −− Adjoining hepatocyte necrosis may or may not be present −− There are little or no portal changes, no or minimal infiltrate, no duct damage, and no portal venulitis −− This form of rejection is not taken into account in the below noted classification ♦♦ Patients with moderate-to-severe acute cellular rejection are most at risk for developing chronic rejection

Fig. 5.50. Explant liver allograft with chronic rejection showing a portal tract devoid of a bile duct. Here is cholestasis and centrilobular hepatocyte dropout. The centrilobular region is paucicellular. This may represent ischemia from chronic transplant vasculopathy as much as direct immunologic injury.

Banff Criteria ♦♦ The Banff committee also suggested that a Rejection Activity Index score be given, 3–9, by adding together the scores for the three parameters as noted in Table 5.11 ♦♦ Acute rejection must be differentiated from −− Viral- and drug-induced hepatitis (recurrent and de novo) −− Mechanical bile duct obstruction −− Recurrent cholestatic disease (primary biliary cirrhosis, primary sclerosing cholangitis) and PTLD – see below ♦♦ Of the above disorders, only rejection is associated with arteriopathy in the allograft

Chronic Rejection ♦♦ Marked elevation of canalicular enzymes, usually seen 6 months or later after transplantation ♦♦ Early changes include oncocytic change and disruption of bile duct epithelium ♦♦ Progressive loss of interlobular bile ducts (Fig. 5.50) ♦♦ Usually associated with chronic transplant arteriopathy (seldom seen in biopsies) and fibrosis that may progress to cirrhosis (Fig. 5.51)

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Fig.  5.51. Explant liver allograft showing classic transplant vasculopathy of chronic rejection. ♦♦ Centrilobular hepatocyte dropout/inflammation/fibrosis marked −− Maybe due to cellular rejection or ischemia secondary to arteriopathy ♦♦ Cholestasis is marked with numerous collection of foamy Kupffer cells ♦♦ Does not respond to therapy resulting in graft loss

Humoral Rejection ♦♦ Hyperacute rejection produces graft necrosis on the operating table after vascular clamps released −− ABO incompatibility is a common cause

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♦♦ Acute humoral rejection most likely exists but is poorly understood and characterized −− C4d (immunoperoxidase) has been advocated as a marker, as in the kidney and heart, but the results from the few studies carried out are difficult to interpret

Centrivenous Necrosis ♦♦ Centrivenous necrosis can be seen and also has a wide differential diagnosis including −− Rejection (acute = severe, chronic transplant arteriopathy) −− Vascular injury (usually a diagnosis of exclusion) −− Autoimmune hepatitis (recurrent or de novo) −− Hepatitis B (recurrent or de novo) −− Drugs (azathioprine and tacrolimus are common culprits) −− Chronic transplant hepatitis ♦♦ Evaluation of all the histologic findings in clinical context often allows for the correct diagnosis (Fig. 5.52)

Fig. 5.53. Central sinusoidal dilation.

Venous Outflow Tract Obstruction ♦♦ Central sinusoidal congestion and dilation are indications of venous outflow tract obstruction (Fig. 5.53) ♦♦ Stenosis of the upper vena cava anastomosis is a common cause but hepatic vein thrombosis, right heart failure from any cause or constrictive pericarditis should also be excluded ♦♦ In some cases, portal vein thrombosis can also produce this pattern of injury

Mechanical Bile Duct Obstruction ♦♦ Can mimic acute rejection exquisitely ♦♦ Mixed portal infiltrate, may show bile duct damage ♦♦ Increased number of neutrophils and bile ductular proliferation more suggestive of obstruction than rejection (Fig. 5.54) not typically associated with endotheliitis – no arteriopathy ♦♦ ERCP diagnostic

Fig. 5.54. Liver allograft with marked bile ductular proliferation and cholestasis. Differential diagnosis would include extrahepatic duct obstruction and sepsis. This is not typical of acute cellular rejection.

Hepatic Artery Thrombosis

Fig. 5.52. Central hepatocyte dropout and endotheliitis.

♦♦ Hepatic artery thrombosis is a more common problem in children often resulting in graft necrosis (coagulative) (Fig. 5.55) ♦♦ If the occlusion is less drastic, one can see necrosis of the biliary tree ♦♦ If distal, only one lobe of the liver may be affected ♦♦ The affected ducts become denuded of epithelium and are lined only by granulation tissue ♦♦ These tracts may be stented but this is often ineffective requiring retransplantation ♦♦ Portal vein thrombosis can be difficult to detect without imaging studies

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Fig. 5.55. Hepatic artery thrombosis produces a zone 3 coagulative necrosis that often results in graft loss.

Fig.  5.56. CMV can be associated with “microabscess” small collections of neutrophils in the lobule. When microabscesses are noted, there should be a careful search for the virus.

Infection Cytomegalovirus ♦♦ CMV is seen beginning at approximately 30  days after transplant ♦♦ Elevated LFTs ♦♦ Histology shows “microabscesses” in the lobule associated with rare hepatocyte inclusions (Fig. 5.56) ♦♦ Can exhibit a portal infiltrate if bile duct epithelium infected (Fig. 5.57)

Adenovirus ♦♦ Adenovirus is also seen beginning at approximately 30 days after transplant with elevated LFTs ♦♦ More common in children ♦♦ Classic nuclear inclusions are seen in bile duct epithelium

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Fig.  5.57. Two classic CMV inclusions in the interlobular duct epithelium of a liver allograft. The inclusions can also be seen in hepatocytes, endothelial cells and stromal cells (not illustrated).

Fig.  5.58. A chronic hepatitis of unknown etiology shows a lymphocytic triaditis without bile duct damage, usually a late occurrence.

De Novo Autoimmune Hepatitis ♦♦ Patients present with moderate-to-marked transaminase elevations in otherwise stable disease ♦♦ The biopsy may show a classic portal infiltrate with plasma cells and or centrilobular injury ♦♦ Serum autoimmune markers are usually present, although some consider this a variant of acute cellular rejection ♦♦ Increased immunosuppression is usually effective

Chronic Hepatitis of Transplantation ♦♦ With prolonged patient survival, biopsies are being seen with portal infiltrates of chronic inflammatory cells where the etiology cannot be determined (Fig. 5.58) ♦♦ The classic findings of rejection are not present, and viral and autoimmune etiologies should be excluded by the clinician

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♦♦ Possible etiologies might include a drug reaction or poorly sampled chronic rejection ♦♦ Continued followup of these cases is required to determine its significance but some cases progress to cirrhosis

Recurrent Disease ♦♦ Congenital diseases manifested in the liver do not recur, i.e., alpha-1 antitrypsin deficiency ♦♦ Recurrent disease has the same histologic features in the allograft as in the native liver, in general

Hepatitis B ♦♦ Incidence of recurrence greatly reduce with the advent of better antiviral therapy, <10% −− Clinically noted 30+ days after transplant ♦♦ Portal chronic inflammatory cell infiltrate usually without bile duct damage, with or without lobular inflammation ♦♦ New nucleoside analogs control the recurrent disease ♦♦ If overimmunosuppressed, fibrosing cholestatic hepatitis (FCH) −− FCH characterized by a relative paucity of inflammation, bile ductular proliferation may be present, cholestasis, and marked portal and bridging fibrosis (Fig. 5.59) −− High viral titer – hepatitis B core and surface antigen in every hepatocyte (Fig. 5.60) −− May be difficult to treat but now rarely seen with lower immune suppression early

Fig. 5.60. Immunoperoxidase stain for hepatitis B core antigen from patient seen in Fig. 5.59. Core antigen is present in almost every cell.

Hepatitis C ♦♦ Almost always recurs, clinically noted 30+ days after transplant ♦♦ Initially mild lobular inflammation and slight disarray, many acidophil bodies (Fig. 5.61)

Fig. 5.59. Fibrosing cholestatic hepatitis secondary to HBV. The patient is over immunosuppressed and the virus is likely directly cytotoxic. HBV recurrence in the allograft was very hard to manage prior to the use of lamivudine and other antiviral medications.

Fig. 5.61. An allograft biopsy 30 days posttransplant show a mild lobular hepatitis with patchy hepatocyte ballooning, prominent Kupffer cells, and scattered acidophil bodies consistent with recurrent HCV infection. ♦♦ Later, classic nodular portal infiltrates appear, fat usually inconspicuous (Fig. 5.62), but may be prominent with some viral subspecies ♦♦ Occasional bile duct infiltrates are not rejection (Poulsen lesion) ♦♦ Treatment of the infection with pegylated interferon and ribavirin often results in hemosiderin being deposited in the reticuloendothelial cells (Fig. 5.63) ♦♦ Overimmunosuppression leads to marked viral proliferation and FCH which may no longer respond to lower immunosuppression and/or interferon (Fig. 5.64) −− It may progress to cirrhosis ♦♦ Marked bile ductular proliferation in a hepatitis C-infected allograft, must be distinguished from extrahepatic bile duct obstruction −− Usually an ERCP and examination of the viral titers allow the distinction

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Fig.  5.62. Classic nodular portal infiltrate of recurrent HCV hepatitis in the allograft. There is slight injury to the interlo­ bular duct, but if only focal, not considered rejection in our institution.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 5.64. Allograft liver 8 months after transplantation for HCV showing a well-developed cirrhosis with ongoing inflammation and ductular proliferation. All hepatic artery branches were normal and there was no bile duct loss. The findings are typical of fibrosis cholestatic hepatitis secondary to unchecked HCV infection. There is often more inflammation compare to cases associated with HBV. The patient was pulsed with steroids 6 weeks after transplantation for “rejection.” The LFTs and viral titers increased and were no longer responsive to interferon/ ribavirin or lowered immunosuppression.

−− Bile duct loss is an indication of rejection and is not seen with HCV infections −− Recurrent HCV infection may progress to cirrhosis

Autoimmune Hepatitis

Fig. 5.63. Recurrent HCV in the allograft may be treated with pegylated interferon and ribavirin. After treatment the biopsy often exhibits hemosidern deposition in the reticuloendothelial system as seen here.

♦♦ It is difficult to distinguish recurrent HCV from rejection because of overlapping histologic features −− Endotheliitis is not classically seen with HCV, but is often not common in late rejection −− Interface hepatitis and lobular inflammatory changes can also completely overlap between the two diseases −− Classic rejection may be seen in the first 2 weeks after transplant, after that only florid bile duct damage (50% or more of the tracts should show damaged ducts) should be diagnosed as rejection (very dependent on immunosuppression protocol used)

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♦♦ 20–30% recurrence rate ♦♦ Classic appearance with dense portal infiltrates and plasma cells ♦♦ May exhibit zone 3 hepatocyte dropout ♦♦ Differential diagnosis includes PTLD ♦♦ Treated with increased immunosuppression

Primary Biliary Cirrhosis ♦♦ 20–50% recurrence rate ♦♦ Cannot follow AMA levels; often do not return to normal after transplant ♦♦ Histology shows chronic portal infiltrate, bile duct damage plus granuloma (florid duct lesion) −− If the hepatic arteries (in explants or at autopsy) show arteriopathy, should be considered as chronic rejection

Primary Sclerosing Cholangitis ♦♦ 20–30% recurrence rate ♦♦ No pathognomonic findings, must exclude rejection, mechanical duct obstruction, vascular stricture, etc

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Alcoholic Hepatitis and Nonalcoholic Steatohepatitis ♦♦ 10–30% recurrence rate for alcoholic hepatitis; 20–40% for nonalcoholic steatohepatitis (NASH) ♦♦ Classic histology ♦♦ Recurrent NASH can be difficult to manage clinically

Drug Effect ♦♦ May exhibit increased eosinophilia compared to other processes (Fig. 5.65) ♦♦ Most commonly a diagnosis of exclusion with clinical correlation

Posttransplant Lymphoproliferative Disorder Fig. 5.65. A lobular hepatitis with scattered acidophil bodies and prominent Kupffer cells presented with transaminase elevations. Infectious causes were clinically eliminated. A recently prescribed drug was discontinued and the transaminitis cleared – a drug reaction.

♦♦ May be seen in the allograft as a dense portal infiltrates of atypical mononuclear cells, as described previously ♦♦ Easily found mitotic figures in a lymphoplasmacytic infiltrate a strong clue ♦♦ Usually there is no or minimal bile duct damage ♦♦ EBV demonstrated by immunohistochemistry or EBER stain

PANCREAS/ISLET CELL TRANSPLANTATION Indication

Rejection

♦♦ Treatment of type 1 diabetes; 60% graft survival at 5 years

♦♦ A consensus document has been developed to grade and classify changes in the allograft pancreas as elaborated in Table 5.12 −− It is complex and developed along the lines of the kidney protocol ♦♦ To evaluate the biopsy it is recommend to examine −− Three hematoxylin and eosin (H&E)-stained levels −− One trichrome (collagen) stain −− One slide for C4d (immunohistochemistry) −− Cut five additional intervening unstained slides for possible additional studies ♦♦ The minimum criteria for an adequate biopsy depend on the findings, but a biopsy with less than three lobular areas and their associated interlobular septa, may be inadequate −− Arteries should also be seen and if not, it should be noted in the report ♦♦ Cell-mediated pancreas rejection shows injury to the ducts (Fig. 5.67A, B), venules (Fig. 5.67C), acini (Fig. 5.67D), and arteries −− The illustrations are from one biopsy, consistent with grade II moderate rejection

Clinical Considerations ♦♦ There are two main approaches, all ectopic, with numerous subvariations −− Cadaveric duodenum with attached pancreas is anastomosed to the recipient urinary bladder; donor splenic artery anastomosed to recipient iliac artery; portal vein to the iliac vein (a) May be biopsied via cystoscope (b) Urinary amylase levels can be monitored; a decrease in levels indicates graft dysfunction −− The allograft is sewn to a Roux-limb or directly sideto-side to the recipient gut and mesenteric vessels (Fig. 5.66) (a) Thought to be more physiologic (b) Difficult to biopsy (c) Serum lipase, amylase, and glucose followed to indicate rejection ♦♦ Pure islet cells may be transplanted under renal capsule or injected into portal vein

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Fig. 5.66. An illustration of a typical enteric hookup of the pancreas allograft. There are many, many variations on this approach. Here the donor duodenum is attached directly to a recipient small bowel loop via a side-to-side anastomosis. Venous drainage into the portal system is felt to be more physiologic than systemic drainage. The arterial supply appears to come from an iliac source. Note the typical surgical position of the renal allograft in the lower right. Kidney and pancreas transplants are often performed together. Reprinted with permission from Elsevier, Larson-Wadd and Belani 2004.

Table 5.12. Working Scheme for Grading Pancreas Allograft Rejection 1. Normal. 2. Indeterminate. Septal inflammation that appears active but the overall features do not fulfill the criteria for mild cell-mediated acute rejection 3. Cell-mediated rejection. Acute cell-mediated rejection • Grade I/mild acute cell-mediated rejection – Active septal inflammation (activated, blastic lymphocytes, +/− eosinophils) involving septal structures: venulitis (subendothelial accumulation of inflammatory cells and endothelial damage in septal veins, ductitis (epithelial inflammation and damage of ducts). Neural/perineural inflammation and/or focal acinar inflammation. No more than two inflammatory foci per lobule with absent or minimal acinar cell injury • Grade II/moderate acute cell-mediated rejection – Multifocal (but not confluent or diffuse) acinar inflammation (³3 foci per lobule) with spotty (individual) acinar cell injury and dropout and/or minimal intimal arteritis • Grade III/severe acute cell-mediated rejection – Diffuse, (widespread, extensive) acinar inflammation with focal or diffuse multicellular/confluent acinar cell necrosis, and/or moderate or severe intimal arteritis, and/or transmural inflammation; necrotizing arteritis Chronic active cell-mediated rejection • Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neo-intima) 4. Antibody-mediated rejection. C4d positivity + confirmed donor specific antibodies + graft dysfunction Hyperacute rejection: Immediate graft necrosis (£1 h) due to preformed antibodies in recipient’s blood Accelerated antibody-mediated rejection: Severe, fulminant form of antibody-mediated rejection with morphological similarities to hyperacute rejection but occurring later (within hours or days of transplantation) Acute antibody-mediated rejection: Specify percentage of biopsy surface (focal or diffuse). Associated histological findings: ranging from none to neutrophilic or mononuclear cell margination (capillaritis), thrombosis, vasculitis, parenchymal necrosis Chronic active antibody-mediated rejection: Features of categories 4 and 5

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Table 5.12.  (continued) 5. Chronic allograft rejection/graft sclerosis. • Stage I (mild graft sclerosis) – Expansion of fibrous septa; the fibrosis occupies less than 30% of the core surface but the acinar lobules have eroded, irregular contours. The central lobular areas are normal • Stage II (moderate graft sclerosis) – The fibrosis occupies 30–60% of the core surface. The exocrine atrophy affects the majority of the lobules in their periphery (irregular contours) and in their central areas (thin fibrous strands crisscross between individual acin) • Stage III (severe graft sclerosis) – The fibrotic areas predominate and occupy more than 60% of the core surface with only isolated areas of residual acinar tissue and/or islets present 6. Other histological diagnosis. Pathological changes not considered to be due to acute and/or chronic rejection, e.g., CMV pancreatitis, PTLD, etc.

Fig. 5.67. (A) Pancreas allograft showing septal inflammation and duct damage. (B) Higher magnification of showing the duct injury. (C) Focal venulitis in the pancreas allograft. (D) Pancreas allograft with acinar damage.

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♦♦ Humoral rejection is a similar process to that seen in other organs and relies on demonstrating circulating antibodies or it derivatives, i.e., C4d −− Positive C4d staining is defined as staining in more than 50% of periacinar capillaries

Other Disorders Seen in Allograft Pancreas Biopsies ♦♦ CMV infection may show many features of rejection −− Careful search for viral inclusions to exclude infection −− Immunohistochemistry or in situ hybridization may be used to identify CMV markers ♦♦ Acute calcineurin inhibitor toxicity presents with acute hyperglycemia −− There is an absence of inflammation and variable degrees of islet cell injury or loss −− Immunoperoxidase stains show markedly diminished beta cells −− Due to high levels of cyclosporine or tacrolimus −− Treated with decreased immunosuppression ♦♦ Posttransplant ischemic pancreatitis presents like rejection; hyperglycemia may be seen if severe −− Neutrophils and foamy macrophages seen in septa if mild, diffusely if severe −− Other features: fat necrosis, edema and interstitial hemorrhage

−− Patchy coagulation necrosis of clusters of acinar cells may be present −− The septa may be expanded due to edema/fat necrosis −− There is no fibrosis ♦♦ Peripancreatitis/peripancreatic fluid collection presents with abdominal pain and rejection symptoms and peripancreatic fluid accumulation on imaging −− Biopsy show mixed infiltrate (lymphocytes, plasma cells, eosinophils, neutrophils) in septa and periphery of lobules −− Other features: dissecting bundles of active fibroblastic proliferation with obliteration of septal structures, relative preservation of the center of lobules (“cirrhotic appearance”) ♦♦ Recurrent autoimmune disease/diabetes mellitus presents with increasing insulin requirements −− Islet cell auto-antibodies may be present (i.e., GAD 65, IA-2, etc.) −− Biopsy shows islet-centered lymphocytic inflammation (isletitis) −− No inflammation in late stages after disappearance of beta cells −− Immunohistochemical stains useful in evaluating beta cells

Posttransplant Lymphoproliferative Disorder ♦♦ Atypical lymphoid infiltrates as previously described

BONE MARROW/STEM CELL TRANSPLANTATION Indication for Transplantation ♦♦ Bone marrow failure ♦♦ Usually clinically induced to destroy bone marrow disease such as leukemia or intensively treat other cancers

Clinical Considerations ♦♦ Active infection; HIV is a general contraindication for transplantation ♦♦ Living donors are used ♦♦ Recipient and organ are HLA and ABO matched

Graft vs. Host Disease ♦♦ Generally affects the GI tract, skin, and liver although any organ can be affected individually or in combination ♦♦ Graft lymphocytes attack host organs as foreign tissue ♦♦ May be seen in immunosuppressed patients without a BMT after transfusion and in rare patients with thymoma or lymphoma ♦♦ Occasionally seen in solid organ transplant patients involving nongrafted organs

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♦♦ Approximately one-half of HLA match BMT patients develop GVHD

Skin ♦♦ Acute GVHD often presents with erythematous maculopapular rash on the trunk, soles, palms and ears 21–100  days posttransplant ♦♦ Often associated with GI and liver symptoms ♦♦ Histology shows paucicellular, mononuclear, dermal infiltrate associated with vacuolization and apoptosis of basal keratinocytes ♦♦ See Table 5.13 for grading of GVHD in the skin ♦♦ Differential diagnosis includes drug reaction, eosinophils favor drug reaction ♦♦ Grading correlates poorly with clinical severity of rash ♦♦ Chronic GVHD is seen as early as 80 days posttransplant −− Lichen planus-like skin changes including oral involvement −− Histology shows lichenoid infiltrates with marked atrophy of epidermis

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Table 5.13. Grading for Cutaneous Graft vs. Host Disease Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Normal skin Basal vacuolar change Dyskeratotic cells in epidermis and follicle Fusion of basal vacuoles to form clefts and microvesicles Separation of epidermis from dermis

See nonneoplastic skin chapter for examples

Table 5.14. Graft vs. Host Disease Grading in the GI Tract Grade 1 Grade 2 Grade 3 Grade 4

Apoptosis but no crypt loss Individual missing crypts More than two contiguous missing crypts Complete loss of mucosa

Gut ♦♦ Usually presents with crampy abdominal pain, nausea, vomiting, and watery diarrhea ♦♦ The main histologic feature of GVHD in the gut, from esophagus to rectum, is apoptosis (Table 5.14) ♦♦ In grade 1, there is patchy apoptosis at the base of the crypt with no crypt loss and generally no architectural changes (Fig. 5.68A, B) −− There is usually no or only a minimal round cell infiltrate −− In the fundus of the stomach, the apoptosis is often found at the level of the gland neck rather than at the base −− In the esophagus, there is apoptosis affecting the basal cells similar to GVHD in the skin −− In the setting of BMT, even one apoptotic body should be considered GVHD −− The differential diagnosis includes viral infection and mycophenolate toxicity ♦♦ Grade 2 GVHD is manifested by crypt apoptosis and single crypt dropout (Fig. 5.69) ♦♦ Grade 3 shows apoptosis and dropout of more than two contiguous crypts ♦♦ Grade 4 is complete loss of the mucosa (Fig. 5.70) with preservation of the lamina propria ♦♦ CMV infections and ischemia/hypotension can produce similar changes although ischemia usually destroys the lamina propria, unlike GVHD

Fig. 5.68. (A) Grade 1 graft vs. host disease in the stomach. There is patchy crypt apoptosis. (B) Patchy crypt apoptosis in the colon consistent with grade 1 graft vs. host disease. The differential diagnosis includes CMV infection and mycophenolate toxicity.

Liver ♦♦ Usually presents 30+ days after the transplant −− Often with involvement of skin and GI tract −− May be seen without skin or gut disease

Fig. 5.69. Grade 2 graft vs. host disease in the stomach. There is crypt apoptosis and focal crypt dropout.

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♦♦ No established grading system ♦♦ If untreated leads to duct paucity (chronic liver GVHD), fibrosis and cholestasis −− Transplant arteriopathy is NOT a feature of chronic GVHD of the liver ♦♦ Liver usually also shows hemosiderosis (from transfusions, not a feature of GVHD) ♦♦ Differential diagnosis includes CMV infection (look carefully for inclusions) −− Chronic viral hepatitis (HBV, HCV) ♦♦ Careful management of immunosuppression required with concomitant viral hepatitis and BMT −− Drug-induced liver disease Fig. 5.70. A colon biopsy from a patient with severe diarrhea after bone marrow transplantation. The crypts are completely destroyed showing only a focus of re-epithelization. There was ongoing crypt apoptosis in other sites – grade 4 graft vs. host disease in the colon.

Venoocclusive Disease ♦♦ Also called sinusoidal occlusion (obstruction) syndrome (SOS) ♦♦ Secondary to cytoreductive chemotherapy toxicity ♦♦ Presents with hepatomegaly, sudden weight gain and jaundice ♦♦ Serum bilirubin >10 mg/dl, often fatal ♦♦ Histology shows fibrinoid occlusion of central veins associated with congestion (Fig. 5.72) −− Usually accompanied by sinusoidal dilation and congestion −− Best seen with trichrome stain −− May be patchy, may or may not see hepatocyte necrosis ♦♦ Defibrotide therapy has produced a 30–60% salvage rate ♦♦ Differential diagnosis includes heart failure, ischemia, and herpetic viral hepatitis ♦♦ Recurrent leukemia may be seen in the sinuses

Fig. 5.71. Liver biopsy from a liver transplant patient showing a scant portal infiltrate but severe injury to the bile duct epithelium. There is no grading system for graft vs. host disease changes in the liver. Note the pigment in the reticuloendothelial cells consistent with marked iron deposition.

♦♦ Presents with increasing bilirubin progressing to jaundice and elevations of the canalicular enzymes (alkaline phosphatase and GGT) ♦♦ Histology demonstrates usually scant mononuclear infiltrate associated with interlobular bile duct injury (nuclear irregularity, hyperchromasia, cytoplasmic vacuoles) (Fig. 5.71) −− The density of the portal infiltrate is dependent on the immunosuppression regimen used (a) Denser infiltrates can be seen with lowered immunosuppression −− Endotheliitis can be seen but uncommon

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Fig.  5.72. Liver biopsy from a BMT patient showed central hepatic vein occluded with a granulation tissue-like proliferation and sinusoidal congestion consistent with venoocclusive disease.

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Table 5.15. Features of Graft vs. Host Disease in the Lung Pattern of injury Diffuse alveolar damage Cryptogenic organizing pneumonia (BOOP) Lymphocytic bronchitis/ bronchiolitis Cellular interstitial pneumonia Bronchiolitis with interstitial fibrosis Bronchiolitis obliterans

Fig. 5.73. Bronchial biopsy from a BMT patient showing atrophy, squamous metaplasia, and apoptosis consistent with graft vs. host disease.

Onset

Potentially reversibility

Early

Yes

Early

Yes

Early Early

Yes Yes

Late Late

No No

Lung

Posttransplant Lymphoproliferative Disorder

♦♦ Pulmonary involvement is not a common acute presentation of GVHD ♦♦ Usually presents with increasing shortness of breath ♦♦ Classic histology demonstrates bronchiolitis obliterans (Fig. 5.38) but lesser degrees of bronchial injury can be seen, i.e., lymphocytic bronchitis/bronchiolitis (Fig. 5.73) ♦♦ Recently broadened findings of pulmonary GVHD (Table 5.15) ♦♦ When a BMT patient has a lung biopsy with pattern of injury noted in the table, we report out the pattern with a note that it has been associated with GVHD

♦♦ Risk factors include T-cell depletion, HLA mismatching, specific antilymphocyte therapy, and primary immunodeficiency as an indication for transplantation ♦♦ Median onset 70–90 days posttransplant ♦♦ May present as adenopathy, mass lesion, fever, unexplained pain, or weight loss ♦♦ Histology, as previously described with a tendency to the monomorphic variant being more common ♦♦ More fulminant disease with up to 90% mortality, improved recently with advent of donor lymphocyte infusion therapy

SMALL BOWEL TRANSPLANTATION Indication for Transplantation ♦♦ Small bowel failure (SBF) results when there is too little small bowel to absorb nutrition −− Treated with TPN −− Adults require a minimum of 100 cm of small bowel with no colon; 60 cm with intact colon −− Children require at least 20% functioning small bowel ♦♦ Causes of SBF in children are intestinal atresia, necrotizing enterocolitis, gastroschisis, volvulus −− Children with small bowel failure often develop endstage liver disease secondary to TPN ♦♦ Causes of SBF in adults are ischemia, trauma, Crohn disease ♦♦ Graft survival 50–60% at 2 years

Clinical Considerations ♦♦ Two clinical procedures −− Isolated small bowel (ileum and jejunum) (a) Arterial inflow from recipient infrarenal aorta

(b) Venous outflow to the inferior cava or splanchnic veins (Fig. 5.74) −− Multivisceral transplant (a) Typically small bowel en bloc with liver, head of pancreas, and duodenum (Fig. 5.75) (b) Stomach may or may not be included (c) This procedure has the advantage of leaving the liver hilum undisturbed

Rejection ♦♦ ♦♦ ♦♦ ♦♦

No good clinical markers Symptoms are vague and nonspecific Patients often exhibit nausea, and increased flow from stoma Protocol biopsies are often employed −− No consensus criteria for diagnosis of rejection, but criteria have been put forth (Table 5.16) −− Nonallograft small bowel biopsies with normal villous architecture and no infiltrate will occasionally show crypt apoptotic bodies

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−− Criteria for rejection in the allograft stomach have been published but are complicated, involving the scoring of 12 variables −− Our modified approach (a) Mild rejection - a mild predominantly mononuclear infiltrate into the lamina propria, crypt apotosis, minimal architectural changes (b) Moderate rejection - prominent mixed inflammatory cell infiltrate, prominent or coalescent crypt apoptosis, minimal architectural changes including erosions (c) Severe rejection - inflammation, apoptosis, marked crypt loss and ulceration

Chronic Rejection ♦♦ Criteria are not well established −− Proposed histologic changes that might be seen in endoscopic biopsies include: patchy, mild fibrosis of lamina propria, and foreshortening or loss of the crypts of Lieberkuhn (Fig.  5.80), pyloric metaplasia, and ulcers/ granulation tissue −− Resected allografts may show transplant arteriopathy and or mesenteric sclerosis ♦♦ The role of C4d in assessing vascular rejection is under investigation Fig. 5.74. Illustration of a typical small intestinal transplant procedure. A proximal anastomosis between donor small bowel and recipient gut is made passed the ligament of Treitz. The distal small bowel is brought out as an ostomy. Venous outflow is sent to the portal vein; the arterial supply is sewn into the aorta. Reprinted with permission from Blackwell, Pascher et al. 2008.

−− This reality was taken into account in the indeterminate for cellular rejection category (Fig.  5.76) in the small bowel rejection grading system −− Slight architectural changes (villous blunting) with a mild cellular infiltrate and six or more apoptotic bodies per ten crypts are characteristic of mild acute cellular rejection (Fig. 5.77A, B) −− Marked architectural changes with crypt loss is consistent with moderate-to-severe rejection (Fig. 5.78) −− When the crypts are completely devoid of enterocytes we describe the lesion and note that it is consistent with severe acute cellular rejection −− The differential diagnosis of cellular rejection includes viral infection (see below), drug effect (mycophenolate), hypotension, ischemia, and PTLD (see below) −− Lymphoid aggregates should not be confused for the infiltrative portion of rejection (Fig. 5.79) −− In multivisceral transplants, rejection can occur in any of the transplanted organs −− Rejection criteria particular to those other organs should be used in their evaluation

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Infection ♦♦ CMV infection may present with clinical symptoms identical to rejection −− Histology may show features of rejection (crypt apoptosis) −− Careful search for viral inclusions to exclude infection −− Immunohistochemistry or in situ hybridization may be used to identify virus −− When multiple biopsies are available for review that exhibit crypt apoptosis, if CMV is noted in even one, the patient should be considered to have viral enteritis rather than a combination of rejection and viral infection ♦♦ Adenovirus may present with clinical symptoms identical to rejection −− Histology may show features of rejection (crypt apoptosis) ♦♦ Nuclear inclusions are present in surface enterocytes only (Fig. 5.81A, B) ♦♦ Careful search for viral inclusions to exclude infection −− Immunohistochemistry or in situ hybridization may be used to identify virus ♦♦ Other gastrointestinal viruses (rotavirus, calicivirus, etc.) that infect the gut may occur but generally do not show any specific findings, just an increased chronic inflammatory cell infiltrate in the lamina propria −− Diagnosis is by culture or serology −− Bacteria and fungal elements are often seen in the luminal mucin in small bowel allograft biopsies, but do not appear to be clinically significant (Fig. 5.82)

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Fig. 5.75. Multivisceral transplants include most of the organs in the abdominal cavity transplanted en bloc. The donor organs are dark in this illustration. At our institution, the transplant is performed as shown in the left panel. The native colon is retained. The small bowel end and proximal colon are brought out as a “shotgun” stoma. The donor arteries are attached to the recipient aorta in a patch (lower figure), the donor and recipient vena cava connections are made and a proximal gut anastomosis is performed. Other possible approaches are illustrated in the center and left panel. Spleen may or may not be transplanted. After healing, the stoma can be taken down and enteric-colonic integrity restored. Used with permission from Blackwell, Pascher et al. 2008.

Table 5.16. Pittsburgh Histologic Criteria for Grading of Small Bowel Acute Allograft Rejection Indeterminate

Mild

Moderate

Severe

• Minimal localized infiltrate • Minimal crypt injury or apoptosis (<6 apoptotic bodies per 10 crypts) • Minimal architectural changes • No ulceration • Mild localized infiltrate • Mild crypt injury or apoptosis (>6 apoptotic bodies per 10 crypts) • Mild architectural changes • No ulceration • Widely dispersed infiltrate • Diffuse crypt injury and increased • Sometime confluent apoptosis • More prominent architectural changes • Possible mild-to-moderate intimal arteritis • No ulceration • Features of moderate rejection plus ulceration • Possible severe or transmural arteritis

Fig. 5.76. Small bowel allograft showing an intact architecture, minimal infiltrate and occasional (less than six crypt apoptotic bodies per ten crypts) crypt apoptosis, indeterminate for rejection.

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Fig. 5.77. (A) Small bowel allograft showing increased crypt apoptosis (six apoptotic bodies per ten crypts) consistent with mild acute cellular rejection. (B) Higher magnification to highlight the apoptotic bodies.

Fig. 5.78. Small bowel allograft biopsy with a chronic inflammatory cell infiltrate and loss of the normal villous architecture. There is marked crypt loss with apoptotic bodies in the remaining crypts consistent with severe acute cellular rejection. This injury can recover with amazing rapidity after treatment.

Fig. 5.79. Small bowel allograft with lymphoid follicles. There is no crypt apoptosis. The differential diagnosis would include posttransplant lymphoproliferative disorder, but this should not be confused with rejection.

Fig.  5.80. Foreshortening of the crypts in the allograft should raise the possibility of chronic rejection.

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Fig. 5.81. (A) Regenerative surface epithelium of allograft small bowel showing the classic homogenous reddish nuclear inclusions of adenovirus. (B) Ultrastructural study of a cell. The intranuclear viral particles are arranged in orderly arrays. Immunohistochemical studies for adenovirus can be helpful but were negative in this case.

Fig.  5.82. Luminal bacteria and fungi (Candida) are often seen in small bowel allograft biopsies but are of no known consequence.

Fig.  5.83. (A) Small bowel allograft biopsy showing a dense mononuclear infiltrate in the lamina propria. At this magnification it is difficult to exclude rejection or some other process. (B) Higher magnification to show the cytologic atypia of some cells in the infiltrate. The infiltrate has a polymorphous appearance with small and intermediate-sized lymphocytes, plasma cells and atypical immunoblast-like cells. Mitotic figures were also noted in the infiltrate and should raise the suspicion of PTLD. (C) EBER stain (an EBV in situ hybridization) showing that most of the infiltrate contains EBV nucleic acid, consistent with PTLD. This polymorphous infiltrate also expresses B-cell markers (not shown).

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Preservation Injury ♦♦ Epithelial denudation with regenerative changes +/− super­ ficial inflammation (often acute) ♦♦ Heals rapidly

Posttransplant Lymphoproliferative Disorder ♦♦ Atypical lymphoid infiltrate (Fig. 5.83A–C)

CORNEA TRANSPLANTATION ♦♦ Indicated for blindness secondary to corneal edema – aphakic or pseudophakic bullous keratopathy, Fuchs dystrophy, and keratoconus ♦♦ Penetrating keratoplasty used to remove old cornea ♦♦ Not typically treated with immunosuppression – anterior chamber = privileged site ♦♦ 10–20% develops rejection over 10 years, good response to topical immunosuppression ♦♦ Risk factors for rejection −− Young recipient

−− Concurrent intraocular inflammation −− Glaucoma −− Previous surgery −− Anterior synechiae ♦♦ Most common cause of graft failure is rejection – diagnosed and managed clinically ♦♦ Failed grafts show peripheral scar with or without vascularization, marked edema, endothelial loss, mononuclear infiltrates (Fig. 5.84A, B)

OTHER Face/Limb Transplantation ♦♦ To restore appearance or limb function ♦♦ Criteria for acute cellular rejection rely on finding perivenular infiltrates, damage to the epidermis and vessels (Table 5.17) ♦♦ Criteria for chronic rejection not established but fibrosis and vascular narrowing would be likely components ♦♦ Criteria for vascular/humeral rejection not established ♦♦ Patients susceptible to the usual complications of heavy immunosuppression

♦♦ C4d does not appear to be useful in evaluating humoral rejection in skin-based allografts

Xenotransplantation ♦♦ Experimental work to develop animal organs for transplantation into humans, i.e., baby Jessica and the baboon heart ♦♦ Would alleviate organ shortage ♦♦ Problems with rejection control

Fig. 5.84. (A) Rejected corneal allograft showing marked edema, vascularization, and a mononuclear infiltrate. (B) PAS stain highlights Descemet membrane in this rejected cornea allograft. Note the marked edema and loss of endothelial cells.

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Table 5.17. Working Classification of Acute Cellular Rejection for Skin-Containing Allografts. From 2007 Banff Consensus Conference Grade 0 Grade I, mild Grade II, moderate Grade III, severe Grade IV

• • • •

No or rare inflammatory infiltrates Mild perivascular infiltration No involvement of the overlying epidermis Moderate-to-severe perivascular inflammation with or without mild epidermal and/or adnexal involvement (limited to spongiosis and exocytosis) • No epidermal dyskeratosis or apoptosis • Dense inflammation and epidermal involvement with epithelial apoptosis, dyskeratosis and/or keratinolysis • Necrotizing acute rejection • Frank necrosis of epidermis or other skin structures

SUGGESTED READING General Abu-Elmagd KM, Zak M, Stamos JM, et al. De novo malignancies after intestinal and multivisceral transplantation. Transplantation 2004;77: 1719–1725.

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Roland ME, Stock PG. Review of solid-organ transplantation in HIVinfected patients. Transplantation 2003;75:425–429.

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Swerdlow SH, Webber SA, Chadburn A, Ferry JA. Posttransplant lymphoproliferative disorders. In: Swerdlow SH, Cancer. IAfRo, Organization. WH, eds. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Geneva, Switzerland: WHO Press; 2008:343–349.

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Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003;3: 665–673. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007;131:1209–1218.

Kidney Chadban S. Glomerulonephritis recurrence in the renal graft. J Am Soc Nephrol 2001;12:394–402. Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 2007;18:1046–1056. Gupta G, Shapiro R, Girnita A, et al. Neutrophilic tubulitis as a marker for urinary tract infection in renal allograft biopsies with C4d deposition. Transplantation 2009;87:1013–1018. Kaplan B, Srinivas TR, Meier-Kriesche HU. Factors associated with long-term renal allograft survival. Ther Drug Monit 2002;24:36–39.

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Mengel M, Sis B, Halloran PF. SWOT analysis of Banff: strengths, weaknesses, opportunities and threats of the international Banff consensus process and classification system for renal allograft pathology. Am J Transplant 2007;7:2221–2226. Montgomery RA, Locke JE, King KE, et  al. ABO incompatible renal transplantation: a paradigm ready for broad implementation. Transplantation 2009;87:1246–1255. Nickeleit V, Andreoni K. The classification and treatment of antibodymediated renal allograft injury: where do we stand? Kidney Int 2007;71:7–11. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003;3:708–714. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999;55:713–723. Ranjan P, Nada R, Jha V, Sakhuja V, Joshi K. The role of C4d immunostaining in the evaluation of the causes of renal allograft dysfunction. Nephrol Dial Transplant 2008;23:1735–1741. Solez K, Colvin RB, Racusen LC, et al. Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 2007;7:518–526. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008;8:753–760. Truong LD, Barrios R, Adrogue HE, Gaber LW. Acute antibody-mediated rejection of renal transplant: pathogenetic and diagnostic considerations. Arch Pathol Lab Med 2007;131:1200–1208.

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Lung Belperio JA, Weigt SS, Fishbein MC, Lynch JP 3rd. Chronic lung allograft rejection: mechanisms and therapy. Proc Am Thorac Soc 2009; 6:108–121. Burlingham WJ, Love RB, Jankowska-Gan E, et  al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 2007;117:3498–3506. Cagle PT, Brown RW, Frost A, Kellar C, Yousem SA. Diagnosis of chronic lung transplant rejection by transbronchial biopsy. Mod Pathol 1995;8:137–142. Chakinala MM, Trulock EP. Acute allograft rejection after lung transplantation: diagnosis and therapy. Chest Surg Clin N Am 2003;13:525–542. Hasegawa T, Iacono AT, Yousem SA. The anatomic distribution of acute cellular rejection in the allograft lung. Ann Thorac Surg 2000;69: 1529–1531. Morrell MR, Patterson GA, Trulock EP, Hachem RR. Acute antibodymediated rejection after lung transplantation. J Heart Lung Transplant 2009;28:96–100. Ng CY, Madsen JC, Rosengard BR, Allan JS. Immunosuppression for lung transplantation. Front Biosci 2009;14:1627–1641. Rosendale B, Yousem SA. Discrimination of Epstein-Barr virus-related posttransplant lymphoproliferations from acute rejection in lung allograft recipients. Arch Pathol Lab Med 1995;119:418–423. Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002;21:271–281.

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Shilling RA, Wilkes DS. Immunobiology of chronic lung allograft dysfunction: new insights from the bench and beyond. Am J Transplant 2009;9:1714–1718.

Heart

Snell GI, Boehler A, Glanville AR, et al. Eleven years on: a clinical update of key areas of the 1996 lung allograft rejection working formulation. J Heart Lung Transplant 2007;26:423–430.

Almuti K, Haythe J, Dwyer E, et al. The changing pattern of humoral rejection in cardiac transplant recipients. Transplantation 2007;84:498–503. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990;9:587–593. Bonnaud EN, Lewis NP, Masek MA, Billingham ME. Reliability and usefulness of immunofluorescence in heart transplantation. J Heart Lung Transplant 1995;14:163–171.

Stewart S, Fishbein MC, Snell GI, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 2007;26:1229–1242.

Liver Adam R, Hoti E. Liver transplantation: the current situation. Semin Liver Dis 2009;29:3–18.

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Bellamy CO, Herriot MM, Harrison DJ, Bathgate AJ. C4d immunopositivity is uncommon in ABO-compatible liver allografts, but correlates partially with lymphocytotoxic antibody status. Histopathology 2007;50: 739–749.

Joshi A, Masek MA, Brown BW, Jr., Weiss LM, Billingham ME. “Quilty” revisited: a 10-year perspective. Hum Pathol 1995;26:547–557.

Demetris AJ, Adeyi O, Bellamy CO, et al. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology 2006;44:489–501.

Luthringer DJ, Yamashita JT, Czer LS, Trento A, Fishbein MC. Nature and significance of epicardial lymphoid infiltrates in cardiac allografts. J Heart Lung Transplant 1995;14:537–543.

Demetris AJ, Eghtesad B, Marcos A, et al. Recurrent hepatitis C in liver allografts: prospective assessment of diagnostic accuracy, identification of pitfalls, and observations about pathogenesis. Am J Surg Pathol 2004;28:658–669.

Reed EF, Demetris AJ, Hammond E, et  al. Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant 2006;25:153–159. Scott RL, Ratliff NB, Starling RC, Young JB. Recurrence of giant cell myocarditis in cardiac allograft. J Heart Lung Transplant 2001;20:375–380. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710–1720.

Demetris AJ, Lunz JG 3rd, Randhawa P, Wu T, Nalesnik M, Thomson AW. Monitoring of human liver and kidney allograft tolerance: a tissue/ histopathology perspective. Transpl Int 2009;22:120–141. Demetris AJ, Sebagh M. Plasma cell hepatitis in liver allografts: Variant of rejection or autoimmune hepatitis? Liver Transpl 2008;14:750–755.

Tan CD, Baldwin WM 3rd, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med 2007;131:1169–1191.

Demetrius Aipico AJ, Batts KP, Dhillon AP, et al. Banff schema for grading liver allograft rejection: An international consensus document. Hepatology 1997;25:658–663.

Uber WE, Self SE, Van Bakel AB, Pereira NL. Acute antibody-mediated rejection following heart transplantation. Am J Transplant 2007;7:2064–2074.

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pancreas allografts: histological differential diagnosis from acute allograft rejection. Hum Pathol 1998;29:569–577. Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. Am J Transplant 2008;8:1237–1249. Gangemi A, Salehi P, Hatipoglu B, et al. Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 2008;8:1250–1261. Geissler EK, Schlitt HJ. Immunosuppression for liver transplantation. Gut 2009;58:452–463. Habib S, Berk B, Chang CC, et  al. MELD and prediction of post-liver transplantation survival. Liver Transpl 2006;12:440–447. Hubscher SG. Transplantation pathology. Semin Liver Dis 2009;29:74–90. Inverardi L, Kenyon NS, Ricordi C. Islet transplantation: immunological perspectives. Curr Opin Immunol 2003;15:507–511. Kashyap R, Jain A, Reyes J, et al. Causes of retransplantation after primary liver transplantation in 4000 consecutive patients: 2 to 19 years followup. Transplant Proc 2001;33:1486–1487. Kerkar N, Hadzic N, Davies ET, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet 1998;351:409–413. Krasinskas AM, Demetris AJ, Poterucha JJ, Abraham SC. The prevalence and natural history of untreated isolated central perivenulitis in adult allograft livers. Liver Transpl 2008;14:625–632. Larson-Wadd K, Belani KG. Pancreas and islet cell transplantation. Anesthesiol Clin North America 2004;22:663–674. Melcher ML, Olson JL, Baxter-Lowe LA, Stock PG, Posselt AM. Antibody-mediated rejection of a pancreas allograft. Am J Transplant 2006;6:423–428.

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de Serre NP, Canioni D, Lacaille F, et al. Evaluation of c4d deposition and circulating antibody in small bowel transplantation. Am J Transplant 2008;8:1290–1296. Eisengart LJ, Chou PM, Iyer K, Cohran V, Rajaram V. Rotavirus infection in small bowel transplant: a histologic comparison with acute cellular rejection. Pediatr Dev Pathol 2009;12:85–88. Garcia M, Delacruz V, Ortiz R, et al. Acute cellular rejection grading scheme for human gastric allografts. Human Pathol 2001;35:343–349. Giovanelli M, Gupte GL, Sharif K, Mayer DA, Mirza DF. Chronic rejection after combined liver and small bowel transplantation in a child with chronic intestinal pseudo-obstruction: a case report. Transplant Proc 2008;40:1763–1767. Klaus A, Margreiter R, Pernthaler H, Klima G, Offner FA. Diffuse mesenterial sclerosis: a characteristic feature of chronic small-bowel allograft rejection. Virchows Arch 2003;442:48–55. Morotti RA, Kaufman SS, Fishbein TM, et  al. Calicivirus infection in pediatric small intestine transplant recipients: pathological considerations. Hum Pathol 2004;35:1236–1240. Parizhskaya M, Redondo C, Demetris A, et al. Chronic rejection of small bowel grafts: pediatric and adult study of risk factors and morphologic progression. Pediatr Dev Pathol 2003;6:240–250. Pascher A, Kohler S, Neuhaus P, Pratschke J. Present status and future perspectives of intestinal transplantation. Transpl Int 2008;21: 401–414. Wu T, Abu-Elmagd K, Bond G, Nalesnik MA, Randhawa P, Demetris AJ. A schema for histologic grading of small intestine allograft acute rejection. Transplantation 2003;75:1241–1248.

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6 Microbiology for the Surgical Pathologist Deborah E. Blue, md and Stephen D. Allen, md

Contents

I. Bacteria...............................................6-3

Aerobic, Facultatively Anaerobic (or Microaerophilic) Bacteria......................6-3 Gram-Positive Cocci................................6-3 Staphylococcus aureus.....................6-3 Staphylococcus epidermidis and Other Coagulase-Negative Staphylococci (CNS)..................6-5 Streptococcus pneumoniae (The Pneumococcus)..................6-6 Streptococcus pyogenes (Group A Streptococcus)...........6-7 Streptococcus agalactiae (Group B Streptococcus)...........6-8 Enterococcus Species.......................6-9 Alpha-Hemolytic Streptococci (Viridans Streptococci)..............6-9 Gram-Positive Bacilli...............................6-9 Bacillus anthracis (Etiologic Agent of Anthrax)......................6-9 Bacillus cereus...............................6-11 Corynebacterium diphtheriae........6-12 Corynebacterium jeikeium (Formerly Group “JK” Bacilli).............................6-12 Listeria monocytogenes.................6-12 Nocardia Species (Nocardiosis)....6-13 Rhodococcus equi..........................6-14 Gram-Negative Bacilli: Enterobacteriaceae............................6-16 Escherichia coli..............................6-16 Shigella Species (Cause Bacillary Dysentery)................6-17

Nontyphoidal Salmonella Infections..................................6-18 Salmonella typhi (Typhoid Fever)........................6-19 Yersinia enterocolitica....................6-19 Yersinia pestis.................................6-20 Klebsiella pneumoniae...................6-21 Infections Caused by Other Klebsiellae..................................6-22 Other Gram-Negative Bacilli................6-22 Campylobacter jejuni.....................6-22 Helicobacter pylori.........................6-23 Vibrio vulnificus.............................6-23 Pseudomonas and Related Genera.......................................6-24 Legionella pneumophila................6-25 Haemophilus influenzae................6-26 Bordetella pertussis........................6-27 Brucella Species and Brucellosis..6-27 Francisella tularensis and Tularemia...........................6-29 Gram-Negative Cocci.............................6-30 Neisseria gonorrhoeae...................6-30 Neisseria meningitidis....................6-31 Anaerobic Bacteria and Diseases....................6-31 Anaerobic Sporeforming Rods: The Clostridia....................................6-31 Clostridium perfringens.................6-32 Clostridium septicum and Bacteremia.........................6-34 Clostridium difficile.......................6-35 C. botulinum and Botulism...........6-36 C. tetani and Tetanus.....................6-36

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_6, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Anaerobic, Nonsporeforming GramNegative Rods: The Bacteroides fragilis Group, Prevotella and Porphyromonas Species, and the Genus Fusobacterium........................6-37 Anaerobic Gram-Positive Cocci: The “Peptostreptococci”...................6-38 Anaerobic Nonsporeforming Gram-Positive Rods..........................6-39 Actinomyces Species and Actinomycosis...................6-39 Mycobacterium Species.................6-39 Spirochetes: Treponema and Borrelia.............6-40 Treponema pallidum (Syphilis)..............6-40 Borrelia burgdorferi (Lyme Disease)...................................6-43 Miscellaneous Other Bacteria.........................6-44 Bartonella henselae.................................6-44 Bartonella quintana................................6-45 Bartonella bacilliformis..........................6-46 Rickettsia rickettsii and Rocky Mountain Spotted Fever...................6-46

II. Fungi..................................................6-47 Hyaline Fungi...................................................6-47 Aspergillus Species..................................6-47 Fusarium Species....................................6-48 Mucor, Absidia, and Rhizopus Species................................................6-48 Penicillium marneffei..............................6-49 Pseudallescheria/Scedosporium.............6-49 Dimorphic Fungi..............................................6-51 Blastomyces dermatitidis.........................6-51 Coccidioides immitis................................6-51 Histoplasma capsulatum.........................6-53 Paracoccidioides brasiliensis..................6-54 Sporothrix schenckii...............................6-54 Superficial Mycoses..........................................6-56 Malassezia furfur....................................6-56 Hortaea werneckii...................................6-56 Piedraia hortae........................................6-56 Trichosporon beigelii..............................6-56 Dermatophytes (Cutaneous Mycoses)............6-57 Subcutaneous Mycoses.....................................6-57 Dematiaceous (Darkly Pigmented) Fungi...................................................6-57 Chromoblastomycosis............................6-58 Phaeohyphomycosis...............................6-59 Yeasts.................................................................6-59 Candida albicans and Other Candida Species.................................6-59 Candida glabrata.....................................6-60 Cryptococcus neoformans.......................6-60 Other Fungi.......................................................6-61

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Pneumocystis jirovecii.............................6-61 Prototheca wickerhamii..........................6-63 Rhinosporidium seeberi..........................6-63

III. Viruses...............................................6-64 Adenovirus........................................................6-64 Creutzfeldt–Jakob Disease..............................6-64 Cytomegalovirus (CMV).................................6-64 Epstein–Barr Virus..........................................6-64 Hantavirus.........................................................6-66 Hepatitis Viruses..............................................6-66 Herpes Simplex Virus 1 and 2.........................6-66 Human Immunodeficiency Virus (HIV 1 & 2)........................................6-66 Human Papillomavirus....................................6-66 Human T-Cell Lymphotropic (Leukemia/ Lymphoma) Virus 1 and 2 (HTLV)...........6-68 Measles Virus....................................................6-68 Molluscum Contagiosum.................................6-68 Parvovirus B19.................................................6-69 Polyomavirus....................................................6-69 Rabies Virus......................................................6-70 Respiratory Syncytial Virus............................6-70 Varicella-Zoster Virus (VZV)..........................6-70 Variola Major Virus (Smallpox).....................6-70

IV. Parasites.............................................6-71 Protozoa.............................................................6-71 Acanthamoeba Species...........................6-71 Babesia microti........................................6-72 Balantidium coli......................................6-72 Cryptosporidium parvum........................6-72 Cyclospora cayetanensis.........................6-72 Entamoeba histolytica.............................6-73 Giardia lamblia........................................6-73 Isospora belli...........................................6-74 Leishmania Species.................................6-74 Microsporidia.........................................6-75 Naegleria fowleri.....................................6-76 Plasmodium Species................................6-76 Sarcocystis Species..................................6-77 Toxoplasma gondii..................................6-77 Trichomonas vaginalis............................6-78 Trypanosoma Species..............................6-78 Helminths..........................................................6-80 Cestodes (Tapeworms)...........................6-80 Nematodes (Roundworms)....................6-82 Trematodes (Flukes)...............................6-88

V. Other.................................................6-89 Myiasis...............................................................6-89 Sarcoptes scabiei...............................................6-89 Tunga penetrans................................................6-90

VI. Suggested Reading.............................6-90

Microbiology for the Surgical Pathologist

6-3

BACTERIA Aerobic, Facultatively Anaerobic (or Microaerophilic) Bacteria Gram-Positive Cocci ♦♦ Along with the Enterobacteriaceae, the gram-positive cocci (GPCs) which grow aerobically or as facultative anaerobes are the microorganisms most commonly encountered in clinical specimens ♦♦ GPCs are frequently encountered in suppurative (purulent), or acute inflammatory lesions ♦♦ In the clinical microbiology laboratory, testing for catalase activity is a simple way to subdivide the GPCs into the catalase-positive (e.g., Staphylococcus, Micrococcus, Kocuria, and Kytococcus) and catalase-negative (e.g., Streptococcus and Enterococcus) genera ♦♦ When vigorous bubbling occurs after a drop of hydrogen peroxide is placed on colonial material of a GPC (test performed on a glass slide), the catalase test is positive ♦♦ Absence of bubbling indicates a catalase-negative result. Cocci of the genera Micrococcus, Kocuria, and Kytococcus commonly colonize skin surfaces ♦♦ Though they can cause opportunistic infections, their presence usually reflects insignificant contamination; thus these genera will not be covered further in this chapter

Staphylococcus aureus ♦♦ This species is both catalase-positive and coagulasepositive −− The cocci (0.5–1.5  µm in diameter) occur in grape-like clusters and packets, but also may occur singly, in pairs or in short chains −− Staphylococcus aureus is one of the most important bacterial pathogens of humans −− Its virulence factors include a capsule, slime layer, peptidoglycan, numerous surface proteins, bound coagulase or “clumping factor,” which reacts with soluble fibrinogen in plasma, producing insoluble fibrin, causing the staphylococci to clump, other enzymes (e.g., hyaluronidase, fibrinolysin, lipases, and nucleases that hydrolyze DNA), teichoic acid, protein A, and various toxins (e.g., cytotoxins, exfoliative toxins, toxic shock syndrome toxin-1) ♦♦ MRSA −− Resistance to methicillin, oxacillin, nafcillin, other penicillins and beta-lactam antibiotics in methicillin-resistant S. aureus (MRSA) strains is mediated by acquisition of the mecA gene that codes for the protein-binding protein, PBP2a −− The mecA gene is located on the staphylococcal cassette chromosome mec (SCCmec) −− There are five gene sequences of the SCCmec cassette (types I–V)

−− Previously associated with hospital-acquired infections, MRSA strains have now emerged as an infectious disease threat in the community (see MRSA in the community [below])

Clinical ♦♦ Skin and soft tissue infections −− Various localized skin and subcutaneous infections (pyoderma) are produced by S. aureus including impetigo, folliculitis, furuncles (boils), carbuncles, and the staphylococcal scalded skin syndrome (SSSS) −− Hidradenitis suppurativa is a chronic, suppurative disease manifested by crops of furuncles involving apocrine sweat glands in the axillae, perineal or genital areas (a) S. aureus, anaerobes (e.g., Bacteroides and anaerobic cocci), streptococci, Enterobacteriaceae and Pseudomonas are commonly isolated from draining lesions −− Mastitis – Staphylococcal breast infections occur in 1–3% of nursing mothers −− S. aureus is a leading cause of nosocomial infections including surgical wound infections (a) MRSA strains have caused infections in hospitalized patients for many years −− MRSA in the community – In recent years, new MRSA strains have emerged in outbreaks of community-acquired cutaneous infections and pneumonia in several countries around the world (a) According to the CDC, pulse field gel electrophoresis genotype USA300 is the predominant US strain, though other strains predominate in other countries (b) Community-associated strains, in contrast to most hospital-associated strains, are characterized by the following * Type IV SCCmec cassette which encodes methicillin resistance * Panton-Valentine leukocidin (PVL) * Susceptibility to most antibiotics (e.g., sulfamethoxazole–trimethoprim) other than methicillin/ oxacillin/nafcillin, and the other penicillins and beta-lactams −− Erysipelas, cellulitis, and fasciitis may be caused by S. aureus, but are more often caused by Streptococcus sp ♦♦ Botryomycotic abscesses −− Their most common location is in subcutaneous tissue −− Other locations include liver, kidney, lung, prostate, and lymph nodes −− Predisposing factors include trauma or foreign bodies; cystic fibrosis −− Botryomycotic abscesses may involve other bacteria (e.g., Pseudomonas aeruginosa)

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♦♦ Organ infections and disseminated infections −− S. aureus is a major cause of life-threatening bacteremia or septicemia. Staphylococcal septicemia has increased in incidence in the past two decades (a) These infections may be healthcare associated – often in patients with infected vascular or urinary catheters (b) They also may be community associated (c) Methicillin-resistant S. aureus (MRSA) is common in both of the above settings −− S. aureus endocarditis (a) Approximately 30% of cases involve patients with previously normal valves

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* Approximately 20% of these patients have prosthetic valves (b) Most cases of endocarditis involving intravenous drug users are due to S. aureus (about 70%) (c) Bulky vegetations tend to occur in S. aureus endocarditis * These infections are very destructive to valve ­tissue (d) Left sided valves are most frequently involved, but they are often right-sided in IV drug abusers (e) A source of bacteremia and septic emboli to distant organs Deep abscesses (often metastatic) occur in various organs (a) However, S. aureus may also cause cellulitis Pulmonary infections including pneumonia due to S. aureus are common and tend to be severe (a) Approximately 10% of community-acquired pneumonia (b) Approximately 20–30% of nosocomial pneumonia is due to S. aureus (c) Necrotizing pneumonia due to PVL (leucocidin) positive S. aureus has emerged recently; it is often preceded by influenza-like syndrome, and frequently lethal Osteomyelitis (a) This is due to S. aureus in 50–70% of cases (b) Bones are infected hematogenously or by contiguous contamination (c) S. aureus ranks second in osteosynthetic prosthesis infections after coagulase-negative staphylococci Septic arthritis (a) Children – S. aureus is the most frequent cause (b) Adults – S. aureus is the most frequent cause of nongonococcal septic arthritis; the major underlying risk factors follow * Rheumatoid arthritis * Diabetes mellitus

♦♦ S. aureus toxin-related diseases −− The staphylococcal scalded skin syndrome (SSSS; or Ritter disease) is a toxin-mediated condition that occurs most often in newborns (less often in older children and rare in adults) (a) It resembles a sunburn-like red rash that spreads over the entire body with formation of large, fragile bullae followed by desquamation * With slight pressure on the bullae, the skin is displaced (positive Nikolsky sign) * The bullae contain clear fluid without inflammatory cells or organisms * Within 10–14 days, the epidermis becomes intact again unless secondary infection occurs (b) SSSS is mediated by exfoliative A and B toxins, both serine proteases that split desmoglein 1 in the epidermis, thereby disrupting intercellular bridges in the stratum granulosum (c) Toxic epidermal necrolysis (Lyell disease), secondary to drug hypersensitivity, involves desquamation at the level of the epidermal – dermal junction and thus differs from SSSS −− Staphylococcal superantigens cause (a) Food poisoning * An estimated 6–8 million US cases of this occur each year * The onset occurs usually within 2–6 h after ingesting preformed heat stable enterotoxin in contaminated food * S. aureus harbors up to 15 enterotoxins – these are defined as superantigens (able to produce vomiting and diarrhea in primate models) (b) Toxic shock syndrome (TSS) * TSS was originally associated with use of hyperabsorbent tampons * TSS is now known to be caused by growth of S. aureus in surgical wounds (as well as vaginas) * Patients develop shock, renal failure, coagulopathy, liver disease, respiratory distress, generalized erythematous rash, and necrosis at the infected site

Macroscopic ♦♦ Varying size abscesses (white, gray, yellow, pink, tan, or brown pus surrounded by viable tissue) are common

Microscopic (Fig. 6.1A, B) ♦♦ Acute pyogenic inflammation which is particularly destructive (no matter if lesion involves skin, subcutaneous tissue, heart valves, lungs, bones, brain, or other deep organ) is characteristic ♦♦ The polymorphonuclear leukocyte is the major cellular component ♦♦ Abscess formation – characterized by a localized area of acute inflammation surrounding a focus of necrosis, is a hallmark

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♦♦ Streptococcus pyogenes is an additional cause of Toxic Shock Syndrome ♦♦ Botryomycosis – the differential includes −− Actinomycotic granules −− Deep mycotic infections

Diagnostic Techniques ♦♦ Culture or other means of demonstrating microorganism may be required for definitive diagnosis ♦♦ Antimicrobial susceptibility testing aids in selecting antibiotics for treatment

Staphylococcus epidermidis and Other ­Coagulase-Negative Staphylococci (CNS) ♦♦ Like S. aureus with respect to their Gram stain features and microscopic appearances, these catalase-positive staphylococci differ from S. aureus by their negative coagulase reaction

Clinical

Fig. 6.1. (A) Staphylococcus aureus in Gram-stained smear of purulent exudate, (B) Botryomycotic abscess (H&E). ♦♦ In H&E stains, dead, dying, or viable cocci often appear as amphophilic granular material ♦♦ In botryomycosis, abscesses contain basophilic granules in an acellular eosinophilic coagulum (Splendore-Hoeppli material)

Special Stains ♦♦ Staphylococci are 0.5–1.5  mm gram-positive spherical to “kidney bean” shaped cocci with a tendency to form clusters ♦♦ Brown–Brenn is generally the best tissue Gram stain for gram-positive bacteria ♦♦ Brown–Hopps is generally the best tissue Gram stain for gram-negative bacteria ♦♦ MacCallum-Goodpasture, another modified tissue Gram stain, can also be used to determine the gram reaction of bacteria

Differential Diagnosis ♦♦ Impetigo – the differential includes Herpes simplex or Varicella zoster ♦♦ Abscess – the differential includes other nonanaerobic bacteria and various anaerobic bacteria ♦♦ Cellulitis and fasciitis – the differential includes Streptococcus pyogenes, anaerobes, and other bacteria

♦♦ The CNS inhabit the normal human skin and mucosal surfaces ♦♦ In the past, the less virulent coagulase-negative staphylococci were generally regarded as insignificant contaminants. Through the years, however, it has become clear that these bacteria are important pathogens, capable of producing human disease ♦♦ In general, S. epidermidis is the most prevalent of the CNS in infections ♦♦ Nosocomial bacteremia – the CNS are the most common cause of nosocomial bacteremia; however −− Typically, 1–3% of blood cultures are contaminated with CNS −− Approximately 25–75% of CNS isolated from blood cultures are contaminants ♦♦ Endocarditis of native and prosthetic valves −− The CNS cause approximately 5–8% of all cases of bacterial endocarditis; the CNS are not common causes of native valve endocarditis −− In contrast, CNS are the most common cause of prosthetic valve endocarditis (approximately 40% of cases) ♦♦ Intravenous catheter infections – S. epidermidis is the single most common cause of these infections ♦♦ Cerebrospinal fluid (CSF) shunt infections – S. epidermidis is the most common microorganism involved ♦♦ Prosthetic joint infections (e.g., of the hip and knee) can involve CNS ♦♦ Urinary tract infections in young, sexually active women may be due to CNS −− S. saprophyticus is a common cause of these infections

Diagnostic Techniques (Fig. 6.2) ♦♦ Microscopic and special stain features of the CNS are indistinguishable from those of S. aureus ♦♦ Identification of isolates in the microbiology laboratory is based on relatively simple biochemical tests

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Fig. 6.2. Coagulase-negative Staphylococcus species in sputum specimen (Diff-Quik).

Fig. 6.3. Streptococcus pneumoniae in sputum (Gram).

Streptococcus pneumoniae (The Pneumococcus) Clinical

−− Complications – empyema, lung abscess, and pericarditis may occur ♦♦ Meningitis −− The CSF is cloudy or purulent (abundant neutrophils and bacteria) −− Leptomeningeal exudate is often the thickest over the cerebral convexities near the sagittal sinus −− Meningeal vessels are engorged and prominent −− The underlying brain is swollen

♦♦ This catalase-negative gram-positive coccus colonizes the nasopharynx of about −− 5–10% of healthy adults −− 20–40% of healthy children ♦♦ It is a common cause of community-acquired pneumonia in adults ♦♦ S. pneumoniae is the most common cause of meningitis in adults, except during a Neisseria meningitidis outbreak ♦♦ S. pneumoniae is the most common cause of meningitis in children in countries where children are vaccinated for Haemophilus influenzae type B ♦♦ This organism is the most prevalent pathogen in otitis media in children (40–50% of cases), and it ranks second only to nontypable H. influenzae in this regard ♦♦ S. pneumoniae also is the most common cause of otitis media in adults ♦♦ In a number of studies, S. pneumoniae has usually ranked as the most common cause of acute paranasal sinusitis or second only to nontypable H. influenzae; acute paranasal sinusitis is often preceded by a viral infection (e.g., common cold)

Macroscopic ♦♦ Lobar pneumonia – most cases are caused by S. pneumoniae; less frequent causes include Klebsiella pneumoniae, staphylococci, streptococci, H. influenzae and Legionella sp ♦♦ The classic stages follow −− Congestion – is usually seen in the first 24 h −− Red hepatization – the lung appears red and firm, with a liver-like consolidation (due to abundant neutrophils and erythrocytes) −− Gray hepatization – there is lytic destruction of erythrocytes with persistent fibrinosuppurative exudate −− Resolution – in this stage, the exudate is destroyed and cleared; the lung is restored to normal

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Microscopic (Fig. 6.3) ♦♦ An acute neutrophilic host response occurs ♦♦ Polysaccharide capsule (90 antigenic serotypes), which ­prevents pneumococci from being phagocytosed, is often suggested by the halo-like area around the cocci

Special Stains ♦♦ Gram stain – the organisms appear as slightly elongated, “lancet,” or “football” shaped gram-positive cocci, usually in pairs in clinical materials ♦♦ A halo-like appearance of capsule against the background is often prominent

Differential Diagnosis ♦♦ Enterococcus sp., although not common in respiratory ­infections or meningitis, can be morphologically similar to S. pneumoniae ♦♦ Other genera and species may form pairs of cocci (including staphylococci and other streptococci), but most are not “Lancet” or “football” shaped ♦♦ S. pneumoniae may be confused with Klebsiella pneumoniae in an overdecolorized Gram stain ♦♦ K. pneumoniae in an underdecolorized Gram stain may resemble pneumococci

Diagnostic Techniques ♦♦ Good quality sputum for culture is essential (microbiology laboratories reject poor quality “sputa” based on established criteria)

Microbiology for the Surgical Pathologist

♦♦ Blood cultures are indicated in patients clinically suspected of having bacterial pneumonia −− Approximately 25% of patients with pneumococcal pneumonia have positive blood cultures ♦♦ Urine assays for pneumococcal polysaccharide are positive in two-third of patients with pneumococcal pneumonia, but also positive in up to 15% of patients with nonpneumococcal pneumonia, and may be positive in healthy children with nasopharyngeal colonization

Streptococcus pyogenes (Group A Streptococcus) ♦♦ Group A streptococci are catalase-negative, gram-positive, spherical to ovoid cocci that occur in pairs or chains ♦♦ Also one of the most important bacterial pathogens of humans, it colonizes throats of 15–20% of asymptomatic school children; the carriage rate in adults is lower

Clinical ♦♦ Pharyngitis and tonsillitis −− S. pyogenes is the most common bacterial cause of these infections −− One of the potential postinfectious, nonsuppurative complications of S. pyogenes pharyngitis is rheumatic fever −− Immune complex glomerulonephritis (poststreptococcal glomerulonephritis), in contrast to rheumatic fever, is a postinfectious nonsuppurative sequela of both S. pyogenes pharyngitis and impetigo (pyoderma; see below) ♦♦ Scarlet fever −− This is a complication involving an S. pyogenes strain lysogenized by a bacteriophage that produces a pyrogenic exotoxin −− It is usually associated with pharyngitis and tonsillitis −− It is most common between the ages of 3 and 15 years −− There is a prominent punctate, erythematous rash that is most abundant over the trunk and inner aspects of arms or legs −− The face is involved but an area around the mouth is unaffected (circumoral pallor) ♦♦ Erysipelas −− This is an acute inflammatory process involving the skin due to S. pyogenes (group C strep occasionally) −− It mostly occurs in infants and in adults over 30 −− It is characterized by rapidly spreading, cutaneous ­swelling and a rash involving the face (“butterfly” distribution) ♦♦ Impetigo (pyoderma) −− This is a focal, purulent infection of the skin caused by S. pyogenes which follows colonization after exposure to fomites or contact with an infected person (a) A minor scratch, insect bite, or another type of break in the skin introduces the organism into the skin and subcutaneous tissue

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−− Groups C and G streptococci have also been implicated −− S. aureus is also commonly encountered in impetigo −− The infection involves the superficial layer of the epidermis with production of pus-filled vesicles that crust over; with scratching, they readily spread ♦♦ Streptococcal cellulitis −− This takes the form of an acute, spreading inflammation of the skin and subcutaneous tissues −− It results from infection of burns, wounds or surgical incisions −− Predisposing factors include intravenous drug injection, and impaired lymphatic drainage from the upper (e.g., postmastectomy) or lower extremities ♦♦ Necrotizing fasciitis (streptococcal gangrene, or “hospital gangrene”) −− It was described in 1924 by Frank Meleney −− Predisposing factors include (a) Trauma or appendicitis in young people (b) Diabetes, congestive heart failure, or surgical trauma in older people −− The infection involves the deeper subcutaneous tissue and fascia −− Extensive/rapidly spreading necrosis, and gangrene of the skin and underlying structures are characteristic features −− The mortality of this condition is high: 20–70% −− Virulent S. pyogenes sometimes called “flesh-eating bacteria” by the media ♦♦ Nonsuppurative poststreptococcal sequelae (described in other chapters) −− Acute rheumatic fever (a) This is characterized by nonsuppurative inflammatory lesions involving primarily the heart, joints, and subcutaneous tissues (b) It follows group A streptococcal upper respiratory infections −− Poststreptococcal glomerulonephritis (a) This is an acute inflammatory disorder of the renal glomerulus characterized by edema, hypertension, hematuria, and proteinuria (b) It is a delayed sequela of pharyngeal or cutaneous infection with certain “nephritogenic” strains

Microscopic (Fig. 6.4) ♦♦ Scarlet fever −− The dermis is edematous and hyperemic with scant perivascular lymphocytes and other mononuclear cells −− Inflammation of the epidermis is followed by hyperkeratosis and desquamation of the skin ♦♦ Erysipelas −− The epidermis shows spongiosis −− There is acute edematous, neutrophilic inflammation in the dermis; it is prominent around vessels and adnexa and extends into subcutaneous tissue

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♦♦ It is an asymptomatic colonizer of the lower gastrointestinal tract and genitourinary tract (20–40% of adult women) ♦♦ Approximately 60% of infants born to colonized mothers become colonized with mother’s S. agalactiae

Clinical

Fig. 6.4. Streptococcus species in positive blood culture (Gram).

♦♦ Impetigo (pyoderma) due to S. pyogenes −− It resembles impetigo caused by S. aureus −− However, abscess formation is less common with S. pyogenes than with S. aureus ♦♦ Streptococcal cellulitis −− This is characterized by diffuse interstitial, neutrophilic infiltrates within cellular connective tissue −− It involves minimal damage to host tissue ♦♦ Necrotizing fasciitis (streptococcal gangrene) −− This is characterized by hemorrhage, edema, and necrosis plus mixed inflammatory cell inflammatory infiltrate that dissects along fascial planes

Special Stains ♦♦ Streptococci may be difficult to see in H&E stained sections ♦♦ Brown–Brenn is the preferred tissue Gram stain ♦♦ These streptococci are spherical or ovoid gram-positive cocci, often in short chains in histologic sections; the finding of >10 cocci per chain aids in recognizing streptococci in stained smears of body fluids, exudates, and cultures

Differential Diagnosis ♦♦ Staphylococci cause similar infections, but tend to form clusters and almost never form long chains ♦♦ Other bacteria including clostridia and anaerobic cocci share similar microscopic features −− Some anaerobes cause similar infections

Streptococcus agalactiae (Group B Streptococcus) ♦♦ Group B streptococci are catalase-negative, gram-positive cocci that occur in pairs or chains ♦♦ This species is an important bacterial pathogen of neonates and infants under 3 months, pregnant women, and also older adults

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♦♦ Early-onset neonatal disease −− This occurs when the organism is acquired in utero or at birth (first week of life) −− It is characterized by sepsis, pneumonia, and meningitis ♦♦ Late-onset neonatal disease (older infants) −− This occurs between 1 week and 3 months of life −− It is acquired from the mother or another infant −− The predominant manifestations are pneumonia with meningitis ♦♦ In pregnant and postpartum women, S. agalactiae can cause urinary tract infections and endometritis ♦♦ In addition, S. agalactiae is an emerging cause of morbidity and mortality (15% to >30%) in men and nonpregnant women −− Generally, in older individuals diabetes mellitus or underlying liver disease (e.g., secondary to alcohol) are the commonest predisposing factors −− The most common manifestations are bacteremia, pneumonia, bone, and soft tissue infections

Microscopic ♦♦ Congenital pneumonia (due to contamination of amniotic fluid after premature rupture of membranes or prolonged labor) often has a lobar distribution −− It is characterized by neutrophilic inflammation; it lacks fibrin (amniotic fluid is fibrinolytic) −− Squamous debris and other elements of meconium are present ♦♦ Perinatally acquired pneumonia due to S. agalactiae −− Hyaline membranes and neutrophilic infiltrates are often present −− Sections show the presence of large numbers of grampositive cocci in hyaline membranes ♦♦ Purulent meningitis −− Meningitis due to S. agalactiae resembles meningitis caused by other bacteria −− Beyond the newborn period, it is rare in infants or in older children

Special Stains ♦♦ Brown–Brenn is the preferred tissue Gram stain ♦♦ The presence of gram-positive cocci in chains aids in diagnosis (see Fig. 6.5)

Differential Diagnosis ♦♦ The distinction from noninfectious hyaline membrane disease can be made by demonstrating bacteria in the hyaline membranes plus a more pronounced neutrophilic inflammation

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♦♦ These bacteria are gram-positive cocci that occur in singles, pairs, and chains of varying lengths ♦♦ They can be encapsulated

Differential Diagnosis ♦♦ They frequently are indistinguishable from Streptococcus pneumoniae on direct microscopic examination ♦♦ Though “lancet-shaped” diplococci are typically formed by S. pneumoniae, it can also form chains ♦♦ Enterococci can vary from spherical to ovoid or somewhat “lancet-shaped”

Alpha-Hemolytic Streptococci (Viridans Streptococci) Fig.  6.5. Enterococcus faecium pneumonia (bronchoalveolar lavage specimen [Gram]).

♦♦ “Viridans” is a descriptive name, not a taxonomic name, for Streptococcus species other than S. pneumoniae that produce partial hemolysis of erythrocytes in blood agar

Clinical ♦♦ S. agalactiae and Escherichia coli are tied for first place as the most common bacterial causes of neonatal meningitis −− Their microscopic features differ

Enterococcus Species ♦♦ Previously included with the group D streptococci, these catalase-negative, gram-positive cocci normally inhabit the gastrointestinal tracts of humans and other animals ♦♦ The most commonly encountered Enterococcus species in infections are E. faecalis (~80–90%) and E. faecium (~10–15% or more of enterococcal isolates)

Clinical ♦♦ Patients at increased risk of infection with enterococci include those hospitalized for long periods of time and those being treated with broad-spectrum antibiotics −− These bacteria are inherently resistant to many commonly used antibiotics (e.g., oxacillin, cephalosporins, and other b-lactam agents) −− They also may acquire resistance genes (e.g., aminoglycosides, vancomycin) ♦♦ They cause approximately 10% of nosocomial infections ♦♦ Enterococcal urinary tract infections are common in patients with urinary catheters ♦♦ Wound infections (e.g., intraabdominal); many such infections are polymicrobial and the significance of the Enterococcus species in these infections is not always clear ♦♦ Bacteremia due to enterococci may be highly clinically significant, especially in patients with intravascular catheters ♦♦ Bacterial endocarditis; Enterococcus species cause ~15% of cases ♦♦ Pneumonia (well-documented but unusual) ♦♦ Meningitis (a rare cause)

Microscopic (Fig. 6.5) ♦♦ Although enterococci have relatively low virulence, acute inflammation is associated with these infections

♦♦ Certain oral species, particularly Streptococcus mutans, play a significant role in dental plaque formation and dental caries ♦♦ Other types of clinical settings from which alpha-hemolytic streptococci (e.g., S. sanguis, S. constellatus, S. intermedius and/ or others) are isolated include bacteremia, infective endocarditis, aspiration pneumonia, and abscesses in multiple organs

Gram-Positive Bacilli Bacillus anthracis (Etiologic Agent of Anthrax) ♦♦ B. anthracis is a sporeforming (subterminal spores), grampositive rod, which grows aerobically and produces catalase −− It differs from other Bacillus species encountered in clinical microbiology laboratories by its lack of hemolysis on blood agar, inability to hydrolyze gelatin or ferment salicin, and its absence of motility ♦♦ Historically, anthrax has been a disease of animals having contact with soil contaminated with spores, and herbivorous animal-associated disease of humans (e.g., “woolsorter’s disease”) −− Although still endemic in many countries, animal-associated disease of humans became uncommon in the USA as a result of vaccinating animals and preventive measures applied to the processing of materials from animals (e.g., wool and hides) −− B. anthracis has also been used as an agent of biological warfare by a number of countries −− In 1992, weaponization of B. anthracis through the years was admitted by the former Soviet Union along with information that in 1979 an accidental release of B. anthracis spores from a Soviet military laboratory in Sverdlovsk resulted in at least 77 cases of inhalational anthrax with 66 mortalities −− Then in 2001 in the USA, both cutaneous and inhalational forms of anthrax were acquired in people exposed to B. anthracis spores that had been sent in contaminated letters as a deliberate act of bioterrorism

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♦♦ The major virulence factors of B. anthracis are the antiphagocytic polypeptide capsule (poly-d-glutamic acid), and anthrax toxins −− Anthrax toxins contain three protein components, the protective antigen (PA), edema factor (EF), and lethal ­factor (LF) (a) The proteins are not toxic by themselves (b) PA + EF forms edema toxin, which has adenylate cyclase activity and is responsible for the major fluid accumulation in anthrax (c) PA + LF forms lethal toxin, which is the major virulence factor −− Accordingly, the zinc metalloprotease activity of the lethal toxin causes macrophages to release tumor necrosis factor-alpha (TNF-a), interleukin-1b (IL-1b), and other cytokines −− Lethal toxin, depending upon its concentration, also blocks macromolecular synthesis in macrophages and causes macrophages to lyse

Clinical ♦♦ Cutaneous −− About 95% or more of naturally occurring cases are cutaneous −− The incubation period is 1–12 days −− The lesions usually occur on exposed skin of the head, neck, or an upper extremity ♦♦ Inhalational (woolsorter’s disease) −− Inhalational anthrax may develop 1–5 days after inhaling spores (a) However, there may be a long latent period (>1 month) with spores in the nasal passages or in the lower respiratory tract that subsequently are phagocytized by macrophages and transported to mediastinal lymph nodes −− The illness begins with a “flu-like” onset with fever, myalgias, and a nonproductive cough −− There is a left shifted neutrophilia −− Severe respiratory distress begins with a sudden onset −− Mediastinal widening is a characteristic radiographic feature −− Without early recognition and treatment, shock followed by death within 1–2 days occurs in most patients ♦♦ Gastrointestinal −− This is rare; most reported cases are from Africa and Southeast Asia −− It is acquired through ingestion of B. anthracis spores (e.g., in contaminated undercooked meat) −− Symptoms include nausea, vomiting, anorexia, fever, abdominal pain, and severe bloody diarrhea

Macroscopic ♦♦ The hallmark is hemorrhage and edema ♦♦ Cutaneous

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−− It begins as a papule that is usually pruritic resembling a bug or spider bite −− By 48 h, the cutaneous lesion becomes a pruritic vesicle surrounded by edematous, blue-black tissue −− The vesicle subsequently becomes necrotic and hemorrhagic, producing the classic black eschar that is painless and usually self-limiting. In contrast, spider bites are usually painful ♦♦ Inhalational −− Hemorrhagic lymphadenitis and mediastinitis are characteristic features −− Manifestations of hematogenous spread occur, especially hemorrhagic meningitis (i.e., ”cardinals cap”) ♦♦ Gastrointestinal −− A localized oropharyngeal lesion may occur (a) This is less common than intestinal involvement −− This may occur as a severe systemic disease with a localized necrotizing lesion in the terminal ileum or cecum containing many organisms

Microscopic ♦♦ Features include hemorrhage, edema, necrosis, fibrin deposition, increased neutrophils, and profound bacillemia ♦♦ Lymphoid necrosis (with sinus histiocytosis and hemorrhage in lymph nodes) is a prominent finding ♦♦ Necrotizing vasculitis in small cerebral vessels is a prominent feature of hematogenous spread

Special Stains ♦♦ B. anthracis is a gram-positive, large “box-car”-shaped bacillus −− It tends to form short chains of vegetative cells in tissue, and long chains in culture ♦♦ Spores are not seen in histologic sections or in smears of fresh clinical specimens

Differential Diagnosis ♦♦ The differential includes staphylococcal cellulitis, ­tularemia, plague, cat-scratch disease, rat bite fever, and sporotrichosis ♦♦ Taking a good history can be the most important step in making a correct diagnosis

Diagnostic Techniques ♦♦ Specimens to be collected from suspected anthrax patients include −− Cutaneous (a) Collect vesicular fluid with swabs for culture and direct smear preparation, full-thickness punch biopsy fixed in 10% neutral buffered formalin (b) If present, biopsies of vesicle and eschar should also be taken −− Intestinal (a) If an adequate history suggests intestinal anthrax, collect feces, and blood for culture

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♦♦ ♦♦

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(b) If there is an autopsy, collect the following for smears and cultures: blood, hemorrhagic fluids from the nose, mouth or anus; aspirates from the spleen and/ or lymph nodes −− Inhalational (a) If the patient is ill and an adequate patient history suggests it, blood for culture should be collected (b) At autopsy, the same materials as described for intestinal anthrax should be collected The organism grows well on sheep blood agar (“Medusa head colonies”) and other media B. anthracis is one of the Category A agents of bioterrorism −− These are agents that pose the greatest threat relative to their infectious nature, ease of spread, or high mortality (e.g., Bacillus anthracis, Clostridium botulinum [botulinum toxins], Francisella tularensis, Brucella species [see text]), Yersinia pestis, Variola major [smallpox], Filoviruses [Marburg virus, Ebola virus], and Arenaviruses [Lassa virus, Machupo virus]) In a healthcare setting, laboratory procedures to be performed with B. anthracis must be done in a facility with a biosafety level of at least 2 −− Activities that are at high risk for creating aerosols with this organism should be done in a biosafety level 3 laboratory If anthrax is suspected in a clinical laboratory or sentinel laboratory, local and state public health authorities must be notified immediately A useful CDC website for laboratory information follows: http://www.bt.cdc.gov/labissues The Laboratory Response Network tollfree HelpDesk: (866) 576-5227 is available for subject matter experts if discussions on individual organisms are needed Another excellent source of laboratory information relative to these types of agents is the American Society for Microbiology website (http://www.asm.org/Policy/index. asp?bid=520)

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(a) It has an incubation period of 10–12  h similar to Clostridium perfringens foodborne illness ♦♦ Non-GI Infections include the following −− Local (ocular, trauma, burn, and wound infections) −− Bacteremia/septicemia (intravenous drug use, indwelling catheters, hemodialysis) −− Central nervous system (shunt or trauma associated) −− Respiratory −− Endocarditis

Macroscopic ♦♦ Cutaneous infections may begin as a single necrotic bulla ♦♦ Reports of bacillus central nervous system infections have described brain abscess, subarachnoid hemorrhage, and necrotic lesions at the gray-white junctions

Microscopic (Fig. 6.6) ♦♦ Vasculitis, coagulative necrosis, and hemorrhage may be seen ♦♦ Large clusters of large bacilli may be found in necrotic areas ♦♦ There may be little to no inflammatory response in neutropenic patients

Special Stains ♦♦ Brown–Brenn Gram stain may reveal sporeforming grampositive or gram-variable bacilli ♦♦ B. cereus is usually PAS+ after diastase digestion

Differential Diagnosis The differential diagnosis includes the following ♦♦ Clostridium species ♦♦ Bacillus anthracis

Diagnostic Techniques ♦♦ Culture is required for definitive diagnosis

Bacillus cereus ♦♦ This is a sporeforming, gram-positive rod, which grows aerobically and produces catalase ♦♦ Unlike B. anthracis, B. cereus produces hemolysis on sheep blood agar and is motile ♦♦ B. cereus is ubiquitous in nature and the hospital environment ♦♦ Other Bacillus species such as B. subtilis and B. sphaericus are common laboratory contaminants

Clinical ♦♦ Gastrointestinal (GI) illness −− One form is the toxin-induced emetic form (associated with consumption of contaminated refried rice) (a) It has a short incubation period of 1–6 h similar to staphylococcal food poisoning −− The second form of GI illness caused by B. cereus is diarrheagenic food poisoning

Fig. 6.6. Bacillus species (microbiologic culture [Gram]).

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Corynebacterium diphtheriae Clinical

Corynebacterium jeikeium (Formerly Group “JK” Bacilli)

♦♦ Diphtheria is caused by C. diphtheriae, a pleomorphic grampositive rod with swollen ends that forms “picket fence” arrangements or “palisades,” “Chinese letters” and other interesting appearances ♦♦ There is respiratory spread ♦♦ C. diphtheriae proliferates at the site of attachment (e.g., oropharyngeal pseudomembrane) ♦♦ Ulcerative cutaneous lesions also may be primary sites of infection ♦♦ A phage-encoded exotoxin damages the heart and peripheral nerves

♦♦ C. jeikeium shows clinically important resistance to most antibiotics except vancomycin. Most infections by this species are nosocomial

Macroscopic ♦♦ The diphtheritic pseudomembrane consists of a thick, gray or black, tenacious exudate −− It adheres to the submucosa −− Bleeding and asphyxiation may result if the pseudomembrane is removed or sloughed away ♦♦ Skin ulcers also may be covered with gray pseudomembranes

Microscopic ♦♦ The pseudomembrane contains fibrin, neutrophils, and necrotic debris ♦♦ Exotoxin damage to the heart is manifested by fatty myocardial change with isolated myofiber necrosis ♦♦ Exotoxin induced neuritis is manifested by degeneration of myelin sheaths

Special Stains ♦♦ Loeffler methylene blue stain, done on smears prepared from overnight growth on Loeffler medium, can aid in providing a preliminary or presumptive diagnosis by revealing diphtheroid forms with metachromatic granules ♦♦ Immunofluorescent staining of 4-h cultures is also useful

Clinical ♦♦ Infections caused by C. jeikeium and other Corynebacterium species include −− Intravenous catheter-related blood stream infections −− Skin and soft tissue infections −− Pneumonia −− Prosthetic valve and native valve endocarditis −− Cerebral spinal fluid shunt infections and meningitis −− CAPD-related peritonitis

Microscopic (Fig. 6.7) ♦♦ C. jeikeium occurs as gram-positive pleomorphic rods; with interesting “oriental letters,” “Chinese letters,” “birds in flight,” and “picket fence” arrangements

Differential Diagnosis ♦♦ Definitive diagnosis requires microbiologic culture and identification of the organism

Listeria monocytogenes ♦♦ L. monocytogenes is a small, coccobacillary gram-positive, nonsporeforming rod that is capable of growth at 4°C, motile at room temperature, poorly motile or nonmotile at 37°C, weakly b-hemolytic on blood agar and catalasepositive ♦♦ It can be isolated from soil, water, sewage, decaying vegetation, the fecal microbiota of >40 animals, and feces of about 1–5% of asymptomatic humans ♦♦ It is a facultative intracellular pathogen that can infect many different domesticated and nondomesticated animals, and humans

Differential Diagnosis ♦♦ The differential includes infectious mononucleosis, streptococcal or viral pharyngitis and tonsillitis, Vincent angina, and acute epiglottitis ♦♦ Definitive diagnosis requires microbiologic culture −− Swab specimens are inoculated onto sheep blood agar, and/or colistin-nalidixic acid agar, along with cystinetellurite blood agar or modified Tinsdale agar for the isolation of C. diphtheriae −− Colonies resembling those of C. diphtheriae must be identified by biochemical testing (nucleic acid sequencing is used in some laboratories) −− Toxigenicity testing is also required (a) This can be done using a modified Elek immunoprecipitation-immunodiffusion test or by alternative immuno methods (b) PCR methods have also been developed that detect gene sequences of toxigenic C. diphthriae

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Fig.  6.7. Corynebacterium jeikeium, in positive blood culture (Gram).

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Clinical

Epidemiology and Clinical Manifestations

♦♦ It causes food-borne illness, both sporadically and in large outbreaks associated with contaminated foods (e.g., contaminated dairy products, undercooked meats, poultry, unwashed vegetables, and cabbage) ♦♦ The organism causes mild illness (e.g., gastroenteritis and flu-like illness) in otherwise healthy adults ♦♦ Pregnant women, usually associated with their decline in cell-mediated immunity during the third trimester, are at increased risk of developing listerial bacteremia clinically manifested as an acute febrile illness usually accompanied by chills, headache, myalgias, arthralgias, and backache −− In contrast to others who are prone to develop listeriosis, meningitis is rare in pregnant women ♦♦ The organism can spread transplacentally resulting in amnionitis, and life-threatening in utero infection −− This can result in spontaneous abortion, premature birth, or death may occur within hours due to a disseminated form of listeriosis (i.e., granulomatous infantiseptica with abscesses of many organs) ♦♦ Listeria is an important cause of clinically significant bacteremia and meningitis in immunocompromised patients (e.g., bone marrow and organ transplant recipients; patients with AIDS)

♦♦ Nocardia species are ubiquitous in soil, organic materials, and water; nocardiosis occurs worldwide ♦♦ Infections arise exogenously (unlike Actinomycosis) from inhalation or direct inoculation ♦♦ Nocardia asteroides complex causes most (about 80–90%) respiratory and disseminated infections ♦♦ N. brasiliensis, and N. otitidis-caviarium cause most cutaneous infections ♦♦ Predisposing factors include the following −− Leukemia/lymphoma −− Immunosuppressive therapy −− AIDS −− Chronic pulmonary disorders (e.g., pulmonary alveolar proteinosis) −− Chronic granulomatous disease of childhood ♦♦ Pulmonary disease – the predominant clinical manifestations follow −− Fibrinosuppurative pneumonia; usually with minimal fibrosis −− Lung abscesses and cavitating lesions (sometimes large) −− Empyema −− There is a tendency for hematogenous spread originating from the lungs as the primary site to other body sites, particularly the CNS (usually with brain abscess) ♦♦ Cutaneous or subcutaneous lesions −− These result either from traumatic inoculation or from systemic dissemination from the lungs ♦♦ The treatment of choice for nocardiosis is trimethoprim/ sulfamethoxazole −− Alternatively, amikacin plus a carbapenem are given in combination intravenously for 3–4 weeks followed by trimethoprim/sulfamethoxazole orally −− In contrast, the treatment of choice for Actinomycosis is ampicillin, amoxicillin, or penicillin G or penicillin V

Microscopic and Special Stains ♦♦ In acute meningitis, the findings are nonspecific and similar to those seen in pyogenic meningitis caused by Neisseria meningitidis or Haemophilus influenzae ♦♦ The presence of small gram-positive rods in cerebrospinal fluid can be diagnostic, though L. monocytogenes may be confused with H. influenzae (if underdecolorized), appear as pairs of cocci suggesting S. pneumoniae, or it may resemble Propionibacterium or Corynebacterium and mistakenly thought to be a skin contaminant ♦♦ Placentitis is characterized by acute inflammation and abscess formation −− In suspected prenatal infection, the placenta and fetal membranes should be examined and cultured −− The mother’s reproductive tract also should be cultured

Nocardia Species (Nocardiosis) ♦♦ Nocardiosis is a disseminated or localized infection caused by obligately aerobic, gram-positive, branching, filamentous rods of the genus Nocardia

Classification ♦♦ The organism is classified with the “aerobic nocardioform” subgroup of the “aerobic actinomycetes,” taxonomically in the class Actinobacteria, order Actinomycetales ♦♦ This is a large and diverse group of bacteria, many of which are only distantly related phylogenetically ♦♦ Genera in this subgroup include, Nocardia, Rhodococcus, Gordona, Tuskamurella, Dietzia, and Mycobacterium ♦♦ In culture, these bacteria produce long, branching filaments that tend to break up into rod-shaped and coccoid forms

Pathology and Stains (Fig. 6.8a–d) ♦♦ The host response in nocardiosis is usually suppurative necrosis with abscesses, or there may be diffuse fibrinosuppurative pneumonia ♦♦ In chronic infections, multiloculated abscesses and sinus tracts filled with purulent exudates occur ♦♦ Fibrinosuppurative pleuritis with empyema is a common complication ♦♦ In pulmonary and systemic infections, Nocardia species almost never form sulfur granules (unlike Actinomyces israelii), and their thin, branching filaments are not stained with H&E or PAS ♦♦ In cutaneous mycetomas, Nocardia species form granules ♦♦ Nocardia filaments stain with Gomori methenamine silver or Grocott stain and with tissue Gram stains (particularly Brown–Brenn)

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Fig. 6.8. Pneumonia due to Nocardia species; (A) H&E, (B) Brown–Brenn, (C) GMS, (D) modified acid-fast stain.

♦♦ Nocardia forms gram-positive, beaded filamentous rods, usually £1  mm in diameter, with more or less right angle branching ♦♦ With the Fite stain or the Fite-Faraco stain (modified acidfast) of tissue sections, Nocardia stains partially acid-fast or positive ♦♦ Nocardia also stains partially acid-fast using a modified Kinyoun stain for fresh tissue imprints or smears of exudates −− Less decolorization occurs with these stains than with the usual Ziehl–Neelsen or auramine–rhodamine acid-fast stains ♦♦ Actinomyces israelii and the other species that cause Actinomycosis are not acid-fast

♦♦ Like Nocardia, it is partially acid-fast. Unlike Nocardia, it does not form thin, branching, beaded filaments ♦♦ The colonies of R. equi often have a salmon-pink color on agar media

Clinical

♦♦ Microbiologic culture is required for definitive identification and susceptibility testing

♦♦ The vast majority of patients (>85%) with R. equi infections are immunocompromised ♦♦ The most common and clinically important manifestations of these infections include the following −− Cavitary pneumonia −− Subcutaneous and soft tissue abscesses −− Brain abscesses −− Osteomyelitis −− Lymphadenitis −− Endophthalmitis

Rhodococcus equi

Macroscopic

♦♦ R. equi has been previously called “Corynebacterium equi,” “Mycobacterium rhodochrous,” and also referred to as the “rhodochrous complex” ♦♦ In culture, this gram-positive organism may first appear rodlike, but then later appear coccoid

♦♦ Radiographic findings often initially suggest tumor ♦♦ Lung tissue removed as lobectomy specimens may reveal cavitary lesions surrounded by consolidated lung ♦♦ Extrapulmonary lesions usually reveal abscesses surrounded by nodular and firm tissue

Other Diagnostic Techniques

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Microscopic (Fig. 6.9a–e) ♦♦ Acute suppurative inflammation or granulomatous inflammation may occur ♦♦ Malakoplakia, a rare chronic granulomatous process seen in R. equi infections of the lung, soft tissue, or elsewhere may occur with sheets and aggregates of histiocytes containing Michaelis–Gutmann bodies ♦♦ Granulation tissue may be prominent

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♦♦ Brown–Brenn stain shows a small, gram-positive coccobacillus ♦♦ Fite or a Fite-Faraco stain of paraffin sections, or a modified Kinyoun stain of fresh touch preparations or tissue imprints reveals partially acid-fast coccobacilli. Note: these bacteria will not stain acid-fast using Ziehl–Neelsen or auramine– rhodamine stains ♦♦ Other useful stains include Gomori methenamine silver, Grocott, Giemsa, and Alizarin-red

Special Stains

Differential Diagnosis

♦♦ PAS stain reveals PAS-positive inclusions in macrophages called Michaelis–Gutmann bodies (which contain lamellated iron and calcium)

♦♦ R. equi is differentiated from Histoplasma capsulatum and other fungi by morphology and culture

Fig. 6.9. Rhodococcus equi infection; wall of soft-tissue abscess; (A) H&E, (B) PAS-positive inclusions, (C) pleomorphic coccobacilli in macrophages (GMS), (D) gram-positive coccobacilli (Brown–Brenn), (E) partially acid-fast coccobacilli (modified Kinyoun).

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♦♦ It is differentiated from Mycobacterium species by morphology and microbiologic culture ♦♦ In pulmonary Whipple disease caused by Tropheryma whippelii, macrophages are more likely to be foamy and not eosinophilic; they are more likely to be found in the pulmonary interstitium and peribronchial smooth muscle ♦♦ In noninfectious processes (e.g., suppurative bronchiolitis, lipid storage disorders, and exogenous lipid pneumonia), R. equi is differentiated using special stains and microbiologic culture

Gram-Negative Bacilli: Enterobacteriaceae Escherichia coli ♦♦ E. coli is a gram-negative, facultatively anaerobic (“aerobic”) rod ♦♦ It ferments glucose and other carbohydrates and is oxidase negative ♦♦ It is the most common gram-negative bacillus in the GI tract that grows aerobically ♦♦ Most infections are endogenous ♦♦ The organism originates from patient’s own microbiota or “normal flora” ♦♦ E. coli accounts for about 50% of the bacterial isolates in clinical microbiology laboratories

Clinical ♦♦ The organism causes extraintestinal infections, both community acquired and nosocomial as listed below ♦♦ Bacteremia – E. coli is the most common cause of gramnegative rod blood stream infections ♦♦ Urinary tract infections (UTIs) −− It is the most common cause of UTIs; usually limited to cystitis, but also causes pyelonephritis or prostatitis ♦♦ Other infections caused by E. coli include −− Neonatal meningitis −− Pneumonia −− Peritonitis: usually polymicrobial −− Wound and soft tissue infections (e.g., cellulitis) −− Osteomyelitis and joint infections ♦♦ Important intestinal illnesses caused by this organism follow −− Traveler’s diarrhea due to enterotoxigenic E. coli (ETEC) −− Bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome due to enterohemorrhagic E. coli (e.g., 0157:H7; EHEC) and other Shiga toxin-producing E. coli (STEC) strains −− Diarrhea caused by enteropathogenic E. coli (EPEC) (a) A leading cause of infant diarrhea in developing countries −− Watery diarrhea in infants in developing countries and in travelers to these countries caused by enteroaggregative E. coli (EAEC) −− Enteroinvasive E. coli (EIEC)

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(a) Foodborne outbreaks in developing countries

Macroscopic ♦♦ Extraintestinal infections −− Apart from clinical settings, there are no distinguishing features of these E. coli associated infections ♦♦ Intestinal infections – the gross findings depend upon the pathogenic mechanisms involved −− Traveler’s diarrhea due to ETEC is associated with abundant watery diarrhea, but without gross pathologic lesions (similar to cholera) −− In EHEC diarrhea, the spectrum of findings varies from grossly unremarkable to patchy mucosal ulceration and hemorrhage; the findings are usually more prominent in the right colon (a) Pseudomembranes may be present −− Gross findings in EPEC and EIEC are unremarkable as they are in ETEC diarrhea −− In EAEC, children may have growth retardation due to the chronic diarrhea

Microscopic (Fig. 6.10) ♦♦ Extraintestinal infections are characterized by acute neutrophilic inflammation −− Findings are similar to those in infections involving pyogenic cocci ♦♦ Intestinal infections −− In ETEC diarrhea, the small intestine is microscopically unremarkable as in cholera (a) The colon also is not involved −− In EHEC diarrhea, the findings vary from mild nonspecific inflammation to severe hemorrhagic colitis

Special Stains ♦♦ E. coli usually is in the form of medium-sized gram-negative rods −− Brown–Hopps is usually better than a Brown–Brenn tissue Gram stain for demonstrating gram-negative rods such as E. coli in tissue sections

Fig. 6.10. Escherichia coli in Gram-stained smear of sputum.

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♦♦ PAS is also a useful stain for observing E. coli and other gram-negative bacteria in tissue sections ♦♦ Diff-Quik and Giemsa stains aid in visualizing E. coli and other gram-negative bacteria in direct smears of body fluids, exudates and touch preparations of fresh clinical materials

Differential Diagnosis ♦♦ Extraintestinal E. coli infections are morphologically similar to infections caused by a wide variety of other bacteria ♦♦ EHEC diarrhea findings are similar to those seen in GI infections caused by Shigella, Salmonella, or Campylobacter species −− If pseudomembranes are present, other causes of pseudo­ membranous colitis (e.g., Clostridium difficile) should be considered

Diagnostic Techniques ♦♦ Microbiologic culture is used in the clinical microbiology laboratory for identifying E. coli from various types of specimens; culture also is a prerequisite for antimicrobial susceptibility testing ♦♦ Sorbitol-MacConkey agar for E. coli 0157:H7 and other STEC is commonly used ♦♦ Immunologic testing may be used to detect E. coli shiga toxin producing strains ♦♦ PCR or DNA probes for enterotoxin genes or other virulence genes may be used in public health or reference laboratories −− New commercially available PNA-FISH probes may aid in specific and rapid identification of E. coli in positive blood cultures or certain other types of specimens

Shigella Species (Cause Bacillary Dysentery) ♦♦ Shigella species are gram-negative, facultatively anaerobic, nonmotile rods that genetically are very closely related to E. coli −− They are differentiated on the basis of antigenic characteristics and fermentation test results −− According to CDC, Shigellosis is the third most common cause of bacterial gastroenteritis in the US – after Campylobacter and Salmonella −− Humans are the only natural hosts −− Of all the bacterial diarrheas, shigellosis is the most communicable −− It is transmitted by the fecal–oral route (a) Principally by person-to-person spread (b) But also by contaminated food and water −− As few as 10–100 viable bacteria cause intestinal illness ♦♦ In terms of pathogenesis, shigellae pass through the stomach (surviving gastric acid) and the small intestine, and cause disease primarily by invading and replicating in mucosal cells of the colon −− Most current information on Shigella pathogenesis mechanisms is based on work with S. flexneri ♦♦ S. flexneri is unable to attach to differentiated mucosal epithelial cells

♦♦

♦♦

♦♦

♦♦

♦♦

−− Instead, it first attaches to and is taken up by microfold cells (M cells) −− M cells are specialized epithelial cells that sample particulate and soluble antigens in the gut lumen and present them to underlying lymphoid tissue (e.g., in Peyer patches) The organism passes through M cells by transcytosis −− After transcytosis, it is released into an intraepithelial pocket on the lamina propria side of the M cell where it is engulfed by a macrophage Shigellae rapidly induce apoptosis in macrophages −− Macrophage death is accompanied by release of proinflammatory cytokines IL-1b and IL-18, attraction of abundant neutrophils to the infected site (characteristic acute inflammation occurs), with epithelial cell lysis, ulceration, and subsequent deeper invasion Once released from dying macrophages, free Shigellae invade mucosal epithelial cells on the basal lateral side, move into the cytoplasm by directed actin polymerization, and spread to adjacent epithelial cells, thus avoiding extracellular exposure to host immune surveillance Shigellae (along with E. coli, Salmonella sp., Yersinia sp., and other bacteria) utilize a type III secretion system (plasmid encoded) that mediates secretion of >25 proteins into epithelial cells and macrophages −− Once inside target cells, Shigellae lyse phagocytic vacuoles, replicate in the cytoplasm and cause actin to polymerize −− Subsequently, they are pushed through the cytoplasm to adjacent mucosal epithelial cells where they continue to replicate Also, certain strains of S. dysenteriae produce Shiga toxin, a potent exotoxin that inhibits host cell protein synthesis leading to intestinal mucosal damage and necrosis −− In addition to its effects in the intestinal tract, Shiga toxin damages glomerular endothelial cells causing renal failure in the hemolytic uremic syndrome

Clinical ♦♦ Most US cases are caused by S. sonnei −− According to CDC there were 208,368 laboratory-­ confirmed Shigella infections reported to CDC during 1989–2002, of which (a) S. sonnei (serogroup A) accounted for approximately 72% (b) S. flexneri (serogroup B) accounted for ~18% (c) S. boydii (serogroup C) accounted for ~2% (d) S. dysenteriae (serogroup A) accounted for <1% −− S. sonnei usually causes milder disease than does S. flexneri or S. dysenteriae −− S. flexneri predominates in the developing world −− S. dysenteriae is the most virulent species ♦♦ Most patients are children (<5 years old) and the range of clinical manifestations includes −− Asymptomatic intestinal carriage, or −− Fever, with

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−− Watery diarrhea, or −− Severe dysentery with abdominal cramps, bloody stools and mucus ♦♦ Shigella is unusual in infections outside the GI tract though life-threatening bacteremia, hemolytic uremic syndrome, and toxic megacolon manifestations have been documented, and sequelae including reactive arthritis occur ♦♦ Shigella bacteremia, though the organism is not commonly isolated from blood cultures, is more likely in patients with AIDS or in other immunocompromised patients ♦♦ Reactive arthritis with urethritis and conjunctivitis (e.g., Reiter syndrome) is a known complication of shigellosis (associated with HLA-B27 haplotype)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ ♦♦

Macroscopic ♦♦ Involvement of the colon is much more pronounced than involvement of the small intestine ♦♦ The extent of the colonic involvement varies from subtotal to total; it may be continuous, diffuse, or patchy ♦♦ The most common gross findings are erythema, edema, and superficial ulceration in 40%; pseudomembranes are present in 20%

♦♦ ♦♦ ♦♦

Microscopic ♦♦ Edema, congestion, focal hemorrhages, crypt hyperplasia, depletion of goblet cells, neutrophilic infiltration and ulcers are common ♦♦ Crypt abscesses and capillary thrombi are also common

Special Stains ♦♦ Gram-negative rods can be demonstrated in the mucosa and crypts ♦♦ The bacteria may also be prominent within the lamina propria ♦♦ Invasion beyond the lamina propria is rare

Differential Diagnosis ♦♦ The differential includes intestinal illness due to the following −− Escherichia coli −− Salmonella species −− Campylobacter species −− Clostridium difficile (pseudomembrane formation)

Diagnostic Techniques ♦♦ Isolation and identification of the organism from fecal specimens is required for diagnosis ♦♦ Recovery of isolates depends upon proper use of selective and differential media

Nontyphoidal Salmonella Infections ♦♦ The Salmonellae are gram-negative, motile (with rare exception) rods that ferment glucose but not lactose −− Members of the family Enterobacteriaceae, they are closely related phylogenetically to E. coli and Shigella

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−− In the clinical microbiology laboratory, they are identified based on antigenic characteristics (O and H agglutinins) and biochemical test results −− Taxonomic classification remains complex, with >2,500 “O” serotypes (referred to as “species”), of a single species now designated as Salmonella enterica In terms of pathogenesis, these organisms invade the mucosa of the small and large intestine Salmonellae ingested in food or from fecal–oral transmission survive the gastric acid barrier if the inoculum size is sufficiently high −− The infectious dose for most serotypes other than Salmonella typhi and Salmonella paratyphi varies (e.g., 106–108 to 200 bacteria), but lower in patients who are elderly, immunocompromised, those with decreased gastric acidity and others Salmonellae that reach the small intestine attach to the mucosa and invade M cells (Peyer patches) and enterocytes There they replicate within endocytic vacuoles Attachment, engulfment, and replication are under the control of two large clusters of genes on the bacterial chromosome called pathogenicity islands −− Pathogenicity island I encodes a type III secretion system that enables Salmonella to enter −− Pathogenicity island II encodes a second type III secretion system that facilitates survival in macrophages

Clinical ♦♦ ♦♦ ♦♦ ♦♦

The incubation period is usually 6–48 h Illness occurs primarily in children There is a range of clinical syndromes Manifestations include diarrhea, often with fever and abdominal cramps ♦♦ Typically, the diarrhea lasts 3–7 days ♦♦ Outbreaks most often are foodborne (e.g., contaminated eggs, ice cream, turkey, chicken, beef) ♦♦ Waterborne spread also occurs

Pathology (of Food Poisoning) ♦♦ The manifestations include the following −− Acute ileocolitis, with mucosal erosion −− Mixed inflammation within the lamina propria −− Presence of neutrophils and red blood cells in patients’ feces −− The mucosa usually returns to normal in about 2 weeks ♦♦ Other Salmonella infections include −− Localized infections (e.g., osteomyelitis associated with sickle cell disease) −− Bacteremia (most commonly due to Salmonella typhi, Salmonella paratyphi, Salmonella choleraesuis, and Salmonella enteritidis)

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Diagnostic Techniques

♦♦ Pneumonia is a frequent complication (superinfection)

♦♦ The principal means of diagnosis is culture: with isolation and identification of Salmonella serotypes from stool ♦♦ Selective media are used

Diagnostic Techniques

Salmonella typhi (Typhoid Fever) ♦♦ Salmonella typhi causes typhoid fever ♦♦ A milder form of illness, paratyphoid fever, is produced by Salmonella paratyphi A, Salmonella (paratyphi B) schottmulleri, and Salmonella (paratyphi C) hirschfeldii −− Humans are the only reservoirs of Salmonella typhi and Salmonella paratyphi −− Chronic carrier states exist for these Salmonellae, which can reside for long periods of time in the gall bladder −− Person-to-person spread is common, as the infectious dose for Salmonella typhi is low −− Typhoid fever is usually acquired from ingesting food or water contaminated by an infected food handler who is a carrier ♦♦ In terms of pathogenesis, the organism passes through the stomach (survives the gastric acid) ♦♦ In the terminal ileum, it is taken up by and invades M cells ♦♦ Salmonella typhi is then engulfed by macrophages in the lymphoid tissue in Peyer patches ♦♦ Unlike most other serotypes of Salmonella enterica, Salmonella typhi disseminates via lymphatics and through the blood stream to the spleen, liver, bone marrow, and other sites

Clinical ♦♦ This is a severe systemic infection referred to as “enteric fever” – characterized by fever and abdominal symptoms ♦♦ The incubation period typically is 7–14 days ♦♦ Symptoms include headache, malaise, abdominal pain and tenderness, constipation, and myalgias, with mental status changes ♦♦ Fever is a classic sign of typhoid fever, but does not always develop ♦♦ “Rose spots” (maculopapular rash on the trunk) develop in 30–50% of patients ♦♦ Cervical lymphadenopathy may be prominent ♦♦ About half of patients develop hepatosplenomegaly

Macroscopic ♦♦ Enlarged lymphatic submucosal nodules in the small intestine and colon may be a prominent finding, especially in Peyer patches of the terminal ileum (where ulcers with the long axes in the direction of bowel flow may be seen)

Microscopic ♦♦ Typhoid nodules, focal collections of macrophages (macrophages with erythrophagocytosis, debris and bacteria) may be seen (e.g., in the liver and/or spleen) ♦♦ Salmonellae may localize in the conjunctivae, meninges, joints, kidneys, and gallbladder (3% carriers)

♦♦ Microbiologic cultures of blood, stool, and urine are indicated −− In the first week of typhoid fever, 80% of blood cultures are positive, with decreasing rates of blood culture positivity in subsequent weeks −− The causative organism is more likely to be isolated from stool or urine in the second week of illness rather than during the first week −− Appropriate selective isolation media are required for culturing stool and urine ♦♦ Other specimens cultured may include Rose spots, and/or bone marrow ♦♦ In addition to testing an isolate suspected of being Salmonella serotype typhi for agglutination using somatic O group D antiserum (which contains antibodies to antigens 9 and 12), testing for the Vi antigen, a heat-labile polysaccharide, is useful

Yersinia enterocolitica ♦♦ Y. enterocolitica is a member of the family Enterobacteriaceae, and a facultatively anaerobic, nonlactose fermenting gramnegative rod or coccoid rod (0.5–0.8 mm × 1–3 mm) −− Pigs are a major reservoir −− Y. enterocolitica has also has been isolated from dogs, cats, and various other animals −− It causes gastrointestinal illness in humans much more frequently than does Y. pseudotuberculosis −− The pathogenesis of enteric infections with this organism bears some similarity to that of salmonellosis ♦♦ The pathogenicity of Y. enterocolitica is related to virulence factors encoded by a virulence plasmid (pYV) and by the bacterial chromosome ♦♦ In the terminal ileum or colon, the organism uses adhesins to adhere to M cells ♦♦ In a manner similar to Salmonella, it uses a type III secretion system (containing pYV encoded proteins) ♦♦ Following adherence, Y. enterocolitica penetrates through enterocytes into the lamina propria ♦♦ Inside a cell it is enclosed within membranous vesicles

Clinical ♦♦ In the USA, Y. enterocolitica is an infrequent cause of diarrhea and right lower quadrant abdominal pain (frequently thought to be due to an attack of acute appendicitis clinically) ♦♦ It is more common in Northern Europe, South America, Africa, and Asia ♦♦ The incubation period is usually 4–6 days ♦♦ Foodborne outbreaks have been associated with various foods (e.g., associated with chocolate milk in New York, pasteurized milk in Tennessee, raw pork intestines [chitterlings] in Atlanta and Baltimore)

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Microscopic (Fig. 6.11) ♦♦ Yersinia enterocolitis may involve the terminal ileum and colon (i.e., as an acute self-limited enterocolitis) or as an acute terminal ileitis (i.e., with the terminal ileum as the main focus) ♦♦ Intestinal lesions may be similar to those seen in typhoid fever (with ulceration involving Peyer patches), but intestinal perforation is rare ♦♦ Enlarged mesenteric lymph nodes with “stellate abscesses” are characteristic; the histologic findings are similar to those in lymphogranuloma venereum or the lymph nodes in catscratch disease ♦♦ The bacterium has been implicated as an uncommon cause of acute appendicitis

Special Stains ♦♦ Gram stain (using Brown–Hopps procedure) reveals gramnegative coccobacilli ♦♦ Silver stains (e.g., Warthin–Starry) may be useful for demonstrating organisms ♦♦ Immunohistochemical stains have sometimes been used

Differential Diagnosis ♦♦ The differential based on morphologic findings alone is broad and includes the following −− Typhoid −− Tuberculosis −− Pseudotuberculosis −− Brucellosis −− Intestinal tularemia −− Lymphogranuloma venereum −− Crohn disease

Microbiologic Culture ♦♦ A cold enrichment technique (enrichment buffer at 4°C) along with selective media can be used for primary isolation

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Yersiniae grow well at refrigerator temperatures whereas other bacteria in feces usually grow less well in the cold; in addition, Yersiniae are motile at 25°C but not at 35°C

Yersinia pestis ♦♦ Y. pestis is an extremely virulent pathogen that causes plague ♦♦ It has two plasmids carrying virulence genes that encode for −− An antiphagocytic capsule −− Plasminogen activator protease (a) Degrades complement components C3b (prevents opsonization), and C5a (prevents phagocytic migration) (b) Plasminogen activator also degrades fibrin clots (enhancing spread of Y. pestis) ♦♦ Virulence of Y. pestis is enhanced by iron −− A pathogenicity island encodes a siderophore-independent iron uptake system (E. coli, Salmonella, Klebsiella, and Enterobacter have similar systems) −− Thus, patients with hemochromatosis or hemolytic anemia are at increased risk for septicemia and death if infected by Yersinia

Clinical ♦♦ Natural reservoir includes rats and ground squirrels ♦♦ Spread of organism: flea bites, direct contact with infected materials or by inhalation of aerosols from individuals with pneumonia ♦♦ Human plague (mortality is high) −− Bubonic (a) Patients have high fever (b) Painful, swollen lymph node with hemorrhagic lymphadenitis – (usually groin or axilla) −− Primary and secondary pneumonic −− Primary and secondary septicemic

Special Stains ♦♦ Gram-negative coccobacillus with characteristic bipolar (“safety pin”) staining can be helpful, but not diagnostic

Diagnostic Techniques

Fig. 6.11. Yersinia enterocolitica; mesenteric lymph node (H&E).

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♦♦ Specimens to collect include aspirates (e.g., of a bubo), ­tissue (e.g., lymph nodes), sputum, bronchoalveolar lavage, blood culture, or CSF −− The organisms grow on ordinary microbiologic culture media ♦♦ Direct microscopic examination of Gram-stained smears or sections of clinical materials typically reveals small, ovoid gram-negative rods (0.5  mm × 1–2  mm) as single cells, in pairs or short chains with bipolar-staining resembling “closed safety-pins” −− Giemsa stain may aid in revealing this morphology, particularly if Gram stains are difficult to interpret ♦♦ Y. pestis is one of the Category A agents of bioterrorism

Microbiology for the Surgical Pathologist

♦♦

♦♦

♦♦ ♦♦

♦♦

−− These are agents that pose the greatest threat relative to their infectious nature, ease of spread, or high mortality (e.g., Bacillus anthracis, Clostridium botulinum [botulinum toxins], Francisella tularensis, Yersinia pestis, Variola major [smallpox], Filoviruses [Marburg virus, Ebola virus], and Arenaviruses [Lassa virus, Machupo virus]) In a healthcare setting, laboratory procedures to be performed with Y. pestis must be done in a facility with a biosafety level of at least 2 −− Activities that are at high risk for creating aerosols with this organism should be done in a biosafety level 3 laboratory If plague is suspected in a clinical laboratory or sentinel ­laboratory, local and state public health authorities must be notified immediately A useful CDC website for laboratory information follows: http://www.bt.cdc.gov/labissues The Laboratory Response Network tollfree HelpDesk: (866) 576-5227 is available for subject matter experts if discussions on individual organisms are needed Another excellent source of laboratory information relative to these types of agents is the American Society for Microbiology website (http://www.asm.org/Policy/index. asp?bid=520)

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Microscopic ♦♦ Pyogenic pneumonia is characteristic; it may be patchy, ­lobular, or lobar ♦♦ An entire lobe may be consolidated as in lobar pneumonia due to S. pneumoniae ♦♦ Although pneumonia caused by K. pneumoniae may be similar to that caused by S. pneumoniae, the pneumonia that is due to K. pneumoniae tends to be more destructive (with abscess formation and empyema) ♦♦ Special stains reveal rods varying from short and ovoid to relatively large rods surrounded by halo-like capsules (Fig. 6.12) ♦♦ These gram-negative bacilli are demonstrated best in tissue sections using Brown–Hopps Gram stain ♦♦ K. pneumoniae can be confused with S. pneumoniae in overdecolorized Gram stains

Diagnostic Techniques ♦♦ Pathologic features of K. pneumoniae infections are not specific ♦♦ Microbiologic culture is required for definitive diagnosis

Klebsiella pneumoniae ♦♦ Also a member of the family Enterobcteriaceae, K. pneumoniae is a nonmotile, gram-negative rod that ferments lactose ♦♦ Most strains encountered in the clinical laboratory produce a prominent polysaccharide capsule that is responsible for the mucoid appearance of the colonies on agar media ♦♦ The capsule also is an important virulence factor of this bacterium; it contributes to the mucoid appearance of “currant jelly” sputum ♦♦ K. pneumoniae inhabits the gastrointestinal tract; it also colonizes the upper respiratory tracts of approximately 5–10% of healthy individuals

Clinical ♦♦ The lobar pneumonia historically known as “Friedländer pneumonia,” is caused by K. pneumoniae ♦♦ K. pneumoniae, along with K. pneumoniae subsp. oxytoca, commonly cause community-acquired and nosocomial infections ♦♦ Predisposing factors include diabetes mellitus, alcoholism, chronic obstructive pulmonary disease and other underlying illnesses ♦♦ Common infections include −− Pneumonia −− Urinary tract infections −− Bacteremia −− Surgical wound infections, and soft tissue infections

Fig. 6.12. Klebsiella pneumoniae; (A) chest X-ray, (B) positive blood culture (Gram).

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Infections Caused by Other Klebsiellae Rhinoscleroma ♦♦ Rhinoscleroma is an unusual granulomatous infection of the upper respiratory tract (e.g., involving the nose, nasopharynx, pharynx, or epiglottis) of patients usually from outside the USA (e.g., Central and South America, parts of Africa, the Middle East, India, and the Philippines) ♦♦ It may be seen in immigrants to the USA, especially those who are immunosuppressed (e.g., due to AIDS) ♦♦ Infections can be severe with airway compromise or obstruction, the infection can spread contiguously, and it can disseminate via the blood stream ♦♦ The causative agent, K. pneumoniae subsp. rhinoscleromatis, is a biochemically inactive strain of K. pneumoniae ♦♦ It is not a normal member of the upper respiratory tract microbiota

Microscopic ♦♦ H&E stained sections reveal sheets of prominent foamy macrophages interspersed with lymphocytes and plasma cells −− The overlying mucosa may show pseudoepitheliomatous hyperplasia, or it may be thin or otherwise unremarkable ♦♦ Although this is a granulomatous infection with sheets of or focal collections of macrophages, well-formed granulomas like those seen in tuberculosis (e.g., tuberculoid granulomas) are not seen ♦♦ “Mikulicz cells” −− Recognition of these foamy macrophages with eccentric nuclei laden with characteristic intracytoplasmic ovoidto-rod shaped bacteria (called Mikulicz cells) is an important clue to the diagnosis −− The number of Mikulicz cells in lesions varies considerably from few to many −− PAS stain is more useful for demonstrating these intracellular bacteria than Brown–Hopps or Brown–Brenn Gram stains −− GMS is not useful for demonstrating these bacteria, and the organisms are not acid-fast

Ozena ♦♦ Ozena is a chronic atrophic rhinitis caused by K. pneumoniae subsp. ozaenae ♦♦ It is not common in the USA ♦♦ The organism is a biochemically inert strain of K. pneumoniae

Granuloma inguinale ♦♦ This is a sexually transmitted granulomatous infection of the genitalia and inguinal area that can be confused with the chancre of primary syphilis ♦♦ The infection is uncommon in the USA, but relatively common in areas of the Caribbean, South America, India, Vietnam, parts of South Africa, Australia, and Papua New Guinea

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♦♦ The causative agent, now called Klebsiella granulomatis, was previously named Calymmatobacterium granulomatis; before that it was called Donovania granulomatis ♦♦ In relation to its former genus epithet, the old name “donovanosis” has persisted for many years, though granuloma inguinale is the preferred name for the infection ♦♦ K. granulomatis cannot be cultured in vitro in microbiologic culture media

Other Gram-Negative Bacilli Campylobacter jejuni ♦♦ This is a small (0.2–0.5 mm × 0.5–5 mm), motile (by means of polar flagella), comma-shaped gram-negative bacterium that is microaerophilic ♦♦ It grows optimally in an atmosphere of 5–10% oxygen plus 10% carbon dioxide and the rest nitrogen ♦♦ An important cause of zoonotic infections, Campylobacter species commonly inhabit the intestines of poultry, domestic animals (e.g., C. upsaliensis can be isolated from dog feces including pets with diarrhea) and wild animals ♦♦ Both foodborne and waterborne outbreaks of Campylobacter intestinal illness are common ♦♦ Fecal–oral spread also occurs ♦♦ Although putative virulence factors of this invasive organism have been described, including surface adhesins, enterotoxins, and cytotoxic enzymes, information is lacking regarding their role in disease

Clinical ♦♦ C. jejuni currently is the most common bacterial cause of enteritis in the USA ♦♦ The spectrum of illness ranges from mild diarrhea to moderately severe enteritis −− At the extreme, there may be fatal colitis with bloody and/ or purulent stools ♦♦ Abdominal pain frequently is the predominant symptom ♦♦ Clinically significant bacteremia may also be caused by Campylobacter species (i.e., in £1% of patients with C. jejuni infection −− C. fetus is the Campylobacter species most commonly implicated in bacteremia) ♦♦ Guillain–Barré syndrome (GBS) is an uncommon complication of Campylobacter jejuni or C. upsaliensis infections −− GBS is thought to be an autoimmune disease due to antigenic cross-reactivity between surface lipopolysacharides of Campylobacter sp. and peripheral nerve gangliosides −− However, GBS has also been reported following certain viral infections (e.g., CMV, certain enteroviruses, influenza virus) and in about 1 in 100,000 recipients of the swine flu vaccine during the 1976 vaccination campaign

Macroscopic ♦♦ The colon may show erythema and friability

Microbiology for the Surgical Pathologist

♦♦ The infection may resemble idiopathic ulcerative colitis or Crohn disease

Microscopic ♦♦ Findings may include cryptitis (neutrophil infiltration), crypt abscesses, preservation of crypt architecture, capillary congestion, and edema in the lamina propria ♦♦ Other nonspecific findings may range from “unremarkable” or mild inflammation, to terminal ileitis, or pseudomembranous colitis

Special Stains ♦♦ Direct microscopic examination of Gram-stained material from positive blood cultures or other microbiologic cultures reveals curved gram-negative rods, “s,” or “gull-wing”shaped bacteria ♦♦ Direct microscopic examination of feces for Campylobacter lacks sensitivity; specificity depends upon the experience and skill of the microscopist ♦♦ Morphologic forms of Campylobacter sp. are seldom documented in histologic sections

Differential Diagnosis ♦♦ Campylobacter gastroenteritis can be confused with idiopathic inflammatory bowel disease ♦♦ Other infectious colitides including Salmonellosis or Shigellosis

Diagnostic Techniques ♦♦ Microbiologic culture requires the use of special media, and the incubation of the inoculated media at elevated temperature (i.e., 42°C), under microaerophilic atmospheric conditions

Helicobacter pylori ♦♦ (See Chapter 34)

Vibrio vulnificus ♦♦ V. vulnificus is a motile (by means of polar flagella), gramnegative, rod-shaped and curved, oxidase positive, and lactose positive, free-living marine bacterium ♦♦ It occurs in the coastal waters of the Gulf of Mexico, the Atlantic and Pacific oceans, and also in the Great Salt Lake in Utah as well as in other lakes (e.g., in New Mexico and Oklahoma) ♦♦ Responsible for 90% of the deaths due to Vibrio infections in the USA, V. vulnificus is the most virulent noncholera Vibrio species ♦♦ A polysaccharide capsule and certain enzymes are its principal virulence factors

Clinical ♦♦ Primary septicemia −− Septicemia due to V. vulnificus has been especially severe in patients with known liver disease (75% in one study), other patients with underlying hematopoietic illness, and patients with renal failure or who are immunocompromised and eat raw oysters or other shellfish containing the organism

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−− Secondary skin lesions occur in 90% (usually ecchymoses, bullae, and necrotizing cutaneous and soft tissue lesions) −− The mortality associated with V. vulnificus septicemia is high (~50%) ♦♦ Wound infections −− Sea water exposure to open wounds or injury (e.g., while fishing, swimming, shucking oysters, and other activities) is a major risk factor −− Findings in these infections include erythema, swelling, intense pain, cellulitis, fasciitis, and/or myositis or gas gangrene, particularly involving the lower or upper extremities −− Bacteremia occurs in ~30% of patients who have a V. vulnificus primary wound infection (a) The mortality is lower for these patients than that of patients with primary septicemia −− Mortality for those with V. vulnificus primary wound infections and underlying liver disease (e.g., cirrhosis) is about 25% (a) The prognosis is better if the patients do not have liver disease ♦♦ Gastroenteritis (by itself) −− Vomiting, diarrhea, and abdominal pain occur in approximately 10% of patients −− The prognosis is generally excellent (i.e., no mortality associated)

Microscopic (Fig. 6.13A, B) ♦♦ Skin lesions from patients with primary septicemia and skin lesions resulting from seawater – related wound infections are similar; the findings include the following −− Intense neutrophilic infiltration of subcutaneous tissue −− Abundant bacteria within the inflammatory cell infiltrate −− Acute vasculitis and thrombosis with a haze of many bacteria in vessel walls −− Acute necrotizing inflammation involving the dermis ♦♦ In addition, there may be areas of intense fasciitis, myositis, necrotizing vasculitis, and myonecrosis

Special Stains ♦♦ The organisms are gram-negative comma-shaped bacilli ♦♦ Brown–Hopps tissue Gram stain can be particularly useful, and is preferable to the Brown–Brenn tissue Gram stain for these bacteria

Differential Diagnosis ♦♦ The necrotizing skin and soft tissue lesions are similar to those produced by Clostridium species, Aeromonas species, and Streptococcus species, as well as polymicrobial infections involving Bacteroides species, the anaerobic and microaerophilic cocci, as well as other anaerobic and nonanaerobic microorganisms ♦♦ The “cloud-like” appearance of bacteria in vessel walls and similar vascular lesions can be seen in necrotizing infections caused by Pseudomonas aeruginosa

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Most occur as small, thin, gram-negative rods; they are motile by means of polar flagella ♦♦ These are nonfermenters; they utilize glucose oxidatively ♦♦ Most of these bacteria produce cytochrome oxidase (Enterobacteriaceae are oxidase negative) ♦♦ The many virulence factors produced by Pseudomonas aeruginosa are summarized as follows −− Adhesins (e.g., flagella, pili, lipopolysaccharide, alginate capsules) −− Various toxins and enzymes (e.g., exotoxin A, pyocyanin, pyoverdin, LasA [a serine protease] and LasB [a zinc metalloprotease], alkaline protease, phospholipase C, and exoenzymes S and T) −− Antibiotic resistance (a) P. aeruginosa is inherently resistant to many antibiotics (b) Porin protein mutations cause resistance to many antibiotics (c) This organism also produces a number of b-lactamases that inactivate penicillins, cephalosporins, and carbapenems −− In addition, type III secretion system is used by P. aeruginosa to deliver its toxins into host cells

Pseudomonas aeruginosa

Fig. 6.13. Vibrio vulnificus wound infection with (A) vascular necrosis and cellulitis (H&E), (B) skeletal muscle necrosis, and neutrophilic infiltrate (H&E).

Diagnostic Techniques ♦♦ Microbiology laboratories should be notified if V. vulnificus or another Vibrio is suspected ♦♦ Thiosulfate citrate bile salts sucrose (TCBS) agar is the primary isolation medium of choice, but is not available in all laboratories, particularly those that are geographically far from coastal areas ♦♦ Even though V. vulnificus is a halophilic, oxidase positive, and a lactose positive Vibrio, it grows on many if not most nonselective blood agar media, and on routinely used enteric selective plating media (e.g., MacConkey, xylose lysine deoxycholate, and Hektoen-enteric agar), as well as in most blood culture media. It can be confused with lactose-positive Enterobacteriaceae

Pseudomonas and Related Genera General Characteristics ♦♦ These bacteria are ubiquitous in the environment (e.g., in/on flowers, sinks, toilets, and respiratory therapy equipment in hospitals) and in upper respiratory and intestinal microbiota of hospitalized patients −− It can contaminate disinfectant solutions, distilled water, and stain solutions

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♦♦ Bacteremia/septicemia −− P. aeruginosa bacteremia is most common in patients with neutropenia, diabetes mellitus, severe burns and hematologic neoplasms, and in patients who have undergone transplant procedures −− The most common underlying infection sites leading to bacteremia are pulmonary, the urinary tract, and skin −− Ecthyma gangrenosum is a well-demarcated, hemorrhagic and necrotic skin lesion with vascular necrosis and large numbers of bacteria that occurs in bacteremic patients with neutropenia ♦♦ Skin infections −− Burns – colonization of burns by P. aeruginosa may be followed by localized necrotizing vasculitis and bacteremia −− Folliculitis – exposure to P. aeruginosa in hot tubs, whirl pools, and swimming pools can predispose individuals to folliculitis ♦♦ Chronic, suppurative, external otitis (swimmer’s ear) is also due to P. aeruginosa ♦♦ Pulmonary infections −− P. aeruginosa is common in cystic fibrosis patients −− The findings vary from asymptomatic colonization to life-threatening, necrotizing bronchopneumonia −− Microscopic features include the following: necrotizing inflammation with large numbers of neutrophils, and masses of bacteria in and around walls of thrombosed vessels −− Chronic infection may lead to bronchiectasis and pulmonary fibrosis

Microbiology for the Surgical Pathologist

♦♦ Urinary tract infections due to this organism occur mostly in catheterized patients ♦♦ Other infections by P. aeruginosa −− Keratitis in wearers of contact lenses or after corneal trauma −− Endocarditis or osteomyelitis (a) These infections due to this organism are seen primarily in intravenous drug abusers

Burkholderia (Formerly Pseudomonas) cepacia ♦♦ Several characteristics of this organism are shared with P. aeruginosa −− B. cepacia causes bacteremia/septicemia (often catheter related and polymicrobial) −− It causes pulmonary infections (a) Frequently in patients with cystic fibrosis or chronic granulomatous disease (b) The findings range from simple colonization to necrotizing pneumonia −− B. cepacia also causes skin and soft tissue infections associated with burns or surgical wounds

Burkholderia mallei ♦♦ This organism causes glanders, a highly communicable disease of livestock (especially in horses, mules, and donkeys) ♦♦ It has been eradicated from many countries around the world, except in the Middle East, Africa, Asia, and in South America where enzootic foci persist ♦♦ B. mallei can also be transmitted to humans ♦♦ Although there has only been one human case in the USA during the past half century (involving a biodefense laboratory worker), B. mallei has been identified as a potential agent of bioterrorism

Burkholderia pseudomallei ♦♦ This is the cause of human melioidosis ♦♦ The organism is acquired in humans primarily in wounds or following nontraumatic exposure to water or soil ♦♦ It is very rare in the Western hemisphere ♦♦ Endemic areas include Vietnam, Indonesia, Thailand, Malaysia, Singapore, China (especially Hong Kong), Taiwan, Cambodia, Laos, the Philippines, India, Pakistan, Papua New Guinea, Fiji, tropical Australia, and parts of Africa ♦♦ Person-to-person spread is unusual −− Laboratory infection has been documented but it is rare ♦♦ Clinical findings range from asymptomatic infection to localized cutaneous ulcers or abscesses, chronic pneumonia with features similar to tuberculosis, or septicemia with metastatic abscesses involving multiple organs ♦♦ Histopathologic findings include −− Abscesses −− Necrotizing and nonnecrotizing granulomas

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Stenotrophomonas maltophilia ♦♦ This organism is rarely pathogenic for healthy individuals, but is a relatively common cause of opportunistic infections including wound infections in debilitated or immunocompromised hosts ♦♦ It is a significant cause of hospital-acquired infections; associated with high morbidity and mortality ♦♦ It is an important cause of pneumonia, particularly in cystic fibrosis patients, and it is a potential problem for patients on ventilators in intensive care units ♦♦ It also is an important cause of life-threatening bacteremia, particularly in patients with central venous catheters ♦♦ Other less frequent infections due to this organism include endocarditis, sinusitis, cellulitis, liver abscess, and meningitis ♦♦ Like Pseudomonas aeruginosa, S. maltophilia is resistant to many antibiotics

Acinetobacter baumannii ♦♦ The organism occurs as gram-negative coccobacilli that may be in the form of cocci that are easily confused with Neisseria species ♦♦ Acinetobacter species cause septicemia, wound infections, pulmonary, and urinary tract infections ♦♦ They are often resistant to multiple antibiotics and treatment can be problematic

Legionella pneumophila ♦♦ L. pneumnphila is a small (0.3–1 mm × 2 mm), pleomorphic, aerobic gram-negative rod that is nutritionally fastidious. It is ubiquitous in aquatic habitats (e.g., lakes, rivers, streams) ♦♦ Its presence in cooling towers and condensers of air conditioning systems and in potable water systems (e.g., pipes, water heaters) has been linked to both outbreaks and sporadic cases of legionellosis ♦♦ Aerosols (e.g., from showers) constitute the usual route of transmission ♦♦ As facultative intracellular parasites, Legionellae multiply within free-living amebae in aquatic habitats −− They multiply within monocytes and macrophages in infected humans ♦♦ Phagolysosome fusion is inhibited within infected macrophages; inside macrophages Legionellae survive exposure to toxic peroxides, superoxide dismutase, and hydroxyl radicals ♦♦ Legionellae produce proteolytic enzymes, lipase, and phosphatase −− The infected macrophages release cytokines which stimulate a vigorous inflammatory response

Clinical ♦♦ Legionnaires disease (legionellosis) is a clinically severe pneumonia with prominent morbidity −− Mortality in previously healthy people is 15–20% −− Mortality due to legionellosis in immunocompromised patients is 75% ♦♦ Extrapulmonary involvement is possible

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♦♦ Patients may have high temperature ³40°C, diarrhea, and hyponatremia ♦♦ Pontiac fever is a less severe, self-limited, flu-like illness

Essentials of Anatomic Pathology, 3rd Ed.

−− For definitive diagnosis, gas–liquid chromatography of cellular fatty acids and nucleic acid sequencing are required

Macroscopic

Haemophilus influenzae

♦♦ Grossly, pneumonia due to Legionellae may be in the form of focal, lobular or lobar consolidation involving one or multiple lobes. Abscesses or cavitary lesions may be present

♦♦ These are small, nonmotile, pleomorphic gram-negative rods ♦♦ Nontypeable strains colonize the upper respiratory tracts of 30–80% of healthy individuals ♦♦ Encapsulated H. influenzae type B colonization has decreased substantially (now in <1%) since the vaccine was introduced

Microscopic ♦♦ Microscopic findings vary from predominantly acute inflammation (with infiltrates containing abundant neutrophils), infiltrates composed mostly of macrophages, or mixed inflammatory cell infiltrates containing a mixture of neutrophils, macrophages, and some lymphocytes ♦♦ Necrosis may be severe in some cases ♦♦ Vasculitis with or without thrombi may also be seen

Microscopic Examination Using Special Stains ♦♦ Using Brown–Hopps tissue Gram stains, these gram-­negative rods are usually coccobacillary −− The organisms may be missed or difficult to see ♦♦ In tissue, Legionellae will stain with nonspecific silver stains (e.g., Dieterle, Steiner, or Warthin–Starry) ♦♦ Giemsa and Gram stains are useful for direct examination of fresh clinical materials ♦♦ In fresh clinical materials, Legionella micdadei can stain partially acid-fast using a modified Kinyoun acid-fast stain −− This stain uses a weaker acid than does the Ziehl–Neelsen acid-fast stain −− Isolates of L. micdadei may retain or lose their partial acid-fastness in vitro in culture media

Diagnostic Techniques ♦♦ Direct Fluorescent Antibody (DFA) stains used for direct examinations of clinical specimens have a relatively poor sensitivity (e.g., 25–75%) ♦♦ Urinary antigen assays are used to detect the lipopolysaccharide antigen of L. pneumophila serogroup 1 (for which the sensitivity is about 60–90%) ♦♦ Culture on buffered charcoal yeast extract is recommended −− Note that for primary isolation, supplementation of the agar medium with l-cysteine is required, and growth is enhanced by supplementation with iron and a-ketoglutarate −− In addition, activated charcoal is added to protect the organism from toxic peroxides and lipids, and an organic buffer (N-[2-acetamido]-2-aminoethanesulfonic acid; ACES) is added to protect against toxic NaCl concentration, and to maintain the necessary pH ♦♦ For clinical isolates, Gram stain features, colony characteristics, DFA stains of growth from colonies, fluorescence under UV light and certain biochemical tests aid in presumptive diagnosis of L. pneumophila

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Clinical ♦♦ Illnesses caused by nontypeable H. influenzae include the following −− Otitis media (the organism causes about 25% of the 25 million episodes per year in the USA) −− Exacerbations of COPD – it is the most common bacterial cause of exacerbations of chronic obstructive pulmonary disease −− Community acquired pneumonia – it is relatively common in adults −− Pneumonia in children – H. influenzae is a major cause of childhood pneumonia in developing countries −− Acute maxillary sinusitis (sinus aspirates are required for diagnosis) −− Neonatal sepsis; this has had an increasing frequency since the 1980s; it is associated with significant morbidity and mortality −− Purulent conjunctivitis – it occurs sporadically and in outbreaks ♦♦ Clinical llnesses caused by Haemophilus influenzae type B include the following −− Pyogenic meningitis (a) This is the most serious form of illness caused by H. influenzae (b) It is now far less frequent than before the vaccine was introduced, and occurs most often in incompletely immunized persons (c) No clinical feature distinguishes it from purulent meningitis caused by other microorganisms (d) At autopsy, the exudate is usually basal; in pneumococcal meningitis the exudate is usually more prominent over the cerebral convexities near the sagittal sinus −− Acute epiglottitis −− Pneumonia and empyema −− Cellulitis −− Bacteremia −− Septic arthritis

Diagnostic Techniques ♦♦ Microbiologic studies (i.e., direct microscopic examination and culture) are required

Microbiology for the Surgical Pathologist

Bordetella pertussis ♦♦ B. pertussis, the etiologic agent of whooping cough, is a very small (0.2–0.5 mm × 0.5–1 mm) gram-negative coccoid rod ♦♦ It is an obligate aerobe that is unable to ferment carbohydrates −− It oxidizes amino acids to obtain energy ♦♦ The organism produces several virulence factors including adhesins that aid in binding of the organism to cilia or host cells (e.g., filamentous hemagglutinin, pertactin, and fimbriae) and toxins (e.g., pertussis toxin, adenylate cyclase/ hemolysin, and dermonecrotic toxin) ♦♦ The vaccines currently used in the USA contain inactivated pertussis toxin, filamentous hemagglutinin, and pertactin

Clinical ♦♦ Whooping cough (or pertussis) is acquired by inhalation of infectious aerosols followed by attachment of the bacteria to and replication on ciliated bronchial epithelial cells. B. pertussis also invades macrophages. Humans are the only reservoir ♦♦ Infants 1–2 months of age are at greatest risk −− In the developing world where vaccination is lacking, mortality due to whooping cough ranges in the hundreds of thousands ♦♦ In recent years in the USA, whooping cough has become more common in older children and adults −− This trend has occurred in an era in which vaccination rates have been high −− The most likely reason for this trend is waning immunity ♦♦ After a 7–10 day incubation period, pertussis occurs as a three-stage illness summarized as follows −− Stage 1 – Catarrhal (a) 1–2 weeks (b) The patient has nonspecific upper respiratory symptoms resembling a cold (c) Pertussis is highly communicable at this stage −− Stage 2 – Paroxysmal (a) 2–4 weeks or more (b) There is increased severity and frequency of cough with the classic inspiratory “whoop” (c) A marked lymphocytosis is present in stage 2 −− Stage – Convalescent (a) 3–4 weeks (b) There is decreased coughing (c) Complete recovery occurs in weeks to months

Microscopic ♦♦ The findings are characterized by laryngotracheobronchitis with abundant mucosal exudate containing inflammatory cells and sloughed, degenerated, mucosal epithelial cells ♦♦ Segments of hyperemic, denuded bronchial wall may be present

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♦♦ An inflammatory infiltrate involving alveoli would most likely be secondary to superinfection

Special Stains ♦♦ Brown–Hopps may reveal very small gram-negative coccobacilli

Diagnostic Techniques ♦♦ A nasopharyngeal aspirate is the specimen of choice −− If swabs are to be used, they should be calcium alginate or Dacron (a) Cotton swabs contain fatty acids, which are toxic for the organisms −− To collect sufficient numbers of cells, posterior nasopharyngeal samples (not oropharyngeal) are necessary ♦♦ A direct fluorescent antibody (DFA) test, done in conjunction with culture, is currently used in some diagnostic laboratories −− The DFA has poor sensitivity and specificity and should not be used by itself ♦♦ Bordet–Gengou agar, traditionally used for primary isolation of B. pertussis, has been replaced by supplemented Regan– Lowe charcoal medium −− The inoculated media require lengthy incubation (7–12 days) at 35°C ♦♦ More sensitive nucleic acid amplification tests (e.g., PCR) are replacing the DFA test and culture in diagnostic laboratories that have the necessary resources −− Because no FDA-approved molecular test had become commercially available until recently for this organism, laboratories sometimes developed their own procedures targeting various genes

Brucella Species and Brucellosis ♦♦ Brucella species are small, gram-negative, nonmotile, coccoid rods ♦♦ They are obligate aerobes that grow very slowly on complex media; do not ferment carbohydrates ♦♦ As facultative intracellular parasites, Brucella species inhibit phagolysosomal fusion and resist intraphagocytic killing by macrophages ♦♦ Brucellosis is an extremely important zoonosis, infecting both humans and a variety of animals around the world ♦♦ Endemic infections due to these bacteria are prevalent in the Mediterranean basin, Middle East, India, Latin America, the Caribbean, Africa, and Asia ♦♦ Humans can acquire the infection in several ways −− Through skin contact (e.g., through a wound or abrasion) −− Through a mucosal surface −− Ingestion of contaminated food −− Through infectious aerosols

Clinical ♦♦ Different Brucella species are acquired by (examples follow) −− Consumption of unpasteurized goat cheese or goat milk (B. melitensis)

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−− Drinking unpasteurized cow milk (B. abortus) −− Occupational exposures to infected cattle by butchers, meat cutters, veterinarians, laboratory workers, and others (B. abortus) −− Exposure to infected swine (B. suis) −− Owners of pet dogs (B. canis) ♦♦ Laboratory workers are at risk of acquiring the infection through −− Improper handling of specimens (e.g., due to exposure of unprotected skin or mucous membranes) −− “Sniffing” of culture plates −− Mouth pipetting −− Aerosols (e.g., exposures to eyes, nose, or mouth) ♦♦ The incubation period varies (1–8 weeks) ♦♦ Brucellosis is characterized by −− Nonspecific fever, chills, sweats, headache, and malaise, with or without hepatosplenomegaly, lymphadenopathy, anorexia, nausea, vomiting, abdominal pain, diarrhea, and constipation −− Sudden death (rare) may occur within days or weeks of delirium and coma −− Recurrent “undulant” fever with intermittent or periodic nocturnal fevers is the most common form; patients are likely to have skeletal involvement −− There also may be a chronic intermittent form with vague symptoms, mild fever, and profound weakness −− Complications include meningitis, endocarditis (the most common fatal complication), pericarditis, hepatic and splenic lesions, osteomyelitis, arthritis, and sacroiliitis

Microscopic ♦♦ The organisms are sequestered in the reticuloendothelial system −− Thus, lymph nodes, spleen, liver and bone marrow are commonly involved −− Pathologic findings vary, and there is a spectrum of findings ♦♦ Lymph nodes and spleen −− Lymphoid hyperplasia is a common finding −− There may be focal collections of macrophages or lymphohistiocytic aggregates that are discrete granulomas (similar to tubercles in appearance) −− Partially calcified splenic granulomas have been observed many years after infection with Brucella suis ♦♦ Liver −− Focal collections of macrophages may be present within portal triads −− Nonnecrotizing granulomas that can be indistinguishable form sarcoid are described −− Nonspecific hepatitis without granulomas also occurs −− There may be chronic suppurative lesions with calcification ♦♦ Bone marrow

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−− Granulomas in bone marrow have been noted in 75% of patients (a) These lesions tend to be small with indistinct borders −− In addition, there may be increased macrophages (a) They may show erythrophagocytosis ♦♦ Other anatomic sites that may be involved less frequently include −− Heart and blood vessels (endocarditis, myocardial involvement, pericarditis, mycotic aneurysms) −− Nervous system (meningitis, encephalitis, radiculoneuritis, cerebral mycotic aneurysm, peripheral neuropathy) −− Bones and joints (sacroilitis, arthropathy of hips, knees or other joints; osteomyelitis of vertebrae and long bones) −− Respiratory tract (pulmonary involvement is rare) −− Gastrointestinal tract involvement due to Brucella melitensis has been described −− Genitourinary tract involvement (chronic pyelonephritis, immune complex glomerulonephritis, salpingitis, and epididymoorchitis) has also been described

Special Stains ♦♦ These very small gram-negative coccoid rods are difficult to stain (e.g., with Brown–Hopps and other special stains) or identify in tissue sections

Diagnostic Techniques ♦♦ Cultures −− When brucellosis is suspected, notification of the microbiology laboratory before collection of specimens for culture is highly recommended −− Specimens to collect for diagnosis include multiple blood cultures, bone marrow, and tissue from infected sites −− Cultures require extended incubation times (a) Incubation of blood cultures for at least 2 weeks in automated systems) −− Serologic tests can also provide useful diagnostic results (a) In the USA, the serum agglutination test (SAT) is used widely ♦♦ Three species of Brucella, B. melitensis, B. suis, and B. abortus, are considered Category A agents of bioterrorism in the USA −− These are among the agents that pose the greatest threat relative to their infectious nature, ease of spread, or high mortality (e.g., Bacillus anthracis, Clostridium botulinum [botulinum toxins], Francisella tularensis, Yersinia pestis, Variola major [smallpox], Filoviruses [Marburg virus, Ebola virus] and Arenaviruses [Lassa virus, Machupo virus]) ♦♦ In a healthcare setting, laboratory procedures to be performed with Brucella species must be done in a facility with a biosafety level of at least 2 −− Activities that are at high risk for creating aerosols with this organism should be done in a biosafety level 3 laboratory

Microbiology for the Surgical Pathologist

♦♦ If brucellosis is suspected in a clinical laboratory or sentinel laboratory, local and state public health authorities must be notified immediately ♦♦ A useful CDC website for laboratory information follows: http://www.bt.cdc.gov/labissues ♦♦ The Laboratory Response Network tollfree HelpDesk: (866) 576-5227 is available for subject matter experts if discussions on individual organisms are needed ♦♦ Another excellent source of laboratory information relative to these types of agents is the American Society for Microbiology website (http://www.asm.org/Policy/index.asp?bid=520)

Francisella tularensis and Tularemia ♦♦ F. tularensis is a very small (0.2 × 0.2–0.7 mm), nonmotile, strictly aerobic, catalase-positive, nonfermentative, gramnegative coccobacillus ♦♦ Virulent strains form a polysaccharide capsule that protects the organism from phagocytosis and from complementmediated killing in serum ♦♦ F. tularensis, like Brucella sp., is a facultative intracellular pathogen that inhibits phagolysosomal fusion and replicates within macrophages

Epidemiology ♦♦ F. tularensis causes tularemia (also sometimes called rabbit fever, deer fly fever, or glandular fever) ♦♦ Naturally occurring tularemia is a zoonosis −− It is worldwide (primarily northern hemisphere) in distribution ♦♦ An estimated 100–200 human cases of tularemia occur in the USA per year ♦♦ F. tularensis infects many mammals including various rodents, rabbits and hares (lagomorphs), squirrels, raccoons, cats, deer, and many other kinds of animals −− Humans are considered accidental hosts ♦♦ It is naturally transmitted in several ways −− Bite of infected tick, particularly including the dog tick (Dermacentor variabilis), wood tick (D. andersoni), and Lone Star tick (Amblyomma americanum) in North America −− Contact with an infected wild animal (e.g., rabbit hunter, muskrat trapper) or domestic animal [e.g., pet cat that caught infected mouse]) −− Inhalation of aerosols (e.g., by a squirrel hunter on a windy fall day) −− Waterborne outbreaks (water contaminated by beavers or other animals) ♦♦ F. tularensis is hazardous for laboratory personnel −− The infectious dose is very small −− The infectious dose is very small also for Y. pestis

Clinical ♦♦ Symptoms may include headache, malaise, and fever chills that usually begin abruptly 3–5 days after a tick bite or exposure to an infected animal

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♦♦ Tularemia is subdivided into six forms −− Ulceroglandular tularemia (a) Skin lesion at site of tick bite (in area of enlarged lymph node) (b) Reddish papule that ulcerates (c) Bacteremia and lymphadenopathy is also usually present −− Glandular tularemia (a) Less common form (b) Enlarged, painful lymphadenopathy (c) No ulcerated skin lesion −− Typhoidal tularemia (a) Also a less common form (b) Patient has sepsis clinically, but no lymphadenopathy or ulcerated skin lesion (c) Patient may have pneumonia or evidence of other organ involvement (d) Diagnosed usually by blood cultures −− Oculoglandular tularemia (a) Rare; through direct contamination of conjunctiva (e.g., fingers; exposure to aerosols) (b) Ulcer on palpebral conjunctiva; enlargement of nearby lymph nodes −− Oropharyngeal (a) It is acquired through ingestion of contaminated, poorly cooked meat (b) It also has been acquired from contaminated water (c) Manifestations include pharyngitis, tonsillitis, and cervical lymphadenopathy ♦♦ Pneumonic tularemia (a) Acquired by inhalation of aerosolized F. tularensis (b) Those at risk include hunters, farmers, sheep shearers, landscapers, and laboratory workers (c) Radiographic findings: bronchopneumonia (may be bilateral), or lobar infiltrates, hilar adenopathy, pleural effusions; or focal infiltrates, or apical infiltrates

Microscopic ♦♦ The inflammatory response includes the following features −− Acute: fibrin, neutrophils, macrophages, and T lymphocytes involved; often with liquefactive necrosis −− Later: characterized by lymphocytes, macrophages, and giant cells −− There also may be caseation, calcification and fibrosis in chronic lesions ♦♦ Lymph nodes: reveal subcapsular or geographic areas of necrosis that may resemble infarcts ♦♦ Lungs: the findings may include extensive necrosis and cavitation

Special Stains ♦♦ F. tularensis is not visualized by use of any of the tissue Gram stains

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♦♦ Silver impregnation stains (e.g., Warthin–Starry, Steiner or Dieterle) may reveal tiny coccobacilli in macrophages ♦♦ Specific direct fluorescent antibody stains or immunohistochemical stains (formalin-fixed tissue) used at CDC

Diagnostic Techniques ♦♦ F. tularensis poses a biosafety hazard −− The collection and processing of specimens is extremely hazardous for all involved ♦♦ It requires a sulfur-containing amino acid for growth (e.g., l-cysteine) and will grow slowly on buffered charcoal yeast extract (the BCYE agar that is used for isolation of Legionella) or on chocolate agar −− It is not readily isolated on the usual unsupplemented sheep blood agar in a microbiology laboratory ♦♦ If tularemia is suspected clinically, the laboratory should be notified for the following reasons −− The high risk of transmission to laboratory workers exposed to this virulent pathogen necessitates special precautions be used for all specimen processing (a) Thus if tularemia is expected, specimen processing (using universal precautions) should be done under at least biosafety level [BSL] 2 conditions, and BSL-3 practices should be used if culture work is to be done −− Prolonged incubation (i.e., 3–4 days to a week or longer) is required to isolate this slow-growing bacterium ♦♦ In addition, F. tularensis is considered a Category A agent of bioterrorism in the USA −− It is listed among the agents that pose the greatest threat relative to their infectious nature, ease of spread, or high mortality (e.g., Bacillus anthracis, Brucella species Clostridium botulinum [botulinum toxins], Francisella tularensis, Yersinia pestis, Variola major [smallpox], Filoviruses [Marburg virus, Ebola virus], and Arenaviruses [Lassa virus, Machupo virus]) ♦♦ If F. tularensis is suspected in a clinical laboratory or sentinel laboratory, local and state public health authorities must be notified immediately ♦♦ A useful CDC website for laboratory information follows: http://www.bt.cdc.gov/labissues ♦♦ The Laboratory Response Network tollfree HelpDesk: (866) 576-5227 is available for subject matter experts if discussions on individual organisms are needed ♦♦ Another excellent source of laboratory information relative to these types of agents is the American Society for Microbiology website (http://www.asm.org/Policy/index. asp?bid=520)

Gram-Negative Cocci Neisseria gonorrhoeae ♦♦ This is a gram-negative, oxidase and catalase-positive coccus (0.6 × 1 mm) that occurs as diplococci (pairs) with adjacent sides flattened

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−− N. gonorrhoeae is second only to Chlamydia trachomatis as the most common bacterial cause of sexually transmitted disease in the USA ♦♦ Virulence Factors of Gonococci −− Pili, PorB, and Opa outer surface proteins that mediate attachment to, and penetration of, epithelial cells −− Lipopolysaccharide (endotoxin) of gonococci (GC), which stimulates secretion of tumor necrosis factor-alpha (TNF-a) (a) TNF-a (along with interleukin-1) is one of the major cytokines that mediates inflammation and the acutephase responses associated with infection or injury (including the hemodynamic effects of septic shock) (b) TNF-a causes most of the symptoms of gonorrhea (e.g., damage to fallopian tubes) −− A protease that cleaves IgA −− Transferrin-, lactoferrin-, and hemoglobin-binding proteins that mediate the acquisition of iron for the metabolism of the organism −− A b-lactamase that hydrolyses the b-lactam ring of penicillin

Clinical Manifestations ♦♦ Acute gonococcal urethritis: with dysuria, pyuria, and frequency ♦♦ Cervicitis: neutrophilic, lymphocytic, and plasmacytic inflammation; focal epithelial necrosis and reactive cellular atypia ♦♦ Pelvic inflammatory disease; manifestations include endometritis, salpingitis, tuboovarian abscess (frequently involves mixed anaerobic and aerobic vaginal flora), pelvic peritonitis, and perihepatitis (Fitz–Hugh–Curtis syndrome) in varying combinations ♦♦ Rectal GC infection: ~40% of women with uncomplicated gonorrhea (also occurs in men who have sex with men) ♦♦ Bacteremia: occurs in ~0.5–3% of patients with gonorrhea ♦♦ Arthritis: in young adults; caused by N. gonorrhoeae relatively frequently ♦♦ Ophthalmia neonatorum (purulent conjunctivitis): the most common clinical manifestation in infants ♦♦ Pharyngitis

Microscopic ♦♦ Acute purulent inflammation −− Granulation tissue and fibrosis (scar) occur later, particularly if the infection is not treated ♦♦ GC causes symptomatic urethritis, urethral stricture, and epididymitis in males ♦♦ GC causes acute inflammation with abscess formation in submucosal glands of females with subsequent spread to fallopian tubes leading to tuboovarian abscess (pelvic inflammatory disease), fibrosis, sterility, or ectopic pregnancy

Special Stains (Fig. 6.14) ♦♦ Gram stain is a sensitive and specific way to diagnose gonococcal urethritis in symptomatic (but not asymptomatic) males only

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♦♦ Principal virulence factors of N. meningitidis include its polysaccharide capsule, pili, and lipopolysaccharide (LOS, which has endotoxin activity) ♦♦ Internalized into phagocytic vacuoles, the capsule protects the meningococcus against phagocytic killing ♦♦ The diffuse vascular damage that occurs in meningococcal infections is largely attributed to the LOS

Clinical Manifestations and Pathology

Fig. 6.14. Neisseria gonorrhoeae; smear of exudate from male urethra (Gram).

♦♦ The finding of neutrophils and intracellular gram-negative cocci in a direct smear of urethral exudate from males is considered diagnostic of gonorrhea ♦♦ For females, Gram stain is not recommended (sensitivity and specificity are lacking) ♦♦ The Gram stain appearance of Acinetobacter species in female genitourinary tract microbiota can be morphologically indistinguishable from that of N. gonorrhoeae

Diagnostic Techniques ♦♦ Culture, the historic “gold standard” diagnostic method, is sensitive and specific but has largely been replaced by amplified DNA probe tests (on discharge swab, urine or Thin Prep) ♦♦ For testing children or persons who have been sexually assaulted for gonorrhoeae, culture is still considered the only appropriate means of diagnosis

Neisseria meningitidis ♦♦ N. meningitidis is a gram-negative, oxidase and catalasepositive, encapsulated coccus that occurs as diplococci (pairs) with adjacent sides flattened ♦♦ It is commonly carried in the nasopharyngeal microbiota of healthy individuals ♦♦ Currently, there are 13 antigenic serogroups: A, B, C, D, X, Y, Z, E, W-135, H, I, K, and L ♦♦ Meningococcal disease occurs mainly when a new strain to which the person is not immune is encountered ♦♦ Transmission of a new strain of the organism (by respiratory droplets) is more likely to happen to young children or young adults living in crowded conditions (e.g., family members in the same household, soldiers in military barracks, college students in dormitories) ♦ ♦ In addition, the risk of developing meningitis is higher if the patient has a C5, C6, C7, or C8 (complement) deficiency

♦♦ Meningitis −− N. meningitidis is the second most common cause of community acquired meningitis in adults −− The majority of cases are due to groups B and C −− It occurs with or without sepsis −− The manifestations include headache, meningeal signs, and fever ♦♦ Meningococcemia with sepsis −− Occurs with or without meningitis (Fig. 6.15A) −− Purpura fulminans (widespread hemorrhage) −− Disseminated intravascular coagulation (DIC) −− Waterhouse–Friedrickson syndrome (bilateral hemorrhagic necrosis of adrenals) (a) Is not unique to N. meningitidis (b) Caused also by H. influenzae

Microscopic (Fig. 6.15B, C) ♦♦ Acute purulent inflammation of the meninges can be prominent ♦♦ Gram stain reveals gram-negative diplococci

Diagnostic Techniques ♦♦ Gram stain of CSF is both sensitive and specific for N. meningitidis −− However, other bacteria including Acinetobacter species are morphologically similar ♦♦ Microbiologic culture is required for definitive diagnosis

Anaerobic Bacteria and Diseases Anaerobic Sporeforming Rods: The Clostridia ♦♦ The genus Clostridium is composed of anaerobic, grampositive, sporeforming rods −− However, a few (e.g., C. tertium and C. histolyticum) are aerotolerant ♦♦ Unlike the genus Bacillus, Clostridium species typically form spores anaerobically but not aerobically −− Clostridium species do not produce catalase ♦♦ Although there are ³200 validly published species, only 30 or so are involved in diseases −− Of these species, about half are toxigenic, capable of causing a number of important diseases (e.g., tetanus; pseudomembranous colitis)

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♦♦ Both toxin-mediated diseases (some with no or limited morphologic changes) and suppurative/necrotizing infections (with profound tissue damage) are produced

Clostridium perfringens ♦♦ Clostridial myonecrosis (gas gangrene), more often than not, has a devastating outcome – with high morbidity and mortality ♦♦ C. perfringens type A is the most common cause ♦♦ Pathogenesis involves the following −− Traumatic injuries, both major and minor −− Spontaneous myonecrosis in absence of trauma; associated with colon cancer, other forms of bowel disease, ­leukemia, and neutropenia −− a-toxin (lecithinase; also called phospholipase C) plays major role in disseminated infection and hemolysis (may be massive) −− q-toxin (also has hemolytic and cytolytic properties) −− Rapid multiplication and metabolic activity of the organism with gas production ♦♦ Other causative agents include C. septicum (especially in patients with spontaneous myonecrosis and/or underlying malignancy), C. novyi, C. histolyticum, and C. sordellii

Clinical ♦♦ This is a rapidly progressive, life-threatening condition with necrosis of muscle and soft tissues, gas (mostly hydrogen and nitrogen), and prominent systemic signs of toxemia and hypotension ♦♦ The patient experiences increasingly severe pain in a traumatic or surgical wound ♦♦ The skin is intensely edematous, red or bronze, often with large hemorrhagic bullae ♦♦ Crepitus (gas) aids in making a diagnosis but is not always present, particularly early in the course of the disease −− This is not specific and occurs also in infections involving other toxigenic as well as nontoxigenic species of Clostridium, Streptococcus, E. coli and other enterics, and in polymicrobial infections involving nonclostridial anaerobes plus other microorganisms ♦♦ Another feature is a thin, watery, sanguinolent or brownish discharge with a foul-sweet odor ♦♦ Shock and renal failure may develop rapidly

Fig.  6.15. Adrenal hemorrhage and necrosis; (A) patient with meningococcal sepsis (Waterhouse–Friedrickson syndrome), (B) cerebrospinal fluid (gram), (C) peripheral blood buffy coat smear (Wright).

Pathology and Microbiologic Diagnosis (Fig. 6.16)

♦♦ The principal habitats are soil and the intestinal tracts of humans and other animals ♦♦ Most of the time, the clostridia coexist peacefully within and around us, but circumstances may change leading to dire consequences (e.g., gas gangrene) ♦♦ Endogenous diseases involving clostridia from the host’s own microbiota are more common than exogenous diseases (e.g., foodborne botulism)

♦♦ Early diagnosis needed to stop rapid progression of devastating disease; drastic surgical measures usually required ♦♦ Involved muscle has poor blood supply and fails to respond to stimuli, indicating it is dead (undergoes liquefactive necrosis; may appear gelatinous) ♦♦ Direct microscopic examination of discharge material, aspirated fluid, or frozen sections reveals a necrotic background with no inflammatory cells and abundant, relatively large, box-car-shaped gram-positive rods −− However, neutrophilic infiltrates will be present in the advancing edge of the lesion

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♦♦ This is a localized or extensive suppurative, gas-forming infection involving soft tissue, but without the systemic ­toxemia that is characteristic of clostridial myonecrosis ♦♦ Neither the cellulitis nor the gas extends into skeletal muscle

Uterine Gas Gangrene

Fig. 6.16. Clostridium perfringens myonecrosis, direct smear of aspirated material from upper extremity lesion (Gram). ♦♦ Spores are almost never seen microscopically in clinical materials when myonecrosis is due to C. perfringens ♦♦ Spores usually are evident microscopically in myonecrosis due to other species of Clostridium (e.g., C. septicum) ♦♦ Other bacteria can cause infections with gas and severe muscle involvement similar to that in gas gangrene (e.g., “streptococcal myonecrosis,” or “anaerobic streptococcal myositis”) −− These can be differentiated by direct microscopic examination and microbiologic cultures ♦♦ Cultures −− Specimens to collect for culture include aspirates and/or fresh tissue −− Blood for culture should also be obtained (positive in about 15% of patients) −− C. perfringens grows rapidly (12–18 h of incubation) in various laboratory media; it produces abundant gas −− Other characteristics include the following (a) Medium to large gram-positive rods (spores not seen initially) (b) Double zone of hemolysis on blood agar (c) Lecithinase activity on egg yolk agar (d) C. perfringens is proteolytic

Clostridial Suppurative Myositis ♦♦ This infection is more benign, with far less muscle destruction than occurs in gas gangrene, and lacks findings of systemic toxemia ♦♦ There is localized pain, tenderness, and fluctuant swelling, usually in a thigh or forearm; patient management includes surgical drainage (not amputation) ♦♦ It is seen mostly in intravenous drug abusers, or associated with injections of therapeutic drugs (e.g., in diabetic patients) ♦♦ Pathologic findings include abscess formation in skeletal muscle and acute inflammation in adjacent soft tissue and fascia

Clostridial Cellulitis ♦♦ Cellulitis without myonecrosis can be caused by C. perfringens, other clostridia or a variety of other bacteria

♦♦ This is a dramatic, fulminating, life-threatening illness due to toxigenic clostridial invasion of the myometrium ♦♦ In the USA, it is now rare −− It once occurred relatively frequently as a consequence of self-induced or illegal abortions −− It also occurs as a complication of spontaneous abortion, vaginal delivery, cesarean section, amniocentesis, and uterine tumors in nonpregnant women ♦♦ Clinical features are dominated by severe toxemia and septic shock, with massive intravascular hemolysis (mostly caused by a-toxin), hemoglobinuria (“port wine” urine), and acute renal failure (acute tubular necrosis) ♦♦ The uterus undergoes necrosis −− The pathology is similar to the findings in myonecrosis involving skeletal muscle (described above)

Intestinal Illnesses Caused by Clostridium ­perfringens ♦♦ Food poisoning −− Is caused by C. perfringens type A strains which produce the enterotoxin (CPE), a 35-kDa polypeptide (a) CPE forms cation permeable pores in intestinal epithelial cell membranes (of CaCo-2 cell cultures) −− This is one of the commonest bacterial causes of foodborne disease in the USA −− The incubation period is usually 7–12 h (a) It typically occurs after eating heated meat or meat products contaminated with about 108 vegetative cells −− In the small intestine, C. perfringens undergoes sporulation, producing the CPE −− There is profuse diarrhea and abdominal pain (nausea and vomiting are infrequent) −− C. perfringens food poisoning is usually self-limited ♦♦ Pseudomembranous colitis −− Although Clostridium difficile (discussed elsewhere) is the major cause of pseudomembranous colitis and ­antibiotic-associated diarrhea, C. perfringens has also been reported to cause these conditions (incidence unknown) ♦♦ Enteritis necroticans (Pig Bel) −− This is caused by b-toxin producing strains of C. perfringens type C −− It is a life-threatening infectious disease characterized by ischemic necrosis of the small intestine −− Pig Bel is most frequently reported from Papua New Guinea (a) It occurs also in other developing countries of the world, and in developed countries including the UK and the USA

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−− There are several factors involved (a) Consumption of pork or other contaminated meat (b) Poor nutrition (c) A diet rich in trypsin inhibitors (e.g., sweet potatoes, peanuts and soy beans) (d) Other trypsin inhibitors (e.g., Ascaris lumbricoides)

Microscopic ♦♦ Although the jejunum is the usual primary site, the entire small bowel may be involved ♦♦ There is acute, patchy, hemorrhagic, necrotizing, ulcerative, and inflammatory disease ♦♦ Pseudomembranes may be present ♦♦ Some have gas cysts but most do not ♦♦ There is prominent mucosal inflammation and ulceration ♦♦ The submucosa is edematous with neutrophilic infiltrates ♦♦ Small vessel thrombosis is often prominent ♦♦ Full thickness necrosis occurs in advanced disease ♦♦ Tissue Gram stains may reveal mixed bacteria but not permit differentiation between pathogenic clostridia and the normal microbiota

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Another important association with C. septicum bacteremia is necrotizing enterocolitis in neutropenic patients

Pathology (Fig. 6.17A, B) ♦♦ Macroscopically in neutropenic colitis, there is thickening, ulceration, and hemorrhagic necrosis of the cecum (with or without involvement of the ascending colon and/or terminal ileum) ♦♦ Microscopic examination of the involved cecum reveals hemorrhagic necrosis of the mucosa, ulceration, marked edema, and thickening of the submucosa, but with few inflammatory cells ♦♦ Gas cysts are sometimes present, particularly in the submucosa ♦♦ Macroscopic and microscopic findings in myonecrosis and other soft tissue infections due to C. septicum are similar to those observed in myonecrosis caused by C. perfringens ♦♦ Tissue Gram stains (i.e., Brown–Brenn) may reveal large numbers of gram-positive, sporeforming rods in the involved tissue

Microbiology ♦♦ Commercially available immunofluorescent antibody stains can aid in identifying the organism in fresh clinical materials or in tissue sections

♦♦ The differential includes ischemic bowel disease and infections due to other bacteria

Diagnostic Techniques ♦♦ PCR methods are used in research settings, but not commercially available ♦♦ Feces, blood, bowel wall, and peritoneal fluid should be collected for microbiologic studies to include isolation, identification, and typing of C. perfringens

Clostridium septicum and Bacteremia ♦♦ This is a microaerotolerant, histotoxic species with the potential of causing severe life-threatening disease ♦♦ C. septicum is rarely recovered from the feces of healthy humans −− It is more commonly present in feces of patients with colon cancer, and in normal appendices ♦♦ It ranked as the second or third most frequent cause of gas gangrene during wartime ♦♦ It is currently recognized increasingly as a major cause of spontaneous (nontraumatic) myonecrosis ♦♦ C. septicum bacteremia occurs frequently in patients with −− Occult colon cancer −− Leukemia/lymphoma −− Diabetes mellitus ♦♦ Patients present clinically with −− Signs of sepsis −− Abdominal pain, tenderness, vomiting, and diarrhea −− Often with rapid metastatic spread of the infection and myonecrosis to distant locations

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Fig.  6.17. Clostridium septicum myonecrosis involving lower extremity [(A) gross photo], (B) gram-positive rods with subterminal spores in a necrotic background (Brown–Brenn).

Microbiology for the Surgical Pathologist

♦♦ Blood, fresh tissue (e.g., bowel wall), peritoneal fluid, intestinal contents, or feces can be cultured for C. septicum

Clostridium difficile ♦♦ This obligately anaerobic, motile, gram-positive rod that forms subterminal spores is the major cause of antibioticassociated pseudomembranous colitis

Epidemiology and Pathogenesis ♦♦ C. difficile and its toxins are commonly present in feces of healthy neonates ♦♦ The carriage rate in feces of children older than 2 years and in healthy adults is 2–3% ♦♦ The organism can be isolated from ³20% of adults who have recently received antibiotics, though toxin is not as frequently detected in their stools ♦♦ C. difficile-associated illness usually follows exposure of patients to antibiotics or chemotherapeutic agents −− Thus, disruption of the patient’s colonic microbiota ­(“normal flora”) by exposure to these agents is a major predisposing factor ♦♦ Some of the more important additional predisposing factors include the following −− Advanced age −− Immunosuppression −− Severe underlying illness −− Length of hospitalization ♦♦ In a number of cases, C. difficile-associated illness has occurred in patients who received proton pump inhibitors

Virulence ♦♦ C. difficile-associated illness is caused by C. difficile strains that produce toxin A (TcdA+) and toxin B (TcdB+) ♦♦ It now is known that some strains are toxin A negative and produce only toxin B (TcdA−/TcdB+) −− These strains also cause antibiotic-associated diarrhea and pseudomembranous colitis ♦♦ Strains producing neither toxin are considered nonpathogenic ♦♦ Eenterotoxin (TcdA) −− Induces a positive fluid response in a rabbit ileal loop model −− It attracts neutrophils with release of cytokines −− It disrupts tight cell–cell junctions, altering permeability ♦♦ Cytotoxin (TcdB) −− Induces cytopathic effects in many tissue culture cell lines −− It causes depolymerization of actin, disrupts the cellular cytoskeleton, and stimulates chemokine release from macrophages −− It also damages tight cell–cell junctions ♦♦ Both toxins induce apoptosis ♦♦ Recently, a more virulent strain of C. difficile referred to as North American Pulsefield Type 1 (NAP1), restriction

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enzyme analysis type “BI,” and PCR ribotype 027 that has been linked to more severe disease with an increased risk of relapse, severe complications, a high mortality rate, and an apparent increased rate of spread has emerged in hospitals and communities in Canada, the USA, and Europe −− The increased virulence of this strain is due to an 18-bp deletion and a frame shift mutation leading to a premature stop codon in tcdC, a gene that serves to downregulate the production of both toxins A and B −− Thus, with the regulatory gene nonfunctional, there is a 16- to 23-fold increase in toxin production by these genes −− In addition, this strain, unlike most wild-type (or older) strains of C. difficile, is resistant to the newer fluoroquinolone antibiotics. More spores are produced by some isolates (a) Thus, fluoroquinolone resistance and increased sporulation may facilitate spread

Clinical Features and Pathology (Fig. 6.18A, B) ♦♦ C. difficile produces a spectrum of findings −− Findings range from asymptomatic colonization with unremarkable mucosa, to −− Antibiotic-associated diarrhea without or with nonspecific inflammation of the colon (colitis), or to −− Pseudomembranous colitis (PMC); the pathologic findings seen in PMC are not diagnostic for C. difficile ♦♦ C. difficile is the major cause of nosocomial diarrhea, and a potentially serious threat to immunocompromised patients −− Spread is by spores on hands −− Spores on bed sheets, bedpans, and various surfaces in the hospital environment

Macroscopic ♦♦ Yellow plaques (usually patchy) overlying an ulcerated mucosa occur

Microscopic ♦♦ There is marked mucosal and submucosal edema with intense neutrophilic inflammation ♦♦ The most characteristic finding is that of a pseudomembrane – particularly a “summit lesion” (sometimes reminiscent of a “volcanic eruption” or a “mushroom cloud”) contains abundant fibrin, mucin, neutrophils, and sloughed mucosa

Diagnostic Techniques ♦♦ Isolation of toxigenic C. difficile that produces toxin B or both toxins A&B (nontoxigenic C. difficile represents colonization not related to disease) ♦♦ Direct detection of toxin B (e.g., by cytotoxin neutralization assay) or toxins A&B (e.g., by a commercial EIA kit) in patient’s feces ♦♦ Test kits designed to detect only toxin A will miss TcdA−/ TcdB+ strains

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♦♦ The clinical hallmark of botulism is acute flaccid paralysis −− It begins with bilateral cranial nerve impairment involving muscles of the face, head, and pharynx −− It then descends symmetrically to involve muscles of the thorax and extremities −− Death may result from respiratory failure due to (a) Paralysis of the tongue or muscles of the pharynx with occlusion of the upper airway (b) Paralysis of the diaphragm and intercostal muscles ♦♦ There are five categories of botulism (which follow) −− Classical foodborne botulism: caused by ingesting preformed botulinal toxin in contaminated food −− Wound botulism: results from growth of C. botulinum and production of toxin in vivo in an infected wound −− Infant botulism (the form encountered most frequently in the USA): caused by growth and production of toxin within the intestinal tract of an infant colonized by C. botulinum −− Botulism due to intestinal colonization in children and adults (with production of toxin within the intestine) −− Inhalational botulism: results from aerosolization of ­botulinum toxin (e.g., as a bioterrorist weapon)

Microscopic ♦♦ No histopathologic findings are attributed to the neurophysiologic dysfunction that occurs in botulism, regardless of category Fig.  6.18. Clostridium difficile – pseudomembranous colitis [(A) gross photo], (B) pseudomembranous colitis (H&E).

Diagnostic Techniques

♦♦ Recently, new FDA-approved real-time PCR tests for the TcdB gene of C. difficile have become commercially available −− These offer improved sensitivity, specificity, and shorter turnaround time compared to the previously available methods mentioned above

♦♦ Most hospital microbiology laboratories are not equipped to process specimens from patients suspected of having botulism ♦♦ Physicians should notify their State Health Department or the CDC immediately if botulism is suspected ♦♦ The CDC phone number for questions and consultation (24  h/7 day emergency service) is (770) 488–7100 (also see the CDC website: http://www.bt.cdc.gov/agent/ botulism)

C. botulinum and Botulism

C. tetani and Tetanus

♦♦ Botulism is a rare, life-threatening neuroparalytic disease caused by the action of one of the most potent toxins known ♦♦ There are seven known antigenic types of botulinal toxin (A–G); types A, B, and E cause most human disease ♦♦ Spores of most strains of C. botulinum survive at 100°C for several hours

♦♦ C. tetani is the only major pathogen among the Clostridia that produces terminal spores ♦♦ The organism and its spores are present in the soil and intestinal contents of animals (including humans occasionally) ♦♦ Tetanus is an extremely dramatic neurologic illness caused by the action of a potent toxin elaborated by C. tetani, “tetanospasmin” ♦♦ Tetanospasmin blocks the release of neurotransmitter, gamma-aminobutyric acid, at synapses in the CNS −− Thus, inhibitory impulses to motor neurons are blocked −− There is uninhibited firing of motor nerve transmissions resulting in prolonged muscle spasms (the hallmark of the disease) ♦♦ Tetanus is rare in the USA

Clinical Features and Pathogenesis ♦♦ The toxin enters the blood stream from the site where it was absorbed or produced ♦♦ It then is carried to peripheral nerve endings, particularly neuromuscular junctions of motor neurons, where −− It binds irreversibly to presynaptic membranes, and prevents release of acetylcholine

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♦♦ It is often associated with puncture wounds that do not appear serious ♦♦ Injecting drug-user associated infections emerged, including −− Recent reports of C. tetani infections in injecting drug users (“skin popping”) in California −− Also, C. novyi infections have been reported in injecting drug users (recently in the UK, particularly Wales) ♦♦ Neonatal tetanus −− It occurs in babies born to inadequately immunized mothers −− It has followed the application of nonsterile materials (e.g., soil) to the umbilicus

Pathology and Microbiology ♦♦ There are no characteristic histopathologic findings of C. tetani wound infections

Diagnosis ♦♦ The diagnosis is based on clinical features, especially the following −− Trismus or “lockjaw” with difficulty opening the mouth (due to painful, contracted masseter muscles) −− Risus sardonicus (involving orbicularis oris contraction) −− Opisthotonic posturing ♦♦ Neither biopsies nor microbiology cultures aid in making the diagnosis

Anaerobic, Nonsporeforming GramNegative Rods: The Bacteroides fragilis Group, Prevotella and Porphyromonas Species, and the Genus Fusobacterium ♦♦ The current frequency of medically important anaerobes isolated from properly collected clinical specimens −− About 35% of all anaerobe isolates are the medically important anaerobic gram-negative rods −− Anaerobic cocci account for 25% of the isolates −− The nonsporeforming gram-positive rods account for about 25% of the isolates −− Clostridia now account for <15% of the anaerobe isolates ♦♦ The anaerobic, nonsporeforming gram-negative rods are among the most important inhabitants of the human microbiota in the oral cavity, gastrointestinal tract, and the vagina ♦♦ Most infections caused by these bacteria are “endogenous” (sources of the organisms are the hosts’ own microbiota) −− Many of the infections caused by these bacteria are polymicrobial (a) These involve gram-negative anaerobes mixed with other anaerobes (e.g., anaerobic cocci or nonsporeforming gram-positive rods) or gram-negative anaerobes mixed with facultative anaerobes ♦♦ Infections in which anaerobic, nonsporeforming gram-negative rods are involved and important include the following −− Blood stream infections

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−− Brain abscess; subdural empyema −− Dental/oral infections (e.g., periodontal disease, root canal infections) −− Chronic sinusitis −− Chronic otitis media and mastoiditis −− Peritonsillar abscess −− Neck space infections −− Aspiration pneumonia −− Lung abscess −− Thoracic empyema −− Pyogenic liver abscess −− Peritonitis; intraabdominal abscess −− Appendicitis and its complications −− Postoperative wound infections following ­intraabdominal/ pelvic surgery −− Endometritis, salpingitis, tuboovarian abscess −− Necrotizing skin and soft tissue infections including the following (a) Necrotizing fasciitis * Although originally associated with group A Streptococcus, it commonly involves Bacteroides species mixed with other bacteria) (b) Synergistic necrotizing cellulitis * High mortality (about 50%); patients often die of septic shock * Most common site is the perineum * Major antecedents include perirectal abscess or ischiorectal abscess; lesions that may spread to pelvis or abdomen, buttocks, or thighs; and lower leg vascular disease or diabetic foot ulcers * About 75% of these patients have diabetes; about 50% have cardiovascular and renal disease; about 50% are obese * This is a polymicrobial infection in which Bacteroides species and various other anaerobes are common (e.g., anaerobic cocci); E. coli and other enterics also common in this condition * Surgical management involves radical debridement (c) Nonclostridial crepitant cellulitis * This is most often seen in diabetic patients * Lower extremities are the most common sites of involvement; the infectious process tracks along fascial planes * The bacteria most commonly involved are Bacteroides species, anaerobic cocci, E. coli, Klebsiella, or other enteric bacteria * These infections are not as serious as those described above for C. perfringens and other histotoxic clostridia * Skeletal muscle remains viable (unlike myonecrosis)

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* The presence of gas in this type of soft tissue infection does not mean the patient has myonecrosis * Surgical management should not be nearly so aggressive as that required for gas gangrene; it should be tailored to the correct diagnosis

Pathology (Fig. 6.19) ♦♦ Macroscopic examination of specimens can provide important clues suggesting the presence of anaerobes (particularly a putrid odor, pus, or necrotic tissue) ♦♦ Direct Gram-stained smears of aspirates, exudates, touch preparations of specimens, or frozen sections can aid in presumptive diagnosis long before results of microbiologic cultures or permanent sections are available ♦♦ Infections involving the anaerobic gram-negative bacteria are characterized by acute suppurative, necrotizing inflammation ♦♦ Abscess formation is considered the hallmark of infections caused by the Bacteroides fragilis group ♦♦ The anaerobic gram-negative bacteria in this group are rod-shaped, and some have vacuoles (e.g., Bacteroides species) −− The sizes of these bacteria vary from medium (Bacteroides) to small (many Prevotella and Porphyromonas species) −− Fusobacterium nucleatum forms thin, needle-shaped rods; F. necrophorum and other species of Fusobacterium tend to be very pleomorphic

Anaerobic Microbiology ♦♦ Anaerobic cultures are indicated in the kinds of serious infections listed above ♦♦ Good anaerobic microbiology depends upon proper selection, collection, and transport of the specimens −− In the selection of specimens, sites contaminated by normal flora should be avoided −− Prior to collection of specimens, skin or mucosal surfaces should be decontaminated

−− Specimens to collect are tissue samples (e.g., biopsy or tissue removed at surgery) or exudates aspirated by needle and syringe −− Tissue should be placed in sterile, screw-capped containers, which then can be sealed in anaerobic gas-impermeable bags for transport to the lab −− Pus should be injected into an anaerobic transport container −− Swabs are not desirable for anaerobic specimens as they tend to dry out and carry only a small volume of material

Anaerobic Gram-Positive Cocci: The “Peptostreptococci” ♦♦ As a group, the anaerobic cocci share similar habitats, but are isolated somewhat less frequently than the anaerobic nonsporeforming gram-negative rods in the microbiology laboratory

Recent Taxonomic Changes ♦♦ In the past, most clinically important species of anaerobic cocci were classified in the genus Peptostreptococcus ♦♦ Recently, this group has been under major taxonomic revision; now, Peptostreptococcus anaerobius is the only remaining species in this genus ♦♦ Those formerly called P. magnus and P. micros are now called Finegoldia magna and Parvimonas micra ♦♦ Peptostreptococcus asaccharolyticus is now called Peptoniphilus asaccharolyticus ♦♦ Peptostreptococcus parvulus, also commonly isolated from clinical specimens, is now Atopobium parvulum ♦♦ While additional taxonomic changes have been made within the anaerobic cocci, many clinicians and microbiologists are still not aware of them −− Thus, the terms “Peptostreptococci” or anaerobic grampositive cocci are still used in discussions about these bacteria

Infections in which the “Peptostreptococci” are Commonly Encountered ♦♦ Many of the types of polymicrobial infections listed for the anaerobic nonsporeforming rods (above) are mixed with anaerobic cocci ♦♦ Anaerobic pleuropulmonary infections, deep wound infections following surgical procedures, anaerobic osteomyelitis (due to Finegoldia magna), and a number of skin and soft tissue infections (e.g., diabetic foot infections) are examples of infections that more commonly involve this group of bacteria

Pathology and Anaerobic Microbiology

Fig. 6.19. Fusobacterium nucleatum (and mixed anaerobes) head and neck infection (Gram).

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♦♦ Gross and microscopic findings are indistinguishable from those described for the anaerobic nonsporeforming gramnegative rods ♦♦ Direct smears and tissue Gram stains reveal varying size gram-positive cocci ranging from relatively large in diameter (e.g., Finegoldia magna) to tiny (e.g., Parvimonas micra)

Microbiology for the Surgical Pathologist

−− Arrangements of these bacteria (e.g., clusters, tetrads, chains, pairs) cannot be distinguished from those of the nonanaerobic cocci ♦♦ Anaerobic culture is complicated by the strict oxygen sensitivity and relatively slow growth of the anaerobic cocci

Anaerobic Nonsporeforming Gram-Positive Rods Actinomyces Species and Actinomycosis ♦♦ Actinomycosis is an endogenous infection caused by anaerobic or aerotolerant filamentous bacteria, mostly of the genus Actinomyces ♦♦ Bacteria that have been reported to cause actinomycosis in humans include A. israelii, A. naeslundii, A. odontolyticus, A. gerencseriae, A. viscosus, A. meyeri, A. georgiae, A. neuii subsp. neuii, Propionibacterium propionicum (formerly Arachnia propionica), Bifidobacterium dentium (formerly B. eriksonii), Rothia dentocariosa, and Eubacterium nodatum −− In humans the major cause of actinomycosis is A. israelii −− In animals, the principal cause is A. bovis ♦♦ Species of Actinomyces inhabit the oropharynx, gastrointestinal tract and vagina of healthy individuals

Clinical ♦♦ There are four forms of actinomycosis based on anatomic regions of the body −− Cervicofacial (“lumpy jaw”) (a) This is the most common form of actinomycosis (b) It may develop without prior injury to the oropharyngeal mucosa (c) It may complicate periodontal disease, dental extractions, or other dental/oral trauma (d) There is characteristic swelling and firmness of local tissues, abscess formation, and sinus tracts, which may extend from the oral cavity through the mandible or other bone as well as soft tissue and skin (e) Material from draining sinus tracts may contain “sulfur granules,” (i.e., yellow or brown-yellow colonies of bacteria surrounded by adherent leucocytes; usually a few to several millimeter in diameter) (f) Cervicofacial actinomycosis may extend into a maxillary sinus or other sinuses, invade the orbit, or cranial bones; or may extend to the thorax, involve other bones, joints, the skin, or the CNS −− Thoracic (a) The thoracic form of actinomycosis develops most often following aspiration of oropharyngeal contents (b) But sometimes, it develops from direct extension from a cervicofacial infection (c) All tissues/organs of the thoracic cavity are potentially susceptible −− Abdominal (a) Abdominal actinomycosis usually arises from the intestine following trauma or perforation (e.g., appendicitis)

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(b) The infection may extend directly within the abdomen to involve any tissue or organ (or it could spread hematogenously) −− Pelvic (a) Pelvic actinomycosis is mostly associated with use of intrauterine devices (b) It also may arise from an intestinal/colonic focus

Macroscopic ♦♦ Specimens may contain yellow (sometimes green) granules in a background of sanguineous material (so-called “sulfur granules”) ♦♦ Sinus tracts with purulent exudates ♦♦ Gray bands of fibrous connective tissue

Microscopic (Fig. 6.20A–C) ♦♦ H&E stained sections typically reveal solitary or multiple abscesses, sinus tracts, granulation tissue, and fibrosis ♦♦ Sulfur granules with Splendore-Höeppli material (having an amphophilic or eosinophilic center with peripherally radiating serrate margins) ♦♦ Actinomycotic branching filaments are not readily seen in H&E or PAS stains

Special Stains ♦♦ GMS-positive staining features thin, delicate filaments with right angle branching ♦♦ Brown–Brenn tissue Gram stain with gram-positive, 1  mm diameter, beaded, branching filaments ♦♦ Fite modified acid-fast stained section revealing negative (not acid-fast, and not partially acid-fast) blue appearing bacteria ♦♦ Modified Kinyoun acid-fast stain of smears or tissue touch preparations – negative (blue or purple staining) as well

Differential Diagnosis ♦♦ Hematoidin crystals, dense clumps of spermatozoa, mucin or fibrin threads in cytologic preparations ♦♦ Nocardia, septate hyphae (eumycotic mycetoma), nonbranching bacilli or cocci (botryomycosis) may form sulfur granules −− These can be differentiated using GMS, Brown–Brenn Gram stain, and the modified acid-fast stains

Diagnostic Techniques ♦♦ Culture ♦♦ Immunofluorescence

Mycobacterium Species ♦♦ Mycobacterium tuberculosis and the nontuberculous Mycobacteria produce necrotizing and nonnecrotizing granulomatous inflammation in the lungs and other organs and tissues ♦♦ A detailed discussion is provided in Chapter 28, and they are considered in additional chapters including Chapters 15 and 44

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Treponema pallidum (Syphilis) ♦♦ Treponema pallidum subsp. pallidum (subsequently referred to as T. pallidum) causes syphilis; it is acquired sexually, transplacentally, or by transfusion ♦♦ Humans are the only known hosts; the disease is worldwide in occurrence ♦♦ In the USA, syphilis increased during 2000–2006 to ~10,000 cases annually ♦♦ T. pallidum ranks third behind Chlamydia trachomatis and Neisseria gonorrhoeae, respectively, as a cause of sexually transmitted bacterial disease ♦♦ T. pallidum is very sensitive to drying and disinfectants (it does not survive on toilet seats) ♦♦ This thin, tightly coiled spirochete with pointed ends has corkscrew motility (owing to three flagella attached at both ends which are inserted within the periplasmic space and extend tightly along the helical body of the organism) ♦♦ T. pallidum does not grow in culture on artificial media; animal models of syphilis are lacking, as is knowledge of the pathogenesis of syphilis

Clinical

Fig. 6.20. Actinomyces israelii; pulmonary actinomycosis; sulfur granule; (A) H&E, (B) GMS, (C) Brown–Brenn.

Spirochetes: Treponema and Borrelia ♦♦ Spirochetes of the genera Treponema and Borrelia are thin, spiral-shaped gram-negative bacteria (0.1–0.5 µm wide × 5.0– 30 µm long)

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♦♦ Primary syphilis −− The initial chancre usually develops about 3 weeks (range 10–90 days) after sexual contact (at the site of initial inoculation) as a solitary, red, firm, nontender, raised lesion (painless ulcer with raised margins); it is usually on the external genitalia, cervix, anus, or mouth (but can be at other sites) −− Regional lymphadenopathy often develops 1–2 weeks later −− Spirochetes, present in large number in the chancre, spread hematogenously and via lymphatics −− The chancre heals spontaneously in 3–6 weeks (even without antimicrobial treatment) ♦♦ Secondary (disseminated) syphilis −− The most florid stage of syphilis – it usually begins 2–8 weeks after the chancre appears in untreated patients, though the time of appearance varies −− The patient develops “flulike” symptoms with pharyngitis, fever, headache, myalgias, arthralgias, and painless lymphadenopathy −− The classic, most characteristic manifestation is the rash (e.g., superficial macular, maculopapular, pustular; with combinations and variations); it is especially noteworthy on the palms and soles −− Condyloma lata (raised, plaque-like lesions) develop in moist areas of the anogenital region, inner thighs, and axillae −− Mucous patches, erosions, and/or ulcers develop in the mouth or throat −− Spirochetes will be present in abundance also at this stage; skin and mucous membrane lesions are highly infectious

Microbiology for the Surgical Pathologist

−− The symptoms and the rash usually resolve spontaneously in a few weeks; the patient subsequently enters the latent phase ♦♦ Tertiary syphilis −− After a few years to decades, approximately one-third of untreated patients will develop clinical features of this stage −− The major manifestations are (a) Cardiovascular syphilis involving the thoracic aorta (syphylitic aortitis) and heart (b) Neurosyphilis * Symptomatic (i.e., chronic meningovascular disease, tabes dorsalis, and general paresis) * Ocular (e.g., Argyll Robertson pupil [small, irregular pupil that does not react to light but accommodates to near vision]) * Asymptomatic (manifested by CSF abnormalities including pleocytosis [increased numbers of white blood cells], elevated protein, elevated glucose, and a reactive CSF VDRL test in a patient with a reactive serum treponemal antibody test (c) “Benign” tertiary syphilis characterized by “gummas” (granulomatous lesions) in bone, skin, oral mucosa or other tissues or organs ♦♦ Congenital syphilis −− T. pallidum can cross the placental barrier at any stage of infection of an untreated or inadequately treated mother to cause serious infection in utero manifested by death in ~25% (intrauterine and perinatal) −− Early (infantile) manifestations (a) Snuffles (a rhinitis) (b) A diffuse maculopapular, desquamative or bullous rash with skin sloughing, especially on the palms and soles and around the mouth and anus (c) Anemia (d) Hepatosplenomegaly −− Late (tardive [or latent period]) manifestations in the untreated child who survives the first 6–12 months (a) Opacification of the cornea due to interstitial keratitis (b) Perforation of the palate (c) Saddle nose (collapse of the bridge of the nose) (d) Eighth nerve deafness (e) Hutchinson teeth (short, screwdriver-shaped or notched incisors) (f) Saber shins, or anterior bowing of the tibias due to periostitis and new bone formation

Macroscopic ♦♦ Primary syphilis −− Chancre begins as a circular, red papule varying from a few millimeters to several centimeters; it later becomes a shallow ulcer with raised edges, and an indurated base

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−− The ulcer surface will be covered with hemorrhagic or brown-yellow material containing abundant spirochetes (these can be seen using dark-field microscopy or by doing a silver impregnation stain on biopsy material) ♦♦ Secondary syphilis −− Cutaneous and mucocutaneous lesions on the soles, palms, oral cavity, and other locations −− Red to red-brown skin lesions measuring 1–2 cm −− Mucous patches (mucosal ulcers in the mouth, esophagus, pharynx, larynx, anorectal and genital areas) may be round, flat or slightly raised, or may be thin and serpiginous −− Lymph nodes may be enlarged −− Hepatosplenomegaly may occur ♦♦ Tertiary syphilis −− Cardiovascular syphilis (a) The ascending/thoracic aorta is one of the sites most frequently involved; findings include a “tree bark” appearance with pitting, aneurysm (saccular type aneurysm which may rupture causing exsanguinations), dilatation of the aortic valve ring with widened commissures (resulting in incompetence of the aortic valve); thickened, shortened aortic valve cusps with rolled edges (due to fibrosis) (b) Atherosclerotic obstruction of one or both coronary ostia −− Neurosyphilis (a) In the meningovascular form, findings may include a chronic meningitis involving the base of the brain, cerebral convexities, and leptomeninges (b) In tabes dorsalis, damage to sensory nerves in spinal roots leads to locomotor ataxia (due to impaired position sense), loss of pain sensation, and “Charcot joints” (due to joint damage) ♦♦ Benign tertiary syphilis −− Gummas are rubbery, nodular, tubercle-like granulomas varying from <1  mm to several centimeters in greatest dimension −− Gummas occur in the skin, subcutaneous tissue, bone, joints, liver (hepar lobatum) and elsewhere

Microscopic ♦♦ The characteristic histologic finding at all stages of syphilis is obliterative endarteritis and plasma cell infiltrates (Fig. 6.21)

Special Stains ♦♦ T. pallidum is too thin to be seen in H&E, Brown-Brenn, Brown–Hopps, GMS, or PAS stains on tissue sections (it is also too thin to be seen on Gram stain of smears or touch preparations in the clinical microbiology laboratory) ♦♦ The organism can be demonstrated in biopsies via immunohistochemistry (which we recommend), or by Warthin– Starry, Steiner, or Dieterle silver stain ♦♦ In freshly collected materials (e.g., exudates or scrapings from ulcerated skin lesions; aspirates from lymph nodes)

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Fig. 6.21. Secondary syphilis; (A ) skin biopsy with band-like infiltrate of lymphocytes and plasma cells in dermis, and mild lichenoid changes in epidermis, H&E. (B) Higher power with perivascular lymphocytic and plasmacytic intiltrate, H&E. (C) Treponema pallidum, positive immunohistochemical stain. (D) Treponema pallidum, dark-field examination.

collected from patients with primary, secondary, or congenital syphilis, T. pallidum can be identified using a direct fluorescent antibody stain ♦♦ Dark-field examination is reliable only when exudates or other very freshly collected materials from suspect skin lesions are examined by an experienced microbiologist or pathologist demonstrating actively motile spirochetes (showing characteristic corkscrew motility) (Fig. 6.21D)

Diagnostic Techniques ♦♦ Serologic tests are used as the means of diagnosis for most patients who have syphilis ♦♦ There are two types of serologic tests for syphilis −− Venereal Disease Research Laboratory (VDRL)/Rapid Plasma Reagin (RPR); in these nontreponemal tests IgG and IgM antibodies in patients’ sera react with reagin (i.e., cardiolipin antigen derived from beef heart); the

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tests become positive usually in the first 3–4 weeks, peak during secondary syphilis, then the antibody titers subsequently decrease −− Treponemal antibody tests in which T. pallidum serves as the antigen (e.g., the fluorescent treponemal antibodyabsorption [FTA-ABS] test, and the T. pallidum particle agglutination [TP-PA] test); these types of tests may be negative early but they usually remain positive for life −− To diagnose neurosyphilis, the only reliable CSF test is the VDRL −− A variety of conditions cause false-positives with both nontreponemal and treponemal tests ♦♦ No culture method is available (as mentioned above) ♦♦ No PCR or other type of nucleic acid amplification test is commercially available for T. pallidum in the clinical laboratory. (They are available only in research or certain reference laboratories.)

Microbiology for the Surgical Pathologist

Additional Treponemes ♦♦ T. pallidum subsp. endemicum is the etiologic agent of Bejel (endemic syphilis) ♦♦ T. pallidum subsp. pertenue causes Yaws ♦♦ Treponema carateum causes Pinta ♦♦ These treponemes are identical morphologically to T. pallidum subsp. pallidum ♦♦ Like T. pallidum, subsp. pallidum, they all are susceptible to penicillin ♦♦ These three nonvenereal diseases – Bejel, Yaws, and Pinta – differ epidemiologically and clinically from the venereal disease syphilis

Borrelia burgdorferi (Lyme Disease) ♦♦ B. burgdorferi, the cause of Lyme Disease in the USA, is a microaerotolerant, weakly gram-negative spirochete that is 0.2–0.3 µm wide × 20–30 µm in length; it has 7–11 endoflagella located within its outer membrane that insert subterminally at both ends of the protoplasmic cylinder ♦♦ With >20,000 cases per year, the incidence of Lyme disease is relatively high (It now ranks as the most common vectorborne disease in the USA); most cases occur in −− The Northeast (from Maryland to Maine) −− The North-central states (mainly Wisconsin and Minnesota) −− The West Coast (especially northern California) ♦♦ The disease also occurs in Europe but there it is caused by Borrelia afzelii and Borrelia garinii ♦♦ B. burgdorferi is transmitted to humans from rodents by Ixodes ticks (i.e., Ixodes scapularis in the Northeast); I. scapularis may also be infected with the etiologic agents of Babesiosis and Anaplasmosis (human granulocytic ehrlichiosis)

Clinical ♦♦ Stage 1: Early Lyme disease is usually characterized by one or more of the following −− An expanding red rash called erythema (chronicum) migrans; the center of this circular or ovoid rash may clear, giving a “bull’s-eye” appearance; the rash appears at the site of a tick bite within 3–30 days after the bite of an infected tick −− Fever −− Lympadenopathy ♦♦ Stage 2: Early disseminated stage; there is hematogenous spread of the organisms throughout the body leading to −− Secondary skin lesions −− Lymphadenopathy −− Migratory arthritis −− Muscle pains −− Cardiac arrhythmias −− Neurologic manifestations (e.g., meningitis) ♦♦ Stage 3: The Late disseminated stage, occurring months to years after the initial infection includes

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−− Chronic arthritis involving one or more joints (may be destructive) −− Neurologic illness (e.g., encephalitis or neuropathy) −− Acrodermatitis chronicum atrophicans

Macroscopic ♦♦ Erythema migans (expanding erythematous target-like rash) can be recognized in up to 85% of patients (frequently seen on knees, axilla, and in the groins) ♦♦ Secondary skin lesions due to hematogenous spread of spirochetes ♦♦ Lymphocytoma cutis – painless, blue-red tumor-like nodule (on ear lobe, nipple, or scrotum); this is usually caused by B. garinii and occurs in Europe (not USA) ♦♦ Acrodermatitis chronicum atrophicans – red-blue atrophic lesions usually on sun-exposed extensor surfaces of extremities; is usually caused by B. afzelii and occurs in Europe (not USA) ♦♦ Arthritis with joint swelling

Microscopic ♦♦ Histologic findings in the skin (in erythema chronicum migrans) include −− A perivascular infiltrate containing predominantly lymphocytes, plasma cells, and macrophages −− Mast cells may be present occasionally (Fig. 6.22) −− Neutrophills occasionally are also present ♦♦ Lyme arthritis findings include −− Villous hypertrophy −− Abundant lymphocytes and plasma cells within the synovium −− A vascular occlusive lesion – with subtotal or total obliteration of vessel lumina by endothelial and medial proliferation (“onion skin” appearance [reminiscent of renal arteriole lesions in malignant hypertension or vascular changes in lupus erythematosus]) ♦♦ Lyme myocarditis with transmural lymphocytic/plasmacytic interstitial infiltrates within the myocardium ♦♦ Lymphocytic/plasmacytic infiltrates may be present in other organs

Special Stains ♦♦ B. burgdorferi, like T. pallidum, is too thin to be seen in H&E, Brown and Brenn, Brown–Hopps, GMS, or PAS stains on tissue sections (it also is too thin to be seen on Gram stain of smears or touch preparations in the clinical microbiology laboratory); recommened stains include −− Immunostain −− Warthin–Starry, Steiner, or Dieterle silver stain

Differential Diagnosis ♦♦ Lyme disease has been confused with many disorders; examples follow −− Lupus erythematosus −− Localized scleroderma

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−− First, an enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence assay (IFA) is done (a) IgM antibodies appear 2–4 weeks after onset of erythema chronicum migrans, peak at 6–8 weeks, then decline (b) IgG antibodies appear later and persist during the late stage of the disease −− Second, a Western immunoblot of samples that tested positive or equivocal by ELISA or IFA is run (the CDC website [http://www.cdc.gov] is recommended for detailed interpretive guidelines)

Miscellaneous Other Bacteria Bartonella henselae ♦♦ Like other Bartonella species, B. henselae is an aerobic, small, pleomorphic gram-negative rod, or coccoid rod ♦♦ It is fastidious, very slow-growing, hemin-dependent, oxidase and catalase-negative ♦♦ Its main reservoir is the domestic cat, and cat fleas (Ctenocephalides felis) serve as the vector for cat-to-cat transmission ♦♦ Evidence is lacking regarding cat flea transmission of B. henselae to humans

Clinical Features

Fig. 6.22. Lyme disease; skin biopsy from rash consistent with erythema chronicum migrans (patient had strongly positive serology); (A, B) cuffed perivascular lymphocytic and plasmacytic infiltrates (plus rare eosinophil), H&E. Immunostain for T. pallidum was negative (not shown).

−− Chronic fatigue syndrome −− Guillain–Barré syndrome −− Idiopathic myocardiopathy

Diagnostic Techniques ♦♦ Microscopic examination of tissues or blood for B. burgdorferi in the microbiology laboratory lacks sensitiviity; the organism has rarely been seen on direct microscopic examination ♦♦ Culture has had limited success; sensitivity is low for all specimens (except an early skin lesion) ♦♦ PCR and other nucleic acid amplification techniques are not commercially available (mostly restricted to research and reference laboratories) ♦♦ Serologic tests for antibody detection – currently a two-stage testing process is recommended by CDC

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♦♦ Bacillary angiomatosis (BA) −− This is a widespread, unusual vascular proliferation; it has been reported mostly in immunocompromised individuals (e.g., AIDS) −− BA lesions may be in any organ system, including the skin, lymph nodes, liver (hepatic peliosis), and spleen (splenic peliosis) (a) Bone, central nervous system, and respiratory tract lesions have also been documented −− Two Bartonella species cause BA; B. henselae and B. quintana ♦♦ Cat-scratch disease (CSD) −− Approximately 25,000 cases of CSD occur in the USA per year −− CSD is a chronic, usually self-limited, regional lymphadenopathy in children −− 90% of patients have cat exposure (bite, scratch or lick usually from a domestic cat less than 1-year-old or a feral cat) −− About 3–10 days after initial contact, a primary papule, erythematous nodule, or pustule develops (e.g., at the site of the bite or scratch) (a) It persists for 1–3 weeks −− Regional lymphadenopathy (e.g., usually cervical or axillary) develops in 1–7 weeks −− A single node (usually tender) is involved in half of the cases (a) In other cases, multiple nodes in a single region may be involved, or there may be lymphadenopathy at multiple locations

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−− Fever, malaise, headache, muscle aches, sore throat, and rash may occur −− In about half of the so-called atypical cases of CSD, Parinaud oculoglandular syndrome occurs (a) This is granulomatous conjunctivitis with preauricular lymphadenopathy −− CSD is usually self-limited (a) Patients recover uneventfully, although lymphadenopathy may persist for 2–4 months −− Complications include encephalopathy in about 1–7% of cases, granulomatous hepatitis, and neuroretinitis

Macroscopic ♦♦ Bacillary angiomatosis −− Cutaneous lesions are papules and nodules ranging from skin colored to pink-red-purple with intact, smooth or ulcerated surfaces −− There are enlarged lymph nodes with punctate red areas −− Hepatosplenomegaly with blood filled spaces occurs ♦♦ Cat-scratch disease −− There may be a single enlarged lymph node or multiple enlarged nodes

Microscopic (Fig. 6.23A, B) ♦♦ Bacillary angiomatosis −− Well-circumscribed lobular vascular proliferation with extracellular purple granular clusters of bacilli and surrounding neutrophils and leukocytoclastic debris −− Large cuboidal endothelial cells with vesicular nuclei and prominent nucleoli line vessels and may protrude into lumen −− Macrophages may predominate if partially treated −− Lymph node effacement; organisms are more abundant than in cutaneous lesions ♦♦ Cat-scratch disease −− Findings include stellate microabscesses, granulomas, and follicular hyperplasia of lymph nodes

Special Stains ♦♦ This is a small, pleomorphic, weakly gram-negative rod, but modified Gram stains, Gomori methenamine silver, periodic acid-Schiff, and acid-fast stains will not show organism well ♦♦ Warthin–Starry, Steiner, and Dieterle silver stains may reveal the organism

Differential Diagnosis ♦♦ Clinically, the skin lesions are identical to those of Kaposi sarcoma and pyogenic granuloma

Diagnostic Techniques ♦♦ Culture (e.g., blood, lymph node drainage, biopsies) −− Requires prolonged incubation, is technically difficult, and tends not to be reliable ♦♦ A definitive diagnosis can be based on the clinical presentation and

Fig.  6.23. Cat-scratch disease; (A) lymph node (H&E), (B) Warthin–Starry.

−− The results of serologic testing for antibodies to B. henselae, or by −− Demonstrating the organism in a Warthin–Starry stained section, or −− By a positive PCR result

Bartonella quintana ♦♦ The reservoir is humans; the vector is the human body louse (Pediculus humanus corporis)

Clinical Features ♦♦ B. quintana, is a causative agent of bacillary angiomatosis (BA) ♦♦ BA is also caused by B. henselae (see above description) ♦♦ Trench fever, prevalent during World War I, was also caused by B. quintana ♦♦ Today, in addition to causing BA, B. quntana causes a number of clinical illnesses including the following, mostly in immunocompromised and homeless people −− Recurrent fevers with bacteremia −− Endocarditis

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Macroscopic

Special Stains

♦♦ See B. henselae

♦♦ It is a weakly staining gram-negative rod (like B. henselae and B. quintana), but modified Gram stains, Gomori methenamine silver, periodic acid-Schiff, and acid-fast stains will not show the organism well ♦♦ Warthin–Starry, Steiner, Dieterle, and Giemsa stains do stain the organism

Microscopic ♦♦ See B. henselae

Special Stains ♦♦ It is a weakly staining gram-negative rod, but modified Gram stains, Gomori methenamine silver, periodic acid-Schiff, and acid-fast stains will not show organism well ♦♦ Warthin–Starry, Steiner, Dieterle, and Giemsa stains do stain the organism

Differential Diagnosis ♦♦ See B. henselae

Diagnostic Techniques ♦♦ Culture ♦♦ B. quintana, like B. henselae, can be isolated from blood culture ♦♦ Isolation from infected tissue has also been accomplished, though culture is technically difficult and prolonged incubation is required ♦♦ Serology can be used for confirmation ♦♦ PCR can be used to confirm the presence of the organism

Bartonella bacilliformis ♦♦ This organism is geographically restricted to Peru, Ecuador, and Columbia ♦♦ The vector is the Sandfly (Phlebotomus)

Clinical Features ♦♦ Oroya fever (Carrion disease) ♦♦ Abrupt or insidious onset 3 weeks to 3 months postbite of infected vector ♦♦ Anorexia, headache, malaise, slight fever for 2–7 days ♦♦ Severe anemia, muscle and joint pain, dyspnea, angina, delirium, coma possible ♦♦ Organisms may be isolated from blood in this stage ♦♦ Verruga peruana ♦♦ Muscle, bone, and joint pain may persist after resolution of Oroya fever ♦♦ It is characterized by nodular lesions on exposed body parts, mucous membranes, or internal organs, developing over 1–2 months and lasting months to years ♦♦ Organisms may be isolated from cutaneous lesions, occasionally blood and bone marrow during this stage

Macroscopic ♦♦ Patients have red-purple, nodular, nontender skin lesions

Microscopic ♦♦ Features are as described for bacillary angiomatosis (see B. henselae), but lymphocytes and plasma cells predominate ♦♦ The colonies of B. bacilliformis are fewer (Rocha-Lima bodies) ♦♦ Verruga peruana can have spindled form

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Differential Diagnosis ♦♦ Clinically, the skin lesions are identical to those in Kaposi sarcoma and pyogenic granuloma

Diagnostic Techniques ♦♦ See above (B. quintana)

Rickettsia rickettsii and Rocky Mountain Spotted Fever ♦♦ These Rickettsiae are small, obligately intracellular bacteria ♦♦ They replicate in endothelial cells, causing vasculitis ♦♦ Tick vectors determine geographic distribution of the disease as follows ♦♦ Dermacentor variabilis (American dog tick); eastern USA (most common in southeast and south central USA) ♦♦ Dermacentor andersoni (Rocky Mountain wood tick); Rocky Mountains ♦♦ Rhipicephalus sanguineus; Mexico ♦♦ Amblyomma cajennense; Mexico, and Central and South America

Clinical ♦♦ The incubation period varies (2 days to 2 weeks) ♦♦ The illness usually starts with fever, myalgia, and severe headache (often nausea, vomiting, or abdominal pain as well) ♦♦ There is a characteristic rash ♦♦ It usually begins around the wrists and ankles 2–5 days after onset; the rash may also begin on trunk ♦♦ Involvement of the hands and soles is considered the “hallmark” (but is not seen in all patients who develop rocky mountain spotted fever (RMSF) rash) ♦♦ Focal neurologic deficits may be prominent ♦♦ Other manifestations may include signs of meningoencephalitis, pulmonary edema, acute renal failure, coagulopathy, shock, and necrosis of the skin ♦♦ RMSF mortality in untreated persons during the preantibiotic era was about 20% ♦♦ In fatal cases, death usually occurs ~7–15 days after onset

Microscopic (Fig. 6.24) ♦♦ R. rickettsii infection injures endothelial cells and vascular smooth muscle cells ♦♦ Vascular lesions may be present in any organ ♦♦ Lesions are characterized by focal hemorrhages, intramural and perivascular lymphocytes and macrophages. Neutrophils are not prominent in these lesions

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♦♦ Thromboses are present in only a small portion of the involved vessels

Diagnostic Techniques ♦♦ Rickettsiae stain poorly in Gram stains of tissue sections; they stain best in Giemsa, but the histologic findings are not specific and not reliable ♦♦ Microbiologic cultures are not helpful ♦♦ The diagnosis is made primarily by serologic testing (i.e., with demonstration of a fourfold or greater rise in antibody titer – by means of immunofluorescent antibody testing of patient’s sera) ♦♦ Specific immunohistologic methods on frozen sections or on formalin-fixed, paraffin-embedded sections are also used

Fig. 6.24. Rocky Mountain spotted fever; (A) skin, (B) cutaneous biopsy (H&E).

FUNGI Hyaline Fungi ♦♦ Many genera of septate hyaline fungi exist and are indistinguishable from one another based upon histology alone ♦♦ These include, but are not limited to, Aspergillus, Fusarium, Pseudallescheria, Penicillium, Paecilomyces, Acremonium, and Scopulariopsis

Aspergillus Species ♦♦ They are found widely in the environment and are commonly contaminants in cultures

Clinical ♦♦ They are the agent of disseminated opportunistic infections in immunocompromised patients ♦♦ Predisposing factors include neutropenia, malignancy (especially hematologic), AIDS, transplant patients, and longterm steroid use

♦♦ Primary pulmonary infection may disseminate hematogenously to skin, or skin may be the primary site of infection

Macroscopic ♦♦ Colonies are initially white then become shades of yellow, green, brown, or black, depending on the species

Microscopic (Fig. 6.25A–D) ♦♦ They are characterized by 2–5 μm septate hyphae with acute angle branching and progressively arborizing branches ♦♦ One may often see vascular invasion with thrombosis and infarction ♦♦ The inflammatory infiltrate is neutrophilic to granulo­ matous ♦♦ Conidiophores (fruiting bodies) allow speciation but are rarely seen in tissue

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Fig. 6.25. (A) Arborizing radial growth of Aspergillus spp. in the lung, H&E. (B) Cytologic preparation of bronchoalveolar lavage fluid demonstrating septate hyphae with acute angle branching, consistent with Aspergillus spp. (and many other septate hyaline fungi), DQ. (C) Pulmonary aspergillosis demonstrating fragments of septate hyphae with acute angle branching, PAS. (D) Perineural and vascular invasion by Aspergillus spp., PAS.

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

♦♦ On a culture plate, a white colony with a pink-violet center that develops over time is characteristic

Microscopic (Fig. 6.26a, b)

♦♦ Many genera of septate fungi exist and are indistinguishable from one another based upon histology alone

♦♦ Abscess or nodular infarct due to septic thrombosis is present histologically. Hyphae are septate with acute angle branching. Conidia are sickle or canoe shaped on lactophenol cotton blue preparation from a colony

Diagnostic Techniques

Special Stains

♦♦ Speciation is based upon conidial arrangement ♦♦ Culture is required for definitive identification

♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Differential Diagnosis

Fusarium Species Clinical ♦♦ It is commonly a contaminant ♦♦ It may cause eye infections, mycetoma, sinusitis, or skin and nail infections ♦♦ Disseminated opportunistic infections occur in immunocompromised patients

Macroscopic ♦♦ Abscess, infarct, or granuloma may be seen grossly

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Differential Diagnosis ♦♦ Many genera of septate fungi exist and are indistinguishable from one another based upon histology alone

Diagnostic Techniques ♦♦ Speciation is based upon conidial morphology ♦♦ Culture is required for definitive identification

Mucor, Absidia, and Rhizopus Species ♦♦ Though not typically grouped with hyaline fungi, they are presented here for purposes of comparison

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♦♦ Hyphae often will fold back on themselves and rare septation is possible ♦♦ A neutrophilic infiltrate predominates ♦♦ Vascular invasion, infarcts and perineural invasion may be present

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acidSchiff (PAS) are useful stains for delineating fungal morphology

Differential Diagnosis ♦♦ Differentiation is based upon presence/location or absence of rhizoids

Diagnostic Techniques ♦♦ Culture is required for definitive identification

Penicillium marneffei ♦♦ It is found in soil of Asia, Far East, and Thailand ♦♦ The reservoir is the bamboo rat ♦♦ It truly is dimorphic

Clinical ♦♦ It can cause disseminated opportunistic infections in immunocompromised patients ♦♦ Keratitis, mycetoma, external ear, respiratory, and urinary tract infections may be seen ♦♦ Endocarditis may occur post valve prosthesis placement

Macroscopic Fig. 6.26. Fusarium osteomyelitis (A, B) with pale/nonstaining septate hyphal fragments (photo center) within necrotic debris, H&E.

♦♦ Colonies are initially white and become blue-green with age ♦♦ A red reverse may indicate P. marneffei

Microscopic

♦♦ They are ubiquitous; present in soil, compost, decaying ­vegetable matter, and water

♦♦ Granulomatous, suppurative, or necrotizing inflammatory patterns may be present ♦♦ 2.5–5 µm intracellular yeasts are characteristic ♦♦ 8  µm extracellular yeasts with rounded ends and a central septum (no budding) are present as well

Clinical

Special Stains

♦♦ Risk factors for infection include uncontrolled diabetes, burns, surgery, severe illness, leukopenia, AIDS, and intravenous drug use ♦♦ They have an affinity for myelin ♦♦ Rhinocerebral infection begins in the sinuses with rapid spread along the optic nerve into the brain ♦♦ Pulmonary, cutaneous and disseminated disease may occur ♦♦ Death can be rapid, and can occur in less than 24 hours

♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Macroscopic ♦♦ They are fast growing “lid lifters” (the Petri dish lid rises because of rapid growth with the colony filling the plate)

Differential Diagnosis ♦♦ Many genera of septate fungi exist and are indistinguishable from one another based upon histology alone ♦♦ The yeast form may mimic Histoplasma capsulatum, but it does not bud

Diagnostic Techniques ♦♦ Histopathology is rapid and reliable

Microscopic (Fig. 6.27A–F)

Pseudallescheria/Scedosporium Clinical

♦♦ They are broad, ribbon-like, aseptate hyphae with right angle branching

♦♦ It may cause disseminated opportunistic infections in immunocompromised patients

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Fig. 6.27. (A) Broad, aseptate hyphae of zygomycosis, H&E. (B) Zygomycosis with vascular invasion similar to that seen with Aspergillus spp., nasal/sinus biopsy, H&E. (C) Pulmonary zygomycosis, GMS. (D) Cytologic preparation of bronchoalveolar lavage fluid. Broad, ribbony hyphae commonly fold back upon themselves, GMS. (E) PAS. (F) Zygomycosis demonstrating vascular invasion, LG-PAS (light green-PAS). ♦♦ Mycetoma with draining sinus tracts at the site of inoculation, pulmonary fungus balls and ocular infections occur ♦♦ It is important to distinguish it from other septate fungi because it is not sensitive to amphotericin B

Macroscopic ♦♦ Infarct, abscess, mycetoma, and fungus ball may be seen ♦♦ If granules are seen in an exudate, they are fungal colonies representative of mycetoma

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♦♦ A fungus ball is spherical, spongy, and usually loose in a cavity ♦♦ The white cottony colony turns gray-brown over time

Microscopic ♦♦ Vascular invasion, necrotizing pneumonitis, pulmonary abscesses, and nodular infarcts may be seen histologically ♦♦ There is random haphazard branching of hyphae ♦♦ A fungus ball is composed of necrotic lung in the center

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♦♦ Loose, randomly branching hyphae are present with a wellorganized periphery and alternating zones of mycelial hyperand hypocellularity ♦♦ Diagnostic conidia may be found superficially

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Differential Diagnosis ♦♦ Many genera of septate fungi exist and are indistinguishable from one another based upon histology alone

Diagnostic Techniques ♦♦ Culture is required for definitive identification

Dimorphic Fungi Blastomyces dermatitidis ♦♦ It is a dimorphic mold and natural inhabitant of warm-moist soil around the Great Lakes and upper Mississippi River, its tributaries and the south-central, south-eastern, and midwestern USA

Clinical ♦♦ Infection may be primarily pulmonary with inapparent, selflimiting illness or with severe symptoms ♦♦ Infection is occasionally progressive and severe, especially if the patient is immunocompromised, but it most commonly resolves spontaneously following a flu-like illness ♦♦ Infection almost always begins in the lungs via inhalation ♦♦ Skin or mucous membrane involvement usually indicates systemic disease and it may be the initial lesion ♦♦ Chronic cutaneous disease may be present with or without occult osseous lesions ♦♦ Generalized, systemic multiorgan disease has a rapid course but single-organ system involvement may be occult for many years

Macroscopic ♦♦ Skin and mucous membrane lesions (including involvement of the larynx) may resemble squamous cell carcinoma ♦♦ Eccentric, well-circumscribed lytic lesions in the metaphyses of long and small bones may form ♦♦ A white to gray-brown delicate silky mold is present at 25–30°C after 7–30 days of incubation

Microscopic (Fig. 6.28a–e) ♦♦ 6–15  mm broad-based budding yeasts with refractile double walls are present at 35–37°C ♦♦ Hyaline septate hyphae with 2–4  mm, oval, single-celled conidia “lollipops” borne singly at the tips of long or short conidiophores are present on a lactophenol cotton blue preparation from the colony ♦♦ The histopathology is diagnostic when pseudoepitheliomatous hyperplasia is present in skin and mucous membranes

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Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Differential Diagnosis ♦♦ Histoplasma capsulatum, Scedosporium apiospermum, and Chrysosporium all produce “lollipops” in mold form as seen on lactophenol cotton blue preparation of colonies ♦♦ Paracoccidioides brasiliensis has multiple buds ♦♦ Coccidioides immitis has immature spherules ♦♦ Mold to yeast conversion in the laboratory may be difficult

Coccidioides immitis ♦♦ It is diphasic and multimorphic ♦♦ It has a hyphal/arthroconidial “saprobic” phase in nature and routine culture, and spherules/endospores in the “parasitic” phase in human tissue ♦♦ It is endemic in hot dry alkaline soil in the Southwestern USA including San Joaquin Valley, northern Mexico, and Central America ♦♦ Arthroconidia develop from the mycelial form in subsurface desert sand and easily become windborne

Clinical ♦♦ Primary disease is pulmonary ♦♦ It results from inhalation of highly infectious arthroconidia −− It may be acute, flu-like, and self-limited −− Sixty percent are asymptomatic −− Only 2% develop chronic pulmonary disease with sequelae ♦♦ Cutaneous disease is usually a complication of disseminated disease −− Primary cutaneous disease from inoculation of open skin lesions is possible but rare −− Erythema nodosum, erythema multiforme, and granulomatous iridocyclitis may be seen ♦♦ Only 0.5% of infections disseminate −− Muscle, tendon, bone, joint, and skin are more common sites of infection −− CNS and genital infections are less common ♦♦ People who are infected are commonly of Filipino, native African, Mexican, or Asian ancestry −− HIV infection is a risk factor for coccidioidomycosis in endemic areas −− Coccidioidomycosis is the third most frequently reported opportunistic infection in HIV

Macroscopic ♦♦ Solitary peripheral “coin lesions” or granulomas that may cavitate in lung may be seen ♦♦ Colonies are variable in morphology ♦♦ Initially, at 25–35°C, they are moist, gray and membranous

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Fig. 6.28. (A) Broad-based bud of Blastomyces dermatitidis (left of center) with a neutrophilic infiltrate in a systemic soft tissue infection, H&E. (B) Multiple broad-based budding yeasts of Blastomyces dermatitidis with scattered neutrophils in a soft tissue infection, H&E. (C) Bronchoalveolar lavage, GMS. (D) Broadbased buds of Blastomyces dermatitidis mimicking empty spherules of Coccidioides immitis, GMS. (E) Blastomyces dermatitidis infection demonstrating pseudoepitheliomatous hyperplasia of skin, H&E. ♦♦ They develop white to gray-tan cottony aerial mycelia with light orange to yellow pigment as arthroconidia form in 1–2 weeks ♦♦ They are highly infectious ♦♦ Do not work in open air with a fungal culture suspected of being Coccidioides

Special Stains

Microscopic (Fig. 6.29a–f)

♦♦ Endospores released from spherules may resemble yeast forms ♦♦ Blastomyces yeast forms may mimic spherules ♦♦ Trichosporon, Geotrichum, Malbranchia, Gymnoascus and Oospora species also produce arthroconidia ♦♦ Yeast forms of Histoplasma capsulatum and Cryptococcus neoformans may mimic free endospores

♦♦ 10–60  mm thick-walled spherules containing 2–4  mm endospores are present in tissue ♦♦ Delicate hyphae break into alternately staining thick-walled barrel-shaped arthroconidia ♦♦ Granulomatous inflammation and necrosis with or without eosinophils may be present histologically

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♦♦ Gomori methenamine silver (GMS) stains endospores only ♦♦ Periodic acid-Schiff (PAS) is also useful for delineating fungal morphology

Differential Diagnosis

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Fig. 6.29. (A, B) Coccidioides immitis, cytologic smear showing single spherule containing endospores, H&E. (C, D) Spherule of Coccidioides immitis with an adjacent giant cell in the lung, H&E. (E) Empty spherule of Coccidioides immitis in a cytologic preparation, DQ. (F) Empty spherules of Coccidioides immitis mimicking Blastomyces dermatitidis, GMS.

Diagnostic Techniques

Histoplasma capsulatum

♦♦ Mold to spherule conversion in the laboratory may be difficult ♦♦ Histopathology and culture are most reliable for diagnosis in specimens from patients with AIDS

♦♦ It is a dimorphic mold that is endemic in drainage basins of the Ohio, Mississippi, and Missouri River valleys, as well as Central America

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♦♦ The mycelial form is present in warm, moist soil rich in organic content, especially with bird or bat excreta (bird roosts, chicken coops, old buildings frequented by bats) ♦♦ Spores produced by mycelia are disseminated by the wind and then inhaled ♦♦ They mature into the yeast form at body temperature

Clinical ♦♦ It is the most common systemic fungal disease in the USA ♦♦ Acute or chronic histoplasmosis may form ♦♦ It is characterized by cough, fever, night sweats, malaise, and weight loss ♦♦ Disseminated histoplasmosis is seen primarily in immunocompromised patients (AIDS and lymphoid malignancy) ♦♦ It may manifest as central nervous system (CNS) histoplasmosis or mediastinal fibrosis ♦♦ It most commonly is an asymptomatic infection with hilar and mediastinal lymphadenopathy ♦♦ Chest x-ray reveals diffuse/patchy interstitial infiltrates with or without nodules

Essentials of Anatomic Pathology, 3rd Ed.

Paracoccidioides brasiliensis ♦♦ It is a dimorphic mold that is endemic in soil in Brazil (most commonly), South and Central America, and Mexico

Clinical ♦♦ Inhalation leads to pulmonary disease (chronic granulomatous disease) ♦♦ It spreads to mucous membranes of nose, mouth, and occasionally the gastrointestinal tract, skin, and lymph nodes

Macroscopic ♦♦ The acute disseminated form consists of mucocutaneous and intestinal ulcers, lymphadenopathy, osteolytic bone lesions, or osteomyelitis ♦♦ The chronic disseminated form consists of pulmonary cavitation, ulceration of mucous membranes, and necrotic/granulomatous adrenal lesions

Microscopic

♦♦ It is a silky or hair like, white to gray-tan mold with tuberculate macroconidia after 10–30 days of incubation at 25–30°C

♦♦ It is characterized by pseudoepitheliomatous hyperplasia in the epidermis and mucosa ♦♦ Suppurative and granulomatous inflammation mimics tuberculosis or sarcoidosis ♦♦ Multiple narrow-necked buds arise from the mother cell, ­giving the appearance of a “mariner’s wheel”

Microscopic (Fig. 6.30a–e)

Special Stains

♦♦ 2–4 mm oval yeast forms with a single eccentric nucleus and perinuclear clearing are seen at 37°C ♦♦ Narrow-necked single buds, clustered within reticuloendothelial cells (histiocytes/macrophages) are present in tissue sections ♦♦ Yeast forms are surrounded by a halo, giving the false impression of a capsule ♦♦ 5–15  µm rough-walled (spiked/tuberculate) macroconidia are seen on lactophenol cotton blue preparations from the colony

♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Macroscopic

Special Stains ♦♦ Gomori methenamine silver (GMS), periodic acid-Schiff (PAS), and Giemsa stains are useful for delineating fungal morphology

Differential Diagnosis ♦♦ Trichophyton rubrum colonies have a red diffusible pigment ♦♦ Sporothrix schenckii forms cigar bodies microscopically ♦♦ Leishmania donovani has a kinetoplast

Diagnostic Techniques ♦♦ It may be difficult to convert from mycelial form to yeast form in culture ♦♦ Culture is the gold standard ♦♦ Serologic immunodiffusion and complement fixation, urinary Histoplasma antigen testing, exoantigen testing, and nucleic acid probe testing are available

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Differential Diagnosis ♦♦ Histoplasma capsulatum, Blastomyces dermatitidis, capsuledeficient Cryptococcus neoformans, and Coccidioides immitis yeast forms may have a similar microscopic appearance

Diagnostic Techniques ♦♦ It may be difficult to convert from mycelial form to yeast form in culture ♦♦ Culture is the gold standard

Sporothrix schenckii ♦♦ It is found worldwide in soil, rose thorns, shrubs, trees, bark, mulch, and moss

Clinical ♦♦ Skin, subcutis and systemic infections may be transmitted by inoculation injury associated with rose bushes ♦♦ Nodules and ulcers along lymphatics and at the site of inoculation may be present ♦♦ Pneumonia may occur in alcoholics

Macroscopic ♦♦ Cutaneous ulcers and verrucous lesions are visible clinically ♦♦ The colony is wrinkled to leathery cream-tan-black or “dark and greasy”

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Fig. 6.30. Intracellular Histoplasma capsulatum, (A) in a lymph node (photo center), H&E, (B) and in tissue, H&E. (C) Predominantly intracellular Histoplasma capsulatum with scattered neutrophils, macrophages and red blood cells in a bronchoalveolar lavage, Giemsa. (D) 2–4 µm yeasts of Histoplasma capsulatum within a macrophage in a bronchoalveolar lavage, Giemsa. (E) Oval 2–4  µm narrow-necked budding yeasts of Histoplasma capsulatum, GMS.

Microscopic ♦♦ Florid pseudoepitheliomatous hyperplasia is present ♦♦ Neutrophilic abscesses are surrounded by granulomatous inflammation ♦♦ Asteroid bodies may be present in microabscesses or in the suppurative center of the granuloma

−− Yeast cell(s) are surrounded by a 20–40  µm, stellate, Splendore-Hoeppli area of intensely eosinophilic refractile material ♦♦ Cigar bodies are fusiform budding yeast cells that are present at 37°C ♦♦ Many daisy-like conidia rosette around a bulbous ended conidiophore at 25°C

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Special Stains

Microscopic

♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

♦♦ Nonspecific hyperkeratosis with a mild mononuclear perivascular infiltrate is present in the dermis ♦♦ Black two-celled oval yeast forms (annelids with a central septum) are in skin scrapings ♦♦ Brown-black hyphae are present in tissue sections ♦♦ Younger hyphae may not be well pigmented

Differential Diagnosis ♦♦ Squamous cell carcinoma, Hamazaki–Wesenberg bodies, sarcoidosis, Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum, and capsule-deficient Cryptococcus neoformans may be mistaken for sporotrichosis

Diagnostic Techniques ♦♦ Culture or direct immunofluorescence is best for definitive diagnosis

Superficial Mycoses Malassezia furfur Clinical ♦♦ It is the agent of tinea versicolor (hypo- and hyperpigmented macules) ♦♦ It may cause vascular catheter and hyperalimentationassociated infections

Macroscopic ♦♦ Lesions are rarely biopsied because organisms are easily seen in skin scrapings

Microscopic ♦♦ Mild hyperkeratosis, follicular plugging, acanthosis, and a neutrophilic infiltrate predominate ♦♦ Yeast forms are shaped like old-fashioned Coca-Cola® bottles ♦♦ Hyphae and yeast forms have the appearance of spaghetti and meatballs

Special Stains

Special Stains ♦♦ They are not necessary for demonstration of dematiaceous fungi

Differential Diagnosis ♦♦ Acral melanoma, clinically

Diagnostic Techniques ♦♦ Direct microscopic examination of skin scrapings

Piedraia hortae Clinical ♦♦ It is the agent of black piedra ♦♦ It occurs in tropical areas

Macroscopic ♦♦ Stony hard black nodules on the hair shaft are characteristic ♦♦ Hyphal colonies are dark green-black with a black reverse (dematiaceous)

Microscopic ♦♦ A black nodule, composed of spore sacs and spores, forms on the hair shaft

Special Stains ♦♦ They are not necessary for demonstration of dematiaceous fungi

♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Diagnostic Techniques

Diagnostic Techniques

♦♦ Direct microscopic examination of hair

♦♦ The organism is lipophilic, requiring olive oil (oleic acid/ long chain fatty acids) to be dropped onto the plate for growth to occur ♦♦ Growth occurs only in areas where the oil actually makes contact with the agar

Trichosporon beigelii Clinical

Hortaea werneckii Clinical

♦♦ It is an agent of superficial mycoses, including white piedra (hair shaft infection) of beard, scalp or pubic hair ♦♦ It is an opportunist, but it may also cause pneumonia, and localized or systemic deep infections, especially in immunodeficient patients

♦♦ It is the agent of tinea nigra palmaris, causing asymptomatic, minimally scaly macules on the palms or soles ♦♦ It is seen mainly in tropical and subtropical areas

Macroscopic

Macroscopic

Microscopic

♦♦ Dark/black macules form on the palm of the hand ♦♦ Colonies on plates are initially yeast-like, and then become hyphal and olive-black with a black reverse (dematiaceous)

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♦♦ Infarcts and abscesses form ♦♦ Soft, cream-colored nodules are present on the hair shaft ♦♦ White nodules, present on the hair shaft, are composed of mycelia that fragment into brick-like arthroconidia ♦♦ True hyphae and pseudohyphae with blastoconidia are seen

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♦♦ Angioinvasion and nodular infarcts may form ♦♦ The fungi may have a radial sunburst growth pattern similar to aspergillosis ♦♦ Abscesses and granulomas may be seen

Special Stains ♦♦ Gomori methenamine silver is useful for delineating fungal morphology

Differential Diagnosis ♦♦ Candidiasis, aspergillosis, pseudallescheriasis, and other opportunistic mycoses are included in the differential

Diagnostic Techniques ♦♦ Culture and demonstration of fungal elements in biopsy specimens ♦♦ There may be cross-reactivity with anticryptococcal antibody latex agglutination

Dermatophytes (Cutaneous Mycoses) ♦♦ Disease is restricted to keratinized layers of skin, hair, and nails −− Keratin is metabolized as a nitrogen source −− Dissemination is reported in immunocompromised patients −− They are the most common cause of all fungal infections and infections are contagious ♦♦ There are three genera – Trichophyton, Epidermophyton, and Microsporum −− Trichophyton is composed of numerous species (a) Microconidia are important for identification but macroconidia are rarely helpful (b) Biochemical tests are useful in distinguishing species −− Epidermophyton has only one species – E. floccosum (a) Macroconidia are important for identification and microconidia are not produced (b) It is killed by refrigeration −− Microsporum has numerous species (a) Macroconidia are important for identification (b) Microconidia are produced but they are not useful for identification (c) Biochemical tests are not useful

Clinical ♦♦ Ringworm, or tinea, manifests as an inner pale ring-like healing area surrounded by a red expanding infection ♦♦ Trichophyton spp. are the most common causes of foot (T. mentagrophytes) and nail infections ♦♦ Trichophyton tonsurans is the most common cause of tinea capitis ♦♦ Trichophyton schoenleinii causes favus with scarring and permanent hair loss

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♦♦ Epidermophyton infects the groin and feet ♦♦ Microsporum audouinii commonly causes tinea capitis in children

Macroscopic ♦♦ Red, scaly skin lesions are present ♦♦ Colonies are generally white and fluffy or granular with a light tan reverse −− Notable notes and exceptions (a) Trichophyton rubrum has a cherry red reverse after about 3 weeks growth (b) Trichophyton mentagrophytes may have a red-brown reverse (c) Trichophyton tonsurans colonies are buff-brown (d) Epidermophyton colonies are olive green/khaki (e) Microsporum canis colonies have a bright yellow reverse (f) Microsporum gypseum colonies are cinnamon with an orange-brown reverse (g) Microsporum audouinii colonies are light gray with a pink reverse

Microscopic (Fig. 6.31A–C) ♦♦ Hyaline septate hyphae are confined to the stratum corneum in histologic skin sections ♦♦ KOH mount −− Trichophyton rubrum microconidia appear as “birds on a wire” −− Trichophyton mentagrophytes microconidia appear in grape-like clusters and spiral hyphae may be seen −− Trichophyton tonsurans has microconidia appearing as elongated balloons or stretched teardrops −− Trichophyton schoenleinii has antler shaped hyphae and “favic chandeliers”

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acidSchiff (PAS) are useful stains for delineating fungal morphology

Diagnostic Techniques ♦♦ A KOH mount of skin scrapings, hair, or nails or a calcofluor white fluorescent stain allows visualization of fungal morphology ♦♦ Growth on cornmeal or potato dextrose agar will enhance production of conidia for identification

Subcutaneous Mycoses Dematiaceous (Darkly Pigmented) Fungi ♦♦ They consist of black or darkly pigmented fungi that produce melanin which is protective against phagocytosis and oxidative burst (Fig. 6.32)

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Fig. 6.32. A neutrophilic abscess in the skin contains fragments of septate dematiaceous hyphae, H&E. ♦♦ There are many Genera which include, but are not limited to, Alternaria (see below), Exophiala, Curvularia (boomerang shaped conidia), and Stachybotrys ♦♦ They are implicated in chromoblastomycosis and phaeohy­ phomycosis

Alternaria Species Clinical ♦♦ They commonly colonize human skin but rarely cause disease ♦♦ Risk factors include immunosuppression, severe illness, and traumatic inoculation ♦♦ Secondary cutaneous disease may occur via hematogenous spread from a pulmonary source

Macroscopic ♦♦ Colonies are darkly pigmented with a jet black reverse

Microscopic ♦♦ Pigmented brown septate hyphae with “snowshoe” or “drumstick”-shaped muriform conidia (longitudinal and transverse septae) are seen

Special Stains ♦♦ Periodic acid-Schiff or Fontana-Masson are helpful, but not necessary, for diagnosing dematiaceous fungi

Diagnostic Techniques ♦♦ Direct examination of the specimen or histopathology Fig.  6.31. Onychomycosis. (A) Abundant branching hyphae within the keratin stain poorly and appear as negative images, H&E. (B, C) Dermatophytosis demonstrating hyphal fragments in the epidermis, skin, PAS. ♦♦ If pigmentation is equivocal, the Fontana-Masson stain may be helpful for confirming the presence of melanoid pigments ♦♦ They exist worldwide as saprophytes and plant pathogens and man is an accidental host

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Chromoblastomycosis ♦♦ There is worldwide distribution, but they are most prevalent in the tropics and subtropics ♦♦ They are present in soil and decaying organic material ♦♦ There are many agents of chromoblastomycosis which include, but are not limited to, Fonsecaea pedrosoi, Phialophora (phialides and conidia look like flowers in a vase), Cladosporium, Cladophialophora, and Rhinocladiella, which are also dematiaceous fungi

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♦♦ The most common cause of chromoblastomycosis in the Americas is Fonsecaea pedrosoi

♦♦ Lymphadenopathy is rare ♦♦ Immunosuppression predisposes one to infection

Clinical

Macroscopic

♦♦ They are acquired by traumatic implantation of dematiaceous fungi (barefoot agricultural workers) ♦♦ They are slow-growing (evolving over years) warty nodules that progress to a cauliflower-like appearance at the inoculation site, generally on the dorsal surfaces of the feet and lower legs ♦♦ They cause chronic infections of skin and subcutaneous tissue and dissemination to deep organs is rare ♦♦ Progression without treatment leads to lymphangitis which leads to elephantiasis, ultimately necessitating amputation ♦♦ There is no evidence that it is contagious

Macroscopic ♦♦ Colonies are darkly pigmented with a jet black reverse

Microscopic ♦♦ It is a chronic suppurative process with neutrophils and fungi ♦♦ Pseudoepitheliomatous hyperplasia, granulomatous infiltrate, and abscess may also be present ♦♦ 5–7 µm muriform cells, also known as copper pennies and sclerotic or Medlar bodies, are characteristic ♦♦ They are copper-colored thick-walled spherical bodies that divide by septation in two planes ♦♦ A wooden sliver or splinter is not found in the tissue section

Special Stains ♦♦ Periodic acid-Schiff or Fontana-Masson are helpful, but not necessary, for diagnosis of dematiaceous fungi

Differential Diagnosis ♦♦ Squamous cell carcinoma, phaeohyphomycosis, keratoacanthoma, leishmaniasis, Kaposi sarcoma, paracoccidioidomycosis, cutaneous tuberculosis, sarcoidosis, and blastomycosis

Diagnostic Techniques ♦♦ Clinical presentation and direct examination of the specimen or evaluation of histopathology for muriform cells will assist diagnosis ♦♦ Greater than 70% of cultures are positive ♦♦ Identification is based upon the predominating type of sporulation

Phaeohyphomycosis ♦♦ It is caused by worldwide saprophytes, present in soil, wood, and decaying vegetable matter ♦♦ There are many agents including, but not limited to, Alternaria, Exophiala jeanselmei, Bipolaris, Wangiella, Curvularia, and Cladophialophora bantiana (neurotropic)

Clinical ♦♦ It is acquired by traumatic implantation of dematiaceous fungi ♦♦ Subcutaneous and systemic infection may occur via a pulmonary route

♦♦ Single or multiple firm to fluctuant painless subcutaneous abscesses form

Microscopic ♦♦ Pigmented moniliform fungal elements are present within giant cells in cyst walls and extracellularly in central necrotic debris ♦♦ Cystic or granulomatous lesions may be seen ♦♦ Dense connective tissue with stellate suppurative necrosis and unaffected overlying epidermis is present ♦♦ Terminal and intercalated vesicular swellings in hyphae resemble chlamydoconidia ♦♦ A wooden sliver or splinter is found in the tissue section

Special Stains ♦♦ Periodic acid-Schiff or Fontana-Masson are helpful, but not necessary, for diagnosis of dematiaceous fungi

Differential Diagnosis ♦♦ Chromoblastomycosis

Diagnostic Techniques ♦♦ Clinical presentation and direct examination of the specimen or histopathology will assist diagnosis

Yeasts Candida albicans and Other Candida Species Clinical ♦♦ They are part of the normal flora of the gastrointestinal tract ♦♦ Clinical presentation includes intertrigo (skin fold) infections, paronychia, diaper rash, thrush, esophagitis, balanitis, vaginitis, urinary tract infections, and pneumonia ♦♦ Infection may disseminate via hematogenous spread from the urinary or gastrointestinal tract ♦♦ Immunosuppression, steroids, antibacterial therapy, and obesity increase the risk of infection ♦♦ There is high mortality. C. tropicalis and C. krusei are the most common agents seen in immunocompromised patients

Macroscopic ♦♦ Superficial infection appears white-tan and velvety with dark red adjacent tissue ♦♦ Locally invasive lesions (ulcers) have sharp margins with a granular base and tan-yellow friable exudates ♦♦ Disseminated candidiasis is invasive infection involving the parenchyma of at least two organs, excluding mucosa of the gastrointestinal, respiratory, or genitourinary tracts

Microscopic (Fig. 6.33a, b) ♦♦ Yeasts have narrow-necked budding and “sausage-link” pseudohyphae. Blastoconidia may be present as well

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Microscopic ♦♦ No pseudohyphae are produced in tissue ♦♦ Only blastoconidia are present ♦♦ Yeasts are typically smaller than other Candida spp. (2–5  µm) and extracellular or intracellular with narrownecked budding ♦♦ There is a spectrum of histologic appearances, from no inflammation to suppuration, necrosis, and abscess formation, as with other Candida spp

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology Fig. 6.33. Yeast forms of Candida spp., Diff-Quik. ♦♦ The epidermis and superficial dermis are marked by a dense neutrophilic infiltrate ♦♦ One may see a spongiform subcorneal pustule that is indistinguishable from psoriasis ♦♦ A chronic inflammatory infiltrate is present in deeper levels ♦♦ Disseminated forms may have leukocytoclastic vasculitis (especially with Candida tropicalis)

Special Stains ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology

Differential Diagnosis ♦♦ Cryptococcus neoformans varies more in size, with yeasts ranging from 2 to 15 µm in greatest dimension

Diagnostic Techniques ♦♦ 95% of germ tube tests are positive in C. albicans ♦♦ They are occasionally positive in C. tropicalis, and all other Candida spp. are negative

Candida glabrata ♦♦ It is a ubiquitous fungus and widely distributed saprophyte ♦♦ It is normal flora of the skin, oropharynx, gastrointestinal tract, urethra, and vagina ♦♦ Virulence is low

Clinical ♦♦ Infections range from asymptomatic to life-threatening and most commonly occur as nosocomial fungemia and funguria ♦♦ Predisposing factors include intravenous and urethral catheters, intravenous drug use, prolonged antibiotic therapy, diabetes mellitus, immunosuppression, and corticosteroid therapy

Macroscopic ♦♦ The findings are nonspecific ♦♦ Abscess and necrosis are possible

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Differential Diagnosis ♦♦ Histoplasma capsulatum is intracellular and has a clear halo or pseudocapsule effect ♦♦ There is more budding and pleomorphism with Candida glabrata

Diagnostic Techniques ♦♦ It is differentiated from other Candida spp. based on fermentation and assimilation reactions from colonial growth

Cryptococcus neoformans ♦♦ It is found in soil and pigeon droppings (attics, belfries, cornices) and can remain viable for years

Clinical ♦♦ Inhalation leads to mild pulmonary disease ♦♦ Meningitis, cutaneous, mucocutaneous, osseous, and visceral infection also may occur

Macroscopic ♦♦ Slimy, glistening white meninges are characteristic ♦♦ Cutaneous lesions range from papules and pustules to solitary, well-circumscribed ulcerated nodules

Microscopic (Fig. 6.34a–d) ♦♦ Yeasts are variably sized (2–15 µm), encapsulated, and bud with a narrow attachment ♦♦ There is often a neutrophilic infiltrate, but the reaction may be granulomatous, especially in immunocompetent patients

Special Stains ♦♦ Historically, India ink direct examination of cerebrospinal fluid (see diagnostic techniques below) ♦♦ Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) are useful stains for delineating fungal morphology ♦♦ Mucicarmine or alcian blue will detect presence of a capsule ♦♦ Fontana-Masson stains the cell wall which produces a melanin-like pigment

Differential Diagnosis ♦♦ Blastoconidia of Candida spp. are more uniform in size

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Fig. 6.34. (A) Refractile, poorly staining yeasts with halos in a kidney glomerulus, Cryptococcus neoformans, H&E. (B) Variably sized yeasts of Cryptococcus neoformans with narrow-necked buds and halos, GMS. (C) PAS. (D) Mucin. ♦♦ Sporothrix schenckii, Candida glabrata, and immature spherules of Coccidioides immitis may resemble cryptococcal yeasts ♦♦ Capsule-deficient forms may mimic Histoplasma and Blastomyces

♦♦ Characteristic bilateral ground glass infiltrates are present on radiologic images ♦♦ It is an AIDS-defining illness and risk of Pneumocystis pneumonia increases when the CD4 count is less than 200 cells/µL

Diagnostic Techniques

Macroscopic

♦♦ Direct antigen testing has much higher sensitivity than the India ink stain and should be recommended for diagnosis of cryptococcosis, rather than performing an India ink stain ♦♦ Colonies are dark brown on birdseed (niger seed) agar and urease is positive

♦♦ Pulmonary parenchyma is firm, granular, and consolidated with occasional nodules and cavities

Other Fungi Pneumocystis jirovecii ♦♦ It has a worldwide distribution and is truly a fungus, most closely resembling Saccharomyces cerevisiae by 16S ribosomal RNA sequencing

Clinical ♦♦ Nonspecific findings mimic other opportunistic infections ♦♦ It causes pneumonia in immunocompromised patients and manifestations are variable

Microscopic (Fig. 6.35A–G) ♦♦ There is a variety of reaction patterns, including a minimal or absent cellular inflammatory reaction, diffuse alveolar damage and fibrosis, or granulomatous inflammation associated with necrosis ♦♦ Pink foamy/bubbly intra-alveolar material is visible with H&E staining ♦♦ In the Gomori methenamine silver stain, extracellular cysts appear as black 4–7  µm spherules with two comma-like internal thickenings of the cell wall ♦♦ They are cup or crescent shaped when collapsed ♦♦ In the Giemsa or Diff-Quik stain, 2–8  µm trophozoites appear in ameboid clusters with bubble like spaces and dotlike nuclei

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Fig.  6.35. (A) Foamy intra-alveolar “exudate” of Pneumocystis pneumonia, lung, H&E. (B, C) Cyst outlines become obvious on higher power, H&E. (D) Trophozoites of Pneumocystis jirovecii in a bronchoalveolar lavage. Cyst outlines become evident if one focuses up and down with the microscope, Giemsa. (E) Cysts with internal thickenings of the cell wall, GMS. (F, G) Sporozoites, trophozoites, and negative image outlines of cysts in a cytologic preparation of bronchoalveolar lavage fluid, Giemsa.

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♦♦ 1–2  µm sporozoites appear as clusters of dot-like purple nuclei surrounded by an unstained cyst wall ♦♦ The classic appearance is eight sporozoites radiating outward like sections of a pie

Special Stains ♦♦ Gomori methenamine silver (GMS) demonstrates cysts ♦♦ The Giemsa or Diff-Quik stains demonstrate trophozoites, sporozoites, and negatively stained cyst walls

Differential Diagnosis ♦♦ Histoplasma, Candida glabrata, and Cryptococcus neoformans may have a similar appearance; however, all of them bud and Pneumocystis does not

Diagnostic Techniques ♦♦ It cannot be cultivated on cell-free media; therefore, diagnosis depends upon demonstration of organisms in biopsy or cytology specimens

Prototheca wickerhamii Clinical ♦♦ It is a ubiquitous saprobe ♦♦ Local cutaneous or (rarely) systemic disease is seen, especially in patients who are immunocompromised or have nonintact skin ♦♦ 50% of infections are cutaneous and mostly due to traumatic inoculation ♦♦ Indolent centrifugal spread of papulonodular, eczematoid, herpetiform dermatitis, verrucous nodules, a wound infection on a limb or the face, and olecranon bursitis may occur

Microscopic (Fig. 6.36A, B) ♦♦ It is a unicellular, achlorophyllic, aerobic alga ♦♦ Distinctive 3–30  µm morulae or soccer ball-like sporangia on wet mount preparations have symmetric endospores ♦♦ A mixed inflammatory infiltrate (predominantly granulomatous) is present in the epidermis and dermis ♦♦ The lesion may be ulcerated, have intraepidermal microabscesses with hyperkeratosis, parakeratosis, and acanthosis ♦♦ Organisms are single or clustered, but most numerous, in areas of inflammation ♦♦ They may be within macrophages or giant cells (foreign body and Langhans types)

Special Stains ♦♦ Periodic acid-Schiff and methenamine silver stains on histologic sections highlight sporangia ♦♦ The organism is gram-positive ♦♦ Lactophenol cotton blue demonstrates characteristic wedge shaped, radially arranged sporangiospores within sporangia

Diagnostic Techniques ♦♦ It may be cultured on conventional fungal media ♦♦ Characteristic morphology of the organism is seen with H&E staining

Fig. 6.36. Prototheca with clusters of sporangia containing ­radially arranged sporangiospores in the skin. (A) H&E. (B) PAS.

Rhinosporidium seeberi ♦♦ It is found in soil and stagnant water ♦♦ It has been reported in East Asia, Ceylon, India, and rural Georgia

Clinical ♦♦ It is presumably acquired by inoculation ♦♦ Nasal, nasopharyngeal or oral polyps appear pink-red with “salt dots” ♦♦ A patient may present with conjunctival, paranasal sinus, and external genital lesions

Macroscopic ♦♦ Friable, pink-red, warty mucosal polyps or papillomas with “salt dots” are characteristic

Microscopic ♦♦ Histopathology demonstrates 6–350 µm round sporangia with a 5  µm thick wall containing 7–9  µm lobulated endospores with globular bodies in the stroma of a polyp with granulation tissue and a chronic inflammatory infiltrate

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♦♦ A granulomatous response is present if rupture of sporangia occurs

Special Stains ♦♦ Gomori methenamine silver (GMS), periodic acid-Schiff (PAS), and Mayer mucicarmine are useful stains for delineating fungal morphology

Differential Diagnosis ♦♦ Coccidioides immitis and Prototheca wickerhamii may have a similar appearance

Diagnostic Techniques ♦♦ It cannot be cultured, so diagnosis depends upon direct examination (histopathologic or cytologic)

VIRUSES Adenovirus

♦♦ An inflammatory response is lacking

♦♦ It is a double-stranded DNA virus

Differential Diagnosis

Clinical

♦♦ Gerstmann–Straussler–Scheinker syndrome, fatal familial insomnia, and kuru are other prion diseases that may have a similar presentation

♦♦ It causes upper and lower respiratory infections, ­conjunctivitis, hemorrhagic cystitis, colitis in AIDS, and gastroenteritis in children ♦♦ Infection may also be asymptomatic

Microscopic (Fig. 6.37A–C) ♦♦ Bronchiolar necrosis, coagulative necrosis, hyaline membranes, and diffuse alveolar damage may be seen histologically ♦♦ Infected nuclei of bronchial epithelium and alveoli appear smudged or may have a round, eosinophilic nuclear inclusion with surrounding halo and marginated chromatin

Diagnostic Techniques ♦♦ Immunohistochemical stains, cell culture, immunofluorescence, PCR, and DNA probes are available

Creutzfeldt–Jakob Disease ♦♦ It is the most common cause of transmissible spongiform encephalopathy

Clinical ♦♦ Types include sporadic, variant, and familial, which are all characterized by rapidly progressive dementia, myoclonus, and ataxia ♦♦ Variant CJD (vCJD) is marked by abnormal behavior, dementia, ataxia and myoclonus −− The patient is typically a young adult at death with illness duration of about 12 months ♦♦ Patients with sporadic CJD (sCJD) have dementia, ataxia and myoclonus with periodic complexes on EEG −− They are older adults with illness duration of only weeks to months

Microscopic (Fig. 6.38) ♦♦ Spongiform change of gray matter with some involvement of white matter is present with a variable degree of cerebellar involvement that is greater with vCJD than sCJD ♦♦ Variably-sized cytoplasmic vacuoles indent nuclei and decrease over time, but gliosis increases over time

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Diagnostic Techniques ♦♦ Diagnosis is based up clinical presentation and ­histopathologic findings ♦♦ One hundred percent of patients with vCJD have PRNP codon 129 Met/Met, whereas only 83% of sCJD have it

Cytomegalovirus (CMV) ♦♦ It is a double-stranded DNA herpesvirus

Clinical ♦♦ It is ubiquitous and can infect almost any body site ♦♦ Transmission is through blood, body fluids, or transplanted organs ♦♦ Infection may also be acquired transplacentally or during birth ♦♦ Infections range from silent to manifestations such as fever, hepatitis, and pneumonitis ♦♦ Severe brain damage in newborns, stillbirth, or perinatal death may occur ♦♦ Immunocompromised patients, especially those with HIV, may have serious disease

Microscopic (Fig. 6.39A, B) ♦♦ Enlarged cells with owl’s eye eosinophilic nuclear inclusions and marginated chromatin are classic ♦♦ Granular cytoplasmic inclusions may or may not be present ♦♦ Interstitial pneumonia and diffuse alveolar damage may be seen

Differential Diagnosis ♦♦ Malignancy

Diagnostic Techniques ♦♦ Immunohistochemical stains, in situ hybridization, and molecular techniques are available

Epstein–Barr Virus ♦♦ It is a double-stranded DNA herpesvirus

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Fig. 6.38. Creutzfeldt–Jakob disease in the brain, H&E.

Fig. 6.37. (A–C) Ground-glass nuclear inclusions of adenovirus in the liver, H&E.

Clinical ♦♦ Infectious mononucleosis in young adults may be asymptomatic, but fever, sore throat, cervical lymphadenopathy,

Fig.  6.39. (A) Centrally located, enlarged cell with abundant cytoplasm, consistent with cytomegalovirus infection in the lung, H&E. (B) Immunoperoxidase stain.

elevated liver function studies, and splenomegaly may be present in symptomatic patients ♦♦ There is association with Burkitt lymphoma and nasopharyngeal carcinoma

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Microscopic ♦♦ Mild acute hepatitis with a predominately portal and sinusoidal lymphocytic infiltrate is present, with little necrosis or cholestasis ♦♦ Mitoses and epithelioid granulomas may be seen ♦♦ Viral inclusions do not form

Differential Diagnosis ♦♦ Cytomegalovirus has characteristic inclusions

Diagnostic Techniques ♦♦ Immunohistochemical stains, serology, and nucleic acid amplification techniques (NAAT) are available

Hantavirus Clinical ♦♦ Fever, cough, myalgia, and gastrointestinal complaints are present ♦♦ There is rapid development of bilateral chest infiltrates and respiratory failure, with death occurring in 3 days ♦♦ Laboratory tests may reveal thrombocytopenia and a left shift

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♦♦ Herpetic whitlow is a painful paronychial HSV1 or HSV2 infection of the distal finger, more often occurring in medical or dental personnel ♦♦ Widespread disseminated systemic disease may occur in immunocompromised patients

Microscopic (Fig. 6.41A–C) ♦♦ The three M’s compose a classic histologic appearance −− Multinucleation −− Molding of nuclei −− Margination of chromatin ♦♦ The nuclei may have a ground-glass appearance or there may be an eosinophilic nuclear viral inclusion ♦♦ Necrosis and diffuse alveolar damage may be present

Differential Diagnosis ♦♦ Varicella-zoster virus

Diagnostic Techniques ♦♦ Immunohistochemical stains, direct immunofluorescence for viral antigen on infected cells, and cell culture are available

♦♦ Pulmonary edema and pleural effusion are seen grossly

Human Immunodeficiency Virus (HIV 1 & 2)

Microscopic (Fig. 6.40A–E)

♦♦ They are retroviruses that infect helper T-cells

♦♦ Mild interstitial pneumonia with delicate hyaline membranes is present and no viral inclusions are seen

Clinical

Macroscopic

Differential Diagnosis ♦♦ Early diffuse alveolar damage may have a similar appearance

Diagnostic Techniques ♦♦ Immunohistochemical stains are available

Hepatitis Viruses ♦♦ See Chapter 44 Nonneoplastic Hepatobiliary Disease for further detailed discussion and images of hepatitis A, B, C, D, E, and G

Herpes Simplex Virus 1 and 2 ♦♦ They are double-stranded DNA viruses

Clinical ♦♦ Generally herpes simplex virus 1 (HSV1) is associated with orofacial infections and HSV2 with genital infections; however, either may occur “above or below the belt” ♦♦ HSV1 −− Primary infection is usually asymptomatic −− Rare keratoconjunctivitis, respiratory infection, or infection of any part of skin or mucosa may occur −− Recurrence is triggered by sunlight, fever, and/or illness ♦♦ HSV2 −− It is acquired via sexual contact or by neonates during vaginal delivery from a mother with active genital lesions

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♦♦ They are the causative agents of acquired immunodeficiency syndrome (AIDS) ♦♦ There are many AIDS indicator diseases, which will not be discussed here ♦♦ Transmission is via blood or semen, and transplacentally ♦♦ There is persistent generalized lymphadenopathy ♦♦ Death is due to opportunistic infection (many possible agents) or malignancy (Kaposi sarcoma, body cavity lymphomas, or nonmelanomatous skin cancer)

Microscopic ♦♦ There is hyperplasia of follicular centers, tangible-body macrophages, and plasma cells ♦♦ Mantle zones are scant or absent. Interfollicular vascular proliferation is present as well as hyperplasia of ­parafollicular B lymphocytes ♦♦ The CD4 to CD8 ratio is decreased, with infiltration of CD8 cells into follicular centers ♦♦ With progression, there is loss of follicular centers with intrafollicular hyalinized vessels and lymphocyte depletion

Diagnostic Techniques ♦♦ Western blotting, serology, HIV RNA detection, viral load, and HIV drug resistance testing are available

Human Papillomavirus ♦♦ They are double-stranded DNA viruses ♦♦ More than 67 types have been identified

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Fig. 6.40. Hantavirus infection of lung. (A) Alveolar edema, H&E. (B) Interstitial pneumonia, H&E. (C) Immunoperoxidase stain. (D, E) Hantavirus infection of the spleen, H&E.

Clinical

Microscopic (Fig. 6.42)

♦♦ Verruca vulgaris (common wart) is caused by human papillomavirus (HPV) types 2, 4, and 7 ♦♦ Condyloma acuminatum with low cancer risk is caused by HPV types 6 and 11 ♦♦ Condyloma acuminatum with high cancer risk is caused by HPV types 16, 18, 31, 33, and 51 ♦♦ Bowenoid papulosis is caused by HPV types 16, 18, 31, 33, and 51 ♦♦ Laryngeal carcinoma is caused by HPV type 30 ♦♦ Verrucous carcinoma is caused by HPV types 2 and 6

♦♦ Raisinoid shrunken nuclei with irregular outlines and a perinuclear halo (koilocytes) are characteristic ♦♦ Multinucleation can occur

Differential Diagnosis ♦♦ Fungal, protozoal, and bacterial infections may cause “inflammatory” halos, similar to those seen with HPV

Diagnostic Techniques ♦♦ Immunohistochemical stains, in situ hybridization, and PCR are available

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Fig.  6.42. Human papillomavirus infection and moderate ­dysplasia of the cervix, H&E.

Clinical ♦♦ They are endemic in the Caribbean and Japan and may be aggressive and widespread at diagnosis ♦♦ Hepatosplenomegaly, skin involvement, and hypercalcemia may be present

Microscopic ♦♦ Pleomorphic, multilobated, lymphoid cells are seen in the peripheral blood ♦♦ A lymph node is characterized by a polymorphous infiltrate with multilobated cells

Diagnostic Techniques ♦♦ Serologic testing is available

Measles Virus ♦♦ It is a single-stranded RNA paramyxovirus with a ­negative-sense genome

Clinical ♦♦ It causes rubeola, pneumonia, encephalitis, and subacute sclerosing panencephalitis

Microscopic (Fig. 6.43) ♦♦ Warthin–Finkeldey giant cells with smudged nuclei are classic and nuclear and cytoplasmic inclusions may be seen ♦♦ Interstitial pneumonia and diffuse alveolar damage may be present Fig.  6.41. Herpes simplex virus infection. (A) Skin, H&E. (B) Multinucleated cells with nuclear molding and margination of chromatin. (C) Ground-glass nuclei with margination of chromatin in a liver infected with herpes simplex virus, H&E.

Diagnostic Techniques ♦♦ Cell culture, RT-PCR (reverse transcription), immunofluorescence, and serology are available

Molluscum Contagiosum Human T-Cell Lymphotropic (Leukemia/ Lymphoma) Virus 1 and 2 (HTLV)

Clinical

♦♦ They are single-stranded RNA retroviruses

♦♦ 1–3 mm skin-colored umbilicated papules form

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♦♦ It is a double-stranded DNA poxvirus

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Fig.  6.43. Multinucleated cells with ground-glass nuclei in ­measles pneumonia, H&E. ♦♦ It can be sexually transmitted ♦♦ Lesions are asymptomatic and may spontaneously disappear

Microscopic (Fig. 6.44A, B) ♦♦ Lobular acanthosis and an inverted (cup-shaped) epidermal proliferation are present ♦♦ Characteristic basophilic homogenous cytoplasmic inclusions (molluscum or Henderson–Paterson bodies) are seen

Parvovirus B19 ♦♦ It is a single-stranded DNA virus

Clinical ♦♦ It causes fifth disease or erythema infectiosum in children ♦♦ Presentation of infection ranges from acute self-limiting disease to chronic illness ♦♦ Bone marrow aplasia, especially in immunocompromised patients, may occur ♦♦ It may also cause hydrops fetalis with placentomegaly, fetal pleural effusion, and pulmonary hypoplasia

Microscopic ♦♦ Pulmonary hypoplasia, numerous erythroblasts and iron deposits in the fetal liver (extramedullary hematopoiesis) are seen

Diagnostic Techniques ♦♦ Immunohistochemistry, serology, and in situ hybridization are available

Polyomavirus ♦♦ JC virus, BK virus, and simian virus 40 (SV40) are polyomaviruses ♦♦ They are double-stranded DNA viruses

Clinical ♦♦ They infect immunocompetent and immunocompromised patients and can cause hemorrhagic cystitis and progressive multifocal leukoencephalopathy

Fig. 6.44. (A, B) Molluscum contagiosum, skin, H&E.

Microscopic ♦♦ Solitary cells (“decoy cells”) with enlarged smudged nuclear inclusions and a surrounding thin halo are present in urine cytology ♦♦ Histologically, lesions are patches of irregular destruction of white matter and may involve the cerebrum, brain stem, ­cerebellum, and spinal cord ♦♦ The lesions consist of central demyelination with ­lipid-laden macrophages and few axons ♦♦ Reactive fibrillary astrocytes and characteristic bizarre giant multinucleated astrocytes with hyperchromatic nuclei are seen ♦♦ Oligodendrocytes with nuclear viral inclusions are present at the periphery

Differential Diagnosis ♦♦ Cytomegalovirus has larger cells and may have cytoplasmic inclusions

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Diagnostic Techniques ♦♦ Immunocytochemical stains, in situ hybridization, and electron microscopy may be helpful ♦♦ In vitro culture is very difficult

Rabies Virus ♦♦ It is a single-stranded RNA rhabdovirus with a ­negative-sense genome

Clinical ♦♦ It causes rabies encephalitis, attacking the posterior horns of the spinal cord ♦♦ Fatal infection of the central nervous system is acquired via saliva from the bite of an infected animal

Microscopic ♦♦ Negri bodies, or oval, eosinophilic intracytoplasmic inclusions are classic

Diagnostic Techniques ♦♦ Direct fluorescent antibody detection of viral antigen, immunoenzymatic tests, molecular and serologic testing are available

Respiratory Syncytial Virus ♦♦ It is a single-stranded RNA paramyxovirus with a negativesense genome

Clinical ♦♦ It causes croup, bronchiolitis, and pneumonia

Microscopic ♦♦ Multinucleated giant cells and small, round eosinophilic intracytoplasmic inclusions may be seen ♦♦ Necrotizing bronchiolitis and interstitial pneumonia may be present

Fig. 6.45. (A, B) Varicella infection of the adrenal, H&E.

Diagnostic Techniques ♦♦ Cell culture, immunofluorescence, enzyme immunoassay, and PCR are available

Varicella-Zoster Virus (VZV) ♦♦ It is a double-stranded DNA herpesvirus

Clinical ♦♦ Varicella (chicken pox) primary infection consists of vesicles with erosion, ulceration, and then crust formation ♦♦ The virus is dormant in spinal or cranial sensory ganglia postinfection ♦♦ Herpes zoster (shingles) occurs in dermatomal distributions ♦♦ It is reactivated infection in adults ♦♦ Widespread generalized infection or pneumonia may occur in immunocompromised patients

Microscopic (Fig. 6.45A, B) ♦♦ Necrosis and eosinophilic inclusions (in the lungs, kidney, liver, and adrenal if infection is disseminated) and diffuse alveolar damage are present

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♦♦ The three M’s are classic features to look for histologically −− Multinucleation −− Molding of nuclei −− Margination of chromatin ♦♦ Nuclei have a ground-glass appearance with or without an eosinophilic nuclear inclusion

Differential Diagnosis ♦♦ Herpes simplex virus

Diagnostic Techniques ♦♦ Cell culture, immunofluorescence, and PCR are available

Variola Major Virus (Smallpox) ♦♦ It is a double-stranded DNA poxvirus and has a strict human host range ♦♦ It is transmitted via large respiratory droplets or, less commonly, by aerosol or direct contact with a rash ♦♦ It has reemerged as an agent of bioterrorism

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Clinical

Differential Diagnosis

♦♦ There is a 10–14 day asymptomatic incubation followed by a quick-rising fever to 103°F with dermal petechiae, headache, backache, and vomiting ♦♦ The rash is centrifugal with greater numbers of lesions on the oral mucosa, face and extremities than on the trunk ♦♦ The rash is initially macular, then papular, then vesicular by day 4–5 and pustular by day 7 ♦♦ Lesions are encrusted and sloughed by day 14 ♦♦ All lesions are deep-seated and at the same stage of development

♦♦ Chicken pox (varicella-zoster virus) has a centripetal rash with superficial lesions in crops ♦♦ Disseminated herpes simplex, drug reactions, and molluscum contagiosum may have a similar appearance

Diagnostic Techniques ♦♦ Suspected cases should immediately be reported to the appropriate local or state health department ♦♦ Electron microscopy, cell culture, serology, PCR, and RFLP (restriction fragment length polymorphism) are available

Microscopic ♦♦ Biosafety level 4 laboratory handling is required

PARASITES Protozoa Acanthamoeba Species ♦♦ It is ubiquitous in water and soil and human exposure is via swimming in warm lakes, rivers, and swimming pools or use of nonsterile contact lens cleaning solutions ♦♦ It is an obligate aerobe containing mitochondria ♦♦ It is inhibited by bile and trophozoites do not survive in the intestinal tract

Clinical ♦♦ Keratitis occurs in contact lens wearers or persons with a history of eye trauma and exposure to contaminated water ♦♦ Corneal ulceration with marked ocular pain may result ♦♦ It causes chronic granulomatous amebic encephalitis ♦♦ Elderly, immunocompromised, or debilitated patients have an increased risk of acquiring infection ♦♦ It can be fatal but spontaneous recovery is not uncommon ♦♦ The course is relatively slow ♦♦ It may disseminate to the skin and elsewhere, especially in patients with AIDS

Macroscopic ♦♦ Hemorrhagic necrosis and infracts are present in the brain

Microscopic (Fig. 6.46A, B) ♦♦ Necrotizing granulomas contain trophozoite and cyst forms

Differential Diagnosis ♦♦ It has a double layered outer membrane on electron microscopy ♦♦ Balamuthia mandrillaris has three layers ♦♦ Herpes keratitis will clinically have a similar appearance

Fig. 6.46. Granulomatous amebic encephalitis due to Acantha­ moeba. (A) A trophozoite with retraction artifact, just below the center of the field, H&E. (B) A cyst in the upper ­center potion of the field, H&E.

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ There are trophozoite and cyst forms ♦♦ An ulcer covered by purulent necrotic material with underlying edema and a lymphoplasmacytic infiltrate is present ♦♦ Trophozoites may be single or in groups in inflamed mucosa, submucosa, or necrotic material overlying the ulcer crater ♦♦ Secondary bacterial infection may occur

♦♦ CSF, corneal scrapings, tissue biopsy, or direct microscopic examination ♦♦ Electron microscopy is helpful for distinguishing between Acanthamoeba and other genera of amebae ♦♦ It can be cultured on water agar that is seeded on the surface with live enteric gram-negative bacilli

Special Stains

Babesia microti

♦♦ They are not necessary, as the organism can be readily identified with a H&E stain

♦♦ It is found in the Great Lakes and northeastern USA ♦♦ It is transmitted by the Ixodes scapularis tick. (Borrelia burgdorferi is transmitted by it as well) ♦♦ Patients are normosplenic, in contrast with severe, fatal infections in splenectomized patients in Europe

Diagnostic Techniques

Clinical

Cryptosporidium parvum

♦♦ There is a spectrum of presentations, ranging from asymptomatic in young, normosplenic, immunocompetent persons to potentially life-threatening hemolytic disease in elderly, asplenic, or immunosuppressed persons ♦♦ Presentation is nonspecific with fever, chills, malaise, nausea, vomiting, weight loss, icterus depending on the extent of hemolysis, and hepatosplenomegaly

♦♦ It is a coccidian with fecal–oral spread ♦♦ Oocysts survive chlorination

Microscopic ♦♦ Tetrads of tiny ring forms within normal-sized red blood cells may be present

Special Stains ♦♦ Giemsa staining of a peripheral blood smear

Differential Diagnosis ♦♦ Plasmodium falciparum also forms small intracellular rings; however, one may also see banana-shaped gametocytes that are not present in Babesia spp

Diagnostic Techniques

♦♦ Cysts or trophozoites in stool or trophozoites in colonic mucosal biopsies may be identified histologically ♦♦ They have rotary boring motility in wet preparations

Clinical ♦♦ Gastrointestinal infection consists of diarrhea in immunocompromised patients (especially in AIDS patients) or patients with high volume infection ♦♦ Infection is self-limited in immunocompetent patients

Microscopic (Fig. 6.47A, B) ♦♦ Organisms are intracellular but extracytoplasmic in parasitophorous vacuoles ♦♦ The oocyst is 4–6 µm with four naked sporozoites inside (no sporocyst) ♦♦ There is mild to moderate villous atrophy, crypt dilation, and a lymphoplasmacytic infiltrate in the lamina propria ♦♦ The jejunum is usually most heavily involved

Special Stains ♦♦ Organisms look like crinkled tissue paper with a modified Kinyoun acid-fast stain on a stool smear

♦♦ A characteristic "Maltese cross" form is not always seen ♦♦ A buffy coat preparation improves detection ♦♦ PCR done in a reference lab (e.g., CDC) may aid in diagnosis

Differential Diagnosis

Balantidium coli

Diagnostic Techniques

♦♦ It causes zoonotic parasitic infections ♦♦ It is a ciliate transmitted by a fecal–oral route ♦♦ Infective oocysts, passed in feces, are ingested by a new host

♦♦ A small intestinal biopsy is diagnostic ♦♦ Immunofluorescence, EIA, and ELISA for antigen in stools are available

Clinical

Cyclospora cayetanensis

♦♦ Gastrointestinal infection yields bloody dysentery ♦♦ Infection is generally mild and self-limited unless the patient is immunocompromised

♦♦ It is a coccidian that is found worldwide ♦♦ It has been associated with Guatemalan raspberries

Macroscopic ♦♦ The early lesion is flask-shaped, similar to that of E. ­histolytica. Colonic ulceration and transmural necrosis occur

Microscopic ♦♦ It is a large ciliate (50–100 × 40–70  mm) with a kidneyshaped macronucleus and a micronucleus

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♦♦ Cyclospora cayetanensis is twice the size

Clinical ♦♦ It is a common cause of traveler’s diarrhea ♦♦ Prolonged self-limited diarrhea may last for weeks ♦♦ Immunocompromised patients have diarrhea

Microscopic ♦♦ The oocyst is 8–10 µm with two sporocysts inside

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♦♦ It is more common in persons with a lower socioeconomic status, immigrants, institutional living, and male homosexuals

Clinical ♦♦ Amebic dysentery, crampy abdominal pain, flatulence, diarrhea (watery stool with mucus and blood), and liver abscess (occasionally lung and/or brain) occur

Microscopic ♦♦ Flask-shaped ulcers with a neutrophilic inflammatory response are present in the colon ♦♦ Ulcers may perforate ♦♦ Trophozoite (12–60  mm and asymmetrical) and cyst forms (10–20 mm and spherical) may be found ♦♦ They have a targetoid nucleus with a tiny central karyosome and scant peripheral chromatin ♦♦ The trophozoite has a single nucleus and the cyst has four or fewer nuclei ♦♦ The cytoplasm is clean and finely granular ♦♦ Organisms ingest red blood cells, which is diagnostic ♦♦ Ten percent of cysts have chromatoid bars with smooth, rounded ends

Special Stains ♦♦ Trichrome of a stool smear

Differential Diagnosis ♦♦ Entamoeba hartmanni and E. dispar (a harmless commensal) have a very similar microscopic appearance

Diagnostic Techniques Fig. 6.47. (A) A small bowel biopsy demonstrating intracellular, extracytoplasmic blue “beads” in the brush border, consistent with Cryptosporidium spp., H&E. (B) A stool smear demonstrating 4–5 µm Cryptosporidium oocysts, MAF.

♦♦ Blunting of jejunal villi (villous atrophy) and crypt hyperplasia are present

Special Stains ♦♦ Organisms look like crinkled tissue paper with a modified Kinyoun acid-fast stain on a stool smear

Differential Diagnosis ♦♦ Cryptosporidium parvum is half the size

Diagnostic Techniques ♦♦ The organism autofluoresces under ultraviolet light

Entamoeba histolytica ♦♦ It is worldwide but more prevalent in the tropics ♦♦ Gastrointestinal amebae are transmitted via cysts (infective form) and a fecal–oral route ♦♦ It is an obligate anaerobe that lacks mitochondria and is resistant to bile

♦♦ Usual testing consists of identification of trophozoites in a colon biopsy, feces, or aspirate ♦♦ Antigen detection is also available

Giardia lamblia ♦♦ It is a gastrointestinal flagellate that is found worldwide ♦♦ It is associated with overcrowding and poor sanitation (fecal– oral transmission) ♦♦ It is the most frequently identified intestinal parasite in the USA ♦♦ The mature cyst is the infective form and it is resistant to chlorine concentrations typically used in city water systems

Clinical ♦♦ It may cause diarrhea and B12 malabsorption in campers, ­hikers, and daycare facilities ♦♦ Abdominal distension due to intestinal gas, lactose intolerance, flatulence, and abdominal cramping occur ♦♦ Less commonly, low grade fever, nausea, and vomiting will be present ♦♦ Infection usually resolves in 1–4 weeks but it may persist for months, especially in children

Microscopic (Fig. 6.48A, B) ♦♦ The trophozoite looks like a face with glasses and whiskers ♦♦ It has six flagellae

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♦♦ There is fecal–oral transmission of sporocysts

Clinical ♦♦ Acute, mild to profuse, nonbloody, watery diarrhea resolves in 2 weeks in immunocompetent patients ♦♦ Diarrhea and malabsorption in immunocompromised patients may last weeks, months, or years and can ultimately lead to death ♦♦ There is a low grade peripheral eosinophilia

Microscopic ♦♦ The 25–30  µm ellipsoid oocyst has two internal spherical sporocysts and four banana-shaped sporozoites within each sporocyst ♦♦ Small bowel villous atrophy, crypt hyperplasia, intraepithelial lymphocytes, and subnuclear, loose-fitting parasitophorous vacuoles are present

Special Stains ♦♦ Modified Kinyoun acid-fast stain of stool smear ♦♦ Alcian blue may be added to a hematoxylin-eosin stain of biopsies ♦♦ A tissue Giemsa gives the best contrast

Differential Diagnosis ♦♦ Cryptosporidium oocysts are much smaller

Diagnostic Techniques ♦♦ Intermittent shedding requires several stool specimens

Leishmania Species Fig.  6.48. (A, B) A small bowel biopsy demonstrating many free-floating binucleated Giardia trophozoites, H&E. ♦♦ The cyst form has four nuclei ♦♦ It is found free-floating or attached to the surface of gastrointestinal epithelial cells with a ventral sucker that is crescent shaped on profile but pear-shaped en face ♦♦ There is minimal to no inflammatory response ♦♦ Cysts are found in formed stools ♦♦ Only the trophozoite is found in diarrheal stools ♦♦ Transit time is too short for cyst formation

Special Stains ♦♦ They are not necessary, as the organism can be readily identified with a H&E stain

Diagnostic Techniques ♦♦ It has “falling leaf” motility on a wet mount ♦♦ Direct immunofluorescence and ELISA for Giardia antigens in stool are available

Isospora belli ♦♦ It is a worldwide gastrointestinal coccidian that is endemic in some tropical and subtropical areas (Chile, Brazil, Colombia, Africa, and Southwest Asia)

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♦♦ It is found worldwide, but not in Australia and Antarctica ♦♦ Old World leishmaniasis is found in tropical and subtropical Asia, India, Africa, and the Mediterranean ♦♦ New World leishmaniasis is found in the Americas

Clinical ♦♦ Infection is acquired via the bite of the Phlebotomous sand fly which is smaller than a mosquito and penetrates standard mosquito nets −− Infection ranges in severity from self-limited cutaneous disease to potentially fatal disseminated disease −− Old World cutaneous leishmaniasis is most often caused by L. tropica complex −− New World cutaneous leishmaniasis is caused by L. braziliensis complex and L. mexicana complex −− L. braziliensis can produce a destructive mucocutaneous form called espundia ♦♦ There are three types of disease: cutaneous (composed of localized, disseminated, recidivans [recurrent] and post-kala-azar postvisceral dermal), mucocutaneous, and visceral −− Cutaneous infection is usually restricted to exposed areas of the skin and 60% are due to L. mexicana −− Chiclero ulcers may occur on earlobes −− Disseminated infection occurs when the immune system fails to respond to invading parasites

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−− Recidivans may occur 1–15 years after primary infection −− Post-kala-azar dermal infection is rare and may occur years after recovering from visceral disease ♦♦ Mucocutaneous infections occur predominantly in rural and jungle regions of the New World −− It occurs when primary cutaneous infection with L. brasiliensis subspecies brasiliensis or panamensis disseminates to the upper respiratory tract −− Frequency is variable −− It is rare in the Yucatán peninsula and Guatemala, but it occurs in 80% of cases in Brazil −− Progression is from a chronic cutaneous ulcer with hema­ togenous and lymphatic dissemination producing lesions in oral, pharyngeal, and nasal mucosa to invasion of nasal septum and paranasal fossae with severe mutilation of the midface to death ♦♦ Visceral (kala-azar) is the most serious form of leishmaniasis −− It occurs in New and Old World infections −− Parasites are found throughout the reticuloendothelial system −− Patients present with fever, malaise, hepatosplenomegaly, anorexia, wasting, pancytopenia, and hypergamma­ globulinemia −− The skin has irregular areas of dark pigmentation ♦♦ Blood-borne transmission and transfusion-associated leishmaniasis are possible

Macroscopic

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Fig.  6.49. Leishmaniasis. (A) Kinetoplasts may be difficult to see, even at a high magnification, H&E. (B) Pseudoepithe­ liomatous hyperplasia of the skin, H&E.

♦♦ A cutaneous centrally ulcerated plaque is present

Microscopic (Fig. 6.49A, B) ♦♦ 2–4 µm organisms contain a bar-shaped paranuclear kinetoplast (specialized mitochondrial structure containing extranuclear DNA) ♦♦ There is irregular acanthosis with or without epidermal ulceration and a dense dermal infiltrate of mixed inflammatory cells ♦♦ Pseudoepitheliomatous hyperplasia may also be present ♦♦ Many organisms may be found early in the infection, but the number will decrease as the immune response mounts ♦♦ In disseminated lesions, the dermis contains sheets of macrophages ♦♦ Organisms disappear in the healing phase, leaving only a granulomatous reaction ♦♦ A nonspecific inflammatory infiltrate with rare organisms in macrophages and few or no tuberculoid formations are seen in espundia

Special Stains ♦♦ Histologic sections or smears stained with H&E, Giemsa, or reticulin stains will reveal the organisms

Differential Diagnosis ♦♦ Histoplasma capsulatum lacks a kinetoplast

Diagnostic Techniques ♦♦ Amastigotes in cutaneous leishmaniasis may be demonstrated in the biopsy of the lesion, skin scrapings, or aspirates by H&E, Giemsa, or Brown–Hopps −− PCR is also available ♦♦ In visceral leishmaniasis, qualitative serology for anti-rK39 and quantitative serology for following the course of infection may be done −− H&E or Giemsa stain of bone marrow, liver, spleen, or lymph node biopsy, as well as PCR assays can be diagnostic −− There is growth of the organism on NNN (Novy– Nicolle–McNeal) media

Microsporidia ♦♦ They are obligately intracellular true eukaryotes that produce spores via a unique, coiled polar tube packaged within a spore, acting as a “hypodermic needle” to inject infectious sporoplasm into a host cell

Clinical ♦♦ They cause infections in the gastrointestinal tract (diarrhea), urinary tract, and lungs, opportunistic infections in AIDS, and cholangitis, myositis, and encephalitis

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Fig. 6.50. A stool smear demonstrating microsporidial spores in the center of the field. In some, the polar filament is evident, Modified Weber trichrome stain.

♦♦ Enterocytozoon bieneusi is the most common microsporidian −− It infects enterocytes in AIDS patients, causing severe protracted diarrhea, weight loss, and malabsorption −− It can cause cholangitis and cholecystitis ♦♦ Encephalitozoon causes diarrhea, keratitis, brain lesions, and disseminated infections

Microscopic (Fig. 6.50) ♦♦ They are oval organisms with a transverse band and intracytoplasmic within superficial small intestinal mucosal cells

Fig.  6.51. Primary amebic meningoencephalitis (A) with three Naegleria fowleri trophozoites in the left of the center of the field, H&E. (B) A single trophozoite in the center of the field, H&E.

Special Stains ♦♦ Modified Weber trichrome, acid-fast, periodic acid-Schiff, and Gram stains reveal the organisms

Diagnostic Techniques ♦♦ Electron microscopy allows diagnosis to the species level

Naegleria fowleri ♦♦ It is a free-living ameba

Clinical ♦♦ Diffuse and fulminant primary amebic meningoencephalitis is acquired from swimming in very warm water in the summer months ♦♦ It typically affects children and young adults, is usually rapidly fatal (within a week of symptom onset) and gains access to the central nervous system by migration across the cribriform plate from the nasal mucosa via the olfactory nerve ♦♦ It also causes amebic rhinitis

Macroscopic ♦♦ Purulent meningoencephalitis with necrotizing abscesses of the brain

Microscopic (Fig. 6.51A, B) ♦♦ There are perivascular trophozoites, but no cysts

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Differential Diagnosis ♦♦ Acanthamoeba spp. have a cyst form as well as trophozoites

Diagnostic Techniques ♦♦ Purulent cerebrospinal fluid may contain trophozoites

Plasmodium Species ♦♦ Many species exist, but four infect humans: P. falciparum, P. ovale, P. malariae, and P. vivax ♦♦ The sexual phase (sporogony) occurs in the gut of an Anopheles mosquito −− The asexual phase (schizogony) takes place in human red blood cells −− Red blood cells are invaded by a single parasite (merozoite), which transforms into a ring form (trophozoite) −− Dark “malarial pigment” forms as the trophozoite grows and the hemoglobin it needs for growth is converted to insoluble iron porphyrin and hematin −− The mature trophozoite divides into a segmented form (schizont), which matures to be recognized as individual merozoites with a nucleus and cytoplasm −− Some merozoites do not develop into schizonts, but mature into sexual forms (gametocytes) instead

Microbiology for the Surgical Pathologist

Clinical ♦♦ Malaria is characterized by anemia, thrombocytopenia, and splenomegaly ♦♦ Although infrequent, blackwater fever, a complication of malaria, consists of fever and dark urine produced with massive intravascular hemolysis and subsequent hemoglobinuria (due to P. falciparum) ♦♦ Delirium, seizure, coma, and death may occur ♦♦ P. falciparum produces the most severe disease (malignant tertian malaria) and is most commonly associated with death; therefore, it is the most important species to recognize ♦♦ P. malariae causes quartan malaria with a 72 hour cycle and it is associated with the M antigen ♦♦ P. vivax causes benign tertian malaria with a 48 hours cycle ♦♦ P. ovale is common in West Africa, but rare elsewhere

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♦♦ A thick smear, more concentrated with lysed red blood cells, allows easier detection of parasites ♦♦ Morphology assessment and specie assignment are based upon thin smear findings

Sarcocystis Species ♦♦ It is a gastrointestinal coccidian that is obtained from eating poorly cooked beef or pork ♦♦ Humans are the intermediate or definitive host ♦♦ The sexual cycle develops in the subepithelium of the small bowel mucosa

Clinical ♦♦ Infection is often asymptomatic or self-limited ♦♦ Polymyositis and eosinophilia are rare ♦♦ Nausea, vomiting, and diarrhea may occur

Microscopic

Microscopic (Fig. 6.52)

♦♦ In the peripheral blood, P. falciparum is characterized mainly by very small ring forms that may have two dots of chromatin per ring −− There may be multiple ring forms per small or normal size red blood cell −− Appliqué forms or rings that look like they are plastered to the side of red blood cells are also present −− Classic banana-shaped gametocytes are diagnostic −− Intermediate forms are not often seen, but schizonts are seen in overwhelming infections and moribund patients ♦♦ P. malariae has rare rings and mature band forms in normalsized red blood cells −− Approximately 6–12 merozoites are present in each ­schizont (fewest) and arranged in rosettes −− Gametocytes are large and round-oval ♦♦ P. vivax has Schüffner dots that look similar to basophilic stippling −− It infects immature red blood cells (enlarged) −− Rings are large with ameboid mature forms −− Schizonts have 12–24 segments and gametocytes are large and round-oval ♦♦ P. ovale has rare Schuffner dots, coarse stippling, and 10–14 merozoites per schizont −− Red blood cells appear to have feathered edges and are enlarged

♦♦ A 25–33  µm oocyst with a “collapsed” wall around two sporocysts is characteristic ♦♦ It may contain up to four sporozoites ♦♦ Encysted sporozoites are present in skeletal or cardiac muscle in the intermediate host

Differential Diagnosis ♦♦ Toxoplasma gondii and Trypanosoma cruzi are both smaller than Sarcocystis

Diagnostic Techniques ♦♦ Identification of sporulated oocysts or sporocysts in stool or examination of a muscle biopsy for encysted sporozoites is diagnostic

Toxoplasma gondii ♦♦ It is an obligate intracellular sporozoan ♦♦ The definitive host is the domestic cat. Both the asexual and sexual phases take place in the gastrointestinal tract of the cat ♦♦ The asexual stage takes place in other animals and in humans ♦♦ It is transmitted via ingestion of oocysts on food, ingestion of meat of infected animals (pork or lamb), and transplacentally

Special Stains ♦♦ Giemsa stains of thick and thin peripheral blood smears are routine for diagnosis of malaria

Differential Diagnosis ♦♦ Babesia spp. rings are smaller than P. falciparum, multiple per red blood cell, and form a Maltese cross ♦♦ Leishmania donovani is extracellular and not ring shaped

Diagnostic Techniques ♦♦ Parasitemia is highest during the febrile paroxysm, and several specimens over time may be required for diagnosis

Fig. 6.52. A sarcocyst containing bradyzoites in skeletal ­muscle, H&E.

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Clinical ♦♦ There are three forms −− Self-limited febrile (cervical) lymphadenopathy consisting of fever, rash, and sore throat −− Severe lethal infection in an immunocompromised host, consisting of necrotizing encephalitis, pneumonitis, and myocarditis −− Congenital infection in infants composed of microcephaly, hydrocephaly, chorioretinitis, cerebral calcifications, seizures, and psychomotor retardation ♦♦ It may also lead to abortion or stillbirth ♦♦ Congenital toxoplasmosis is in the differential of the “blueberry muffin baby” that has generalized blue-red papules and nodules due to dermal erythropoiesis ♦♦ Infection is asymptomatic in most patients who have normal immunity

Microscopic (Fig. 6.53A–F) ♦♦ A 3–4 by 6–7 µm crescent-shaped trophozoite invades nucleated host cells ♦♦ In chronic disease, a 200 µm tissue cyst surrounded by a protective membrane is present in brain, heart, and skeletal muscle ♦♦ It contains several hundred organisms

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ There is no cyst form and the trophozoite can exist away from the host for 1–2  hours, and in secretions, urine, and water for up to 24 hours ♦♦ Four apical flagella, one flagellum in association with an undulating membrane that extends half the length of the organism, and a single nucleus are classic

Special Stains ♦♦ Papanicolaou, Giemsa, and acridine-orange allow visualization of the organism

Diagnostic Techniques ♦♦ The motile organism (“jerky” motility) may be identified in a wet mount of vaginal or urethral discharge ♦♦ The organism may be seen in a Papanicolaou smear, but it is generally not identified on biopsy ♦♦ It can be cultured under anaerobic conditions on Diamond medium

Trypanosoma Species

♦♦ A Wright–Giemsa stain of a lymph node reveals trophozoites during the lymphadenopathy stage ♦♦ Cysts are strongly periodic acid-Schiff positive

♦♦ Trypanosoma cruzi is found in Mexico and South America −− It is transmitted by the triatomid, reduviid or kissing bug that defecates while biting −− The host scratches the bite, inoculating infected feces into the skin −− Trypanosoma brucei gambiense is found in West Africa and is transmitted by the tsetse fly −− Trypanosoma brucei rhodesiense is found in East Africa and is transmitted by the tsetse fly

Differential Diagnosis

Clinical

♦♦ Isospora, Microsporidia, Leishmania, Trypanosoma cruzi, Pneumocystis jirovecii

♦♦ Trypanosoma cruzi is the etiologic agent of Chaga disease (South American trypanosomiasis), which affects the viscera, especially the heart −− There is an acute form with fever, lymphadenopathy, anorexia, hepatosplenomegaly, edema, and Romaña sign (bites around the eyes) −− A chronic form with cardiomyopathy, interstitial myocarditis, megaesophagus, megacolon, and CNS (central nervous system) involvement may occur ♦♦ Trypanosoma brucei gambiense is the etiologic agent of African sleeping sickness and lymph node and CNS involvement −− It is a more chronic form −− Winterbottom sign (enlarged posterior cervical lymph nodes) forms as well ♦♦ Trypanosoma brucei rhodesiense causes African sleeping sickness that is more acute and fulminant (rapid onset and rapidly progressive) −− CNS involvement also occurs

Special Stains

Diagnostic Techniques ♦♦ By adulthood, approximately 50% of Americans have antibodies to T. gondii ♦♦ Serologic testing consists of indirect immunofluorescent antibody, indirect hemagglutination, and ELISA

Trichomonas vaginalis ♦♦ It is a vaginal protozoan flagellate with a worldwide distribution. It is the most prevalent nonviral, sexually transmitted disease and has a 4–28 day incubation

Clinical ♦♦ It is a sexually transmitted infection with an intermittent but persistent foul-smelling, yellow-green, frothy discharge ♦♦ Chronic vaginitis, dyspareunia, vaginal pruritus, and dysuria due to urinary tract infection may occur ♦♦ Clinical examination reveals erythema of vaginal and cervical mucosa and a friable granular cervix (strawberry cervix) ♦♦ Urethritis and prostatitis occur in men but most are asymptomatic

Microscopic ♦♦ There is only a trophozoite form which is oval and 7–23 µm

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Microscopic (Fig. 6.54A, B) ♦♦ 15–30  µm trypanosomes have a whip-like polar flagellum originating from a dot-like kinetoplast located posterior to the central nucleus and an undulating membrane running the length of the body, projecting beyond the anterior point of the organism

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Fig. 6.53. (A) Two Toxoplasma cysts are in the center of the field and a third is above the center. (B) A single cyst. (C, D) A Toxoplasma cyst and chronic inflammatory infiltrate in the brain. (E, F) A Toxoplasma cyst in a squash preparation of brain tissue, H&E. ♦♦ Trypanosoma cruzi has C-shaped trypomastigotes in a peripheral blood smear that are characteristic but not diagnostic

−− Amastigotes are present in reticuloendothelial cells or cardiac muscle, but they do not circulate in peripheral blood

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Essentials of Anatomic Pathology, 3rd Ed.

Helminths Cestodes (Tapeworms) Diphyllobothrium latum ♦♦ It is a broad fish tapeworm that is found in temperate climates and transmitted via ingestion of undercooked fish

Clinical ♦♦ Most infections are asymptomatic, but weight loss, fatigue, abdominal pain, vomiting, constipation, diarrhea, and B12 deficiency (worms live in small intestine) may occur

Macroscopic ♦♦ Worms are 3–10 m long with greater than 3,000 proglottids

Microscopic ♦♦ Proglottids are broader than they are long with a central rosette appearance of uterine branches ♦♦ A suctorial groove on the “head” is formed by two (di-) ­longitudinal folds (bothria) ♦♦ 75 µm ova are operculated with a terminal knob ♦♦ It is the only operculated tapeworm that is found in man

Differential Diagnosis ♦♦ Paragonimus westermani ova are bigger (80–100 µm)

Diagnostic Techniques ♦♦ Identification of ova in stool Fig.  6.54. Trypanosoma cruzi. (A) A trypomastigote with a prominent terminal kinetoplast in a peripheral blood smear, Giemsa. (B) Amastigotes in a myofiber in acute chagasic ­myocarditis, H&E.

Echinococcus Species ♦♦ It is a dog or hydatid tapeworm ♦♦ Humans are accidental hosts

Clinical ♦♦ Rupture of a cyst may lead to death from anaphylactic shock

Macroscopic ♦♦ Trypanosoma brucei gambiense has S-shaped trypomastigotes in the peripheral blood smear ♦♦ Amastigotes are present in lymph nodes

Special Stains ♦♦ Giemsa

Differential Diagnosis

♦♦ Hydatid cysts in the liver, lungs, and brain have an inner lining with a germinal membrane from which protoscolices develop ♦♦ The worm is never found in the human, but it is 0.3–0.6 cm in length with three proglottids and a scolex with a double row of hooklets ♦♦ There are few uterine components in the segments

Microscopic ♦♦ Hydatid sand (scolices and free hooklets) are present within the cyst

♦♦ Leishmania donovani has amastigotes with a similar histologic appearance, but organs in which they are found differ ♦♦ Toxoplasma and Histoplasma do not have kinetoplasts

Diagnostic Techniques

Diagnostic Techniques

Hymenolepis Species

♦♦ Peripheral blood smear evaluation and antigen identification by ELISA are diagnostic

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♦♦ Ultrasound may be performed, but needle biopsy is not recommended because it could cause dispersal of cyst contents and subsequent anaphylactic shock ♦♦ They live in the small intestine ♦♦ H. nana is the most common tapeworm in the USA

Microbiology for the Surgical Pathologist

♦♦ It may have a flea or beetle intermediate host ♦♦ It is acquired via the fecal–oral route ♦♦ H. diminuta is the rat tapeworm and the rat is the definitive host ♦♦ The meal beetle is the intermediate host

Clinical ♦♦ Infection is usually asymptomatic

Macroscopic ♦♦ H. nana has a tiny scolex with a spiny rostellum, four suckers, and a ring of spines −− The proglottids are wider than they are long ♦♦ H. diminuta has a small, spherical scolex with four deep suckers and a rounded rostellum with no hooklets −− The proglottids are nondescript

Microscopic ♦♦ H. nana has 40–60  µm round-oval ova with a large clear space between the embryo and shell −− There are polar filaments and thickenings ♦♦ H. diminuta has 70–85 µm round-oval ova with a large clear space between the embryo and shell −− There are no polar filaments and the shell is thicker than that of H. nana

Differential Diagnosis ♦♦ Hymenolepis ova are differentiated based upon size and presence or absence of polar filaments

Diagnostic Techniques ♦♦ Identification of ova in stool

Spirometra Species (Sparganosis) ♦♦ It is found in Southeast Asia and Africa and the eastern and southern USA ♦♦ Dogs and cats are definitive hosts, crustaceans are first intermediate hosts, and fish, snakes, and frogs are second intermediate hosts ♦♦ Infection is acquired by ingesting water containing infected copepods (Cyclops) or uncooked snake

Clinical ♦♦ Painful subcutaneous lesions, Romaña sign, elephantiasislike swelling or frontoparietal cerebral abscesses form ♦♦ Sparganosis is invasion of extraintestinal tissue by the plerocercoid stage (sparganum) ♦♦ An allergic edematous, urticarial response occurs due to subcutaneous migration

Macroscopic ♦♦ Subcutaneous, visceral, and skeletal muscle nodules are seen ♦♦ It rarely migrates to the brain ♦♦ The worm is similar to Diphyllobothrium latum

Microscopic ♦♦ The appearance is similar to Diphyllobothrium latum

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Differential Diagnosis ♦♦ Diphyllobothrium latum

Diagnostic Techniques ♦♦ Tissue examination via biopsy or CT and MRI scans

Taenia Species ♦♦ Taenia solium is the pork tapeworm −− Humans are definitive hosts after ingesting undercooked pork containing encysted larvae −− Disease rarely occurs in the USA but is quite common in parts of Asia, Africa, Europe, and Central and South America ♦♦ Taenia saginata is the beef tapeworm −− Humans are definitive hosts after ingesting undercooked beef containing encysted larvae −− Disease is fairly common in regions with overcrowding and poor sanitation, such as parts of Africa, South America, and Russia −− It is rare in the USA but occasionally occurs in ­southwestern states

Clinical ♦♦ Taenia solium larvae are in the intestines, but eggs (cysticercosis) may be anywhere, especially in the eyes and brain ♦♦ Taenia saginata larvae mature in the intestines and attach to jejunal mucosa to produce eggs −− There is no cysticercosis in humans, only in herbivorous animals −− Patients are usually asymptomatic and infection is recognized only when proglottids are passed in the stool −− The patient may have weight loss, nausea, and ­abdominal pain

Macroscopic ♦♦ Taenia solium is 2–4 m in length with hooks on the scolex and 800–1,000 proglottids that are longer than they are wide ♦♦ Taenia saginata is 4–10 m in length with no hooks on the scolex and up to 2,000 proglottids that are longer than they are wide −− The adult worm may live for 20 years

Microscopic ♦♦ Taenia solium and Taenia saginata eggs are indistinguishable from one another −− They are round with thick shells, radial striations, and three pair of internal hooklets ♦♦ Taenia solium gravid segments have a central uterine stem and <13 lateral branches ♦♦ Taenia saginata gravid segments have a central uterine stem and >13 lateral branches

Differential Diagnosis ♦♦ Taenia solium and Taenia saginata eggs have an identical appearance

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Diagnostic Techniques ♦♦ Identification of proglottids or eggs in the stool

Nematodes (Roundworms) Intestinal Ancylostoma duodenale and Necator americanus ♦♦ Infection occurs worldwide but is limited to warm climates with heavy rainfall −− An infected individual defecates, depositing feces containing eggs in the soil −− The eggs develop into rhabditiform larvae, which migrate through the soil and become filariform larvae, the infective form −− Disease is transmitted when unprotected skin comes into contact with filariform larvae that penetrate the skin, most commonly between the toes (“ground itch”), and migrate to the lymphatics, heart, and lungs −− They are coughed up by the host, swallowed, and carried to the gut where they mature into adult worms, produce eggs, and can live for up to 15 years ♦♦ Ancylostoma duodenale, or Old World hookworm, occurs in India, the Middle East, Asia, and the Mediterranean ♦♦ Necator americanus, or New World hookworm, occurs in the southern USA and tropical areas of the Americas

Clinical ♦♦ The majority of infections are asymptomatic due to low worm burden ♦♦ Gastrointestinal blood loss, peripheral eosinophilia, cough, wheezing, fever, abdominal pain, cramping, and impaired peristalsis are symptoms that may occur ♦♦ Microcytic anemia results from chronic blood loss caused by attachment and feeding of the worm in the gut. Ancylostoma extracts 0.2 mL of blood each day and Necator extracts about 0.02 mL

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ It most commonly affects children, especially in areas of poor sanitation or crowded living conditions ♦♦ Eggs are deposited in the soil when an infected person defecates ♦♦ They require 3 weeks to embryonate and become infectious but may remain infectious for 5 years or more ♦♦ They are transmitted by ingestion of eggs via foodborne, fomite, or airborne routes

Clinical ♦♦ Appendicitis, biliary obstruction, hepatic abscess, pancreatitis, malabsorption, intestinal obstruction, and peripheral eosinophilia may occur

Macroscopic ♦♦ Worms are 25–35 cm in length ♦♦ Males are smaller with a curved tail

Microscopic (Fig. 6.55) ♦♦ Fertile eggs are 60 µm and round-ovoid with a thick shell and albuminous coat (mammillated) ♦♦ Various states of cleavage give a lobulated internal appearance ♦♦ Decorticate eggs lack an albuminous coat, leaving a smooth surface resembling vegetable cells ♦♦ Infertile eggs have a 90 µm elongated shell, often lacking an albuminous coat and having nondescript globules internally

Diagnostic Techniques ♦♦ Worm cross-sections are identified in the appendix ♦♦ Eggs are identified in the stool

Dracunculus medinensis ♦♦ It is the Guinea worm and it is found in Pakistan, India, and west coast Africa ♦♦ Cyclops (a copepod) is ingested from water

Macroscopic ♦♦ The adult worm is 10 mm in length with a hooked tail ♦♦ Ancylostoma has two pair of chitinous teeth and Necator has two cutting plates

Microscopic ♦♦ The oval, thin-shelled, 50 µm ova has a four-to eight-lobed embryo ♦♦ Rhabditiform larvae have a long buccal cavity (as long as the body is wide) and an inconspicuous genital primordium

Differential Diagnosis ♦♦ Eggs of the two Genera are identical in appearance ♦♦ Strongyloides eggs and larvae have a very similar appearance

Diagnostic Techniques ♦♦ Identification of eggs or rhabditiform larvae (rare) in stool

Ascaris lumbricoides ♦♦ It is found worldwide but most commonly in warm climates

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Fig. 6.55. Ascariasis. An appendix containing a cross-section of a worm with a thick outer cuticle, prominent musculature, and centrally located digestive tract, H&E.

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♦♦ The worm migrates to the feet and may cause skin blisters and soft tissue calcifications ♦♦ Larvae develop into adult worms in serous cavities and gravid females migrate to subcutaneous tissue ♦♦ The cycle takes about 1 year to complete

Clinical ♦♦ The female gravid worm may emerge through a skin ulcer ♦♦ There may be a burning sensation and ulceration of the skin at the site of infection ♦♦ Worms may be surgically removed from subcutaneous tissue by slowly winding them on a stick

Macroscopic ♦♦ The adult worm is up to 100 cm in length and it is the longest nematode that infects humans

Microscopic ♦♦ Subcutaneous abscess, central necrosis surrounded by a granulomatous reaction, soft tissue erosion, epithelioid cells, histiocytes, neutrophils, plasma cells, eosinophils, and giant cells are present ♦♦ Larvae have a smooth annulated cuticle with prominent ­musculature and digestive tube

Diagnostic Techniques

Fig.  6.56. An appendix containing a cross-section of a worm with prominent lateral spines and numerous eggs, diagnostic of Enterobius vermicularis, H&E. ♦♦ The worm has lateral alae at the head and contains ­diagnostic eggs ♦♦ Worm cross-sections in the appendix are common

Diagnostic Techniques

♦♦ Diagnosis is made clinically

♦♦ A cellulose tape preparation is the most reliable method for diagnosing the infection

Enterobius vermicularis (Pinworm)

Strongyloides stercoralis

♦♦ It is one of the most common parasitic infections and it is found worldwide ♦♦ It is most common in children and persons with crowded ­living conditions ♦♦ Adult worms live in the cecum ♦♦ The female migrates through the colon to the anus during the night and deposits eggs on perianal skin and bedcovers ♦♦ Eggs are transferred to host fingers by scratching ♦♦ They may also be airborne off sheets or clothing and remain viable and infectious for several days ♦♦ Infection is transmitted when eggs are ingested or inhaled and swallowed

Clinical ♦♦ Gastrointestinal disturbance is possible, but perianal pruritis is prominent and worse at night ♦♦ Secondary bacterial infection secondary to excoriation, vaginitis, endometritis, and salpingitis may occur ♦♦ Usually there is no peripheral eosinophilia

Macroscopic ♦♦ The 0.8–1.3  cm adult female worm with a pointed tail is sometimes seen on perianal skin ♦♦ The male is smaller and usually not seen

Microscopic (Fig. 6.56) ♦♦ The egg is ovoid with one flattened side

♦♦ It is the smallest of intestinal nematodes and the geographic distribution is similar to the hookworm ♦♦ Filariform larvae penetrate the skin and follow a transpulmonary route ♦♦ Autoinfection is possible

Clinical ♦♦ Intestinal infection is only symptomatic with large worm loads ♦♦ Peptic ulcer-like pain occurs and may be aggravated by eating ♦♦ Peripheral eosinophilia and malabsorption may be found ♦♦ Fever, dyspnea, cough, and wheezing take place with the pulmonary phase ♦♦ Immunosuppressed patients may have disseminated infection

Microscopic (Fig. 6.57A–C) ♦♦ The larva has a curved tail and is very similar to hookworms, but has a shorter buccal cavity and longer primitive genitalia ♦♦ Calcified worm fragments may be seen in histologic sections of the colon

Differential Diagnosis ♦♦ Hookworm larvae

Diagnostic Techniques ♦♦ Identification of 0.75–1  mm rhabditiform larvae with a short buccal cavity and prominent genital primordium

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Trichinella spiralis ♦♦ It is found worldwide, excluding Asia and Australia, where there are rare cases ♦♦ Infection is acquired by eating undercooked meat (pork, bear) containing encysted larvae ♦♦ Freezing for 20 days destroys cysts, while salting and drying does not

Clinical ♦♦ Most infections are asymptomatic due to low worm load, but abdominal pain, diarrhea, fever, myalgia, and weakness may occur ♦♦ There is marked peripheral eosinophilia

Macroscopic ♦♦ The adult male and female (0.2–0.4 cm in length) live in the intestine for 4 months, producing >1,000 larvae that will become encysted in skeletal muscle ♦♦ Larvae that enter skeletal muscle survive, grow, encapsulate, calcify and may live for up to 10 years

Microscopic ♦♦ Spiral larvae are encysted in skeletal muscle ♦♦ The most often infected muscles include the diaphragm, extraocular muscles, tongue, deltoid, and intercostal muscles

Diagnostic Techniques ♦♦ Spiral larvae may be detected in trypsin-digested tease mounts of deltoid or gastrocnemius muscle

Trichuris trichiura (Whipworm) ♦♦ It is worldwide but is more common in warm, humid areas where defecation in soil is standard practice, in institutions, or crowded communities with poor sanitation ♦♦ The eggs require 21 days in the external environment for maturation ♦♦ Transmission is fecal–oral and fertile eggs are infective ♦♦ Eggs hatch and mature in the duodenum, then move to the cecum

Clinical ♦♦ Infection is asymptomatic if there is a low worm burden ♦♦ Diarrhea, rectal itching, abdominal pain, nausea, and anemia may occur ♦♦ Colonic or rectal prolapse may result with a high worm load

Macroscopic Fig. 6.57. Fragments of a Strongyloides worm deep in intestinal mucosa [(A) center and left, (B) center, (C) multiple partially calcified worm fragments], H&E.

in the stool, duodenal aspirates, jejunal biopsy, or sputum ♦♦ Eggs are usually not seen

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♦♦ Adult worms are 3.5–4.5 cm in length with a whip-like anterior and thick handle-like posterior

Microscopic ♦♦ Eggs are barrel-shaped and 54  µm in greatest dimension, with bipolar hyaline plugs ♦♦ 5,000–10,000 eggs are produced per day

Diagnostic Techniques ♦♦ Identification of eggs in stool

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Microfilaria (Tissue Roundworms)

Diagnostic Techniques

♦♦ Generally, filariae (adults) living in various tissues produce microfilariae that circulate in the peripheral blood (excluding Onchocerca) and can survive for 1–2 years ♦♦ Microfilariae are not infective and require an intermediate host ♦♦ They are reintroduced to humans during blood feedings by a vector. It may take months or years to develop symptoms

♦♦ Identify microfilariae in a peripheral blood smear or direct mount of blood or the adult in the eye or calabar swelling ♦♦ Microfilariae are released on a diurnal schedule; the blood sample should be drawn during the day

Brugia malayi ♦♦ Anopheles and Aedes mosquitoes are the vectors ♦♦ The third stage larva is the infective form

Clinical

Mansonella perstans ♦♦ It is transmitted by midges

Clinical ♦♦ Rash and fever occurs, but infection is not serious

Microscopic ♦♦ It is unsheathed and nuclei extend to the end of the tail

♦♦ Lymphatic and lymph node involvement and elephantiasis may occur

Special Stains

Macroscopic

Differential Diagnosis

♦♦ The adult worm reaches 10 cm in length

♦♦ Other microfilariae ♦♦ It may be differentiated from Onchocerca by the position of the nuclei

Microscopic

♦♦ Giemsa thick and thin smears of peripheral blood

♦♦ The microfilariae are sheathed and 245–295 × 7.5–10 µm ♦♦ They have a long cephalic space with two discrete nuclei at the tail end

Diagnostic Techniques

Special Stains

Onchocerca volvulus

♦♦ The sheath stains pale pink on Giemsa thick and thin smears of peripheral blood

♦♦ It is transmitted by Simulian black flies, which breed in and around fast-flowing rivers in Africa and Central and South America

Differential Diagnosis ♦♦ Other microfilariae

Diagnostic Techniques ♦♦ Identify microfilariae in a peripheral blood smear

Loa loa ♦♦ It is an eye worm, with a Chrysops deer fly vector and is found in the African rainforest

Clinical ♦♦ Calabar swellings (painful or pruritic subcutaneous nodules), fever, urticaria, and pruritis occur ♦♦ It may migrate across the eye below the conjunctiva, causing tearing and pain ♦♦ Peripheral eosinophilia is found ♦♦ The adult worm lives in subcutaneous tissue and migrates about 1 cm/h under the conjunctiva or skin

Microscopic

♦♦ Identify microfilariae in a peripheral blood smear

Clinical ♦♦ Dermatitis with dense fibrous subcutaneous nodules (up to 2.5 cm in diameter) containing adult worms are found at the site of the bite (onchocercoma) ♦♦ Iritis may lead to blindness. “River blindness” is the most serious complication ♦♦ Nonfatal lymphatic obstruction, elephantiasis, and wrinkling of the skin or “leopard skin” may occur

Macroscopic ♦♦ The female worm is up to 50 cm in length, but the male only reaches 5 cm

Microscopic ♦♦ A granulomatous inflammatory reaction is induced by the worms

Diagnostic Techniques

Special Stains

♦♦ Microfilariae are identified in skin snips since they only circulate in the blood in heavy infections ♦♦ Enzyme immunoassay can be performed for diagnosing river blindness

♦♦ Giemsa thick and thin smears of peripheral blood

Wuchereria Bancrofti

Differential Diagnosis

♦♦ The vector is the Culex mosquito ♦♦ The third stage larva is the infective form

♦♦ Microfilariae are sheathed with a column of nuclei that extends completely to the tail tip

♦♦ Other microfilariae

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Clinical

Diagnostic Techniques

♦♦ Filariasis, elephantiasis of genitalia and lower extremities, fever, chills, headache, and local redness may occur

♦♦ Histologic sections of brain or spinal cord

Macroscopic ♦♦ The adult worm reaches 10 cm in length

Microscopic

Anisakis Species ♦♦ The source is herring, marine animals, and fish in Japan and the Netherlands, although it may be acquired anywhere that humans ingest undercooked fish

♦♦ Microfilariae are sheathed and 245–295 × 7.5–10 µm with a short cephalic space ♦♦ The column of nuclei terminates 15–20 µm proximal to the tail tip ♦♦ The worm is embedded in fibrous stroma and surrounded by a chronic inflammatory infiltrate ♦♦ It may be found in distended lymphatic vessels or nodes

Clinical

Special Stains

Macroscopic

♦♦ Giemsa thick and thin smears of peripheral blood

♦♦ The cuticle, lateral chords and esophagus are evident on worm cross-sections of 1.0–2.9 cm larvae

Differential Diagnosis ♦♦ Other microfilariae

Diagnostic Techniques ♦♦ It is nocturnal or subperiodic, depending on the region of world, which makes timing of blood collection important

Zoonotic Roundworms Angiostrongylus Species ♦♦ It is the rat lung worm, which is found in China, Hawaii, the tropics, and Central America ♦♦ It is acquired by ingestion of infected snails, prawn, or contaminated water and vegetables

Clinical ♦♦ Meningitis, blood and CSF eosinophilia, and gastrointestinal disturbance occur

Macroscopic ♦♦ Often there are no gross lesions of the brain and spinal cord ♦♦ The distal small intestine and ascending colon show inflammation and tumor-like masses ♦♦ The female filariform worm is 2.1–3.5  cm and males are 1.6–1.9 cm in length ♦♦ There is a bursa copulatrix at the posterior end with bursal rays and spicules, the configuration and length of which, respectively, are of taxonomic importance

Microscopic ♦♦ It is one of the most common causes of eosinophilic meningitis ♦♦ Worm fragments, granulomas of mesentery, brain, or spinal cord may be seen ♦♦ Glial scars containing hemosiderin, microscopic hemorrhages, eosinophils, and Charcot–Leyden crystals are present

Differential Diagnosis ♦♦ Schistosomiasis, echinococcosis, gnathostomiasis, paragonimiasis, cysticercosis and ascariasis

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♦♦ Acute infection consists of abdominal pain, nausea, vomiting, and diarrhea occurring 1–12 hours after eating infected fish ♦♦ Chronic infection results in intermittent abdominal pain, nausea, and vomiting lasting weeks to years ♦♦ Peritonitis, peripheral leukocytosis, eosinophilia, and penetration of the gastric mucosa can occur

Microscopic ♦♦ Abscess and eosinophilic granulomas are present in the stomach ♦♦ Larvae cause deep tunnels surrounded by granulomatous inflammation in the stomach and also migrate into the omentum, liver, pancreas, and lungs

Differential Diagnosis ♦♦ Ascaris species

Diagnostic Techniques ♦♦ The whole worm (from vomitus, stool, surgery or endoscopy) may be preserved in 70% ethanol and cleared in phenol to facilitate visualization of morphologic features

Capillaria philippinensis ♦♦ It is found in the Far East (Philippines and Thailand) ♦♦ The source is ingestion of undercooked fish ♦♦ The worm develops and multiplies in the intestine but predominates in the jejunum

Clinical ♦♦ Malabsorption syndrome, diarrhea, abdominal pain, borborygmi (“gurgling stomach”), Pudoc mystery disease, proteinlosing enteropathy, and death may occur

Macroscopic ♦♦ 2.3–5.3 mm female and 1.5–4 mm male worms have an anterior end that is narrower than the posterior end

Microscopic ♦♦ There is crypt atrophy, and infiltration of the lamina propria with lymphocytes, plasma cells, neutrophils, macrophages, and a few eosinophils ♦♦ Villi are blunted, flattened, or destroyed with sloughed mucosa ♦♦ Worm fragments may be present in small intestinal crypts ♦♦ Peanut or barrel-shaped ova have flattened bipolar plugs and a radially striated thin shell

Microbiology for the Surgical Pathologist

Differential Diagnosis ♦♦ Trichiuris eggs, strongyloidiasis, hookworm infection, giardiasis, and tropical sprue

Diagnostic Techniques ♦♦ Ova, larvae, and adults all may be seen in the stool

Dirofilaria immitis ♦♦ It is the dog heartworm ♦♦ Adult worms develop in the heart and microfilariae circulate in the blood ♦♦ Culex, Aedes, and Anopheles mosquitoes are the vectors and intermediate hosts ♦♦ Humans are an accidental host ♦♦ It is found in temperate and tropical regions including the USA, the post-Soviet states, Canada, Australia, Japan, Sri Lanka, Malaysia, and many Mediterranean countries

Clinical ♦♦ It causes larval migrans with a serpiginous red rash and intraparenchymal lung nodules that appear as coin lesions on chest x-ray ♦♦ Human infection is rare, spurious, and benign

Macroscopic ♦♦ The female worm is 25–30 cm and the male is 12–16 cm in length ♦♦ The pulmonary nodule is gray, 2–3  cm, and may have a coiled worm inside it

Microscopic (Fig. 6.58) ♦♦ The worm cross-section shows a smooth multilayered cuticle projecting inward to form internal diametrically opposed ridges that look like inverted lateral spines ♦♦ Prominent muscles and two uterine tubes may be evident ♦♦ Worms may be faintly eosinophilic and easily overlooked ♦♦ Larvae lodge in pulmonary arterioles and form granulomatous nodules

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♦♦ The nodules consist of central coagulation necrosis with surrounding histiocytes, monocytes, lymphocytes, eosinophils, and Langhans giant cells

Special Stains ♦♦ A Movat pentachrome stain helps distinguish the vessel wall, worm’s cuticle, muscle, and internal organs

Differential Diagnosis ♦♦ Etiologies of other coin lesions: carcinoma, tuberculosis, fungal infections, hamartomas

Diagnostic Techniques ♦♦ ELISA, indirect immunofluorescence

Gnathostoma Species ♦♦ It is found in the Far East (predominantly Japan and Thailand) ♦♦ Cats and dogs are definitive hosts ♦♦ Humans are accidental hosts that are infected through ingestion of undercooked fish, chicken, or pork ♦♦ Larvae do not mature but penetrate the gastric wall and migrate to other tissues

Clinical ♦♦ It causes acute visceral larval migrans, nausea, and swelling ♦♦ Meningitis, encephalitis, uveitis, retinal detachment, and blindness are possible ♦♦ CNS invasion may be life-threatening

Macroscopic ♦♦ The immature larval form causes human disease and has four rows of hooklets on the head bulb instead of eight ♦♦ The female larvae are 1.0–4.5 cm and males are 1.0–2.5 cm in length

Microscopic ♦♦ The 70 × 40  µm transparent egg has a unipolar cap and thick wall ♦♦ Necrotizing inflammatory tracts are present in soft tissue ♦♦ Edema, necrosis, hemorrhage, eosinophils, plasma cells, and neutrophils may be found ♦♦ The acute inflammatory reaction becomes fibrogranulomatous

Differential Diagnosis ♦♦ Sparganosis, cutaneous paragonimiasis, cutaneous larva migrans, trichinosis (eye swelling), and myiasis, clinically

Diagnostic Techniques ♦♦ Tissue biopsy and identification of third stage larvae

Toxocara canis (Visceral Larva Migrans)

Fig. 6.58. Pulmonary dirofilariasis demonstrating a fragment of worm with a smooth cuticle and prominent musculature, H&E

♦♦ It is a large intestinal roundworm of cats and dogs ♦♦ It is found worldwide and is common in the southeastern USA ♦♦ It thrives in warm humid climates ♦♦ Humans become incidental hosts by ingesting embryonated eggs in soil deposited by an infected animal

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♦♦ Embryonation requires 2 weeks before eggs become infectious ♦♦ They remain infectious for months to years ♦♦ Eggs hatch in the intestine, penetrate the mucosa and travel via the portal circulation into the lung and pulmonary capillaries until their growth limits vascular travel and they migrate into tissue

Clinical ♦♦ Visceral larva migrans, granulomatous endophthalmitis, and blindness occur ♦♦ Larvae deposit in various organs, usually the liver ♦♦ Manifestations are related to tissues that are invaded by larvae, most commonly skeletal muscle, heart, brain, liver, lung, and eye ♦♦ Most cases are self-limited and asymptomatic ♦♦ Symptomatic cases are often associated with asthma due to high IgE levels ♦♦ Fever, hepatosplenomegaly, focal neurologic deficits, seizure, pulmonary infiltrates, cardiac arrhythmias, decreased visual acuity, and peripheral eosinophilia may be present ♦♦ Disease is more severe in young children and when the number of invading larvae is high

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Ova in the water hatch miracidia, which infect snails, multiply, and release cercariae that attach to water plants and become encysted

Clinical ♦♦ It causes bile duct obstruction and cholangiocarcinoma

Macroscopic ♦♦ Worms are in the biliary tree ♦♦ The adult worm is 3  cm in length with a cone-shaped anterior

Microscopic ♦♦ Ova are 150 µm and operculated

Differential Diagnosis ♦♦ Fasciolopsis buski eggs appear identical

Diagnostic Techniques ♦♦ Identification of ova in stool ♦♦ Adult worms are seen only if surgically removed

Fasciolopsis buski

♦♦ Necrosis, hemorrhage, abscess, and granuloma formation with numerous eosinophils may be found

♦♦ It is acquired by eating contaminated uncooked aquatic plants from the Far East ♦♦ Ova in water hatch miracidia, which infect snails, multiply, and release cercariae that attach to water plants and become encysted

Diagnostic Techniques

Clinical

Microscopic

♦♦ Tissue biopsy; there are no eggs or worms in the stool because the organism does not mature in the human

Trematodes (Flukes) Clonorchis sinensis ♦♦ It is also known as the Chinese liver fluke and it is found in the Far East ♦♦ Ova in water hatch a miracidium which infects a snail ♦♦ It multiplies and releases cercariae that infect fish and become encysted ♦♦ Humans acquire infection by eating undercooked fish

Clinical ♦♦ It causes bile duct obstruction and patients have an increased risk of cholangiocarcinoma

♦♦ The small intestine is the site of infection

Macroscopic ♦♦ The adult worm is 2–7.5  cm in length with a rounded anterior

Microscopic ♦♦ Ova are 150 µm and operculated

Differential Diagnosis ♦♦ Fasciola hepatica eggs appear identical

Diagnostic Techniques ♦♦ Identification of ova in stool ♦♦ Adult worms are seen only if surgically removed

Macroscopic

Paragonimus westermani

♦♦ 1.5 cm worms are present in the biliary tree

♦♦ Identification of eggs in stool

♦♦ It is the Oriental lung fluke that is acquired by eating contaminated raw/undercooked crab ♦♦ Ova hatch miracidia that infest snails, multiply and release cercariae that infect crabs and crayfish ♦♦ Human ingestion releases larvae that migrate through the bowel to the lung and ova are coughed up and swallowed to be released in feces

Fasciola hepatica

Clinical

♦♦ It is also known as the sheep liver fluke which is acquired by eating contaminated/undercooked watercress

♦♦ Pleural pain, persistent morning cough, and hemoptysis are common

Microscopic ♦♦ Ova are 27–35 µm, operculated, and urn-shaped with shoulders and an abopercular boss/knob

Diagnostic Techniques

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Macroscopic ♦♦ It causes cystic cavities in the lung. The adult worm is ­0.8–1.6 cm in length and spoon-shaped

Microscopic ♦♦ An 80–120 µm operculated egg with shoulders and abopercular thickening is classic

Differential Diagnosis ♦♦ Differentiate from other operculated eggs based upon size (D. latum, F. buski, F. hepatica)

Diagnostic Techniques ♦♦ Identification of ova in stool or sputum

Schistosoma Species ♦♦ Three species of Schistosoma cause disease in humans −− S. hematobium is a bladder fluke with a snail host and is found in India and Africa −− S. japonicum is a blood fluke found in Asia and the Philippines −− S. mansoni is also a blood fluke and is found in Africa, Asia, South America, and the Caribbean islands ♦♦ The life cycle consists of eggs hatching in freshwater to form miracidia which infest snails and divide to form hundreds of cercariae which are released −− These free-swimming forms penetrate the skin and enter the circulation, and will mature to the adult form in the portal venous system

Clinical ♦♦ In endemic areas, S. hematobium is a major predisposing factor to squamous cell carcinoma of the bladder −− Hematuria and hydronephrosis may occur

−− Adult worms live in the venus plexuses of the bladder and rectum −− Ova may be found in urine and stool ♦♦ S. japonicum is found in veins of the small intestine, liver, and brain −− It causes portal hypertension and esophageal varices ♦♦ S. mansoni is found in veins of the colon −− It releases ova in stool and causes portal hypertension and esophageal varices ♦♦ Venous obstruction and tissue damage due to egg deposition may occur −− Swimmer’s itch is due to penetration of nonpathogenic species of schistosome cercariae

Macroscopic ♦♦ Adult worms are 2.5–3 cm in length. The female resides in the gynecophoral canal of the male

Microscopic ♦♦ Look for calcified ova and a foreign-body type granuloma in target organs −− S. hematobium ova (110–170 µm) have a terminal spine −− S. japonicum ova (70–100 µm) have a small, delicate lateral hook-like spine −− S. mansoni ova (115–180 µm) have a lateral spine

Differential Diagnosis ♦♦ They are easily differentiated from other roundworms based upon their comparatively large sizes

Diagnostic Techniques ♦♦ Spines and shells of S. japonicum and S. mansoni, and only the spine of S. hematobium, are modified Ziehl–Neelsen acid-fast positive

OTHER Myiasis Clinical ♦♦ Fly larvae (maggots) invade skin or soft tissue and are extremely painful ♦♦ Wound myiasis with swarming maggots on the surface, due to Chrysomia spp. may be disfiguring ♦♦ Furuncular myiasis, or papule/nodule formation with a central opening, may be due to Dermatobia hominis (bot fly)

Microscopic ♦♦ A tunnel from the epidermis to the lower dermis with larva inside, surrounded by a mixed inflammatory infiltrate, focal collagen degeneration, and a foreign body reaction is present ♦♦ The larva has abundant striated muscle, respiratory tubules, and a thick cuticle with pigmented spines

Differential Diagnosis ♦♦ Tunga penetrans (flea) invades as an adult, not larva, contains eggs, and has no tunnel ♦♦ A wood splinter, scabies mite, and ticks may have a similar appearance

Sarcoptes scabiei ♦♦ Scabies is an allergic dermatitis caused by burrowing of the mite in the epidermis ♦♦ It is found worldwide, with the highest incidence in people <20 years old ♦♦ It is acquired via close contact ♦♦ The female mite may live up to 19 days without a human host

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Clinical ♦♦ Intense pruritis occurs, especially at night, and most commonly in the axillary folds, buttocks, and interdigital folds ♦♦ Thin elevated serpiginous tracts are formed ♦♦ Pustules may form with secondary infection

Microscopic ♦♦ Burrows are confined to the stratum corneum ♦♦ A mite may be found in the upper stratum malpighii in a blind end ♦♦ Mild parakeratosis surrounds the burrow ♦♦ Spongiosis and vesicles are at the burrow head ♦♦ A nonspecific inflammatory infiltrate with lymphocytes and eosinophils is in the dermis

Special Stains ♦♦ Excrement, eggs, and mites are PAS-positive

Diagnostic Techniques ♦♦ Biopsy or mineral oil skin scrapings may contain adult mites

Tunga penetrans Clinical ♦♦ An adult gravid female flea (jigger or chigger flea) invades the skin

♦♦ It mostly affects the feet but it may involve any area of the body, either singly or in crops ♦♦ A tiny black spot (opening of the flea’s posterior end through which it breathes and discharges eggs) will be visible after the flea invades ♦♦ It becomes pruritic as it enlarges and is painful if adjacent to a nailbed ♦♦ Overlying keratin is white with an erythematous edge ♦♦ The flea matures in 10–14 days, discharges eggs, and the collapsed carcass sloughs

Microscopic ♦♦ The flea is present within the epidermis, surrounded by elongated rete ridges, with the head penetrating into the upper dermis ♦♦ The flea contains dilated loops of gut, developing eggs, branching tracheae, and bands of hypertrophied striated muscle ♦♦ The host dermis is hyperemic with mixed inflammation consisting of eosinophils, lymphocytes, and plasma cells ♦♦ The host–flea interface hold-fast apparatus (jigsaw interlocking) adheres flea tegument tightly to the patient’s keratin

Differential Diagnosis ♦♦ Ticks and fly larvae may have a similar appearance

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Cunningham MW. Pathogenesis of group A streptococcal infections and their sequelae. Adv Exp Med Biol 2008;609:29–42. Cutaneous leishmaniasis in U.S. military personnel--Southwest/Central Asia, 2002–2004. MMWR Morb Mortal Wkly Rep 2004;53:264–265. Damjanov I, Linder J, Anderson WAD, (eds.). Anderson's pathology. Mosby, St. Louis, 1996. Daum RS. Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. N Engl J Med 2007;357: 380–390. Driscoll JA, Brody SL, Kollef MH. The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections. Drugs 2007;67: 351–368. Dutra WO, Gollob KJ. Current concepts in immunoregulation and pathology of human Chagas disease. Curr Opin Infect Dis 2008;21:287–292.

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Hadfield TL, McEvoy P, Polotsky Y, Tzinserling VA, Yakovlev AA. The pathology of diphtheria. J Infect Dis 2000;181 Suppl 1:S116–120. Hage CA, Davis TE, Egan L, Parker M, Fuller D, Lemonte AM, Durkin M, Connelly P, Joseph Wheat L, Blue-Hnidy D, Knox KS. Diagnosis of pulmonary histoplasmosis and blastomycosis by detection of antigen in bronchoalveolar lavage fluid using an improved second-generation enzyme-linked immunoassay. Respir Med 2007;101:43–47. Hage CA, Wheat LJ, Loyd J, Allen SD, Blue D, Knox KS. Pulmonary histoplasmosis. Semin Respir Crit Care Med 2008;29:151–165. Haldar K, Murphy SC, Milner DA, Taylor TE. Malaria: mechanisms of erythrocytic infection and pathological correlates of severe disease. Annu Rev Pathol 2007;2:217–249. Hawkes M, Kain KC. Advances in malaria diagnosis. Expert Rev Anti Infect Ther 2007;5:485–495. Hoppa E, Bachur R. Lyme disease update. Curr Opin Pediatr 2007;19: 275–280. Hotez PJ, Brooker S, Bethony JM, Bottazzi ME, Loukas A, Xiao S. Hookworm infection. N Engl J Med 2004;351:799–807. Janka J, O'Grady NP. Clostridium difficile infection: current perspectives. Curr Opin Crit Care 2009;15:149–153. Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS, Galbraith M, Tapper M, Fisk TL, Zaki S, Popovic T, Meyer RF, Quinn CP, Harper SA, Fridkin SK, Sejvar JJ, Shepard CW, McConnell M, Guarner J, Shieh WJ, Malecki JM, Gerberding JL, Hughes JM, Perkins BA. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg Infect Dis 2001;7:933–944. Johnson DR, Wotton JT, Shet A, Kaplan EL. A comparison of group A streptococci from invasive and uncomplicated infections: are virulent clones responsible for serious streptococcal infections? J Infect Dis 2002;185:1586–1595. Jones JL, Dargelas V, Roberts J, Press C, Remington JS, Montoya JG. Risk factors for Toxoplasma gondii infection in the United States. Clin Infect Dis 2009;49:878–884. Kauffman HF. Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling. Front Biosci 2003;8:e190–196. Kaur R, Domergue R, Zupancic ML, Cormack BP. A yeast by any other name: Candida glabrata and its interaction with the host. Curr Opin Microbiol 2005;8:378–384. Keiser PB, Nutman TB. Strongyloides stercoralis in the Immuno­ compromised Population. Clin Microbiol Rev 2004;17:208–217.

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7 Forensic Pathology Frank P. Miller III, md and Jeffrey J. Barnard, md

Contents

I. General Concepts................................7-3

Cause of Death���������������������������������������������������7-3 Manner of Death�����������������������������������������������7-3 Mechanism of Death�����������������������������������������7-3

II. Identification.......................................7-3 Positive Identification����������������������������������������7-3 Circumstantial Identification............................7-3 Anthropological Identification..........................7-3

III. Time of Death and Postmortem Changes...............................................7-3 General................................................................7-3 Livor Mortis (Lividity).......................................7-3 Rigor Mortis (Rigidity)......................................7-4 Algor Mortis (Body Cooling).............................7-4 Decomposition....................................................7-5 Gastric Emptying...............................................7-5 Forensic Entomology..........................................7-5 Postmortem Chemistry......................................7-6

IV. Sudden Death from Natural Disease...................................7-6 Classification.......................................................7-6 Cardiovascular Causes of Death.......................7-7 Atherosclerotic Heart Disease.................7-7 Hypertensive Cardiovascular Disease....7-7 Aortic Stenosis..........................................7-7 Long QT Syndrome..................................7-7 Hypertrophic Cardiomyopathy...............7-8 Dilated Cardiomyopathy..........................7-8 Restrictive Cardiomyopathy....................7-8 Myocarditis................................................7-8

Mitral Valve Prolapse...............................7-8 Aortic Dissection.......................................7-9 Pulmonary Thromboembolism...............7-9 Cerebrovascular Disease..................................7-10 Intracerebral Hemorrhage (Apoplexy)..........................................7-10 Ruptured Berry Aneurysm....................7-10 Nonvascular Causes of Death..........................7-11 Chronic Alcoholism................................7-11 Epilepsy...................................................7-11 Bronchial Asthma...................................7-11 Waterhouse-Friederichsen Syndrome............................................7-12 Colloid Cyst of Third Ventricle.............7-12 Diabetic Ketoacidosis.............................7-13 Anaphylaxis.............................................7-13 Sudden Infant Death Syndrome............7-13

V. Physical Injuries.................................7-15 Mechanical Trauma.........................................7-15 Principles and Effects.............................7-15 Blunt Force Injuries.........................................7-16 Abrasion..................................................7-16 Contusion.................................................7-16 Laceration...............................................7-18 Fractures.................................................7-18 Head Injuries..........................................7-19 Shaken Baby Syndrome.........................7-23 Firearms Injuries..............................................7-24 General Principles..................................7-24 Handguns.................................................7-24 Shotguns..................................................7-25 Rifles.........................................................7-28

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_7, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Sharp Force Injuries........................................7-28 Incised Wound........................................7-28 Stab Wound.............................................7-28 Chop Wound...........................................7-29 Defense Wound.......................................7-29 Asphyxia............................................................7-29 Compression of Neck..............................7-29 Obstruction of Airway...........................7-32 Mechanical Asphyxia.............................7-34 Drowning.................................................7-35 Atmospheric Pressure Changes......................7-36 Decreased Atmospheric Pressure..........7-36 Increased Atmospheric Pressure...........7-36 Barotrauma.............................................7-37 Thermal Injuries Related to Temperature Changes........................................................7-37 Local Hypothermia.................................7-37 Systemic Hypothermia...........................7-37 Immersion Hypothermia........................7-37 Wind Hypothermia.................................7-37 Paradoxical Undressing.........................7-37 Hide and Die Syndrome.........................7-37 Local Hyperthermia (Burns).................7-38 Smoke Inhalation....................................7-38 Systemic Hyperthermia..........................7-38 Electrical Injuries.............................................7-39 General Concepts....................................7-39 Electrical Injury......................................7-39 Lightning.................................................7-40

VI. Toxicology..........................................7-40 Alcohols and Acetones.....................................7-40 Ethanol (Drinking Alcohol)...................7-40 Methanol (Wood Alcohol)......................7-41

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Isopropyl (Rubbing Alcohol).................7-41 Acetone....................................................7-41 Ethylene Glycol.......................................7-41 Cocaine and Cocaethylene...............................7-41 Cocaine....................................................7-41 Cocaethylene...........................................7-42 Opiates...............................................................7-42 Amphetamines..................................................7-43 Barbiturates......................................................7-43 Psychoactive Drugs..........................................7-43 Lysergic Acid Diethylamide...................7-43 Phencyclidine..........................................7-43 Marijuana................................................7-44 Gamma-Hydroxybutyrate (GHB).........7-44 Antidepressants................................................7-44 Tricyclic Antidepressants.......................7-44 Antipsychotics...................................................7-44 Phenothiazine..........................................7-44 Haloperidol (Haldol)..............................7-45 Analgesics..........................................................7-45 Acetaminophen.......................................7-45 Acetylsalicylic Acid (Aspirin)................7-45 Metals................................................................7-45 Arsenic.....................................................7-45 Lead.........................................................7-46 Mercury...................................................7-46 Cobalt.......................................................7-46 Thallium..................................................7-46 Other Chemicals...............................................7-46 Organophosphates..................................7-46 Strychnine...............................................7-46 Freons......................................................7-47

VII. Suggested Reading.............................7-47

Forensic Pathology

7-3

GENERAL CONCEPTS Cause of Death ♦♦ Injury, disease, or a combination of the two responsible for initiating the events leading to death; may be brief or prolonged. If prolonged with survival, sequelae may develop from the initiating or proximate cause, which leads to intermediate causes of death such as pneumonia, pulmonary embolism, or bronchopneumonia ♦♦ Examples of causes of death −− Coronary artery atherosclerosis −− Blunt force injury of head −− Gunshot wound of head −− Hanging −− Mixed drug intoxication

Manner of Death

♦♦ Separated into two categories −− Natural −− Unnatural (a) If unnatural, then further subdivided into accident, suicide, homicide, or undetermined (undetermined could be natural)

Mechanism of Death ♦♦ Physiologic derangement or biochemical disturbance that is incompatible with life and is initiated by the cause of death; does not appear on death certificate ♦♦ Examples of mechanism of death −− Ventricular fibrillation −− Respiratory arrest −− Exsanguination

♦♦ Circumstances in which the cause of death arose

IDENTIFICATION Positive Identification

Circumstantial Identification

♦♦ Visual identification −− Family and friends −− Personal identification (driver’s license, social security card) −− Tattoos, scars, congenital defects, fingerprints, dental examination (comparison of pre- and postmortem dental x-rays and charting), x-ray (pre- and postmortem x-ray comparison: frontal sinus, vertebral column, ribs, unique bony, or therapeutic identifying features), foreign objects (orthopedic hardware) −− DNA (blood, tissue, bone)

♦♦ For use on significantly altered decedents such as burned and decomposed bodies −− Secured residence or motor vehicle associated with suspected decedent −− Personal effects on body or at scene (wallet, clothing, credit cards, unique jewelry, etc.)

Anthropological Identification ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Age (range) Race (more complicated with interracial procreation) Sex (most consistent) Stature Hair examination (may help identify race as well as hair color)

TIME OF DEATH AND POSTMORTEM CHANGES General

Livor Mortis (Lividity)

♦♦ No time of death test exists ♦♦ Eyewitness is best determination of time of death ♦♦ Generally give estimates and ranges for time of death −− Sepsis and heat accelerate decomposition −− Cold delays decomposition

♦♦ Blue-purple discoloration in dependent areas of body (Fig. 7.1A, B) ♦♦ Minimal with blood loss and dark pigmentation ♦♦ Usually visible within 24 h following death, maximum usually 8–12 h postmortem −− After 8–12 h postmortem, lividity may become fixed and will no longer blanch

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−− Fluoroacetate: cherry red (excessive oxygen retention from inhibition of cytochrome oxidase) −− Hydrogen sulfide: green (sulfhemoglobin) ♦♦ Advanced livor mortis in which dependent capillaries and venules become overextended, rupture, and coalesce, forming pinpoint hemorrhages called Tardieu spots (Fig. 7.1C)

Rigor Mortis (Rigidity) ♦♦ Begins at death ♦♦ Due to cellular loss of adenosine triphosphate (ATP) and accumulation of lactic acid with lowering of pH ♦♦ Occurs in all cells, but is externally manifested most prominently in the musculature ♦♦ Usually visible within 2–4 h following death ♦♦ May be fully developed 6–12 h following death (Fig. 7.2) ♦♦ Accelerated in infants, febrile illnesses, sepsis, increased environmental temperatures, electrocution, seizures, and any excessive muscular activity prior to death ♦♦ Reduced or delayed in emaciated, elderly, and cold ♦♦ Disappears with decomposition ♦♦ Loss of ATP prevents detachment of cross-bridges between actin and myosin and increased free calcium ions ♦♦ Can affect involuntary muscles (pupil disparity postmortem) ♦♦ Cutis anserina: rigor mortis of arrector pili muscles (goose flesh) ♦♦ Cadaveric spasm: rigor mortis in agonal contraction (e.g., clenched fist, articles still held in hand)

Algor Mortis (Body Cooling) ♦♦ Postmortem cooling −− Conduction: heat transferred by direct contact to another object

Fig.  7.1. Pressure pallor of anterior livor over weight-bearing points (A). Patterned anterior livor (B). Tardieu spots and anterior livor (C). ♦♦ May form antemortem with prolonged hypotension ♦♦ Accelerated rate of fixation with increased temperature and decomposition ♦♦ Delayed with cool temperature ♦♦ Lividity may appear different from −− Refrigeration: pink to cherry red (retained oxygen cutaneous vessels) −− Carbon monoxide: cherry red (carboxyhemoglobin) −− Cyanide: pink to cherry red (excessive oxygen retention from inhibition of cytochrome oxidase)

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Fig.  7.2. Rigor fixed opposite gravity, indicating subsequent movement of deceased from original position.

Forensic Pathology

−− Radiation: heat transferred to adjacent air by infrared rays −− Convection: heat transferred through moving air currents adjacent to body −− Heat loss decreased by an insulator such as clothing and increased body fat −− Heat loss increased in cold water −− Body temperature will approach environmental temperature −− Body temperature prior to death may be increased by sepsis, hypothyroidism, exercise, heat stroke, seizures, drugs (cocaine, amphetamines, anticholinergics, phen­ cyclidine), and head injuries −− Body temperature may decrease prior to death due to shock, cold environment, and drugs (alcohol, sedatives, opiates, and phenothiazines) −− No exact formula to calculate the time of death from body temperature (a) Ideally, body temperature decreases 2–2.5°F/h for the first few hours (b) Decreases at an average of 1.5–2°F/h in first 12 h (c) In the following 12–18  h, decreases an average of 1°F/h

Decomposition ♦♦ Involves two processes −− Autolysis: breakdown of cells and organs by intracellular enzymes; accelerated by heat and slowed by cold −− Putrefaction: process due to bacteria and fermentation; accelerated in patients with sepsis and increased temperature ♦♦ Decomposition is accelerated with higher environmental temperatures, obesity, heavy clothing, and sepsis ♦♦ Delayed by cold environment ♦♦ Generalized sequence of decomposition −− Decrease of rigor mortis and fixation of livor mortis −− Green discoloration in the right lower quadrant of the abdomen −− Green discoloration of the head, neck, and shoulders −− Swelling of face (bacterial gas formation) −− “Marbling” (hemolysis of blood with hemoglobin and hydrogen sulfide reaction, creating green-black discoloration along blood vessels) −− Generalized bloating and skin slippage (body discoloration: green to black) ♦♦ Additional terminology −− Mummification: dehydration of body, most prominently seen in dry, hot climates in which skin develops a dry, leathery appearance −− Miliaria: white-gray pinpoint discoloration seen below capsule of liver, kidney, and spleen, and below endocardium due to precipitation of calcium and other salts

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−− Adipocere: gray-white, waxy material seen in bodies immersed in water or in damp warm environments in which neutral fats are converted to oleic, palmitic, and stearic acids −− Tache noir: brown to black band of discoloration of the bulbar conjunctivae and sclerae from drying, in which eyes are open −− Embalming: delays decomposition −− Intrauterine maceration is a result of autolysis, not putrefaction

Gastric Emptying ♦♦ In general, there is variation from day to day in gastric emptying, even in healthy subjects ♦♦ Larger meals associated with longer emptying time than smaller meals ♦♦ Liquids empty faster than solids ♦♦ Mean emptying half-time for liquids is ~1½ h ♦♦ Mean emptying half-time for solids is ~4½ h ♦♦ Gastric emptying is delayed in diabetes mellitus, anorexia nervosa, illness, emotional stress, exercise, severe injury, and drugs (alcohols, narcotics, phenothiazines, atropine, and beta-adrenergic drugs) ♦♦ Gastric emptying times are increased in certain medications (e.g., Valium) and certain types of exercise

Forensic Entomology ♦♦ Different insects are attracted at different stages of decomposition and may aid in the determination of how long a body has been dead ♦♦ Temperature and humidity are major factors controlling the deposition of eggs and the rate of development of necrophagous insects ♦♦ Flies are the most common insects −− Eggs are deposited soon after death in the daytime and take 24–48 h to hatch into maggots −− Maggots grow larger to pupa stage (6–10  days); adult flies emerge in 12–18 days ♦♦ As body decomposes, insects settle on body ♦♦ The following factors determine how soon and how many insects appear −− Rate of decomposition −− Burial −− Immersion in water −− Mummification −− Geography ♦♦ Must differentiate injury postmortem artifacts created most commonly by −− Roaches −− Ants −− Mice and rats

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♦♦ Scene markers, unscientific, but helpful −− Date of uncollected mail −− Newspapers in front of house −− Television guide open to specific date −− Clothing attire −− Sales receipts −− Interviews with neighbors ♦♦ Vitreous humor −− Vitreous potassium not reliable for estimation of time of death −− Intracellular potassium released after death, but not a reliable mathematical rate −− Anything that accelerates decomposition increases the release of potassium

Postmortem Chemistry ♦♦ Vitreous humor −− Hypertonic dehydration pattern (a) Increased sodium (>155 mEq/L) (b) Increased chloride (>135 mEq/L) (c) Increased urea nitrogen (VUN) (40–100 mg/dL) −− Uremia pattern (a) Normal to minimal increase in sodium and chloride (b) VUN >150 mg/dL −− Low salt pattern (alcoholic, pyloric obstruction, diuretic treatment) (a) Sodium <130 mEq/L (b) Chloride <105 mEq/L (c) Potassium <15  mEq/L (low relative to decomposition pattern)

−− Decomposition pattern (a) Sodium <130 mEq/L (b) Chloride <105 mEq/L (c) Potassium >20 mEq/L −− Diabetic pattern (a) Glucose >200 (b) In ketoacidosis, may get acetone (c) Cannot diagnose hypoglycemia because glucose decreases postmortem ♦♦ Blood, postmortem stable −− Creatinine stable −− Total cholinesterase stable (can rule out organophosphate poisoning) −− Cortisol stable −− TSH stable −− Calcium stable ♦♦ Blood, postmortem increase −− Alkaline phosphatase, increase −− Creatine phosphokinase (CPK), increase −− Amylase, increase −− Catecholamines, increase −− Insulin, increase −− Magnesium, increase −− Potassium, increase ♦♦ Blood, postmortem decrease −− T4, decrease −− Glucose, decrease −− Sodium, decrease −− Chloride, decrease

SUDDEN DEATH FROM NATURAL DISEASE Classification Classification in which an autopsy discloses the cause of death from disease with regard to certainty ♦♦ Class 1 −− Autopsy discloses cause of death with 100% certainty −− Accounts for ~5% of natural deaths in medicolegal population −− Examples (a) Myocardial infarct with rupture (b) Dissecting aortic aneurysm with rupture (c) Intracerebral hemorrhage ♦♦ Class 2 −− Does not have structural changes inconsistent with life, but advanced disease is present, sufficient for death

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−− Accounts for 90% of natural deaths in medicolegal population −− Examples (a) Advanced heart disease (b) Chronic lung disease (c) Metastatic malignancy (d) Complications of chronic alcoholism ♦♦ Class 3 −− A disease with lethal potential present, but not sufficiently advanced that under ordinary circumstances would be a competent cause of death (a) Requires a compelling history and exclusion of other causes to allow for marginal pathologic findings to be determined to be responsible for the fatality −− Infrequent in medicolegal population

Forensic Pathology

−− Example: witnessed collapse with moderate coronary artery disease present at autopsy and negative toxicology, with no other significant pathologic findings (a) Despite marginal findings at autopsy, one must conclude that death was due to heart disease (b) Conduction disorders should be considered ♦♦ Class 4 −− Disease in which lethal structural findings are not readily demonstrable at autopsy −− Autopsy fails to disclose alternative explanation −− Example: epilepsy ♦♦ Class 5 −− Cause of death is undetermined after autopsy and toxicologic studies −− There is no evidence that death is due to unnatural causes

Cardiovascular Causes of Death Atherosclerotic Heart Disease Clinical ♦♦ Most common cause of unexpected natural death in the western world

Autopsy ♦♦ Marked narrowing of coronary arteries, typically >75% of lumen, in which a thrombus may or may not be present

Microscopic ♦♦ Recent or remote myocardial infarct may be present −− May see perivascular and interstitial fibrosis only −− In some cases, no significant microscopic findings are present −− Contraction band necrosis may be present in cases of ischemia, but may also be an artifact of resuscitation

Mechanism ♦♦ Pump failure ♦♦ Sudden arrhythmia

Hypertensive Cardiovascular Disease Clinical ♦♦ May or may not have a history of hypertension ♦♦ No other symptoms, other than sudden cardiac arrest, may exist

Autopsy ♦♦ Concentric left ventricular hypertrophy ♦♦ Granular kidneys

Microscopic ♦♦ Myocardial fiber hypertrophy ♦♦ Sclerosis of mural cardiac arteries ♦♦ Arteriolar nephrosclerosis

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Mechanism ♦♦ Sudden arrhythmia with an increased oxygen demand of hypertrophied muscle mass −− Hypertensive cardiovascular disease may coexist with atherosclerotic heart disease and lead to the acceleration of coronary atherogenesis

Aortic Stenosis Clinical ♦♦ Bicuspid aortic valve (males, 50–70 age group) ♦♦ Rheumatic valvular disease (women, 35–55; mitral involvement also) ♦♦ Degenerative (Monckeberg calcification) changes (> age 60, involving all three cusps)

Autopsy ♦♦ Calcification and obstruction of aortic valve ♦♦ Left ventricular hypertrophy

Microscopic ♦♦ Calcification of valve ♦♦ Myocardial fiber hypertrophy

Mechanism ♦♦ No findings distinctive for aortic stenosis mechanism ♦♦ Sudden arrhythmia due to instability from obstructive blood flow to coronary arteries

Long QT Syndrome Clinical ♦♦ May be etiology of some cases of sudden infant death syndrome (SIDS) ♦♦ Affects approximately 1 in 5,000 individuals ♦♦ QT interval prolongation greater than 460 ms ♦♦ 60% of affected individuals present with syncope, seizures, or sudden death ♦♦ 40% of affected individuals are asymptomatic throughout life ♦♦ Six variants LQT1–LQT6 −− LQT1 (KVLQT1, potassium channel gene, chromosome 11) – 25% of cases −− LQT2 (HERG, potassium channel gene, chromosome 7) – 20–25% of cases −− LQT3 (SCN5A, sodium channel gene, chromosome 3) – 5% of cases −− May suffer drowning or near drowning (LQTS1 most commonly)

Autopsy ♦♦ Rule out cardiomyopathy ♦♦ Must do molecular workup to rule out channelopathy

Mechanism ♦♦ Cardiac ion channelopathy leading to lethal dysrhythmia

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Hypertrophic Cardiomyopathy Clinical

Microscopic

♦♦ Most common cause of sudden death in athletes <35 years of age ♦♦ Male: female = 2:1 ♦♦ Autosomal dominant ♦♦ Affects 1 in every 500 people

Myocarditis Clinical

Autopsy ♦♦ May be symmetrical or asymmetrical thickening of interventricular septum at distal outflow tract ♦♦ Wide range of phenotypes

Microscopic ♦♦ Myofiber disarray most prominent in septum ♦♦ Plexiform interstitial fibrosis mechanism of action ♦♦ Thickened intramural coronary arteries

Genetics ♦♦ Autosomal dominant with variable penetrance ♦♦ Mutations in genes that encode sarcomere proteins ♦♦ Gene defect for cardiac myosin-binding protein C may be late onset (middle age and favorable prognosis)

Dilated Cardiomyopathy Clinical ♦♦ May be associated with progressive congestive heart failure with early death ♦♦ May be associated with sudden death ♦♦ May develop secondarily in viral myocarditis, chronic alcoholism, peri- or postpartum, or secondary to Duchenne’s or myotonic dystrophy

Autopsy ♦♦ Enlarged dilated heart ♦♦ Flabby heart with all four chambers dilated ♦♦ Frequent endocardial thickening; may have mural thrombi

Microscopic ♦♦ Interstitial fibrosis ♦♦ Hypertrophied and attenuated myocytes

Restrictive Cardiomyopathy Clinical ♦♦ Associated with systemic diseases such as amyloidosis, hemochromatosis, and glycogen storage diseases ♦♦ Clinically less common than hypertrophic and dilated cardiomyopathy; affects both sexes and all ages ♦♦ Decreased diastolic relaxation and elevated ventricular filling pressure

Autopsy ♦♦ Myocardium is stiff due to either infiltration from benign or malignant process, scarring, or intracellular accumulations

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♦♦ Dependent on etiology of cardiomyopathy

♦♦ May be associated with sudden death or progressive heart failure ♦♦ May be associated with virus, bacteria, fungus, protozoa, or autoimmune reaction ♦♦ Most common in forensic field is viral related ♦♦ May have history of recent viral-like symptoms

Autopsy ♦♦ Heart may be slightly dilated and flabby ♦♦ May have focal areas of mottling or may be grossly normal

Microscopic ♦♦ Diffuse or patchy cellular infiltration, mainly lymphocytes ♦♦ In some cases, accompanied by marked myocardial fiber necrosis

Mechanism ♦♦ Ectopic focal cardiac irritability leading to ventricular dysrhythmias

Mitral Valve Prolapse Clinical ♦♦ ♦♦ ♦♦ ♦♦

Occurs in ~5–10% of general population Primary form may be inherited as autosomal dominant Mid systolic click Most common presenting symptom = palpitations (PVCs) −− PVCs associated with Marfan syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum, osteogenesis imperfecta, straight thoracic spine syndrome, and pectus excavatum ♦♦ Predisposed to infectious endocarditis and mitral regurgitation

Autopsy ♦♦ Redundancy of leaflets with prolapse into left atrium (Fig. 7.3) eventually get secondary fibrosis of leaflets ♦♦ Elongation of chordae tendineae ♦♦ Ventricular friction lesion

Microscopic ♦♦ Myxomatous degeneration with acid mucopolysaccharides and thickening and mucinous infiltration of zona fibrosa of mitral valve

Mechanism ♦♦ Frequent PVCs from impact of anterior mitral leaflet on atrial septum ♦♦ Rare progression to lethal dysrhythmia (Fig. 7.4)

Forensic Pathology

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Autopsy ♦♦ Initiating event is a tear in the aortic intima in which blood dissects into the media ♦♦ Dissection propagates distally and proximally ♦♦ Most common cause of death is rupture of aortic dissection either in the pericardial space or into the left chest cavity

Microscopic ♦♦ Variation from medial necrosis to no specific pathologic changes

Mechanism ♦♦ Exsanguination

Pulmonary Thromboembolism Clinical

Fig. 7.3. Redundant mitral valve and left ventricular hypertrophy.

♦♦ Predisposing factors −− Cardiovascular disease (CVD) −− Malignant tumors −− Pregnancy −− Morbid obesity −− Immobility −− Postoperative bed rest −− Trauma ♦♦ Hereditary predispositions −− Congenital deficiencies of antithrombin III, protein C, protein S, and plasminogen −− Activated protein C resistance (Factor V Leiden) −− Hyperhomocysteinemia −− Elevated levels of antiphospholipid antibody ♦♦ Prevalence of venous thromboembolism in antithrombin III, protein C, or protein S deficiency is >50% ♦♦ Clinical symptoms −− Sudden death −− Chest pain −− Shortness of breath

Autopsy

Fig. 7.4. Mitral valve stenosis.

Aortic Dissection Clinical ♦♦ Hypertension (coexists in 70–90% of patients) and weakness of aortic wall (e.g., Marfan syndrome) ♦♦ Male predominant (3:1) ♦♦ Increased incidence in pregnancy ♦♦ Dissection usually heralded by onset of severe chest pain or back pain

♦♦ Coiled thrombi, not conforming to the shape of the pulmonary arterial tree ♦♦ >95% arise in the large deep veins of lower legs, including popliteal, femoral, and iliac vein ♦♦ Occasionally, thrombi are also recovered in pelvic veins, especially in pregnancy and periprostatic veins ♦♦ Rarely, thromboembolus may cross through interatrial or interventricular defect to systemic circulation (paradoxical embolus)

Microscopic ♦♦ Platelet-fibrin-red blood cell mass with lines of Zahn ♦♦ Thrombi within lower extremity ♦♦ Veins may demonstrate organization

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♦♦ May see organizational changes in pulmonary arterial wall if survival for several days postembolism

Mechanism ♦♦ Occlusion of pulmonary trunk and right ventricle ♦♦ Minimal flow to left ventricle, leading to sudden death or cardiovascular collapse ♦♦ Occlusion of smaller arteries may lead to sudden death by vasospasm, sudden increase in blood pressure and right heart failure, or bradycardia due to vasovagal reflex

Cerebrovascular Disease Intracerebral Hemorrhage (Apoplexy) Clinical ♦♦ Associated with hypertension ♦♦ Most common in middle-aged and elderly ♦♦ May present with headaches and seizures

Autopsy ♦♦ Common sites of hemorrhage −− External capsule with hemorrhage into basal ganglia −− Cerebellum −− Thalamus −− Pons

Microscopic ♦♦ Sharp demarcation of hematoma from surrounding brain with death of neurons and glia in adjacent tissue ♦♦ If survival >24 h, cerebral edema present with early organizational changes consisting of monocytes and macrophages invading into edges of hematoma ♦♦ If preexisting hemorrhage has occurred, hemosiderin may be present, and if small hematoma occurs with survival after several years, residual cysts with brown-orange discolored walls may be present with hemosiderin and gliosis (so-called apoplectic cyst)

Ruptured Berry Aneurysm Clinical ♦♦ Accounts for 4–5% of sudden, rapid natural death; occurs at bifurcations of intracranial arteries ♦♦ Exists in 1–2% of population ♦♦ Median age of rupture = 50 years ♦♦ Increased incidence of saccular aneurysms in certain disorders −− Fibromuscular dysplasia −− Polycystic kidney disease −− Moyamoya disease −− Coarctation of the aorta

Autopsy ♦♦ Large saccular aneurysm at branch points may be easily identified (Fig. 7.5A–C); however, in other cases, aneurysms

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Fig.  7.5. Berry aneurysm (A). Circle of Willis with ruptured berry aneurysm (B). Subarachnoid hemorrhage due to intracranial carotid artery aneurysm (C). may be small and destroyed when they rupture and may be difficult to detect at autopsy ♦♦ Aneurysms may rupture into and dissect into brain parenchyma

Preferential Locations ♦♦ 40% related to intracranial portion of internal carotid artery, usually at juncture of internal carotid and posterior communicating artery ♦♦ 30% anterior communicating artery

Forensic Pathology

♦♦ 20% middle cerebral artery ♦♦ 5–10% associated with posterior cerebral arteries and basilar and vertebral artery

Microscopic ♦♦ Typically thin-walled pouch in which endothelium may be incomplete with adjacent blood clot ♦♦ Muscle coat and elastic lamina typically stop abruptly at neck of aneurysm, and wall of aneurysm is fibrotic

Mechanism ♦♦ Cerebral ischemia with cerebral infarction

Nonvascular Causes of Death Chronic Alcoholism Clinical ♦♦ May see in binge drinkers where alcohol can be a cardiac irritant and lead to sudden arrhythmia ♦♦ Long-term alcohol abuse with well-known compli­ cations ♦♦ Alcohol withdrawal with delirium tremens and Wernicke disease

Autopsy ♦♦ May include a variety of findings −− Alcoholic cardiomyopathy −− Acute pancreatitis −− Cirrhosis of the liver (Fig. 7.6) −− Wernicke encephalopathy −− Fatty metamorphosis of the liver −− Central pontine myelinolysis (seen with rapid correction of hyponatremia)

Microscopic ♦♦ Specific to particular disease processes

Mechanism ♦♦ Alcohol may function as a cardiac irritant or may cause electrolyte abnormalities (e.g., magnesium deficiency)

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Epilepsy Clinical ♦♦ Must have antemortem diagnosis of epilepsy ♦♦ Agonal convulsive episode is not adequate for diagnosis of epilepsy

Autopsy ♦♦ ♦♦ ♦♦ ♦♦

May be normal anatomic brain May have mesiotemporal sclerosis within Sommer sector May find contusion of tongue May have nonspecific pulmonary edema

Microscopic ♦♦ When present, cell loss may be seen in CA1 and CA4 sectors of hippocampus

Mechanism ♦♦ May have prolonged tonic-clonic seizures with cardiac and respiratory exhaustion ♦♦ May have nonvisible seizure with paroxysmal autonomic dysfunction

Bronchial Asthma Clinical ♦♦ History of asthmatic bronchitis; death typically occurs during acute asthmatic paroxysm ♦♦ Death may not correlate with the severity of the autopsy findings ♦♦ Death more common at night or in early morning ♦♦ Higher incidence of death in African Americans than Caucasians (rule out concomitant sickle cell disease trait)

Autopsy ♦♦ Mucoid plugging of bronchi ♦♦ Edema of mucosa ♦♦ Voluminous hyperexpanded lungs with indentation by ribs

Microscopic ♦♦ Prominent mucus in bronchus ♦♦ Goblet cells and eosinophils in mucus (Charcot–Leyden crystals) ♦♦ Hyaline thickening of basement membrane in bronchial mucosa ♦♦ Bronchiolar and bronchial smooth muscle hyperplasia ♦♦ Goblet cell hyperplasia ♦♦ Peribronchial neutrophilic lymphocytic and eosinophilic inflammation

Mechanism

Fig. 7.6. Cirrhosis and hepatic steatosis.

♦♦ Decreased oxygenation ♦♦ Elevated carbon dioxide retention ♦♦ Increased pulmonary vascular acidosis ♦♦ Eventual exhaustion and death

resistance,

metabolic

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Waterhouse-Friederichsen Syndrome Clinical ♦♦ Toxic febrile illness of acute onset with rapid deterioration classically seen associated with Neisseria meningitidis

Autopsy ♦♦ Bilateral adrenal hemorrhages ♦♦ Petechiae to purpura on skin surface ♦♦ Cerebral hemispheres may or may not be visibly suppurative (Fig. 7.7A–D)

Microscopic ♦♦ Adrenal glands with varying degrees of hemorrhage ♦♦ Affected skin and adrenal glands may show acute neutrophilic infiltrate

Essentials of Anatomic Pathology, 3rd Ed.

Mechanism ♦♦ Bacterial toxemia and adrenal insufficiency catastrophic rapid onset of shock

Colloid Cyst of Third Ventricle Clinical ♦♦ Sudden episodes of headache associated with position of head ♦♦ Appearance in adult life

Autopsy ♦♦ Sudden acute hydrocephalus due to obstruction of foramen of Monroe ♦♦ 1–4 cm in diameter ♦♦ Cerebral edema

Fig. 7.7. Purulent bacterial meningitis (A). Bacterial meningitis (B). Bacterial meningitis, fixed brain, superior view (C). Bacterial meningitis, fixed brain, inferior view (D).

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Forensic Pathology

♦♦ Mass originates from anterior part of third ventricle ♦♦ Cross-section of cyst reveals gelatinous hyaline material

Microscopic ♦♦ Epithelial layer of collagenous capsule ♦♦ Mucus goblet cells present ♦♦ + stain for mucin with mucicarmine and PAS

Mechanism ♦♦ Acute hydrocephalus with herniation and compression of brainstem

Diabetic Ketoacidosis Clinical ♦♦ History of diabetes mellitus in most cases; however, onset may precede formal diagnosis of disease

Autopsy ♦♦ May be unremarkable ♦♦ Large amounts of glucose and acetone, often detected in vitreous humor ♦♦ Blood may contain acetone

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Hyperosmolar nephrosis of proximal tubules Kimmelstiel–Wilson glomerulopathy Pancreatic islet cell changes (rare) Armanni–Ebstein lesion

Mechanism ♦♦ Metabolic acidosis ♦♦ Dehydration ♦♦ Cerebral edema (rarely)

Anaphylaxis Clinical ♦♦ Sudden onset of shortness of breath and edema of face, hives, and vascular collapse ♦♦ May develop from insect bites, medication, or food

Autopsy ♦♦ Edema of epiglottis and airway obstruction

Microscopic ♦♦ Edema and eosinophilic infiltration in airway occasionally −− Hypereosinophilia within vasculature of liver and heart

Mechanism ♦♦ Cardiovascular collapse with sudden onset of shock from systemic vasodilatation that includes pulmonary edema and obstructive angioedema of upper airway

Toxicology ♦♦ Elevated total tryptase level with beta tryptase level >1 ng/mL, indicating mast cell degranulation

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Manner of Death ♦♦ Manner of death determined to be natural or accidental dependent on local convention

Sudden Infant Death Syndrome ♦♦ Sudden death of infant <1 year of age, which remains unexplained after performance of a complete postmortem investigation ♦♦ Investigation includes −− Review of the case history −− Examination of the scene of death −− Complete autopsy with toxicologic studies and metabolic screening

Clinical ♦♦ ♦♦ ♦♦ ♦♦

SIDS represents 10–12% of deaths in the first year of life Majority of deaths occur between 2 and 4 months of age Incidence is 1–2 per 1,000 infants Recurrence rate in a family is ~1–2%

Risk Factors Associated with SIDS ♦♦ Maternal risk factors −− Poor prenatal care −− Multiparity at a young age −− Unmarried mother −− Low education level −− Tobacco use −− Drug use −− Lack of breast-feeding −− Maternal anemia −− Low weight gain in pregnancy ♦♦ Neonatal risk factors −− Male gender −− Prematurity −− Small for gestational age infant −− Low birth weight −− Low Apgar scores (<7) −− Respiratory distress −− Tachycardia −− Tachypnea −− Cyanosis −− Fever −− Hypothermia −− Irritability −− Poor feeding −− Prone sleeping position −− Infant of twin birth −− African American −− Native American

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Pathogenesis ♦♦ Theories proposed include −− Congenital apneic spells or abnormal respiratory control −− Brainstem dysfunction −− Abnormal sleep and arousal patterns −− Upper airway or small airway disease −− Cardiovascular abnormalities −− Undetected metabolic defects −− Abnormal temperature regulation −− Infections that are undetected, especially botulism −− “Developmental vulnerability” ♦♦ Preventative measure suggested is putting an infant to sleep on its side or back instead of on its stomach ♦♦ SIDS very likely represents a group of disorders that have not yet been delineated as causes of sudden death in infants ♦♦ Metabolic disorders and inapparent viral syndromes may comprise a significant part of this group of deaths ♦♦ A very small number of infant deaths diagnosed as due to SIDS are undoubtedly concealed homicides, particularly smotherings

Autopsy ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Petechiae of the thymus, pleura, or epicardium Gliosis of the brainstem and central nuclei Pulmonary edema or intraalveolar hemorrhage Pulmonary hemosiderosis has been described Histologic evidence of recent viral illness Extramedullary hematopoesis Increased amounts of brown fat in periadrenal adipose tissues

Manner ♦♦ SIDS is a death due to natural causes ♦♦ A second death in the same family can be ruled “manner undetermined” ♦♦ A third death in the same family is extremely suspect, and one or more of the infants’ deaths are probably homicides

Inborn Errors of Metabolism Resulting in Sudden Death ♦♦ Disorders of b-oxidation of fatty acids ♦♦ Glycogen storage disorders ♦♦ Other disorders

Disorders of b-Oxidation of Fatty Acids ♦♦ Fatty acids are an important source of energy for neonates ♦♦ Enzymes necessary to carry out b-oxidation can be developmentally immature and inadequate in the perinatal period ♦♦ Infants usually present with sudden death or hypoketotic hypoglycemia

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♦♦ Collapse of metabolic pathways due to concurrent illness or physiologic stress can precipitate symptoms after depletion of hepatic glycogen stores ♦♦ Myopathy, cardiomyopathy, and liver dysfunction result from the accumulation of fatty acids in the mitochondria and microsomes ♦♦ Fatty changes of the liver are indistinguishable from Reye syndrome

Specific Disorders ♦♦ Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) −− MCAD is the first step in fatty acid oxidation (a) MCAD deficiency may represent 1–10% of SIDS deaths (b) Autosomal recessive disorder (c) Carrier rate may be as high as 1 in 50 people, resulting in an incidence of 1 in 2,500 to 1 in 7,000 individuals (d) Two known DNA point mutations at positions 985 (A to G) and 583 (S to A) −− Diagnosis (a) Elevated levels of cis-4-decanoic acid and dodecanoic acid in postmortem fluids (b) Organic acid analysis in urine or vitreous fluid (c) Fatty acid oxidation assay in fibroblasts, liver homogenate, or cells obtained at amniocentesis ♦♦ Long-chain acyl-CoA dehydrogenase deficiency (LCAD) −− Inability to metabolize fatty acids longer than 12–14 carbons ♦♦ Short-chain acyl-CoA dehydrogenase deficiency (SCAD) −− Inability to metabolize fatty acids smaller than six carbons ♦♦ Multiple acyl-CoA dehydrogenase deficiency (MADD) −− Inability to metabolize fatty acids regardless of length ♦♦ Disorders of carnitine metabolism −− Carnitine is a required cofactor of fatty acid oxidation −− Low maternal carnitine can result in deficiency in the neonate −− Sudden death has been reported in infants with carnitine deficiency in the plasma membrane −− Carnitine palmitoyl transferase type 1 deficiency −− Carnitine palmitoyl transferase type 2 deficiency −− Carnitine palmitoyl translocase deficiency ♦♦ Diagnosis −− Carnitine levels in blood −− Bile acylcarnitine levels −− Palmitoyl-carnitine oxidation assay using cultured fibroblasts −− Therapy for carnitine-related disorders ♦♦ Therapy for carnitine-related disorders −− Carnitine supplementation −− Diet modification

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♦♦ Glycogen storage disorders −− Myophosphorylase deficiency (McArdle disease) −− Glycogen storage disease 1a (Glucose-6-phosphatase deficiency) −− Glycogen storage disease 1b (Transport protein T1 deficiency) −− Glycogen storage disease 1c (Transport protein T2 deficiency)

♦♦ Other disorders −− Lactic acidemias −− Aminoacidopathies −− Disorders of carbohydrate metabolism −− Hyperglycinemia −− Urea cycle defects

PHYSICAL INJURIES Mechanical Trauma

Local Effects of Mechanical Injury

♦♦ When force applied to any part of the body results in harmful disturbance of function or structure

♦♦ Hemorrhage −− Once bleeding begins, it will continue until thrombosis, vasoconstriction, or equalization of intravascular and extravascular pressure occurs −− Rate of hemorrhage is important. A slower rate of blood loss may allow the body to adapt and tolerate greater accumulations prior to symptom development. A rapid rate of accumulation in similar locations may be lethal (e.g., rapid accumulation of 150  mL of blood in the pericardium or 50 mL of blood in the intracranial cavity may be lethal) ♦♦ Aseptic inflammation: noninfected inflammatory response to injury ♦♦ Local infection occurs when protective layer of tissue is injured; infectious agent may be carried into wound during traumatic event

Principles and Effects Amount of Force ♦♦ Wound-producing capacity for kinetic energy is determined by weight and velocity −− Formula: KE = MV2/2 g (a) M = weight (mass) (b) V = velocity (c) g = acceleration of gravity ♦♦ Kinetic energy of a moving object increases arithmetically with weight, but geometrically with velocity (example: doubling the weight of a bullet doubles the kinetic energy, but doubling the velocity quadruples the kinetic energy) ♦♦ Further energy may be present if a rotational component exists, again best demonstrated in bullets −− Formula: RE = Mr2/2 g (a) M = weight (mass) (b) r = cross-section radius (c) g = acceleration of gravity −− Or RE = IW2/2 g (a) I = rotational inertia (b) W = angular velocity in radians/s or W = 2 × number of rotations/s (c) g = acceleration of gravity

Rate of Energy Transfer ♦♦ The shorter the duration of impact, the greater energy transfer and the greater the potential for injury

Surface Area ♦♦ The larger the area through which force is transmitted, the less the intensity and potential for injury

Target Area ♦♦ Some tissues are more fragile than other tissues and a fixed amount of force applied to one tissue may cause no injury versus the same force applied to another tissue

Systemic Effects of Mechanical Injury ♦♦ Primary shock −− Reflex vasodilatation −− Decreased blood pressure and loss of consciousness (e.g., dilatation of rectum, puncture of pleura, pressure to carotid sinuses) ♦♦ Secondary shock −− Excessive reduction of blood volume (hypovolemic shock) −− Hemorrhage necessary to produce circulatory collapse governed by rate of loss −− One-third blood volume lost rapidly leads to hemorrhagic shock −− Half of blood volume lost rapidly leads to death ♦♦ Shock injuries to organs −− Shock kidney: ischemic damage (shunting of blood from cortex to medulla) −− Shock lung: hyaline membranes, alveolar and interstitial edema, and interstitial inflammation ♦♦ Embolism −− Thromboembolism −− Thrombus may occur as a result of direct venous injury or stasis of blood flow from edema or inactivity

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−− Thrombus may detach, resulting in fatal pulmonary thromboembolism ♦♦ Fat embolism −− Occurs with fracture of long bones and injury to adipose tissue ♦♦ Fat embolism syndrome −− Progressive pulmonary insufficiency −− Petechial rash −− Mental deterioration 1–3 days following injury −− May have fever, tachycardia, and renal failure −− Occurs in 90–100% of cases with major fractures, especially in motor vehicle collisions −− Usually lethal when brain involved and with massive fat embolism to lung, AV anastomoses in lung, tearing of lung parenchyma, or interatrial or interventricular defect ♦♦ Air embolism −− Air enters into dilated veins of gravid uterus during orogenital intercourse or instrumentation, through incision or laceration of veins (especially neck region), disconnection of catheters, and intraoperative procedures of posterior cranial fossa −− Air enters right side of heart, forming air-lock; x-ray of chest may reveal right heart filled with air −− Air may enter left side of heart with injury to lung in which air may then embolize to cerebral or coronary artery

Blunt Force Injuries Abrasion ♦♦ A superficial scrape or scratch injuring the upper layers of skin −− Types of abrasions (a) Linear abrasion: a scratch (b) Friction abrasion: a brush-burn, such as from dragging on a road surface (Fig. 7.8A, B) (c) Graze: superficial skin injury from a projectile such as a bullet (d) Impact abrasion: can result in a patterned injury that provides information about the object that caused the injury −− Abrasions can occur antemortem or postmortem (a) Postmortem abrasions *  Lack the vital reactions such as hemorrhage, hyperemia, and edema that occur antemortem *  Postmortem loss of epithelium will result in a dried, parchment-like, yellow-tan lesion (Fig. 7.9) *  Postmortem abrasions in areas involved by dependent lividity must be carefully examined

Fig. 7.8. Brush-burn abrasion (A). Brush-burn and linear abrasions (B).

Contusion ♦♦ An area of hemorrhage into the tissues causes tearing of blood vessels by blunt trauma −− May be larger or smaller than the impacting object −− May be difficult to see in dark-skinned persons

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Fig. 7.9. Abrasions with skin margin rolled to distal end.

Forensic Pathology

Fig. 7.10. Abrasions and contusions.

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−− A deep bruise may not appear on the body surface if death follows a short time after the injury −− A contusion may appear at a location other than a point of impact −− Contusions due to accidents usually involve protuberant or prominent parts of the body, especially areas overlying bone (Fig. 7.10) −− Patterned contusions can provide information about the object that caused the injury (Fig. 7.11A, B) ♦♦ Dating of contusions −− Contusions resolve from the center outward and from the periphery inward −− Contusions are often of different ages due to separate episodes of trauma

Fig. 7.11. Patterned contusion with ABFO ruler for future pattern comparison (A). Patterned contusion (B).

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−− The coloration of contusions can provide a crude approximation of their age, but contusions of the same age can vary in their degree of resolution in a single individual (a) Colors and their approximate ages are as follows * Red: immediate * Blue-purple: 1–4 h * Green: 4–7 days * Yellow: 7–10 days * Return to normal coloration: 14–21 days

Essentials of Anatomic Pathology, 3rd Ed.

−− Microscopy can be used to identify hemosiderin in an injury that is 24-h old −− Iron stains are helpful in identifying hemosiderin in an injury −− Hematoidin requires several days to be detected

Laceration ♦♦ A tear produced by a blunt instrument −− The edges of the tear have (a) Abraded margins (b) Ragged edges (c) Tissue bridging of the defect by vessels, nerves, and connective tissue (Fig. 7.12A, B) −− The tear is produced by stretching the tissues beyond their elastic tensile strength or crushing and forcible separation of the tissues during compression between two hard surfaces, such as a weapon and the bone underlying the skin

Fractures ♦♦ Broken bones due to blunt force injury: (Fig. 7.13) −− Fractures are produced by a combination of compressive, tensile, and shearing forces acting on the bone −− Special types of fractures (a) Spiral fractures are due to a twisting motion applied to a long bone of an extremity, usually the legs (b) Bucket handle fractures result from pulling on an extremity and fracturing the bone through a growth plate or pulling off the bone attached to a tendon or ligament that supports a joint (c) Spiral fractures and bucket handle fractures in children are highly suggestive of child abuse

Road Traffic Injuries ♦♦ Motor vehicle accidents can cause massive blunt force injuries −− The most common cause of death is head injury

Fig.  7.12. Laceration with prominent tissue bridging (A). Laceration with marginal abrasion (B). Laceration of liver (C).

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Fig. 7.13. Open tibial fracture with laceration and grease-stained abrasions.

Forensic Pathology

♦♦ The tempered side window glass of an automobile produces a special type of injury known as a “dicing” abrasion −− The tempered glass shatters into small cubes as it breaks and can cause a patterned injury on the side of the face that is nearest the tempered window (Fig. 7.14) −− The safety glass of the front windshield of an automobile is laminated between two layers of plastic (a) Windshields do not cause dicing abrasions

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Head Injuries ♦♦ Blunt force injuries of the head result in several interrelated traumatic lesions

External Scalp Injuries ♦♦ ♦♦ ♦♦ ♦♦

Lacerations (Fig. 7.15A, B) Contusions Abrasions Thermal injuries

Subscalpular Hemorrhage ♦♦ ♦♦ ♦♦ ♦♦

Occurs directly beneath the area of impact (Fig. 7.16) May be larger or smaller than the impacting object Can result in hematoma formation Can occur in the setting of consumptive coagulopathy

Skull Fractures ♦♦ Fracture seen in 80% of fatal head injuries ♦♦ Bone is more susceptible to tensile than compressive stress ♦♦ Skull fractures may occur without significant brain injury Fig. 7.14. Dicing abrasions of left face – MVA driver.

Fig.  7.15. Patterned laceration (A). Patterned depressed skull fracture underlying laceration in Fig. 7.15A (B).

Fig. 7.16. Subgaleal hemorrhage.

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Types of Skull Fractures

♦♦ Linear fractures: (Fig. 7.17) −− Local deformation by an intermediate-sized (>5  cm2) object −− Originate in the inner table of the skull after tensile failure ♦♦ Depressed fractures −− Result from impacts with small objects that have areas of impact <5 cm2 −− Cerebral injuries often occur due to intrusion of bone into the cranial cavity ♦♦ Comminuted fractures −− Multiple fragments result from high energy impacts −− Fractures radiate from the site of impact ♦♦ Diastatic fractures −− Separation of cranial sutures >2 mm −− Primarily seen in children ♦♦ Contrecoup fractures −− Fracture of bone away from the blow due to forces transmitted from the site of impact to the thin bones of the skull −− Can occur with large impact areas or impacts of a fixed skull ♦♦ Basilar fractures: (Fig. 7.18) −− Fractures of the floor of the skull involving the anterior, middle, or posterior cranial fossa −− Lateral impacts produce side-to-side fractures −− Frontal or occipital impacts cause sagittal fractures −− Result from significant impact injury ♦♦ Ring fractures −− Basilar fractures that circumscribe the foramen magnum (a) Can be caused by a vertex impact or a fall onto the buttocks, resulting in axial loading of the floor of the skull (b) Implies significant impact injury

Fig. 7.18. Basilar skull fracture, hinge type.

Intracranial Hemorrhages Epidural Hemorrhage

♦♦ Usually underlies the temporal bone ♦♦ 85% of patients with epidural hemorrhage have skull fracture ♦♦ Caused by laceration of vessels on the inner table of the skull, most commonly the middle meningeal artery and its branches ♦♦ Hemorrhage dissects the dura away from the inner table ♦♦ Hematoma compresses the underlying brain ♦♦ Fatal cases have >75 mL of blood clot ♦♦ Death occurs due to increased intracranial pressure and herniation

Subdural Hematoma

Fig.  7.17. Temporoparietal skull fracture, temporalis muscle and subgaleal hemorrhages.

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♦♦ Caused by disruption of bridging veins between the cortical surface and dural sinuses ♦♦ Usually caused by rotational injury ♦♦ Atrophy of the cerebrum increases the distance spanned by bridging veins and promotes the occurrence of subdural hematoma

Forensic Pathology

♦♦ Blood spreads freely in the subdural space and often covers the entire hemisphere ♦♦ Slow accumulation of blood clot is tolerated much better than rapid accumulation with sudden increases in intracranial contents −− The volumes of subdural hematoma that accumulate slowly can be quite large ♦♦ Clinically significant acute hemorrhage is >50 mL in an adult and >30 mL in children ♦♦ 100 mL of blood clot is often fatal in normal adults ♦♦ In contrast to flattening produced by epidural hemorrhage, subdural hemorrhage preserves the outline of the gyri because the blood is distributed over the hemisphere ♦♦ Older patients and chronic alcoholics, both of whom develop cerebral atrophy, can tolerate larger amounts of subdural blood clot

Classification of Subdural Hematomas ♦♦ Acute subdural hematoma: blood and clot present for the first 48 h ♦♦ Subacute subdural hematoma: a mixture of clotted and fluid blood is present for 2–14 days ♦♦ Chronic subdural hematoma: only fluid blood is present after 14  days. Chronic subdural hematomas can be a cause of dementia

Autopsy ♦♦ Liquid clot for the first 1–3 days ♦♦ At 4 days, there is nonuniform adherence of the clot to the dura ♦♦ Neomembrane is visible at 7–10 days and well developed in 2–4 weeks

Microscopic ♦♦ Dating of subdural hematomas is inaccurate after 1 month of age ♦♦ Healing is a continuum and the healing times must be generalized ♦♦ Neutrophils are present in the clot at approximately 24–48 h ♦♦ Edematous nuclei are present at the dural edge in about 2–3 days ♦♦ Macrophage infiltration occurs in approximately 2–5 days ♦♦ Erythrocytolysis occurs at about 4–5 days ♦♦ Two to five fibroblast layers are present at approximately 2–5 days ♦♦ Angiogenesis is usually visible by 1 week ♦♦ Giant capillaries are present at about 2 weeks ♦♦ Arachnoid neomembrane develops at approximately 2 weeks ♦♦ The inner and outer neomembranes are usually well developed at 4 weeks ♦♦ Hyalinization occurs at 1–3 months

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♦♦ Secondary hemorrhages into a subdural hematoma occur from the thin-walled giant capillaries ~1  month after the original injury ♦♦ Growth of chronic subdural hematomas is secondary to repeat episodes of bleeding from the giant capillaries

Subarachnoid Hemorrhage

♦♦ Blood is present in the subarachnoid space following localized trauma (Fig. 7.19) ♦♦ Often accompanies cerebral contusions ♦♦ May be due to rotation of the brain in the subarachnoid space ♦♦ Death can occur from pure subarachnoid hemorrhage due to vasospasm or acute hydrocephalus ♦♦ Posterior fossa subarachnoid hemorrhage can result from vertebral artery laceration following relatively minor injuries ♦♦ Examination of the vascular system for aneurysm, vascular malformation, or vessel lacerations should be performed at time of autopsy ♦♦ Small lesions can be obscured by adherent clot following fixation

Cerebral Contusions Coup Contusions

♦♦ Result from temporary deformation of the skull at the site of impact ♦♦ Occur in a head that is at rest relative to a moving object ♦♦ The skull impacts the tips of the gyri with destruction of the molecular layer ♦♦ An alternative theory proposes that there is a local suction effect following temporary deformation of the skull ♦♦ The term should only be used when skull fractures are absent at the site of impact

Contrecoup Contusions

♦♦ Contusions occurring distant from the site of impact ♦♦ Occur in a moving head, often as it strikes a fixed object

Fig. 7.19. Frontal and temporal subarachnoid hemorrhage.

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♦♦ Typically involves the inferior frontal and temporal lobes and the anterior tips of the frontal and temporal poles ♦♦ Often accompanies falls with occipital impacts ♦♦ Proposed mechanisms include −− Cushioning of the brain by cerebrospinal fluid accumulation as the inertia of the brain causes it to lag behind the moving skull as the skull impacts −− The CSF cushion minimizes coup injury and the lack of CSF in the contrecoup areas opposite the impact maximizes the contact of the brain with irregular bony surfaces of the floor of the skull and the skull opposite the impact −− The development of cavitation and negative pressure opposite the site of impact −− Tensile strain of the contrecoup areas as the brain moves toward the site of impact

Fracture Contusions

♦♦ Injuries of the brain surface underlying skull fracture (Fig. 7.20) ♦♦ Can be remote from the site of impact if skull fracture is present

Fig. 7.20. Contusions of cerebral cortex.

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Herniation

♦♦ Produced by subfalcial, transtentorial, or cerebella tonsillar herniation ♦♦ Can result from herniation related to cerebral swelling or transitory motion of brain structures

Diffuse Axonal Injury Clinical ♦♦ Symptoms can vary from transitory loss of consciousness with concussion to irreversible coma ♦♦ The white matter, especially the corpus callosum, is most involved ♦♦ Ethanol intoxication increases the clinical severity of the head injury

Autopsy ♦♦ Hemorrhages of corpus callosum (Fig. 7.21A, B) ♦♦ Can involve the interventricular septum and fornix ♦♦ Hemorrhage of the superior cerebellar peduncle

Fig. 7.21. Diffuse axonal injury. Hemorrhages in corpus ­callosum (A). Diffuse axonal injury with petechiae of corpus callosum (B).

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−− Other organ injuries such as acute lung injury, systemic hypotension, and anemia related to trauma contribute to the cerebral insult

♦♦ Cerebral edema ♦♦ Hemorrhage of the basal ganglia

Microscopic ♦♦ Axonal retraction balls are visible in the white matter using routine H&E and silver stains within 24 h of injury ♦♦ Groups of retraction balls of similarly oriented axons may be seen ♦♦ Immunohistochemical stains can detect axonal injury within 1–2  h (GFAP, beta-amyloid precursor protein, ubiquitin) ♦♦ Astrocytes or microglia proliferate after a period of weeks

Pathophysiology

♦♦ Caused by rotational acceleration or deceleration resulting in sheer strain characterized by the change in acceleration over time (dA/dt) ♦♦ Transection of the axon at the time of injury is not necessary ♦♦ Mild injury may be limited to transmembrane ionic disturbances in the axon, which will spontaneously recover ♦♦ More severe injury produces reactive changes that result in delayed axotomy (Wallerian degeneration) ♦♦ Damage to structural elements of cytoskeleton ♦♦ Swelling of mitochondria occurs followed by increases in axonal diameter ♦♦ Microtubules become misaligned and are damaged, halting antegrade or retrograde axonal flow of organelles ♦♦ Cytoskeleton can also disintegrate at the point of damage ♦♦ The axolemma separates from the myelin sheath ♦♦ Proteins continue to be transported from the cell body to the site of injury ♦♦ Axonal bulb or swelling develops and axotomy occurs (Wallerian degeneration) ♦♦ Calcium influx into leaking axolemma may be responsible for cytoskeletal collapse

Brainstem Avulsion

♦♦ Laceration of the brainstem or avulsion related to severe hyperextension of the head due to facial impact ♦♦ Most common is a pontomedullary tear ♦♦ Often accompanied by atlantooccipital dislocation, ring fracture, or high cervical fracture ♦♦ Most commonly produced by motor vehicle accidents

Complications of Head Injuries

♦♦ Hypoxic ischemic encephalopathy −− Occurs in 90% of head injury deaths −− The brain is particularly sensitive to hypotension and inadequate perfusion −− Hypoxia and hypotension combine to cause particularly severe ischemic injury −− Trauma may sensitize the brain to ischemia mediated by increased glycolysis, increased extracellular glutamate, and potassium flux

Cerebral Swelling

♦♦ Localized swelling can occur due to hemorrhage or contusion ♦♦ Diffuse swelling can occur related to hypoxic ischemic insults ♦♦ Vasogenic edema with increased hydrostatic pressure and damage to the blood–brain barrier can occur ♦♦ A cytotoxic component due to membrane pump failure and glutamate accumulation following ischemia is present ♦♦ Cerebral swelling may be increased by reperfusion injury following the restoration of blood pressure

Fat Embolism Clinical ♦♦ Occur 1–4 days following injury −− Petechial rash −− Respiratory distress −− Neurologic deterioration

Autopsy ♦♦ Petechial hemorrhages of white matter ♦♦ Necrosis of foci in cortex, cerebellum, and brainstem ♦♦ Atrophy of white matter with long-term survival

Microscopic ♦♦ Intravascular fat present in tissues stained with fat stains (ORO) ♦♦ Perivascular hemorrhages and/or infarcts of white matter ♦♦ Perivascular infarcts of gray matter

Shaken Baby Syndrome ♦♦ ♦♦ ♦♦ ♦♦

Major cause of fatal child abuse deaths due to head injury Mortality rate = 20–25% Most children <1 year of age and almost all cases <2 years The major problem is diffuse axonal injury following stretching and tearing of axons during vigorous shaking ♦♦ Vigorous shaking is shaking that occurs 2–3 cycles/s

Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Unconsciousness Coma Seizures Respiratory depression Bradycardia Xanthochromic spinal fluid Intracranial hemorrhage Other injuries of child abuse are often present

Autopsy ♦♦ Cerebral edema ♦♦ Subdural and/or subarachnoid hemorrhages

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Handguns Revolvers and Pistols Bullet Caliber

♦♦ Bullet diameter measured in hundredths of an inch or millimeters ♦♦ May be small caliber: 0.22 and 0.25; medium caliber: 0.32, 0.38, 0.357, 9  mm; or large caliber: 0.40, 0.41, 0.44, and 0.45

Cutaneous Entrance Wound

Fig. 7.22. Retinal hemorrhages, as seen with rear illumination. ♦♦ Retinal hemorrhages are seen in 75–90% of cases (Fig. 7.22) ♦♦ Evidence of head impact or skull fractures need not be present ♦♦ Detachment of the retina may occur ♦♦ Neck injuries can be present

Microscopic ♦♦ Diffuse axonal injury ♦♦ Cerebral edema

Associated Injuries ♦♦ Rib fractures can be present laterally or posteriorly just lateral to the spine, caused by squeezing the child’s chest during shaking ♦♦ Victims of shaken baby syndrome with a prolonged survival interval develop −− Cerebral fluid collections −− Cerebral atrophy −− Cystic encephalomalacia −− Cerebral infarcts due to hypoxic ischemic damage related to cerebral edema and intracranial hemorrhage

Firearms Injuries General Principles ♦♦ Firing progression −− Trigger pull: firing pin strikes cartridge case −− Primer detonates: ignites gunpowder −− Gunpowder combustion: gas production −− Pressure formation: expulsion of bullet ♦♦ Handguns and rifle barrels have spiral grooves in interior with elevated area between grooves called “lands” −− Lands impart spin to projectile ♦♦ Typical primer material includes lead styphnate, barium nitrate, and antimony sulfide

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♦♦ Diameter of defect not directly comparable to caliber of bullet ♦♦ Abraded margin occurs when bullet impacts skin ♦♦ If impact to skin is perpendicular, abrasion will be symmetrical and uniform ♦♦ When skin impact is at an acute angle, asymmetrical abrasion is widest on the side from which the bullet approached

Range of Fire

♦♦ Terminology −− Soot: black carbonaceous particles of residue consisting of completely burned gun powder and vaporized metals from primer, bullet, and cartridge case, which has a black disk-like appearance −− Powder tattooing or stippling: larger particles, mainly consisting of burning, partially burned, and unburned gunpowder, but also metal shavings and other debris from barrel and cartridge case (a)  Numerous red-brown to orange-red punctate lesions ♦♦ Contact range of fire −− Barrel tip in contact with skin surface (Fig. 7.23A, B) −− Soot on skin and in wound track −− If tight contact, then the majority of soot in depth of the wound with cherry-red discoloration of surrounding skin where carbon monoxide from combustion of gases binds to muscle to form carboxymyoglobin −− If loose contact, then prominent soot on skin surface (Fig. 7.23C) ♦♦ Close range of fire −− Soot and gunpowder stippling surrounding wound (Fig. 7.24A, B) −− Soot generally travels no more than 6–8 in ♦♦ Medium or intermediate range of fire −− Gunpowder stippling only, no soot −− Gunpowder stipples routinely 3–3½ ft, but certain gunpowder may travel farther ♦♦ Distant range of fire −− No residue on skin −− Indicates barrel tip to skin distance of at least 3–3½ ft ♦♦ Indeterminate range of fire −− Cannot determine range of fire because of interposed target between barrel tip and skin −− Example of interposed target: doors, windows, metallic wall

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Fig. 7.24. Close gunshot wound with soot and dense stippling (A). Close and intermediate gunshot wounds with dense and loose stippling (B). ♦♦ Exit wound has external beveling (defect larger on outer table than inner table) ♦♦ With gunshot wound through skull, there is energy propagation through bone with orbital plate fracture and subsequent spectacle hemorrhage from dissection of blood, which spares the supraorbital ridge, differentiating it from a blunt force injury (Fig. 7.33)

Shotguns Fig. 7.23. Contact. Muzzle stamp abrasion and laser sight abrasion compared with suspected gun (A). Contact gunshot wound with muzzle stamp (B). Near contact gunshot wound (C).

Cutaneous Exit Wounds

♦♦ Typically larger than entrance wound, but may be slit-like ♦♦ Rarely has abrasions, but if skin is supported by elastic bands of undergarments or firm external surface, then may have a “shored” abrasion (Figs. 7.25 and 7.26)

Gunshot Wounds of Head

♦♦ Entrance wound in skull has internal beveling (larger on internal table than outer table) (Figs. 7.27A–C, 7.28–7.32)

♦♦ Smooth bore weapon; no lands and grooves ♦♦ May fire more than one projectile: single projectile, slug, multiple projectiles, buckshot or birdshot ♦♦ “Gauge”: number of lead balls of a given diameter equal to one pound −− Example: 12 gauge = 12 spherical lead balls of a bore diameter of 0.729 in. equal to one pound ♦♦ Shotgun bore diameter can also be described in thousandths of an inch −− Example: .410 = “4–10” ♦♦ Choke describes constriction of muzzle end of barrel used to reduce pellet dispersion −− Ranges from full to none

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Fig. 7.25. Shored gunshot exit wounds.

Fig. 7.27. Contact entrance wound. Dura stripped by gases. Soot deposit between skull and dura (A). Inward beveling of gunshot entrance wound with soot and fractures (B). Inward beveling of skull entrance wound – soot present (C).

Range of Fire Fig.  7.26. Gunshot wound with exit and reentry. Soot around initial entrance. −− Is determined as percentage of shot falling, in 30 in circle when weapon fired at distance of 40 yards (a) Full choke: 60–75% (b) No choke (cylinder): 25–35%

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♦♦ Contact: round defect with soot on skin and in depths of wound ♦♦ Barrel tip 1½–2 ft from skin surface: single defect ♦♦ Barrel tip 3  ft from skin surface: single defect with slight discontinuous irregular margin (Fig. 7.34) ♦♦ Approximately 3½–4 ft, barrel tip to skin: central defect with individual satellite perforations

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Fig. 7.28. Fractures radiating from gunshot wound.

Fig. 7.31. Bullet in temporalis muscle. No exit in scalp. Fig. 7.29. Keyhole entrance wound of skull with loosening of sagittal suture.

Fig. 7.30. Gunshot wound track through frontal lobes. ♦♦ As barrel tip is farther withdrawn, get more individual perforations until only separate perforations and no single central defect

Fig.  7.32. Gunshot wounds with stellate splits resembling lacerations. ♦♦ Broad rule of thumb is for every 1 in of pattern, you have up to 3 ft of distance from barrel tip to skin ♦♦ Wadding enters central defect up to 5–10 ft, then drifts laterally, striking the skin and creating an abrasion

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Wadding in birdshot loads: small Winchester: cupwad with plastic shot cup Remington: power piston Federal: plastic wad column Buckshot: have white filler material that surrounds shot, can impact skin, and must be differentiated from gunpowder stippling

Rifles

Fig. 7.33. Bilateral periorbital ecchymoses – spectacle hemorrhages.

♦♦ Rimfire rifles can fire projectiles at relatively low velocity, as seen in handguns (650–1,400 ft/s) ♦♦ Center fire rifles can fire projectiles at high velocity (2,400–4,000 ft/s) ♦♦ By increasing velocity, the kinetic energy and wounding potential is markedly increased ♦♦ Center fire rifle ammunition may be subdivided into hunting type ammunition and fall jacketed ammunition ♦♦ The goal of hunting ammunition is to expend all of its energy so that it frequently does not exit body, but fragments inside; has a characteristic “lead snowstorm” x-ray pattern ♦♦ Full metal jacketed ammunition usually exits body without fragmenting and its goal is to injure the victim, but not expend all of its energy ♦♦ Temporary cavity may be large and organs not directly perforated may still be injured ♦♦ Entrance wound is typically small and round, similar to a handgun entrance wound ♦♦ Exit wounds are often large and irregular

Sharp Force Injuries ♦♦ Sharp versus blunt ♦♦ Sharp: mechanically cuts and divides tissue to depth of object inserted ♦♦ Blunt: crushes and tears tissue with bridging in wound depth

Incised Wound

Fig. 7.34. Shotgun wound of arm and chest.

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Wadding marks the skin up to 15–20 ft ♦♦ Soot will travel out to 1 ft ♦♦ Gunpowder will travel up to 2–3 ft

Stab Wound

Ammunition ♦♦ Shotgun shells consist of a plastic or paper body (the tube), a brass head, cardboard or composite wads, and lead shot

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Caused by a sharp-edged object drawn over tissue (Fig. 7.35) Wound defect is longer on skin than it is deep Edges may be straight or jagged No marginal abrasion No tissue bridging Bleeding may be extensive Typically seen on head, neck, and extremities (Fig. 7.36) If the wound is on the neck or through visible large vein, then x-ray for embolism ♦♦ On margin of wounds, may see superficial parallel incisions, consistent with serrated knife ♦♦ Caused by pointed or sharp object being forced into tissue in a thrusting manner (Fig. 7.37A–C, E, and F) ♦♦ Wound track is deeper than the surface defect is long

Forensic Pathology

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Defense Wound ♦♦ ♦♦ ♦♦ ♦♦

Occurs when one is defending one’s self from assailant Usually seen on upper extremities (Fig. 7.38A–C) Appearance of wound varies with weapon May be seen in both stab and incised wounds

Asphyxia ♦♦ A condition in which there is an absence or reduction of oxygen in body tissues and increased carbon dioxide tension

Autopsy

Fig. 7.35. Linear incised wound.

♦♦ Tends to be fairly classical and nonspecific (may be seen in other causes of death as well) ♦♦ Visceral congestion ♦♦ Cyanosis ♦♦ Petechiae (Fig. 7.39A, B) ♦♦ Fluidity of blood

Compression of Neck Hanging ♦♦ Compression of neck by noose, with compression of arterial and venous blood supply to and from brain ♦♦ Suspension may be complete or incomplete (Fig. 7.40) ♦♦ Hanging is almost always suicidal and very rarely accidental or homicidal ♦♦ Consciousness lost rapidly

Autopsy Fig. 7.36. Healed superficial incised wounds – suicidal hesitation mark scars.

♦♦ No tissue bridging and no marginal abrasions, with the exception of possible hilt mark ♦♦ Skin surface may reflect characteristics of weapon: single or double edged, Phillips screwdriver, serrated knife ♦♦ Skin defect appearance variable due to orientation with respect to Langer lines (Fig. 7.37D) ♦♦ Exsanguination, infection, or air embolism may cause death ♦♦ X-ray for knife tip fragments ♦♦ Depth of wound not equal to length of blade: wound may be shorter due to partial insertion or longer due to compressibility of body, especially in the abdominal area

Chop Wound ♦♦ Caused by sharp heavy instruments: ax, hatchet, cleaver; intermediate between sharp and blunt force injuries ♦♦ Deep gaping wounds that may have deep bruising and fracture ♦♦ May have marginal abrasion and contusion

♦♦ Fractures uncommon, but increased in elderly with calcification of cartilage ♦♦ “Hangman’s fracture”: fracture of odontoid process of C2 with fragments of bone driven into medulla oblongata ♦♦ Hangman’s noose: classic hangman’s noose with knot on left side to throw head backward to fracture neck ♦♦ Crease or groove in neck where ligature is located is called a “furrow” (Fig. 7.41A–C) ♦♦ Soft material may leave no furrow ♦♦ Dependent areas of body with gravitational effect get lividity, punctate hemorrhages, and Tardieu spots

Strangulation Ligature Strangulation

♦♦ Most common in females ♦♦ Vascular occlusion with loss of consciousness in ~10–15 s ♦♦ Ligatures include electrical cords, telephone cords, sheets, and neckties

Autopsy ♦♦ Marked congestion above ligature; confluent scleral hemorrhages with conjunctival petechiae; furrow when present is usually horizontal and below the thyroid cartilage (Fig. 7.42) ♦♦ May get fracture of thyroid and hyoid cartilage

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Fig. 7.37. Stab wound of neck with anterior incised component (A). Stab wounds – ice pick (B). Stab wound with incised wound tail at sharp angle (C). Reduction of elastic lines of force to show wound shape and dimensions (D). Multiple stab wounds, some with a yellow-brown drying perimortem appearance (E). Inward beveling of rectangular stab wound in bone (F).

Manual Strangulation

♦♦ Compression of internal structures of neck by hands or forearms ♦♦ Compression of blood vessels with rapid loss of consciousness ♦♦ All manual strangulations are homicides

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Autopsy ♦♦ Petechiae of sclerae, conjunctivae, and face, with cyanosis above level of compression ♦♦ Usually, hemorrhage is located in neck musculature (Fig. 7.43A, B) and sometimes there are fractures of hyoid bone and thyroid cartilage (usually over the age of 30)

Forensic Pathology

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Fig. 7.39. Conjunctival petechiae (A). Cephalic congestion and petechiae (B).

Choke Hold (Shime-Waza) ♦♦ Also called bar arm control ♦♦ Forearm is placed against the front of the neck with force applied in a front to back direction, causing compression of the neck ♦♦ This is used to occlude the upper airway and carotid artery ♦♦ Excessive force can distort the larynx, leading to fractures of the larynx and, in some cases, the hyoid bone ♦♦ Carotid sinus stimulation may occur, leading to arrhythmia and death Fig. 7.38. Defense wound with parallel abrasions from serrated knife (A). Defense wounds – incised wounds and abrasions (B). Defense wounds – abrasions (C).

♦♦ Frequently see abrasions and fingernail marks on skin ♦♦ Victim is usually female ♦♦ Sexual assault should always be considered in manual strangulation ♦♦ Note: Petechiae are not confined to strangulation and may be seen in asphyxial deaths, heart failure, vomiting or coughing, and postmortem lividity in prone position

Carotid Sleeper Hold (Lateral Vascular Neck Restraint) ♦♦ Symmetrical force is applied by the forearm and the upper arm to the side of the neck, such that the compression is on carotid arteries and jugular veins and not the larynx ♦♦ Consciousness is lost in 10–15 s ♦♦ Blood flow to the brain is decreased 85% ♦♦ May cause stimulation of carotid bradycardia and there may be increased catecholamines and arrhythmia that can lead to death if compression of arteries and veins is prolonged

Autoerotic Asphyxia ♦♦ Asphyxia by compression of the neck induced to enhance sexual enjoyment, usually during masturbation

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Fig. 7.40. Suicidal hanging. ♦♦ Almost always male ♦♦ Scene investigation: typically, the male is found nude or wearing female clothing, in a private area, and bound with a rope around the neck ♦♦ Virtually always has an escape mechanism in place ♦♦ Frequently, pornographic literature surrounds the scene ♦♦ Death typically occurs when there is a miscalculation of timing during the act of sexual gratification in which consciousness is lost and death occurs ♦♦ Investigation is important to ensure that these cases are not certified as suicide

Obstruction of Airway Smothering

Fig. 7.41. (A) Pale wide ligature furrow. Posterior view of furrow in (A). (B) Note pattern on right neck. (C) Belt used as ligature in (A) and (B).

♦♦ A mechanical obstruction or occlusion of external airway (nose and mouth) ♦♦ Usually homicide or suicide ♦♦ Most common suicidal smothering is a plastic bag over the head

♦♦ Gags can cause smothering, obstructing airway and swelling by saliva, creating a greater obstruction (even though unintentional, this is homicide) ♦♦ Most homicidal smotherings occur in the very young, very old, debilitated, or incapacitated by disease or drugs

Autopsy

Entrapment (Environmental Suffocation)

♦♦ Nonspecific, often without petechiae ♦♦ Accidental smothering occurs when an infant is trapped between a small mattress and railing, with face against mattress

♦♦ Smothering in which individual is located in a confined space and uses all of oxygen −− Example: child in refrigerator

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Fig.  7.43. Nuchal strap muscle hemorrhages over larynx (A). Larynx with posterior soft tissue hemorrhages (B).

Fig. 7.42. Dried ligature furrow above larynx. ♦♦ May also occur when an individual enters an area with a deficiency of oxygen (e.g., excessive carbon dioxide in underground wells produced by plants that produce CO2 and deplete oxygen)

Autopsy ♦♦ Nonspecific

Obstruction of Airway by Foreign Material (Choking) ♦♦ Caused by obstruction of air passages ♦♦ Most are accidents that occur in children aspirating foreign bodies (e.g., balloons, buttons, pen tops, peanut butter, and hot dogs) ♦♦ May occur homicidally with gags in oral airway ♦♦ In adults, airway obstruction frequently involves food (Figs. 7.44 and 7.45) ♦♦ In neurologically impaired or acute intoxication (with alcohol or drugs), food lodges in larynx and the individual cannot breathe ♦♦ Cafe coronary: individual eating in restaurant suddenly stands up and collapses – CPR performed with the idea that this is of cardiac origin

Fig. 7.44. Bolus of food in distal trachea. ♦♦ Small amount of food in airway at autopsy is not indicative of choking; individuals aspirate food agonally in cardiac arrest (20–25%) ♦♦ Food must be bolus in larynx, or, if aspiration of food, must extend from larynx to main bronchi, with complete obstruction by food ♦♦ Aspiration of food seen in neurologically impaired, intoxicated, and schizophrenics

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Fig. 7.46. Marked facial livor from mechanical compression (A). Patterned impression on chest following mechanical compression of thorax (B).

Autopsy ♦♦ Purple to blue-black congestion of head, neck, and upper chest, with numerous petechiae of sclerae, conjunctivae, and periorbital skin (Fig. 7.46A, B) ♦♦ Retinal hemorrhages may occur ♦♦ Also seen with constricting snakes Fig. 7.45. Foreign body (latex glove) in airway.

Swelling of Airway ♦♦ Occurs in acute inflammatory processes with subsequent swelling and obstruction of airway ♦♦ Acute epiglottitis ♦♦ Clinically have sore throat and hoarseness, with difficulty swallowing ♦♦ Can get rapid airway obstruction and need a tracheal tube or tracheostomy ♦♦ Haemophilus influenzae, most common cause in both children and adults

Autopsy ♦♦ ♦♦ ♦♦ ♦♦

Large edematous epiglottis with soft tissue obstructing airway Neoplasms of larynx (polyps or cancer) Diphtheria Asthma (see previous description)

Mechanical Asphyxia Traumatic Asphyxia ♦♦ Almost always accidental ♦♦ Occurs when a large weight falls or compresses the chest or upper abdomen, making respiration impossible ♦♦ Most common when a car jack slips on an individual repairing a car, causing the vehicle to fall on top of the victim

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Positional Asphyxia ♦♦ Associated with intoxication by alcohol or drugs ♦♦ Individual falls into a confined area and, due to intoxication, is unable to extricate him- or herself ♦♦ By virtue of body position, is unable to breathe and, therefore, dies

Autopsy ♦♦ Congestion ♦♦ Cyanosis ♦♦ Petechiae

Chemical Asphyxia ♦♦ Death not due to toxicity of gas, but to displacement of or inability to use oxygen

Carbon Dioxide

♦♦ Nontoxic and odorless ♦♦ Located in sewers, mines, and underground wells ♦♦ Death due to hypoxic environment and lack of oxygen

Methane

♦♦ A component of natural gas ♦♦ Sewers and mines −− Toxicology is negative −− Rarely does autopsy reveal cyanosis −− Environment must be analyzed to determine what gases are present

Forensic Pathology

Hydrogen Cyanide ♦♦ ♦♦ ♦♦ ♦♦

Prevents utilization of oxygen at cellular level May be either potassium or sodium cyanide Rapid-acting poison Cyanide binds to the ferric ion atom of the intracellular cytochrome oxidase ♦♦ Cyanide deaths are usually suicide and usually by persons who have availability of cyanide at place of employment (chemists, photographers, and engravers) ♦♦ Hydrogen cyanide used for execution in gas chamber for judicial executions

Autopsy ♦♦ If taken orally, the body and stomach contents may smell like bitter almonds ♦♦ Ability to smell cyanide is genetic; most persons cannot smell it ♦♦ Gastric mucosa and livor mortis are bright red due to excessive oxyhemoglobin ♦♦ If inhalation of hydrogen cyanide, the livor mortis and blood are bright red ♦♦ If cyanide is present, it will decrease postmortem ♦♦ In decomposition, bacteria can produce cyanide

Hydrogen Sulfide

♦♦ Produced by fermentation of organic matter ♦♦ Found in sewers, sewage plants, cesspools, and oil and chemical industries ♦♦ “Sewer gas”: hydrogen sulfide, carbon dioxide, and methane ♦♦ Deaths from hydrogen sulfide are usually accidents ♦♦ Smell of rotten eggs

Autopsy ♦♦ May get formation of methemoglobin ♦♦ Dark colored blood ♦♦ Organs may have green to blue-green appearance

Carbon Monoxide

♦♦ Colorless, odorless, and tasteless ♦♦ Sources: fires, automobile exhaust, defective heaters, incomplete combustion of burning product ♦♦ Produced whenever materials are burned with inadequate oxygen to produce complete combustion ♦♦ Get tissue hypoxia and competes with oxygen for binding sites on oxygen carrying heme proteins (hemoglobin, myoglobin, cytochrome C oxidase, cytochrome P-450) ♦♦ Carbon monoxide has 250–300 times greater affinity for hemoglobin than oxygen ♦♦ Smokers have regular levels of carboxyhemoglobin of ~3–6% ♦♦ Number one source of carbon monoxide in fatalities is fire ♦♦ Number two source of carbon monoxide in fatalities is inhalation of exhaust fumes

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♦♦ Symptoms of carbon monoxide poisoning −− 0–10%: generally no symptoms −− 10–20%: headache and weakness −− 30–40%: severe headache, dizziness, nausea, and vomiting −− 40–50%: slurred speech, blurred vision, stupor, difficulty breathing −− >50%: comatose, respiratory failure, and death in preexisting disease or elderly; carbon monoxide as low as 20–30% may be fatal −− House fire carbon monoxide averages 50–60% −− Car exhaust fatalities average 70%

Autopsy ♦♦ Cherry-red livor mortis ♦♦ Common lesion, if survival, is bilateral necrosis of globus pallidus (nonspecific) ♦♦ Brain is sensitive to effects of carbon monoxide ♦♦ Half-life elimination of carbon monoxide with 100% oxygen is 90 min ♦♦ Flash fire: can see rapid combustion of fire, such as from gasoline in which motor vehicle explodes and incinerates ♦♦ Individuals may not have significantly elevated carbon monoxide levels

Drowning ♦♦ Submersion in liquid and irreversible cerebral hypoxia ♦♦ Volume of water inhaled can range from small to large

Dry Drowning ♦♦ 10–15% of all drownings get −− Small volume of water inhaled −− Laryngospasm prevents further water from entering airway −− Nondemonstrable at autopsy ♦♦ Most cases get inhalation of large volume of water in process of drowning ♦♦ Type of water inhaled has little to do with drowning −− Fresh water alters or denatures surfactant −− Salt water dilutes or washes surfactant away

Near Drowning ♦♦ Submersion victim is transported to hospital and survives for ~24 h ♦♦ Rare instances get prolonged survival in cold water, especially in children

Autopsy ♦♦ No specific findings ♦♦ Diagnosis of exclusion ♦♦ Submersion wrinkling (washerwoman’s hands, 1–2  h in water) ♦♦ Edema fluid in mouth and airways ♦♦ Heavy lungs with edema fluid and foam cone in trachea and bronchi (Fig. 7.47)

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♦♦ Develop pulmonary arterial hypertension and damage to capillary endothelium and alveolar pneumocytes

Acute Mountain Sickness

Fig. 7.47. Drowning – Froth cone in nose and mouth. ♦♦ May have hemorrhage in petrous temporal ridge or mastoid bone ♦♦ Occasionally have right ventricular dilation ♦♦ No drowning test exists

Drowning in Bathtubs ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Seen in children Seizure disorders Cardiac arrhythmia Drug overdose Must rule out natural death with subsequent submersion and body dumped into water after death

Scuba Diving ♦♦ Most common cause of death is drowning ♦♦ May get carbon monoxide in tanks that is mixed with air from gasoline-driven compressors ♦♦ With rapid ascent to surface, may develop air embolism, pneumothorax, or interstitial emphysema

Atmospheric Pressure Changes ♦♦ Gas volume increases with decreased barometric pressure ♦♦ Solubility of gas in liquid (e.g., blood) is proportional to partial pressure of gas in ambient atmosphere ♦♦ Injurious effects are dependent on three characteristics when atmospheric pressure is abnormal −− Direction and magnitude of change −− Rate of change −− Duration of change

Decreased Atmospheric Pressure ♦♦ Lowering of pressure by as little as 50% can result in significant systemic hypoxia leading to death ♦♦ Increase in atmospheric pressure is tolerated better than decrease ♦♦ Hypoxia from decreased pressure results in significant shifting of blood volume to pulmonary system from peripheral vasoconstriction

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♦♦ Majority occurs when there is ascension rapidly to elevations >2,500 m (8,200 ft) ♦♦ Symptoms include headache, nausea, vomiting, and insomnia ♦♦ May become life-threatening when develop acute highaltitude pulmonary edema and cerebral edema ♦♦ Usually develops first 8–24 h at high altitude ♦♦ In addition to lower oxygen tension, also have lower environmental temperatures, increased ultraviolet radiation, and decreased humidity and get hyperventilation, dehydration, and hypokalemic alkalosis ♦♦ Hypobaric dysbarism (aviator bends)

Autopsy ♦♦ Congested lungs and interstitium with prominent alveolar edema and hyaline membranes ♦♦ Retinal hemorrhage and cerebral edema may also occur ♦♦ May also develop sickle cell crisis in persons with hemoglobin SC and sickle thalassemia ♦♦ Symptoms have been seen in pilots, especially early on with the advent of flight to heights capable of creating hypobarism

Increased Atmospheric Pressure ♦♦ Injuries occur on return from elevated to normal barometric pressure ♦♦ Rate of change of atmospheric pressure important in injury production ♦♦ Unless pressure is lowered slowly to normal, decompression sickness (dysbarism, Caisson disease, the bends, staggers, or chokes) can occur ♦♦ With increase in atmospheric pressure, get net flow of nitrogen (4/5 of air) from alveoli through blood in which gas dissolves into tissue ♦♦ Upon return to normal pressure, rapid gas bubble formation develops in tissue and blood because nitrogen forms faster than can be transported to lungs for expiration ♦♦ Ocean surface under pressure of 1 atmosphere ♦♦ Every 33  ft descended adds 1 additional atmosphere of pressure

Acute Decompression Sickness ♦♦ Associated with Henry law in which rapid ascension with inability to exhale rapidly leads to accumulation of gas bubbles with mediastinal interstitial emphysema, subcutaneous emphysema, pneumothorax, and, in some cases, air embolism ♦♦ May get arterial gas embolism from ruptured alveoli, which may lodge in cerebral vessels with symptoms ranging from focal neurologic deficits developing hours after dive to rapid collapse and unconsciousness immediately after surfacing ♦♦ Females and obese predisposed

Forensic Pathology

♦♦ Fatalities most associated with pulmonary and central nervous system (CNS) involvement ♦♦ Chronic complications of decompression sickness characterized by demyelination of dorsal and lateral columns of thoracic spinal cord

Barotrauma ♦♦ Associated with Boyle law and due to failure of a gas-filled space to equalize its internal pressure to that of the outside environment ♦♦ Effects are most severe in cavities within bone that cannot expand or contract ♦♦ Barotrauma of middle ear is most common disorder in divers; may lead to pain and conduction hearing loss due to rupture of the tympanic membrane ♦♦ Barotrauma of inner ear may lead to sensorineural hearing loss and tinnitus ♦♦ Barotrauma of paranasal sinus is the second most common disease of divers, especially in frontal sinus −− May be associated with chronic dysfunction of sinuses with either anatomic abnormalities or chronic allergies

Thermal Injuries Related to Temperature Changes ♦♦ General principles −− Narrow range of internal temperature must be maintained (a) Increase in tissue temperature more likely to cause injury than decrease (b) Cellular injury or death occurs if tissue temperature is maintained at a level >5°C above or >15°C below that which is normal for blood (c) Skin is principal site of heat loss or heat gain −− Heat load = heat generated from oxidation of metabolic products + heat acquired from environment (a) Normal body temperature = 98.6°F (37°C) orally (b) 1°F (0.6°C) higher rectal (c) Temperature variations by age, time of day, physical exertion (exercise may increase temperature 3–4°) −− Newborn and elderly have temperatures 1°C higher −− Heat loss occurs from four mechanisms (a) Conduction (b) Radiation (c) Evaporation (d) Convection

Local Hypothermia ♦♦ Localized injury from cold classified as immersion foot or frostbite −− Immersion (or trench) foot occurs with prolonged exposure to wet and cold, nonfreezing conditions (a) Primary injury is neuromuscular, resulting from ischemic tissue injury

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−− Frostbite: exposure to freezing conditions involving damage to the skin and vasculature (a) Get vasomotor alterations, aggregation, and stasis of erythrocytes leading to vascular obstruction (b) Typically involves exposed body surfaces, most prominently those farthest away from central circulation (ears, nose, and extremities) (c) May be superficial, involving the skin, or may cause gangrene of deep tissues

Systemic Hypothermia ♦♦ Results when heat loss exceeds heat production and allows body temperature to fall below 95°F −− Heat loss expedited by decreased humidity, wetness or immersion, or wet clothing ♦♦ Three stages of hypothermia −− Sensation of cold and shivering: body approximately 90°F −− Stage of depression with developing bradycardia, hypotension, and bradypnea: body temperature 75–90°F −− Cessation of thermal regulatory control: body temperature <75°F ♦♦ Unconsciousness develops at ~86°F ♦♦ Cardiac dysrhythmias common with ventricular fibrillation developing at core temperature of 77–82°F

Immersion Hypothermia ♦♦ More rapid loss of heat in water than in air −− Water temperature 4–9°C = death in 70–90 min −− 0°C = fatalities in ½ h −− In water temperatures >70°F, survival time depends solely on the fatigue factor of the individual −− When individuals die within 10–15 min after entry into frigid water, death is, apparently, not related to reduced body temperature, but to shock of rapid entry into cold water

Wind Hypothermia ♦♦ Body will lose heat more rapidly with increasing wind velocity ♦♦ Infants are more susceptible to hypothermia than adults (greater surface area to body mass)

Paradoxical Undressing ♦♦ Term employed when individual is found undressed in cold environment, believed to be caused by hallucination of warmth due to paralysis of thermal regulatory system

Hide and Die Syndrome ♦♦ Seen in elderly, paradoxical undressing: hidden in closets, cupboards, etc ♦♦ Most cases of hypothermia involve elderly or people under the influence of alcohol −− Other predisposing conditions: infancy, exhaustion, or debilitating disease or injury −− May also be associated with disease processes such as myxedema and sepsis

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Autopsy ♦♦ No pathognomonic findings of hypothermia ♦♦ If rapid death, usually no findings except cherry-red discolo­ ration from retained oxyhemoglobin ♦♦ If prolonged survival, then may develop thromboses; pancreatitis; ulceration and hemorrhage of stomach, ileum, and colon; and bronchopneumonia

Local Hyperthermia (Burns) ♦♦ Inverse relationship between intensity of thermal exposure and amount of time required to produce burn (e.g., higher the temperature, the shorter duration of exposure necessary to create injury) ♦♦ Earliest evidence of hyperthermal injury is capillary dilation with increased capillary permeability and eventual capillary leakage ♦♦ Cutaneous burns may be identified as first-, second-, or thirddegree or as partial thickness or full thickness −− First-degree burn (e.g., sunburn) −− Second-degree burn involves vesication or blister −− Third-degree burn: scar formation in repair −− Fourth-degree burn: charring −− Partial thickness: no permanent damage to dermis; includes both first- and second-degree burns; regeneration of epithelium (second-degree burn) from margins of burned area and underlying hair follicle −− Full thickness burns: damage to dermis and adnexal structure including hair follicles (third-degree); form scar ♦♦ Get secondary shock with extensive burns due to loss of plasma at injury site ♦♦ Get bacterial infection where tissue sloughed ♦♦ Other complications include phlebothromboses, ulcers of stomach and small intestine (Curling ulcer), renal failure, and inhalation damage (when associated with fire) ♦♦ Estimation of total body surface area: “Rule of 9s” −− Head: 9% −− Upper extremities: 9% each −− Front of torso: 18% −− Back: 18% −− Each lower extremity: 18% (front and back) −− Neck: 1% ♦♦ Household fires rarely exceed 1,600°F −− Cremation at 1,800–2,000° F for 1½–2½ h

Smoke Inhalation ♦♦ Get cherry-red lividity ♦♦ Soot in nares and oral cavity and may coat larynx, trachea, and bronchi (Fig. 7.48) ♦♦ Absence of soot does not preclude carbon monoxide inhalation ♦♦ Cyanide produced in burns from synthetic substances only rarely contributes to death

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Fig.  7.48. Soot in airway of fire victim. Note extent of soot beyond carina into bronchi.

♦♦ In fourth-degree charring, may see “pugilistic attitude” with boxer appearance of arms secondary to contraction of muscles of upper extremity ♦♦ “Fire epidural hematoma”: postmortem artifact with fairly large aggregate of chocolate-brown dried blood overlying frontal, parietal, and temporal areas

Systemic Hyperthermia ♦♦ Failure of thermal regulation and may occur if exposed to significant heat from environment or inability of body to eliminate heat from metabolic processes

Mechanism of Heat Loss Radiation

♦♦ Heat loss via energy emission from skin surface (65% of body heat loss)

Convection

♦♦ Cooling by air current (12–15% body heat loss)

Conduction

♦♦ Direct contact with cooler surfaces (very little heat loss)

Evaporation (Perspiration)

♦♦ Only heat loss mechanism that works when ambient temperature exceeds 92°F ♦♦ Amount of sweat vaporized is limited by ambient humidity ♦♦ Transpiration heat loss through exhaled water vapor (dissipates 5% of body heat) ♦♦ Important mechanism of heat loss in animals ♦♦ Functionally elevated temperatures lead to generalized vasodilatation, rapid pulse, and stimulation of respiratory centers

Heat Stroke

♦♦ Uncontrolled overproduction of body heat or impairment of body’s ability to lose heat ♦♦ Commonly occurs in spell of hot (>90°F) humid weather

Forensic Pathology

♦♦ Predisposing conditions include old age; cardiovascular disease and other debilitating conditions; skin disorder; medications including neuroleptic, diuretic, and anticholinergic or anesthetic agent; alcoholism; disorders with impaired heat loss; and failure to curtail physical activity ♦♦ Also increased risk in healthy young people, especially military recruits, laborers, and athletes who overexert themselves in hot, humid weather −− Especially prominent in individuals with sickle cell trait ♦♦ Environmental factors contributing to heat stroke include poor ventilation, residence of upper floors of buildings, and closed automobiles in direct sunlight ♦♦ Individuals >65 have 10–12 times risk of heatstroke as compared to younger adults

Autopsy ♦♦ Nonspecific ♦♦ If survive following hyperthermia, may get complications, including pneumonia, renal failure, hepatic failure, and sepsis

Malignant Hyperthermia ♦♦ Drug-induced syndrome occurring during and after administration of general anesthesia ♦♦ Characterized by increased oxygen consumption and rapid rise in temperature ♦♦ Genetic predisposition that allows release of calcium from smooth endoplasmic reticulum with overload of calcium in mitochondria ♦♦ Previously associated with halothane and succinylcholine ♦♦ Symptoms include tachycardia, hyperthermia, rhabdomyolysis, and skeletal muscle rigidity

Neuroleptic Malignant Syndrome ♦♦ Seen in individuals on antipsychotic medication, most notoriously phenothiazine therapy ♦♦ Estimated between 0.5 and 1% of patients exposed to neuroleptic ♦♦ Young men predominate ♦♦ Predisposing factors include physical exhaustion, dehydration, organic brain disease, and long-acting depo neuroleptic drugs ♦♦ Clinical symptoms include hyperthermia, hypertonicity of skeletal muscles, and fluctuating consciousness with instability of autonomic nervous system ♦♦ Mortality ranges from 20 to 30% ♦♦ Causes of death include respiratory failure, cardiovascular collapse, renal failure, arrhythmias, and thromboembolism (if prolonged survival) ♦♦ Respiratory failure may result from aspiration pneumonia ♦♦ May see in Parkinson patients with sudden discontinuation of medication

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Electrical Injuries General Concepts ♦♦ Degree of injury dependent on −− Voltage of current −− Type of current −− Resistance at point of contact −− Location of current path, critical −− Duration of current −− Body must complete a circuit between two conductors −− Death may be produced with low voltage from alternating current (46 and 60 V) −− Any voltage >25 should be considered potentially lethal −− Alternating current is more dangerous than direct current −− Voltages <220 tend to fibrillate heart without affecting respiratory center −− Voltages >1,000 tend to produce paralysis of respiratory center without affecting heart ♦♦ Amount of current: C = V/R −− C = Current in amperes −− V = Potential in volts −− R = Resistance in ohms (body’s opposition to flow of current) ♦♦ Effective current dependent on resistance of tissues involved −− Callused, thick skin may reach resistances of 1 million ohms or more −− Wet or moist skin may have resistance of 1,000 W ♦♦ More prolonged contact, more serious effect ♦♦ One-third of electrical injuries occur at work (usually linemen or construction workers in contact with high voltage power line) ♦♦ Remaining one-third occur in residences with low voltage current ♦♦ 5% of all admissions to burn hospitals are related to electrical injury

Electrical Injury ♦♦ ♦♦ ♦♦ ♦♦

Greatest resistance to flow of current is skin Electrothermal injury limited to skin (Fig. 7.49) Death occurs from primary fibrillation of the heart Failure of respiratory center from fibrillation with paralysis of respiratory center or prolonged fibrillation of respiratory muscle

Autopsy ♦♦ Small, circumscribed, indurated lesion, central necrosis, and “nuclear streaming” of dermal nuclei ♦♦ High voltage burns: large area of contact with deep charring injuries, even amputation of extremities ♦♦ May get coagulative necrosis of muscle nerve and skin, with thrombosis of blood vessel and eventual renal failure

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Fig. 7.51. Lightning print (ferning).

Fig. 7.49. Electrical burns.

♦♦ Highest conductor of electricity preferentially stuck includes trees, poles, antennae, pylons, and unprotected buildings ♦♦ Geographic features predisposing to strikes include caves, fissures, faults, metallic oars, and natural radioactivity ♦♦ Humans most exposed live on mountain or work outdoors (e.g., farmers or herders) ♦♦ Lightning may strike directly (entering through head or arm) (Fig. 7.50) or indirectly

Fig. 7.50. Exit path of lightning strike.

♦♦

♦♦ Heart and central nervous system: arm to arm conduction involves heart; head to foot conduction involves nervous system and heart ♦♦ Small current through chest can be fatal; large current through extremity alone may have limited effect

♦♦ ♦♦

Lightning ♦♦ Typical lightning discharge occurs during storms, but may occur with clear skies; most commonly occurs in afternoon

♦♦

−− Direct strikes also occur in the open when carrying something metallic, such as umbrella, golf clubs, jewelry, or hearing aids −− Indirectly as victim is secondarily struck following primary strike of tree or another person Effects of lightning depend on nature of strike (direct or indirect), intensity of current, time spent through body, pathway taken, and activity of person at time of strike Lightning may depolarize the entire myocardium or cause fracture or rupture of blood vessels and viscera If survive strike, victims may develop complications, including cardiac arrhythmias, infarction, cataracts, and renal failure Skin may show arborescent cutaneous hyperemia known as ferning or lightning print (Fig. 7.51)

TOXICOLOGY Alcohols and Acetones Ethanol (Drinking Alcohol) Source

Metabolism

♦♦ Beer: 3–6% ethanol content ♦♦ Wine: 6–12% ethanol content ♦♦ Distilled liquor: 20–85% ethanol content

♦♦ Absorbed from stomach and small intestine ♦♦ Metabolized in liver to acetaldehyde and acetic acid ♦♦ Elimination of alcohol: 0.015–0.02 g/dL/h

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♦♦ Trace endogenous production ♦♦ Cough syrup, mouthwash, and solvents contain ethanol

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Toxic Effects

Unique pathologic findings

♦♦ Central nervous system: respiratory depression (lethal concentration ~0.4 g/dL, some survivors have had levels above this), Wernicke–Korsakoff syndrome, delirium tremens ♦♦ Liver: steatosis, cirrhosis, and hepatitis ♦♦ Heart: cardiac arrhythmia and cardiomyopathy

♦♦ Calcium oxalate crystals (kidneys and central nervous system) (Fig. 7.52A–D) ♦♦ Lethal dose = 100 mL

Methanol (Wood Alcohol) Source ♦♦ Solvents, fuel, antifreeze, trace endogenous production

Metabolism ♦♦ Methanol metabolized to formaldehyde, which is metabolized to formic acid

Toxic Effects ♦♦ Central nervous system depressant, blindness, acidosis ♦♦ Lethal dose = 100–200 mL

Isopropyl (Rubbing Alcohol) Source ♦♦ Solvents, rubbing alcohol

Cocaine and Cocaethylene Cocaine Source ♦♦ Erythroxylon coca plant

Route ♦♦ Injection, snorting, sniffing, and ingestion

Metabolism ♦♦ Metabolizes to three different compounds −− Benzoylecgonine, norcocaine, and ecgonine methyl ester (a) Benzoylecgonine and ecgonine methyl ester will metabolize to ecgonine (b) When alcohol is present, cocaine combines with ethanol to form by-product cocaethylene

Active metabolites ♦♦ Norcocaine and cocaethylene

Metabolism

Half-life

♦♦ May be absorbed through skin or orally ingested −− Isopropanol is metabolized to acetate and formate −− Acetone may be present in blood and urine (glucose will not be elevated)

♦♦ Cocaine: ½–1½ h ♦♦ Benzoylecgonine: 5–10 h ♦♦ Cocaethylene: 1–2 h

Acetone Source ♦♦ Fingernail polish remover, solvent, small amount of endogenous production

Metabolism ♦♦ Ingested and absorbed, acetone metabolized to acetate, formate, and isopropanol

Toxic Effects ♦♦ Acidosis, endogenous level may also be associated with ketoacidosis

Ethylene Glycol Source

Mechanism ♦♦ Blocks reuptake of sympathomimetic neurotransmitters into nerve terminal

Biological Effects of Cocaine ♦♦ Increased blood pressure, heart rate, body temperature, and respiration ♦♦ Dilated pupils ♦♦ Anxiety, talkativeness, agitation, hyperactivity, and mood swings ♦♦ Central nervous stimulation followed by central nervous depression ♦♦ Addiction, tolerance, and withdrawal

Toxicity

♦♦ Antifreeze

♦♦ Cardiovascular: arrhythmia, hypertension, infarction ♦♦ CNS: seizures, strokes, psychosis

Route

Autopsy

♦♦ Ingestion

♦♦ Hypertrophic heart, scarred injection sites, intravenous “drug tracks”

Metabolism ♦♦ Many compounds including oxalate

Toxic Effects ♦♦ Central nervous system depressant, acidosis, and renal failure

myocardial

Microscopic ♦♦ Myocardial fibrosis, pulmonary hemorrhage, and giant cell reaction in skin ♦♦ Lethal dose: variable

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Fig. 7.52. Kidney with oxalate crystals following ethylene glycol poisoning (A). Kidney with oxalate crystals following ethylene glycol poisoning – polarized light (B). Leptomeninges with oxalate crystals (C). Leptomeninges with oxalate crystals – polarized light (D).

♦♦ Blood should be placed in sodium fluoride tubes to inhibit plasma esterases

Opiates

Cocaethylene Source

♦♦ Oriental poppy (Papaver somniforum)

♦♦ Only metabolite formed from a combination of cocaine and ethanol

Source Drug of Abuse ♦♦ Heroin

Metabolism

Prescription Drugs

♦♦ In vitro studies found that conversion occurs in liver by nonspecific carboxylesterase, which catalyzes the transesterification of cocaine to cocaethylene

♦♦ Morphine, hydrocodone, methadone, and codeine

Route

Effects

♦♦ Injection, ingestion, and smoking

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Metabolism

Increase of blood pressure and pulse Improvement in psychomotor performance More pleasant euphoria Increases in plasma norcocaine concentration Longer half-life

Toxicity ♦♦ Greater cardiotoxicity than cocaine

448

♦♦ Heroin metabolized rapidly to 6-monoacetyl-morphine, which is metabolized to morphine

Half-life ♦♦ Heroin: 5 min ♦♦ 6-monoacetyl-morphine: 15–45 min ♦♦ Morphine: 1–7 h

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♦♦ CNS effect through antiserotonin action

Barbiturates Source ♦♦ Abusive use of medication (e.g., phenobarbital, secobarbital, and amobarbital)

Route ♦♦ Ingestion, injection, drug rarely abused nowadays

Physiologic Effects Fig. 7.53. Healed injection site scars – track marks.

♦♦ Sedative-hypnotic, anticonvulsant

Metabolism ♦♦ P-hydroxylation and conjugation in liver

Physiologic Effects ♦♦ Analgesia, euphoria, drowsiness, respiratory depression, pinpoint pupils, antitussive, hypotension, and lower seizure threshold

Toxicity

Toxicity ♦♦ Central nervous system: hypersensitivity

Autopsy

♦♦ Central nervous system depressant and respiratory depressant

♦♦ Barbiturate “blisters” (6–9% of acute barbiturate intoxication) ♦♦ Globus pallidus necrosis (nonspecific)

Autopsy

Lethal Level

♦♦ Needle tracks (Fig. 7.53), skin popping, foam cone in airway

♦♦ Long-acting, barbiturates 8 mg/dL ♦♦ Short-acting, 3.5 mg/dL

Microscopic ♦♦ Foreign body granulomata in both skin and lungs ♦♦ Lethal levels: variable

Mechanism

Mechanism ♦♦ CNS depressant

♦♦ Bind to opiate receptors in thalamus, limbic system, substantia gelatinosa, periaqueductal gray, blocks nociceptive (pain) reflexes

Psychoactive Drugs Lysergic Acid Diethylamide Source

Amphetamines

♦♦ Drug of abuse

Source

Route

♦♦ Drugs of abuse including designer drugs, amphetamine, methamphetamine, MDA, and MDMA

♦♦ Ingestion

Route ♦♦ Ingestion, injection, and smoking

Physiologic Effects ♦♦ Stimulation, sympathomimetic, and anorectic

Physiologic Effects ♦♦ Hallucination, flashbacks, recurrent episodes of acute intoxication after days or weeks of abstinence, psychosis, and hyperthermia

Metabolism

Metabolism

♦♦ Biotransformation by N-demethylation, N-deethylation, and hydroxylation

♦♦ Methamphetamine metabolizes to amphetamine, which metabolizes to norephedrine

Toxicity

Toxicity ♦♦ CNS and behavior changes ♦♦ Cardiovascular system, arrhythmias, and hypertension ♦♦ Lethal level: variable

♦♦ CNS behavioral effects

Mechanism ♦♦ CNS effect through antiserotonin action

Mechanism

Phencyclidine Source

♦♦ Sympathomimetic

♦♦ Drug of abuse

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Route

Toxicity

♦♦ Ingestion, injection, smoking, and snorting

♦♦ Respiratory depression, seizures, coma, hypotension, and death

Physiologic Effects ♦♦ Hallucinations, lethargy, hypertension, and decreased respiratory rate ♦♦ CNS behavioral effects, respiratory depression, sudden death

Antidepressants Tricyclic Antidepressants Amitriptyline Source

Metabolism

♦♦ Prescription medication

♦♦ Oxidative metabolism to two inactive metabolites

Route

Mechanism

♦♦ Ingestion and injection

Toxicity

♦♦ Blocks dopamine uptake and release of stored cate­ cholamines

Marijuana Source ♦♦ Cannabis sativa plant

Physiologic Effects ♦♦ Mood elevation

Toxicity ♦♦ Hyperthermia, cardiac arrhythmia, coma, and con­vulsions

Mechanism

♦♦ Smoking and ingestion

♦♦ Not well known, but inhibits pump mechanism responsible for uptake of epinephrine and serotonin in adrenergic and serotonergic neurons

Active Component

Metabolism

♦♦ Tetrahydrocannabinol (THC), stored in adipose tissue

♦♦ Amitriptyline metabolizes to nortriptyline (active)

Metabolism

Fluoxetine (Prozac) Source

Route

♦♦ THC (active) is metabolized to 11-hydroxy-THC (active) and 8-hydroxy-THC (active) −− 11-hydroxy-TH metabolized to 11-carboxy-THC (inactive) −− 8-hydroxy-THC metabolized to 8,11-dihydroxy-THC (inactive)

Physiologic Effects

♦♦ Medication

Route ♦♦ Oral

Physiologic Effects ♦♦ Antidepressant, can have side effects of insomnia, anxiety, manic behavior, and suicidal ideation

♦♦ Euphoria, lethargy, drowsiness, anxiety, paranoia, and psychosis

Toxicity

Toxicity

♦♦ Hypertension, tachycardia, and lethargy

♦♦ Rarely lethal, but may have hallucinations

Mechanism

Analysis

♦♦ Blockade of serotonin reuptake

♦♦ THC in blood indicates recent use (within 24–48 h) ♦♦ Carboxy-THC in urine indicates use in past 3–4 weeks

Gamma-Hydroxybutyrate (GHB) Source

Antipsychotics Phenothiazine Source ♦♦ Prescription drug

♦♦ Metabolite of gamma aminobutyric acid

Route

Route

♦♦ Ingestion and injection

♦♦ Ingestion and injection

Physiologic Effects

Physiologic Effects

♦♦ Psychotropic and antiemetic

♦♦ None until combined with alcohol, then drowsiness, euphoria, amnesia, and loss of consciousness

Toxicity

450

♦♦ Central nervous system: behavioral effects

Forensic Pathology

♦♦ Cardiovascular effects: sudden death, tardive dyskinesia, neuroleptic malignant syndrome

Mechanism ♦♦ Strong antiadrenergic and weaker peripheral anticholinergic activity

Metabolism ♦♦ Elimination, slow ♦♦ Conversion to sulfoxide ♦♦ Demethylation

Haloperidol (Haldol) Source ♦♦ Prescription medication

Route

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Acetylsalicylic Acid (Aspirin) Source ♦♦ Over-the-counter medication

Route ♦♦ Ingestion

Physiologic Effects ♦♦ Analgesic, antipyretic, antiinflammatory, and anticlotting effects

Metabolism ♦♦ Hydrolyzed by liver and blood esterases; to salicylic acid (analgesic that accounts for most pharmacological activity of parent drug)

Toxicity

Physiologic Activity

♦♦ Sudden death by hypersensitivity, Reye syndrome, respiratory alkalosis, metabolic acidosis, hemorrhage, or chronic interstitial nephritis

♦♦ Antipsychotic

Lethal Dose

♦♦ Oral, injection

Toxicity

♦♦ 2–5 g

♦♦ Tardive dyskinesia, neuroleptic malignant syndrome, extrapyramidal symptoms, tachycardia, muscular rigidity, ­hypotension, sudden death

Toxic Concentration

Metabolism

Metals Arsenic Source

♦♦ Extensively biotransformed to inactive metabolites

Mechanism ♦♦ Unknown

Analgesics Acetaminophen Source ♦♦ Over-the-counter medication

Route

♦♦ 500 mg/L

♦♦ Pesticides, ceramics, wood preservatives

Route ♦♦ Ingestion, inhalation

Mechanism ♦♦ Inhibition of enzymes by binding to sulfhydryl groups, including respiratory enzymes ♦♦ Predilection for vascular endothelium, increasing permeability

♦♦ Oral ingestion

Toxicity

Physiologic Effects

Lethal Dose

♦♦ Gastrointestinal: nausea and vomiting, abdominal pain, “rice water diarrhea” ♦♦ Cardiovascular: dysrhythmia ♦♦ CNS: peripheral motor and sensory neuropathy ♦♦ Cutaneous: Bowen disease, “Mees lines,” hyperkeratosis of palms and soles, garlic odor

♦♦ 20 g

Autopsy

Toxic Concentration

♦♦ Multiple keratoses, generalized visceral hyperemia, cerebral edema, many have fatty metamorphosis of liver ♦♦ In chronic poisoning, may have hyperkeratosis of hands and soles of feet

♦♦ Analgesic and antipyretic

Toxicity ♦♦ Hepatotoxicity (24–48 h after overdose)

♦♦ >160 mg/L

Autopsy ♦♦ Centrilobular hepatic necrosis

Metabolism ♦♦ Conjugated with glucuronide (45%), sulfate (20%), and cysteine (15–55%)

Microscopic ♦♦ Hepatocellular necrosis, interstitial myocarditis, subendocardial hemorrhage, renal tubular degeneration, hemorrhagic arsenical encephalitis

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Lethal Dose

Autopsy

♦♦ 200–300  mg (normally present in tissues in low concentrations)

♦♦ Hemorrhage in liver and adrenal glands, renal and pancreatic degeneration, pericardial effusions, cardiac dilatation and hypertrophy (beer drinker’s heart disease)

Lead Source ♦♦ Paints, battery, glazing putty, moonshine whiskey

Route ♦♦ Ingestion and inhalation

Toxicity ♦♦ Convulsions, intestinal cramps, hemorrhage, vomiting, ­anemia, peripheral motor neuropathy, Fanconi’s syndrome (aminoaciduria, glycosuria, hyperphosphaturia)

Microscopic ♦♦ Sudanophilic droplets in myocardium

Mechanism ♦♦ Inhibition of enzymes, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase

Thallium Source ♦♦ Medication, over-the-counter preparation, pesticides

Autopsy

Route

♦♦ Lead line in gums at base of teeth, cerebral edema, eosinophilic intranuclear inclusions in proximal convoluted tubules, perivascular PAS + droplets in CNS, basophilic stippling, and increased red blood cell fragility

♦♦ Ingestion

Mechanism ♦♦ Inhibits aminolevulinic acid dehydrase, ferrochelatase, and nucleotidase, which leads to blocked synthesis of hemoglobin

Mercury Source ♦♦ Paint industry, dentistry

Route ♦♦ Inhalation, ingestion, transdermal absorption

Toxicity ♦♦ CNS: emotional lability, depression, outbursts of anger, insomnia ♦♦ Kidney: acute renal failure

Autopsy

Toxicity ♦♦ Alopecia with sparing of axillary, facial hair, and inner onethird of eyebrows, abdominal pain, vomiting, and ataxia

Autopsy ♦♦ Alopecia

Microscopic ♦♦ Degenerative changes in the neurons and nerve fibers

Other Chemicals Organophosphates Source ♦♦ Insecticides

Route ♦♦ Inhalation, ingestion, and absorption

Toxicity ♦♦ Muscular paralysis, respiratory failure, blurred vision, salivation, sweating, and convulsions

♦♦ Swollen kidney with dark pyramids, atrophy of cerebral cortex and cerebellum

Autopsy

Microscopic

♦♦ Nonspecific

♦♦ Neuronal loss and gliosis

Mechanism

Mechanism

♦♦ Cholinesterase inhibition with accumulation of acetylcholine (look for decreased cholinesterase in blood)

♦♦ Precipitation of proteins and inhibition of multiple enzyme systems, such as oxidative mitochondrial phosphorylation, and cytochrome C oxidase

Strychnine Source

Cobalt Source

Route

♦♦ Industry, medication, beer, radioactive cancer therapy

♦♦ Ingestion, injection, inhalation

Route

Toxicity

♦♦ Ingestion, inhalation, radiation

♦♦ Stimulant, seizures (sardonic rigor), muscular paralysis

Toxicity

Autopsy

♦♦ Nausea, vomiting, paralysis, hypotension

♦♦ No specific finding

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♦♦ Rodenticides

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Mechanism

Route

♦♦ Blockade of post synaptic neuronal inhibition

♦♦ Inhalation

Lethal Dose

Toxicity

♦♦ 60–100 mg

♦♦ Arrhythmias, central nervous depression, simple asphyxia

Freons Source

Autopsy ♦♦ No specific findings

♦♦ Air conditioners, refrigerators, aerosol cans

Suggested Reading General Ackerman MJ, Tester DJ, et al. Molecular diagnosis of the inherited long QT syndrome in a woman who died after near-drowning. N Engl J Med 1999;341:1121–1125. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001;286:2264–2269. Adelson L. Pathology of Homicide. Springfield, IL: Charles C. Thomas; 1974. Berastein T. Effects of electricity and lightning on man and animals. J Forensic Sci 1973;18:3–11. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240–1244. Case ME, Graham MA, Handy TC, et al. Position paper on fatal abusive head injuries in infants and young children. Am J Forensic Med Pathol 2001;22:112–122. Cebelin MS, Hirsch CS. Human stress cardiomyopathy-myocardial lesions in victims of homicidal assaults without internal injuries. Hum Pathol 1980;11:123–132. Coe JI. Postmortem chemistry update: emphasis on forensic application. Am J Forensic Med Pathol 1993;14:91–117. Committee on Child Abuse and Neglect. American Academy of Pediatrics. Shaken baby syndrome: inflicted cerebral trauma. Pediatrics 1993;92: 872–875. Corey TS, Hanzlick R, Howard J, et al. A functional approach to sudden unexplained infant deaths. Am J Forensic Med Pathol 2007;28:271–277. Croft PR, Reichard RR. Microscopic examination of grossly unremarkable pediatric dura mater. Am J Forensic Med Pathol 2009;30:10–13. Davis GG. Mind your manners. Part I: history of death certification and manner of death classification. Am J Forensic Med Pathol 1997;18:219–223. Davis JH, Wright RK. The very sudden cardiac death syndrome – a conceptual model for pathologists. Hum Pathol 1980;11:117–121. Dec GW, Fuster V. Idiopathic dilated cardiomyopathy. N EngI J Med 1994;33l:1564–1575. DeSanctis RW, Doroghazi RK, Austen WG, et  al. Aortic dissection. N Engl J Med 1987;317:1060–1065. Dolinak D. Review of the significance of various low force fractures in the elderly. Am J Forensic Med Pathol 2008;29:99–105. Dolinak D, Matshes E, Lew E. Forensic Pathology, Principles and Practice. Burlington, MA: Elsevier Academic Press; 2005. Donoghue ER, Graham MA, Jentzen JM, et al. Criteria for the diagnosis of heat related deaths: National Association of Medical Examiners. Position paper. Am J Forensic Med Pathol 1997;18:11–14.

Duncanson E, Richards V, Luce KM, Gill JR. Medical homicide and extreme negligence. Am J Forensic Med Pathol 2009;30:18–22. Ely SF, Hirsch CS. Asphyxial deaths and petechiae: a review. J Forensic Sci 2000;45:1274–1277. Frohlich ED, Apstein C, Chobanian AV, et al. The heart and hypertension. N Engl J Med 1992;327:998–1007. Geddes JF. What’s new in the diagnosis of head injury. Clin Pathol 1997;50:271–274. Gill JR, Goldfeder LB, Armbrustmacher V, et  al. Fatal head injury in children younger than 2 years in New York City and an overview of the shaken baby syndrome. Arch Pathol Lab Med 2009;133:619–627. Gill JR, Goldfeder LB, Hirsch CS. Use of “therapeutic complication” as a manner of death. J Forensic Sci 2006;51:1127–1133. Gilman S. Advances in neurology. N Engl J Med 1992;326:1671–1676. Goodin J, Hanzlick R. Mind your manners. Part II: general results from the National Association of Medical Examiners manner of death questionnaire. Am J Forensic Med Pathol 1997;18:224–227. Gulino SP. Examination of the cardiac conduction system-forensic application in cases of sudden cardiac death. Am J Forensic Med Pathol 2003;24:227–238. Guze BH, Baxter LR Jr. Neuroleptic malignant syndrome. N Engl J Med 1985;313:163–166. Hanzlick R, Goodin J. Mind your manners. Part III: individual scenario results and discussion of the National Association of Medical Examiners manner of death questionnaire, 1995. Am J Forensic Med Pathol 1997; 18:228–245. High KA. Antithrombin III, Protein C, and Protein S. Arch Pathol Lab Med 1988;112:28–36. Hirsch CS, Adelson L. Absence of carboxyhemoglobin in flash fire victims. JAMA 1969;210:2279–2280. Hirsch CS, Flomenbaum M. Problem-solving in death certification. ASCP Check Sample. FP95-1 1995;37. Hirsch CS, Zumwalt RE. Forensic pathology. In: Damjanov I, Linder J (eds) Anderson’s Pathology, 10th edn. St Louis, MS: CV Mosby; 1996:80–109. Iafolla AK, Browning IB, Roe CR. Familial infantile apnea and immature beta-oxidation. Pediatr Pulmonol 1995;20:167–171. Kemp PM, Little BB, Bost RO, et al. Whole blood levels of dodecanoic acid – a routinely detectable forensic marker for a genetic disease often misdiagnosed as Sudden Infant Death Syndrome (SIDS): MCAD deficiency. Am J Forensic Med Pathol 1996;17:79–82. Knudson MM, Collins JA, Goodman SB, et al. Thromboembolism following multiple trauma. J Trauma 1992;32:2–10.

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Koiwai EK. Deaths allegedly caused by the use of choke holds (ShimeWaza). J Forensic Sci 1987;32:419–432. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997;336:267–276. Levy V, Rao VJ. Survival times in gunshot and stab wound victims. Am J Forensic Med Pathol 1988;9:215–217. Ludemose JB, Kolvraa S, Gregersen N, et al. Fatty acid oxidation disorders as primary cause of sudden unexpected death in infants and young children. Mol Pathol 1997;50:212–217.

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Schievink WI. Intracranial aneurysms. N Engl J Med 1997;336:28–40. Schwartz AJ, Ricci LR. How accurately can bruises be aged in abused children? Pediatrics 1996;97:254–257. Spirito P, Seidman CE, McKenna WJ, et al. The management of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775–785. Spitz WU, ed. Spitz and Fisher’s Medicolegal Investigation of Death, 4th ed. Springfield, IL: Charles C. Thomas; 2006. Splawski I, Timothy KW, Vincent GM, et al. Molecular basis of the long QT syndrome associated with deaf. N Engl J Med 1997;336:1562–1567.

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Moritz AR, Henriques FC Jr, Dutra FF, et al. Studies of thermal injuries. Arch Pathol 1947;43:466–488.

Strauss RH, Prockopld LD. Decompression sickness among scuba divers. JAMA 1973;223:637.

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Sutton JR. Mountain sickness. Neurol Clin 1992;10:1015–1029.

Nimura H, Bachinski LL, Sangnatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein and late onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248–1257. Patten BM. Lightning and electrical injury. Neurol Clin 1992;10:1047–1057.

Tester DJ, Ackerman MJ. The role of molecular autopsy in unexplained sudden cardiac death. Curr Opin Cardiol 2006;21:166–172. Tomashefski JF, Hirsch CS. The pulmonary vascular lesions of intravenous drug abuse. Hum Pathol 1980;11:133–145.

Pearl GJ. Traumatic neuropathology. Clin Lab Med 1998;18:39–64.

Wetli CV. Keraunopathology – an analysis of 45 fatalities. Am J Forensic Med Pathol 1996;17:89–98.

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Priori SG, Schwartz PJ, et al. Risk Stratification in the long QT syndrome. N Engl J Med 2003;348:1866–1874.

Wright RK, Davis JH. The investigation of electrical deaths: a report of 220 fatalities. J Forensic Sci 1980;25:514.

Randall BB, Fierro MF, Froede RC, et al. Practice guideline for forensic pathology. Arch Pathol Lab Med 1998;122:1056–1064.

Zumwalt RE, Hirsch CS. Medicolegal interpretation of gunshot wounds. Am J Emerg Med 1987;5:133–139.

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8 AUTOPSY Dean A. Hawley, md

Contents

I. Before the Autopsy...............................8-2

Universal Precautions........................................8-2 Routine......................................................8-2 Prion Diseases...........................................8-2 Medicolegal Jurisdiction....................................8-2 Trauma......................................................8-3 Child Deaths and Specific Medicolegal Cases...............................8-3 Consent................................................................8-3 Legal Requirements for Informed Consent................................8-3 Legal Next-of-Kin.....................................8-3 Restrictions on Examination.............................8-4 Complete and Partial Autopsy................8-4 Resolving Issues with Autopsy Restrictions...........................8-4 Retention of Organs and Tissues......................8-4 Organ and Tissue Donation...............................8-4 Review of the Medical Record...........................8-5

II. During the Autopsy..............................8-5

Internal Examination.........................................8-7 Organ-by-Organ Removal by the “Virchow Method”..............................8-7 In Situ Block Dissection by the “Rokitansky method”.........................8-7 Examination of the Organs...............................8-9 Ancillary Procedures........................................8-11

III. After the Autopsy...............................8-12 Death Certificate...............................................8-12 Cause of Death........................................8-12 “Unknown” Cause of Death..................8-13 Sudden Death..........................................8-13 Autopsy Conference Presentation...................8-13 Discussion with Clinicians and Family...........8-13 Autopsy Quality Management Programs......................................................8-13 ACGME/RRC Case Log System.....................8-13

IV. Suggested Reading.............................8-14

External Examination........................................8-5

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_8, © Springer Science+Business Media, LLC 2002, 2006, 2011

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BEFORE THE AUTOPSY Universal Precautions Routine ♦♦ Strict observation of universal precautions ♦♦ Pathogens are not ameliorated by refrigeration, embalming, or time since death, and risks are significant

−− The physician conducting the autopsy must mandate that all participants are properly versed and follow the specialized universal precautions −− Special precautions on autopsy procedures for patients with prion diseases are specified by College of American Pathologists (CAP) laboratory accreditation requirements

Prion Diseases

Medicolegal Jurisdiction

♦♦ With alleged or presumptive prion diseases (Creutzfeldt– Jakob, Mad Cow, Gerstmann–Sträussler–Scheinker), the autopsy service director needs to be informed before the autopsy −− Consult your autopsy room procedure manual for special requirements

♦♦ The logical sequence of events beginning with a request for a hospital autopsy, and leading up to examination of the body, is illustrated in Fig.  8.1. This process starts with an independent determination of whether the medicolegal authority needs to be contacted and then follows through the determination of validity of the consent process

Fig. 8.1. Logical diagram for the sequence of procedures involved for ascertaining medicolegal jurisdiction, validating a consent, identifying the body, and examining the body at autopsy.

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Autopsy

8-3

Trauma ♦♦ Review circumstances of the case ♦♦ Independently determine that the case must or must not be reported to the medicolegal authorities −− The hospital admitting office may have already made a determination, but this must be checked before beginning. If the patient was admitted to the hospital for treatment of an injury, such as a motor vehicle collision or a fall, then it is likely to be a legal duty to contact the proper authority −− In general, but not specific to any location, a death must be reported prior to autopsy if the death is a complication of trauma −− The autopsy physician must first seek a release from the medicolegal authority before entertaining an autopsy in such a case

Child Deaths and Specific Medicolegal Cases ♦♦ Some states have laws mandating that certain deaths be reported to the authorities −− Commonly encountered statutes include mandatory reporting for child deaths, death of patients referred from extended care facilities, or other special circumstances −− The autopsy room procedure manual should be a resource for information about specific legal duties for reporting deaths

♦♦

♦♦

♦♦

Consent Legal Requirements for Informed Consent ♦♦ Determine that the consent for autopsy is proper −− The legal duty for the pathologist is to prepare a policy and follow a procedure, whereby the consent process fulfills legal requirements −− Legal requirements for informed consent are somewhat variable among the states. Be knowledgeable about local requirements, and review the autopsy room procedure manual instructions −− Medicolegal cases under the authority of a medical examiner or coroner have consent requirements different from routine hospital cases −− Routine hospital autopsies require informed consent from the person who is the closest surviving relative of the patient, the legal next-of-kin

Legal Next-of-Kin ♦♦ Observe the requirements for determining that the death need not be reported to the medicolegal authorities ♦♦ Inspect the consent form to determine if the form follows, in good faith, a proper informed consent ♦♦ The person giving consent for autopsy must be the legal next-of-kin −− Local laws will exactly spell out a sequence for the determination of the one person who is the legal next-of-kin

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−− Only that person, and no one else, can sign the autopsy consent −− Check the hospital admitting record to see if the admitting clerk has filled in the name of a person as the legal next-of-kin at the time the patient was admitted. If so, this is the person who shall have signed the autopsy consent, and the consent is probably not valid if any other person signed the consent −− It is, however, quite possible that the admitting clerk has made a mistake in completing that information, or that the patient was admitted with that information field blank on the admitting form, so the accuracy of the information must always be checked The priority for next-of-kin is established in law, and it does vary. In some jurisdictions there can be a “common law spouse,” who may be the legal next-of-kin, whereas other jurisdictions do not recognize such a status In general, but not in every jurisdiction, the top priority for consenting an autopsy goes to the lawful spouse, and no other person can give consent, even if the spouse is “estranged,” “legally separated,” “incarcerated,” or “of unknown whereabouts” −− In such a case, no one else can give consent, and the autopsy process must stop without autopsy −− There is no remedial solution for this problem If a spouse does not exist because the patient was never married, or the spouse has died, or there is a finalized legal divorce, then in most jurisdictions the consent is next obtained from an adult child, if an adult child exists −− If there is more than one adult child, there is no legal provision for determining which adult child is the nextof-kin −− If there is apparent discord, disagreement, or dysfunction within the family, seek advice from the autopsy service director For a patient without a spouse, and without an adult child, the autopsy consent becomes extremely unclear in many jurisdictions −− Quasi-legal documents of “power of attorney,” or “medical power of attorney,” or “durable power of attorney,” or “legal guardian” do not ever, in any circumstance, afford the power to consent an autopsy. All of these legal appointments end immediately upon death, and cannot be used to provide consent for autopsy, even when the guardian is court appointed or represents a state social service agency For pediatric autopsies, the ideal consent is from the mother. If mother is herself a child, it is best for the consent to be cosigned also by the maternal grandmother of the infant. Lesser levels of signature present potential problems, especially if the consent is only signed by the alleged father, where paternity has not been established by any mechanism other than the name on the birth certificate −− Always check with the autopsy service director before starting an autopsy if the consent is q­ uestionable

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Restrictions on Examination Complete and Partial Autopsy ♦♦ After confirming the consenting person, check the consent form to see if there are any restrictions placed on the autopsy examination −− Typically, autopsy consents allow “complete autopsy,” or “chest and abdomen” −− Additional specific limited requests, like “chest only,” “heart only,” or even “liver biopsy only,” do sometimes appear on consents, and such restrictions must be followed exactly ♦♦ A complete autopsy is an unrestricted examination of the body, and at least includes the brain, and internal organs of the neck, chest, abdomen, and pelvis −− In some hospitals, or for certain types of diseases, the word “complete” also mandates a complete removal and examination of the spinal cord, such as for Guillain–Barré Syndrome, where the diagnosis simply cannot be made unless the dorsal root ganglia of the cord are obtained and submitted for microscopic examination −− This means checking with an autopsy reference book, such as Ludwig’s Handbook of Autopsy Practice, to determine if there is something special needed for diagnosis −− Eyes are needed for von Hippel–Lindau syndrome, and many other conditions, and these may not be part of a “routine complete autopsy” at many institutions ♦♦ For autopsies that are restricted by consent to particular organs or body topography (i.e., “chest and abdomen only” or “chest only”) the examination is restricted or limited to the organs within the consented body cavity only

Resolving Issues with Autopsy Restrictions ♦♦ If the autopsy has a medical issue wherein the diagnosis cannot be established due to the limitations of the dissection, it is always best to call the physician who requested the autopsy to see if that physician was aware of the restrictions, and aware of the impact these restrictions will have on the quality of information obtained by the autopsy ♦♦ In a “chest only” autopsy, there will not be an examination of the liver, even if the liver is visible during the dissection. There will not be an examination of the larynx even though the intrathoracic portion of the trachea is examined ♦♦ The clinicians need to be aware if restrictions prevent answering specific questions about locations of therapeutic devices, such as the endotracheal tube or a vena cava filtration device

Retention of Organs and Tissues ♦♦ Retention of organs and tissues after an autopsy, especially the brain, is a controversial practice −− Historically, retention of the organs has been done by pathologists worldwide for decades, but public outcry is

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beginning to limit that practice in some countries and some institutions −− Retention of tissues and organs by formalin fixation does simplify the process of learning proper autopsy procedure, because the organs are available for future consultation with pathologists. However, not all institutions permit the autopsy physician to retain organs −− There will be a procedure or consent policy statement concerning retention of organs and tissues, and that policy must followed. In Great Britain, and in a spreading list of geographic locations, retention of tissues, even the brain, may be forbidden. In that case, staffing of the autopsy may be compelled to happen directly during the procedure, and the only specimens retained may be the microscopic tissue block specimens ♦♦ Before the autopsy, review the procedure manual or discuss the policy with autopsy staff, and comply with the policy. Most pathology residents will be working at institutions where complete retention of organs is the ordinary practice

Organ and Tissue Donation ♦♦ Laws pertaining to organ and tissue donation vary across the United States and worldwide ♦♦ The consent to obtain tissues for medical or commercial donation, even corneas, from the body before or after autopsy is determined by the tissue bank facility, usually coordinated with the autopsy facility ♦♦ Ultimately, consent for collection of medical, commercial, or research human tissues is to be provided by the tissue bank, not the pathology lab ♦♦ It is always incumbent upon the physician conducting the autopsy to coordinate the autopsy, and access to the body, with any organ or tissue procurement agency once that agency has proper consent −− The medical suitability of tissues for donation is not determined by the pathologist, it is made by the tissue bank; but the history of risk factors for communicable diseases and metastatic cancer should be made clear in communication with the procurement agency if the pathologist determines that a risk factor MAY exist −− The medical suitability of tissues is dependent on the overall postmortem interval, so timely discussion and coordination with the procurement agency may require scheduling the autopsy to best permit donation −− Autopsy can be done either before or after donation of skin, bones, corneas, and other tissues. From the standpoint of the procurement agency, they will generally want to go first, but that can change from case to case −− Any organ or tissue removed for donation will not be examined at autopsy. The whole heart is removed to obtain heart valves for donation, so if heart valves are to be obtained, then there will be no autopsy examination of the heart

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Review of the Medical Record ♦♦ Review and approve the consent ♦♦ Prepare for the autopsy with a review of the hospital chart, as mandated by CAP and Residency Review Committee (RRC) requirements −− Become completely familiar with the past medical history prior to the current hospitalization, as this history is always pertinent to the dissection and examination of the organs −− Read through the medical chart, radiograph reports, and clinical laboratory data ♦♦ Determine if there are any clinical lab tests, such as microbiologic cultures, that might be pending when the patient died −− Many hospitals direct the clinical laboratory to discontinue pending clinical lab testing upon death of the patient.

If there are pending microbiologic cultures, make sure these are not discarded −− If cultures are pending, call the microbiology lab or the resident on microbiology to ensure that the cultures get completed under the autopsy case number if they have been deleted from the patient admitting number ♦♦ Determine if the diseases indicated in the clinical history will require any sort of specialized dissections as outlined above under “Restrictions on Examination” ♦♦ If spinal dorsal root ganglia or eyes are needed to establish a diagnosis then the time to prepare for that dissection is during your review of the medical history −− You may need special preservation media for cultures or electron microscopy and you should get those media or containers in the autopsy room before opening the body

DURING THE AUTOPSY External Examination ♦♦ Check the hospital identification tags on the body to make sure the correct patient is on the autopsy table ♦♦ If the hospital identification bracelet or tag does not agree with the name and hospital number on the autopsy consent then do not proceed. Identity must be assured before conducting the internal examination ♦♦ Make a list and take photos of any property or jewelry with or upon the body using nonspecific descriptive language, such as yellow or white metal rings on fingers, earrings, dentures −− Example: Do not describe “a gold band ring and diamond on the left ring finger;” instead describe “a yellow-colored band ring with clear stone on the left ring finger” ♦♦ Regardless of the limitations from the consent, the entire external body must be examined and documented −− Record all clothing, jewelry, medical hardware devices, surgical scars, and deformities −− Undress the entire body and remove all bandages, but leave all the medical lines and tubes in place ♦♦ Diagrams are useful to locate medical therapeutic devices, even when there is temporary uncertainty about the technical function of the external device. At this preliminary stage in the autopsy, it is entirely possible to have a tube come out through the skin, and to be unsure whether that particular tube is intravenous, arterial, or even into a body cavity or drainage site as in Fig. 8.2 −− Nonspecific terminology like “vascular catheter” and “surgical drainage tube” is far preferable then to guess and potentially misidentify a peritoneal dialysis catheter as a gastric feeding tube

−− Locations of needle puncture sites should be marked −− Measure surgical wounds, indicating sutures and staples −− Describe scars by location and length, but not by surgical type. For example, do not describe a lower abdominal scar as a “hysterectomy scar,” when a patient may have had a cesarean section, and then later had a vaginal hysterectomy −− Describe all skin injuries, including burns from defibrillator paddles, ecchymoses around needle puncture sites, senile purpura, vascular stasis ulcers, and remarkable skin lesions −− Describe locations of tattoos, but use only brief nonspecific language to describe tattoos. It is preferable to say “multicolor tattoo with wording” than to be graphic in describing a nude image with vulgar inscription. Photos are to be obtained, and those photos are the ultimate reference for tattoo specifics, so the description should be left quite brief −− Do specifically examine the sacrum for evidence of decubitus ulcer and document by written description, the presence OR the absence of such an ulcer ♦♦ Photograph the whole body after removal of all the clothing, gowns, drapes, and surgical wound bandages −− Take the photos while the medical hardware is still in the body to assist later with documenting the nature of the medical tubes in the final autopsy report −− Photograph the front and back of the body, the face for identity, the hospital identification tag on the body, and take a photograph of the hospital autopsy case number −− If a decubitus ulcer was found during the external examination, photograph it with a measuring device within the field of the image

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Fig. 8.2. This example illustration of a typical body diagram chart shows nonspecific terms for medical hardware devices often found on the body, where the actual name or internal location of the device will only be revealed during the internal examination, so the description of the device should be generic on the external diagram.

♦♦ Measurements of the body, at least height and weight, should always be documented −− Further measurements like arm span, eye spread, and ear placement may be indicated in certain pediatric cases. Consult Handbook of Autopsy Practice and Potter’s Pathology of the Fetus, Infant and Child for tables of measurements ♦♦ Decomposition begins at the moment of death −− The rate of progression of decomposition depends on the overall health at death −− Sepsis at death can greatly accelerate decomposition by putrefaction −− Additional factors include the rate of cooling of the body by use of refrigeration, where some patients do not promptly go to refrigerated storage immediately after death, and some patients have obesity or fever or other factors that inhibit cooling of the internal organs

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−− The end result is a degree of autolysis of the internal organs by way of enzymatic degradation of the cells, and putrefaction by postmortem bacterial colonization and fermentation ♦♦ Decomposition is happening in every case, but the extent of autolysis is multifactorial, and not consistent when viewed as simply a factor of the duration of time since death ♦♦ External manifestations of postmortem decomposition changes need to be documented at the time of autopsy, to include −− the presence of livor mortis, blanching or not −− rigor mortis, generalized or regional, and −− the beginning putrefaction ♦♦ When death is attended by septicemia and any factor that prevents or slows the process of cooling the body by refrigeration, it is typical to see evidence of beginning putrefaction

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within just a few hours of death, perhaps to the point of bloating, skin slippage, purging of malodorous fluids from the mouth and nose, and green marbling of the cutaneous vessels. Such findings need to be documented as a way to establish a rationale for a failure to determine diagnosable diseases

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Internal Examination ♦♦ Begin by checking a specific autopsy reference book, such as Handbook of Autopsy Practice, to see if there are any special specimens or dissection protocols that are indicated in the patient’s medical history −− Cultures of blood, and blood for toxicology, should be obtained before opening the body at autopsy −− The quality of autopsy microbiologic cultures is greatly improved if the blood is obtained by percutaneous needle puncture before opening the body. This is not always possible. Fetuses and small infants have a very low blood volume, small vessels, and difficult access. Adults can have significant blood loss after surgery or gastrointestinal bleeding, and can have extensive postmortem coagulation of blood, making it difficult to obtain a percutaneous clean sample −− With adults, try to get blood via percutaneous subclavian needle puncture for blood culture, if indicated. Some autopsy services request this on every case, other autopsy services handle it on an “as needed” basis, so check with autopsy staff if the policy is uncertain ♦♦ The value of postmortem microbiologic culture is quite debatable, where the result of the culture is rarely helpful in determining an etiology for infection, and the cost of the culture testing is large −− If cultures were obtained in life, and those cultures have been secured with the microbiology lab so that they will be completed even after the patient’s death, then they are the best evidence for etiology of sepsis ♦♦ Toxicology may be desirable in some cases, and highly recommended if the patient was on a patient-controlled anesthesia machine ♦♦ When blood for cultures and/or toxicology cannot be obtained via subclavian venipuncture, then it must be obtained from inside the body after opening the body ♦♦ If consented for chest and abdomen, make a “Y” incision through the skin from each distal clavicle to the base of the xiphoid, continuing from there down the midline of the abdomen to the left of the umbilicus and on to the pubic symphysis ♦♦ If only the chest is consented, then make a “U” incision from one distal clavicle directly down the anterior axillary line to the lowest rib, then across the anterior chest to the opposite anterior axillary line and back up to the opposite distal clavicle. Keep the breasts medial to the line of incision ♦♦ If only a limited abdominal exam is consented, make a “T” incision starting with a transverse horizontal line across the anterior abdomen below the diaphragm, and then connect

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the midpoint of this incision down the anterior abdominal wall to the pubis With the organs in place, examine the interior of the pleural and peritoneal cavities for hemorrhage (Fig. 8.3A), exudates (Fig. 8.3B), effusion (Fig. 8.3C), and adhesions −− Measure any fluid accumulations in the pleural cavities, pericardial sac, and peritoneal cavity −− Weigh solid blood clots that lie in the body cavities −− Confirm the position of any medical therapeutic lines or tubes (Fig. 8.3D) −− Check for pulmonary hyperinflation due to asthma (Fig. 8.3E) The chest dissection begins by opening, the pericardial sac and incising the pulmonary trunk to check for a large, conspicuous pulmonary thromboembolism, or froth in blood from air embolism Air embolism is not common but, when present, it is usually evident as froth and bubbles in the pulmonary artery, so documentation by photography is essential if this is a possibility based on your clinical evaluation of the medical record Even though pulmonary thromboembolism is common and obvious, it is often missed at autopsy because clots can fall into the chest cavity during removal of the heart, and the autopsy technical assistant may dismiss it as postmortem clot −− If thromboembolism is present, then a dissection of the leg veins should be done (if permitted by the consent) after the examination of the organs of the chest and abdomen to confirm the location of the clotted vein. Once an examination for large pulmonary artery embolism has been done, then the organs of the chest and abdomen can be removed

Organ-by-Organ Removal by the “Virchow Method” ♦♦ Organ removal, organ-by-organ (so-called “Virchow method”), is the best way for the beginning autopsy physician to learn the autopsy dissection procedure, and to guarantee that the continuity and integrity of the viscous organs has been examined and confirmed −− The organ-by-organ dissection may not be helpful, even detrimental, in determining vascular supply to organ systems, such as thrombosis of the superior mesenteric artery, or for determining the vascular connections in congenital heart disease

In Situ Block Dissection by the “Rokitansky method” ♦♦ For cases of bowel infarction (Fig.  8.3F), and for cases of congenital malformations, a classic in situ block dissection for confirmation of anatomic continuity of organ systems, followed by individual organ or block removal, as directed by the in situ inspection as in the so-called Rokitansky method, may be desirable −− Complete block dissection is performed by isolating the trachea, esophagus and aorta at the cervicothoracic inlet,

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Fig. 8.3. (A) This hemoperitoneum needs to be measured, by weighing solid blood clot and scooping out the liquid for measurement. (B) The peritonitis needs to be documented by description and microscopic slide examination. Note that the entire peritoneum is not inflamed, the peritonitis is localized. (C) This pericardial effusion needs to be scooped out and measured. (D) Medical devices can be found sometimes in errant positions. This chest tube has lacerated the visceral pleura and penetrated the right lung. (E) This lung is hyperinflated by air-trapping from acute asthma. The hyperinflation is best evaluated while the lungs and heart are still inside the chest cavity. (F) This bowel shows segments of dark ischemic change. Examination of the mesenteric vasculature in patients with segmental bowel infarct may be done by Rokitansky block dissection to look for obstruction or clot in the arterial supply vessels. (G) Subarachnoid hemorrhage in the absence of subdural hemorrhage. (H) The adventitial surface of a dissected aorta, in this case a true “double barrel” aorta without rupture of the adventitia into a body cavity. (I) The intimal separation and medial dissection of the aorta shown in H, in this case resulting in arterial outflow obstruction of the celiac axis, superior mesenteric artery, renal arteries, and spinal perforator arteries. and dissecting these away from the spine down through the diaphragm to the pelvic floor. The resulting block can include the larynx, heart, lungs, aorta, liver, spleen, small and large bowel, kidneys, adrenals, ureters, bladder, and uterus −− The complete block excision procedure yields a large and cumbersome anatomically complex specimen that is difficult for the beginning residents to properly orient and interpret, but this technique yields the best specimens for surgical anatomy comparisons

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♦♦ Pediatric patients with complex congenital heart disease are frequently best examined by removal of the heart, lungs, thoracic aorta, and thoracic segment of the esophagus as a single contiguous block, with subsequent formalin fixation of the entire specimen, and then dissection later using a surgical or dissecting microscope ♦♦ Pediatric patients with hydronephrosis and/or cystic kidneys may have obstruction or congenital anomaly of the lower genitourinary tract. In this specialized circumstance, a desirable dissection can include both kidneys attached to the

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abdominal aorta and inferior vena cava, and in continuity with both ureters attached to the bladder and upper portion of the urethra. Consult Potter’s Pathology of the Fetus, Infant and Child for suggestions and illustration of these specialized dissections

Examination of the Organs ♦♦ NOTE: The following suggested dissection procedures and histology block list apply to the examination of organs and organ systems where no gross pathologic lesions are recognized, and those organs appear normal. If lesions are present, then those lesions need to be submitted for histology, where the sections are best obtained at the edge of the lesion, including both the lesion and the adjacent normal tissue in the same block.

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The Brain ♦♦ Examination of the brain starts with examination of the scalp for surgical scars, traumatic injury, or subcutaneous placement of interventricular shunt devices −− Most cases of traumatic brain injury will have been deferred to the local medical legal authority, so it will not be a frequent issue at hospital autopsy. However, as a surprise finding during routine hospital autopsy, the presence of a completely unknown or unexpected head trauma can happen, and this should not be a complete surprise to the hospital autopsy physician −− Blunt force injuries of the brain must be interpreted in the context of scalp injury, so careful attention must be paid to the external scalp skin, and to the undersurface of the reflected scalp −− It is possible to have a fatal head trauma without external skin evidence of injury, but such cases should have internal evidence of injury under the scalp −− The so-called shaken baby syndrome may be an exception, where there is a fatal head injury but no contusion under the scalp skin −− Photographs of areas of hemorrhage on the undersurface of the scalp will be very helpful to prove specific locations, and to discern relationships of bleeding to sites of medical intervention such as neurosurgical procedures or scalp intravenous lines or needle punctures. Subarachnoid bleeding can be found in the absence of scalp contusion or subdural hematoma (Fig. 8.3G) ♦♦ Following documentation of the scalp, the saw incision around the circumference of the skull will permit examination of the epidural and subdural spaces, as per the procedures outlined in Manual of Basic Neuropathology −− A hand saw may be required in the event of potential prion disease, but electric saw is typically used for routine cases −− If the convexity dura is completely adherent to the calvarium, then no epidural hematoma exists −− If the dura is not adherent to the calvarium, then it should be left over the brain as the calvarium is removed −− Subdural hematoma may be evident at the gross dissection and then completely absent when the formalin-fixed brain is examined later, so subdural blood needs to be

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documented by photographs and measurements during removal of the brain. This is typically done by incising and reflecting the dura around the circumference of the cut bone edges around the circumference of the base of the skull −− The brain should be removed with the olfactory bulbs, optic nerves and chiasm, pituitary, carotid arteries at the dural insertion, and vertebral arteries at the dural insertion −− The dura from the base of the skull should then be stripped out and saved with the brain for examination after formalin fixation Short segments of spinal cord can be sampled by anterior laminectomy through the anterior vertebral bodies, but a complete examination of the cord is best done by dorsal laminectomy with removal of the entire theca and dorsal root ganglia −− A dorsal laminectomy must be done in order to get the dorsal roots, as these are not readily accessible by anterior dissection The theca must be opened down the entire length of the cord before formalin fixation, or shrinkage of the theca during fixation will produce an artifactual damage of the cord Once the organs are removed, examine the internal body cavities for evidence of fractures of the ribs, spine, or pelvis Obtain a bone sample for bone marrow examination Strip the dura from the base of the skull and examine for basilar skull fracture Look for chest wall, peritoneal, or boney sites for metastasis or abscess and sample as needed Check the aorta for dissection (Fig. 8.3H, I)

The Neck ♦♦ Examine the muscles for evidence of hemorrhage ♦♦ Remove the thyroid gland from the larynx ♦♦ Section through the thyroid for nodules and submit Block 1 from lesions or normal tissue (Fig. 8.4A) ♦♦ Identify parathyroids and include the largest in Block 1 with the thyroid ♦♦ Open the esophagus and pharynx ♦♦ Open the larynx posteriorly, through the anterior wall of the esophagus

The Heart ♦♦ Weigh the heart ♦♦ Identify the anatomic distribution of the epicardial coronary arteries to confirm the location of the right main, left anterior descending, and circumflex (usually left circumflex) coronary arteries, as shown in Fig. 8.4B ♦♦ If the arteries are not so calcified so as to prohibit crosscutting with a scalpel blade, section across each vessel at segment intervals about every 5 mm from the origin, continuing out at least 3–4 cm along the length of each vessel, and identify the worst segment of atherosclerotic narrowing in each vessel. In Blocks 2–4, submit samples of each separate artery

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Fig.  8.4. (A) Illustration of a typical method for cutting through the thyroid gland to look for lesions, and a typical location for ­obtaining a block of tissue to submit for histology if the thyroid does not have a lesion. (B) Illustration of the typical process for cross-sectioning the major coronary arteries, at 5 mm intervals, to evaluate for atheroma or thrombosis, and to obtain sections for routine histology. The typical location for making cross-sections through the ventricles is also shown. (C) Illustration of a “ring” of left and right ventricle with interventricular septum as produced by a crosscut as in B above. The resulting ring permits thickness measurements for the left ventricle free wall, septum, and right ventricle, and permits blocking out sections to submit for routine histology. (D) Illustration of the dissection of the tracheobronchial tree, and the location where routine histology blocks should be obtained.

to show the worst areas of atherosclerosis. Decalcify these blocks if needed −− If the vessels cannot be sectioned with a scalpel due to extensive calcification, then use heavy scissors and crush each segment to cut through with the ­scissors. This destroys some plaque, but protects fingers from potential injury −− Never open the vessels by longitudinal cutting, as this prohibits estimation of narrowing by plaque ♦♦ If the vessels are normal, they can be commingled in a single cassette to save expense on unnecessary blocks ♦♦ Crosscut the apex of the heart to create three to four “rings” of the ventricles as shown in Fig.  8.4C. Do not cut higher than the base of the posterior papillary muscle bundle of the left ventricle, so that tendineae cordae are not cut off their papillary muscle insertions

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♦♦ Measure the wall thicknesses of the left ventricular free wall, interventricular septum, and right ventricle for the highest of the “ring” sections ♦♦ Using scissors, open the heart valves in the direction of blood flow through the heart ♦♦ Measure the total circumference of each separate heart valve ♦♦ Submit sections of normal heart as follows (see Fig. 8.4C) −− Block 5 is lateral free wall of left ventricle, to include epicardium and endocardium −− Block 6 is interventricular septum so that endocardium is on both sides of the tissue −− Block 7 is free wall of right ventricle to include epicardial fat and endocardial surface

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The Lungs ♦♦ Separate each lung from the trachea and pulmonary artery trunk ♦♦ Examine each main pulmonary artery for thrombo­ embolism ♦♦ Examine each main stem bronchus for aspirated gastric contents or foreign objects, and look for bronchial mucosal tumor or ulceration ♦♦ Weigh each lung ♦♦ Evaluate anthracosis of subpleural lymphatics and hilar lymph nodes ♦♦ Describe air trapping, emphysema, atelectasis, bullae, nodules, or focal consolidation ♦♦ Open the tracheobronchial tree for each lung using scissors to cut down the length of the bronchi, extending at least 3–4 cm into each lobe of each lung to look for tumor, mucus plugs, or aspiration, as in Fig. 8.4D ♦♦ For normal lungs, submit a single histology block, filling the whole cassette with tissue, for each lobe of each lung, as Blocks 8–12 −− Any nodules or focal consolidation needs to be sampled by including adjacent normal tissue in the block −− Blocks containing calcified granulomas or calcified bronchial cartilage will need decalcification

The Hepatobiliary System ♦♦ ♦♦ ♦♦ ♦♦

Examine the liver capsule for lesions Examine the biliary tract and gallbladder for obstruction Weigh the liver Cross-section the liver (bread-loaf sectioning) in the transverse plane so that the liver segments are all about 1 cm thick (Fig. 8.5A) ♦♦ Submit Block 13, a full cassette containing a small sample of gallbladder and a piece of liver tissue where the liver is at least 1 cm2 ♦♦ Section through the pancreas and submit Block 14, one block from the tail of the pancreas (Fig. 8.5A)

The Hematopoietic System ♦♦ Weigh the spleen ♦♦ Dissect the spleen into 1 cm thick segments, look for infarcts or nodules, and submit Block 15 from the spleen pulp (Fig. 8.5B) ♦♦ Using the bone saw, cut off the anterior third of the vertebral body bone from a lower thoracic vertebral artery, and then using the saw make a shallow cut parallel to the plane of the first cut to make a flat thin section of vertebral body bone. Submit this bone for decalcification as Block 16

The Gastrointestinal Tract ♦♦ Using scissors or enterotomes open the entire gastrointestinal tract from esophagus to rectum; clean out and exam the specimen to identify areas of erosion, inflammation, tumor, or necrosis. Submit any lesions and submit esophagus and stomach in Block 17 as shown in Fig. 8.5C ♦♦ Submit duodenum in Block 18 and submit colon in Block 19

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The Urinary Tract, Male Reproductive System, and Adrenal Glands ♦♦ Weigh each kidney ♦♦ Section through each adrenal gland to look for nodules ♦♦ Bivalve each kidney by cutting from the pelvis out to the cortex in a coronal plane through the center of each kidney as shown in Fig.  8.5D. Look for nodules, infarcts, and cysts. For each kidney, submit a sample to include one complete pyramid of cortex, medulla, and papillary tip as Blocks 20 and 21. In each of those blocks, also submit a section of the respective adrenal gland ♦♦ Open the urinary bladder to look for erosion, inflammation, or tumor. In Block 22, submit urinary bladder. In the same cassette, for males, submit a sample of prostate and testis

The Female Reproductive System ♦♦ Routine histology will include at least one block of cervix, one block containing tissue from the endometrial cavity, and one or both ovaries

Ancillary Procedures ♦♦ As discussed at the beginning of the section “Internal Examination,” the best procedure for obtaining blood for clinical laboratory testing is via percutaneous subclavian needle puncture prior to making the autopsy incision. This reduces the circulation of postmortem putrefactive microorganisms that will contaminate microbiologic cultures. At autopsy, the term “peripheral blood specimen” refers to liquid blood obtained by venipuncture of the subclavian or femoral vein, while the term “central blood specimen,” also sometimes called “heart blood,” refers to a liquid blood specimen obtained by opening the chambers of the heart. It is not always possible to obtain a postmortem peripheral blood specimen. Some patients have extensive postmortem coagulation, some have extensive internal bleeding, some pediatric patients are simply too small, and some bodies are too decomposed. Peripheral blood is always the preferred specimen, but central blood will work if peripheral cannot be obtained. Note the specific source for the specimen ♦♦ Common ancillary testing includes microbiologic cultures of blood, lung tissue, spleen, and caseous granulomas. Cultures should specify bacteria, mycobacteria, fungi, and viruses as indicated by the circumstances of the patient history and autopsy findings in the tissues. So-called routine autopsy cultures are a waste of lab resources due to the ubiquitous presence of postmortem putrefactive organisms in autopsy material. The postmortem identification of a specific causative pathogen is an infrequent finding in autopsy cases ♦♦ Toxicology can be very helpful when drug interaction or drug intoxication is a possibility. If the patient was on a patient-controlled anesthesia device, or had access to drugs from outside the hospital then screening and confirmation should be done. Levels of drugs in the blood need to be interpreted with knowledge of the phenomenon of postmortem redistribution, especially with respect to blood samples obtained exclusively as “central blood specimen,” or “heart blood.”

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Fig. 8.5. (A) Illustration of the method for cutting through the gallbladder, liver, and pancreas; and the location where routine histology blocks for the gallbladder, liver, and pancreas should be obtained. (B) Illustration of the method for sectioning through the spleen, and the location for a routine histology block from the spleen pulp and capsule. (C) Illustration of the procedure for opening the GI tract, and the location where routine histology blocks should be obtained. (D) Illustration of coronally bisected kidneys, and the location where routine histology blocks should be obtained from the kidneys and urinary bladder.

AFTER THE AUTOPSY Death Certificate ♦♦ The RRC requires that there be an opinion on cause of death ♦♦ It may be necessary to provide a death certificate at the end of the autopsy ♦♦ While it is permissible to create a death certificate citing the cause of death as “pending completion of autopsy,” it is not ever a desirable practice, as such a practice puts an excessive burden on the family and the funeral home

Cause of Death ♦♦ The best practice is to provide, as accurately as possible, a complete and final death certificate by stating the cause of death in such terms as to be useful for epidemiologic

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purposes, yet broad enough to encompass the findings that may arise as the result of pending histology, microbiology, and toxicology ♦♦ For example, it is not necessary to know whether or not there is microscopic evidence of acute myocardial infarction for a death certificate. Sufficient information would be, “arteriosclerotic heart disease.” It is not necessary to know whether the lungs are heavy due to passive congestion or infection, if the underlying cause of death is “metastatic breast cancer.” ♦♦ If there is real suspicion that the cause of death has actually been missed at the autopsy, because the brain was excluded by the autopsy consent and something is suggested in the patient history to impugn an undiagnosed brain condition as the primary disease process, then every effort should be

Autopsy

made at the autopsy to secure a proper consent to include the brain ♦♦ The factors that are the complications of surgery and medical treatment are not ever the cause of death, but merely complications of the treatment for the underlying disease process that is the cause of death. Acute myelogenous leukemia, status post chemotherapy, and bone marrow transplantation, now presenting with graft versus host disease and opportunistic pulmonary infection, can be certified as “acute myelogenous leukemia.” The complications are probably very important for the clinicians, but not the death registry process, where the original leukemia is the most important information

“Unknown” Cause of Death ♦♦ Forensic cases occasionally (not frequently but occasionally) end up as truly “unknown” cause of death, whereupon the medicolegal authority can certify the death as “cause of death undetermined after complete autopsy.” But that circumstance is highly, highly unlikely to occur with hospital autopsy cases ♦♦ The factor that creates confusion with hospital autopsy death certification is not how to determine the cause of death, but it is simply a misunderstanding of how the pathologist should state the cause of death. It is not necessary to know the causation or pathophysiologic mechanism of terminal cardiac standstill in patients with extensive medical documentation of complex medical and surgical treatment for terminal illnesses. Those events are never the underlying cause of death ♦♦ When there are multiple combined independent illnesses, like chronic obstructive pulmonary disease and arteriosclerotic heart disease and metastatic prostate  cancer, then the one illness for which the patient presented to the hospital should be certified as the “cause” and the others listed as “significant contributory factors.” If all independent illnesses are actually working in concert then all can be listed as per Gorina and Lentzner (2008) ♦♦ Complications of diseases and treatments are not ever the cause of death. The underlying disease being treated, even when that disease is remote in time and no longer independently diagnosable in the body (except by review of the past medical record), that disease is the real cause of death ♦♦ Alcoholism is a disease. Death occurring as a result of prolonged alcoholism, alcohol withdrawal, or complications of alcohol-related medical disability such as chronic pancreatitis, alcoholic dementia, alcoholic cardiomyopathy, or alcoholic liver disease should be certified as “alcoholism”

Sudden Death ♦♦ Sudden, unexpected death during hospital recuperation from medical or surgical treatment can happen −− The usual causes, pulmonary thromboembolism or perforated myocardial infarct may be absent at autopsy −− Determine first, whether or not this death event really is “sudden” or “unexpected,” where those words really do not apply to patients with complex treatments for serious, life-threatening, or terminal illnesses. Follow every resource to find the causation for an electrophysiologic

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cardiac event, but always use the underlying disease as the “cause” −− Toxicology is occasionally the final answer, especially if there is clinical suspicion of possible medical mishap with intravenous or administered narcotics in the hospital

Autopsy Conference Presentation ♦♦ Pathology residents will likely need to prepare the collection of wet dissected specimens for presentation to staff pathologists, clinicians, and students. Alternatively, photographs of the autopsy and dissection may be used when it is not practical to get the audience into the autopsy room. After formalin fixation, the tissues can be handled with attenuated universal precautions. Fixed organs should be rinsed in water prior to display. Tissues should be handled with gloves. Respiratory cover is necessary if there is an issue of potential acid-fast microorganism infection. The integrity of the organs should be maintained such that the tissues are not too macerated or over-dissected, to the point where it is impractical to orient other observers to the gross anatomy

Discussion with Clinicians and Family ♦♦ Contact the physician who requested the autopsy, as soon as possible after the gross examination is completed, to communicate the preliminary gross pathologic findings ♦♦ Ascertain institutional policy concerning distribution of the autopsy data. In some institutions, this task falls directly on the pathology department, while other institutions may delegate this chore to the clinician who arranged the autopsy ♦♦ If a discussion is to be made with the family, then reduce the autopsy findings to a short list of findings and express those findings in plain English. It is preferable to talk to family about “cancer” or about “birth defect” than to try to be technical with “multiple myeloma” or “tetrology of Fallot” ♦♦ If the family inquires about issues specific to “quality of care” or “standard of care,” refer such questions to the autopsy service director. There may be questions about the effectiveness of surgery, or the efficacy of medical therapies, or the causation of complications of care, and these discussions must be left to the treating physicians

Autopsy Quality Management Programs ♦♦ The RRC requires that pathology residents on the autopsy service “participate in laboratory ­administrative activities (e.g., quality assurance [QA]/quality control [QC])” ♦♦ A common mechanism of QA/QC function for the hospital setting is through the clinical service morbidity and mortality conferences

ACGME/RRC Case Log System ♦♦ The RRC requires that pathology residents log qualifying autopsy cases on the Accreditation Council for Graduate Medical Education (ACGME) internet-based case log system at http://www.acgme.org

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SUGGESTED READING General References Clark SC, Ernst MF, Haglund WD, Jentzen FM, eds. Medicolegal Death Investigator: A Systematic Training Program for the Professional Death Investigator. Big Rapids, MI: Occupational Research and Assessment (for the National Association of Medical Examiners); 1996. Collins KA, Hutchins GM, eds. Autopsy Performance and Reporting. 2nd ed. Northfield, IL: College of American Pathologists;2003. Diagrams of body topography, organ systems, and individual organs are publicly available from the Office of the Armed Forces Medical Examiner (OAFME), through the web site for the Armed Forces Medical Examiner Service (AFMES) at the Armed Forces Institute of Pathology (AFIP), accessed at: http://www.afip.org/consultation/ AFMES/forms/index.html Finkbeiner WE, Ursell PC, Davis RL, eds. Autopsy Pathology: A Manual and Atlas. Philadelphia, PA: Churchill Livingstone;2004. Gilbert-Barness E, Kapur R, Oligny LL, Siebert J, eds. Potter's Pathology of the Fetur, Infant and Child. 2nd ed. St. Louis, MO: Mosby (Elseview B.V.);2007. Gorina Y, Lentzner H. Multiple causes of death in old age. Aging Trends, February 2008, Centers for Disease Control and Prevention, National Center for Health Statistics, U.S. Dept. of Health and Human Services, accessed at http://www.cdc.gov/nchs/agingact.htm Gray F, De Girolami U, Poirier J, eds. Escourelle and Poirier's Manual of Basic Neuropathology. 4th ed. Oxford, UK: Butterworth-Heinemann (Elsevier Science);2003. Hoyert DL, Kung HC, Xu J, and the Division of Vital Statistics: Autopsy ­patterns in 2003: Data on mortality. Centers for Disease Control and Prevention, National Center for Health Statistics, U.S. Dept. of Health and Human Services, 2007, series 20, number 32, DHHS publ. no. (PHS) 2007-1851. Ludwig J, ed. Handbook of Autopsy Practice. 3rd ed. Totowa, NJ: Humana Press;2002.

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National Association of Medical Examiners: Policy and Guidelines on Human Organ and Tissue Procurement, 2002 Aug., accessed at Position Papers, http://www.thename.org The Laboratory Accreditation requirements for autopsy services are from the College of American Pathologists, Commission on Laboratory Accreditation, Laboratory Accreditation Program, Anatomic Pathology Checklist, accessed at http://www.cap.org The Residency Review Committee requirements for autopsy service are from the Residency Review Committee (RRC) of the Accreditation Council for Graduate Medical Education accessed at http://www.acgme. org/acWebsite/downloads/RRC_progReq/300pathology_07012007. pdf

Journal Articles College of American Pathologists Conference XXIX: Restructuring Autopsy Practice for Health Care Reform. A compendium of articles from the May 1995 Conference, Arch Pathol Lab Med 1996; 120:693–785. Ironside JW, Bell JE. The “high-risk” neuropathological autopsy in AIDS and Creutzfeldt–Jacob disease: principles and practice. Neuropathol Appl Neurobiol 1996; 22:388–393. National Guidelines for Death Investigation, by the National Medicolegal Review Panel, 1997 Dec, National Institute of Justice, Office of Justice Programs, U.S. Dept. of Justice, publ. no. NCJ 167568, available at http://www.ncjrs.org Powers JM and the Autopsy Committee of the College of American Pathologists: Practice guidelines for autopsy pathology: Autopsy procedures for brain, spinal cord, and neuromuscular system. Arch Pathol Lab Med 1995; 119:777–783. Randall BB, Fierro MF, Froede RC, and the Forensic Pathology Committee of the College of American Pathologists: Practice guidelines for forensic pathology. Arch Pathol Lab Med 1998; 122:1056–1064.

9 Biomedical Informatics for Anatomic Pathology Waqas Amin, md, Uma Chandran, phd, Anil V. Parwani, and Michael J. Becich, md, phd

Contents

I. Introduction.........................................9-2

II. The Role of Pathology in Managing Information.........................................9-2 III. Historical Perspective..........................9-2

1960–2000�����������������������������������������������������������9-2 2000 Onwards����������������������������������������������������9-3

Data Analysis�����������������������������������������������������9-8 Class Discovery����������������������������������������9-8 Class Comparison������������������������������������9-8 Class Prediction���������������������������������������9-9 Biological Pathway Analysis�������������������9-9 Integrative or Systems Biology Approaches������������������������������������������9-9

VII. Analysis and Management IV. Laboratory Information Systems of Molecular Data...............................9-9 Overview.............................................9-3 V. Tools....................................................9-4 Imaging in Anatomic Pathology����������������������9-4 Telepathology�����������������������������������������������������9-4 Whole Slide Imaging�����������������������������������������9-5 Structured Data Entry (Synoptic Reporting)������������������������������������9-6

VI. Informatics Challenges........................9-8 Data Management���������������������������������������������9-8

Cancer Biomarker Studies�������������������������������9-9 Key Components of Biomarker Studies�����������������������������������������������������������9-9 Tissue Resources����������������������������������������������9-10 Clinical Annotation�����������������������������������������9-10 Laboratory Procedures�����������������������������������9-10 Data Analysis���������������������������������������������������9-10 Data Sharing����������������������������������������������������9-10

VIII. Suggested Reading.............................9-11

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_9, © Springer Science+Business Media, LLC 2002, 2006, 2011

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INTRODUCTION ♦♦ Biomedical informatics development is moving rapidly to keep up with the pace of advances in pathology diagnostics −− Advances in information technology are resulting in faster computers and more integrated systems to facilitate the workflow of laboratories −− Vendors continually seek to satisfy the requirement of their customers ♦♦ Improvements facilitate billing and insurance needs (automated coding), quality assurance, internal workflow (voice recognition, templates), clinical services (autodelivery, image-embedded reports), and academic endeavors (World Wide Web-based educational databases) ♦♦ Rapid advances are also occurring in the fields of digital imaging, telepathology, and whole slide imaging −− The utility of an integrated workstation with the capability of photographing, scanning, presenting, and sharing images is not far from becoming a reality

♦♦ When considering a change or upgrade to the surgical pathology biomedical informatics systems, it is imperative that one adequately assesses the needs of the laboratory and takes a proactive and aggressive approach −− The selection process should be viewed as an opportunity to truly advance a pathology practice ♦♦ Experience has shown that selection, implementation, and deployment are usually most successful when the pathologist is directly involved −− Detailing the most desired improvements in a request-forproposal is particularly beneficial and may even advance vendor biomedical informatics system development ♦♦ Active participation in vendor user groups can do the same −− The pathologists have to be the leaders of the information management to continue to play a central and pivotal role in the management of the surgical patient

THE ROLE OF PATHOLOGY IN MANAGING INFORMATION ♦♦ Pathology workflow requires an efficient way to collect, store, display, and distribute data generated by the pathologist ♦♦ In surgical pathology, a patient’s specimen is received, accessioned, and analyzed, resulting in a product that is the final surgical pathology report ♦♦ A final pathology report serves to provide information to the health care team as well as various other members of the treatment teams tasked with patient care ♦♦ Pathology information has to be accurate, timely, concise, and easy accessible

♦♦ The report has to be provided in a confidential and secure fashion for the patient ♦♦ The pathologist is responsible for specimen acquisition, analysis, and capturing the accuracy of the data in the surgical pathology report ♦♦ It is important for the pathologist to have a good working knowledge of biomedical informatics and the information systems where the data is entered, stored, displayed, and archived (Fig. 9.1)

HISTORICAL PERSPECTIVE 1960–2000 ♦♦ Interdisciplinary field at the cross-section of biology, medicine, computer science, statistics and mathematics, and information technology ♦♦ Traditional definition of biomedical informatics includes computational techniques to solve biological problems −− Therefore, biomedical informatics is not a new ­discipline, and the earliest examples include studies on  protein sequences

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♦♦ With the advent of sequencing technologies, computational methods to study genomic sequences were developed ♦♦ One such method is the BLAST sequence alignment algorithm ♦♦ DNA sequences can be used for the study of comparative genomics, evolutionary genomics, biological diversity, protein prediction, for biological annotation, and for the findings of mutations in cancer and other diseases ♦♦ Complex software tools and databases are being developed for these studies

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Fig. 9.1. Barcode scanning at gross station equipped with barcoding scanners for material tracking.

♦♦ National Center for Biotechnology Information (NCBI) established in 1988 (http://www.ncbi.nlm.nih.gov/) −− NCBI provides/creates computational tools for biomedical research such as GenBank for sequence data ♦♦ Because of large-scale genome sequencing projects including the human and other genomes, there has been exponential growth in the volume of data deposited into GenBank ♦♦ Development of high-throughput experimental methods, such as expression chips, allows for simultaneous measurement of thousands of molecular events

2000 Onwards ♦♦ A number of genomic processes can be studied using highthroughput “omic” technologies −− These include DNA sequence, methylation, copy number changes, single nucleotide polymorphisms (SNP), microRNA levels, and mRNA expression levels ♦♦ Numerous competing technologies such as cDNA chips, short or long oligonucleotides affixed to chips, and beadbased technologies are available

♦♦ Current mRNA expression chips measure the binding of RNA in biospecimens to greater than 50 K probes −− SNP chips can genotype approximately 1.5 million polymorphisms and copy number variations ♦♦ Proteomic methods using profiling of thousands of serum or  tissue markers can be quantitated simultaneously using mass spectrometry ♦♦ Tissue microarrays (TMAs), where multiple ­biospecimen cores are placed on glass slides, can be used to study protein expression in multiple samples simultaneously ♦♦ Microarray experiments are data intensive and require complex data analysis strategies ♦♦ There are a number of national and international biomedical informatics projects to create databases and tools −− Large database efforts such as NCBI, Ensembl (http://www. ensembl.org/index.html), and UCSC genome databases (http://genome.ucsc.edu/) are free online resources for highly annotated genomic data for vertebrate and other eukaryotes −− Nuclei Acids Research publishes an annual issue devoted to biomedical informatics databases

LABORATORY INFORMATION SYSTEMS OVERVIEW ♦♦ The Laboratory Information System (LIS) provides an efficient method for managing information for enabling and disseminating diagnosis for the patients encountered within the surgical pathology practice

♦♦ There are many dedicated vendors offering a broad range of LIS solutions −− The Anatomic and Pathology Laboratory Information System (APLIS) may exist as a separate standalone entity

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with interface to other hospital information systems or may be a module within a larger all-inclusive clinical laboratory or hospital-wide system −− Both these solutions are applicable for a wide spectrum of surgical pathology practices including academic and private practices

♦♦ LIS functionality has been progressing significantly with added enhancements enabling the handling and distribution of pathology reports more easily −− There are three categories: basic functions that are to be expected in almost any system, advanced functionality, and future functionality

TOOLS Imaging in Anatomic Pathology ♦♦ Imaging is a key component of an anatomical pathology practice along with other biomedical informatics tools −− It is an emerging technology that has the potential to modify and improve diagnostic methods in pathology ♦♦ Advancement in imaging technology is due to an overall improvement in computer technology, more rapid networking, and cheaper storage; soon we will arrive at a time when pathologists are able to manage images almost as easily and flexibly as they are able to handle text ♦♦ Imaging systems have the capability to provide provisions such as the permanent storage capability of static images and their incorporation in signout and reporting, including multiple cameras, network connectivity to an image server and the pathologists’ workstations, a storage device and database, and image capture and image display software ♦♦ These systems are largely used in gross image management and for microscopic single field documentation ♦♦ Imaging software is highly diverse and performs many functions −− Image processing software permits the adjustment of brightness, contrast, hue, and resolution, and that is very helpful to embellish the pathologic images for academic use (Fig. 9.2) ♦♦ Image-embedded reports assist in patient care by providing detailed information with inclusion of graphs and diagrams −− These reports allow the clinicians to have better understanding of the pathology practice, augment more understanding between disciplines, and serve as a powerful marketing tool for expanding the boundaries of one’s practice ♦♦ Images are commonly used in many areas of daily pathology practice such as gross pathology of autopsy and surgical pathology specimens and for the microscopic documentation of normal and abnormal tissues (Fig. 9.3)

Telepathology ♦♦ Development in video microscopy and digital imaging capabilities enables light microscopic examination and diagnosis at remote sites ♦♦ General approaches adopted in telepathology are dynamic, static, and hybrid systems; each having its own advantages and disadvantages

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♦♦ Dynamic systems are essentially remote-controlled microscopes that give the pathologist a live view of the distant microscopic image while allowing him or her to move the stage, focus, and change the magnification, remotely −− The lucid advantage of dynamic systems is that they give  the pathologist great flexibility in viewing the entire slide, to examine in detail any specific field at any power −− Disadvantages of dynamic telepathology systems include the expensive and proprietary nature of the host and client stations and the great bandwidth needed to carry live, full-motion video ♦♦ Static (“store-and-forward”) telepathology requires that the referring pathologist captures a collection of still digital images for transmission to the consultant −− The major disadvantage is the loss of control experienced by the consulting telepathologist, who must rely on the referring pathologist to capture all of the necessary diagnostic fields to support an adequate examination −− Static systems can be very flexible −− Any system that captures images in standard file formats, when combined with any file transfer protocol program or adequate e-mail system can be used to perform static telepathology ♦♦ Hybrid systems are developed by combining some of the better features of both static and dynamic systems −− Hybrid telepathology systems combine with remote-controlled high-resolution microscopy still image capture and retrieval −− This approach requires a considerably lower bandwidth than purely dynamic systems, while providing high-quality static images for diagnostic, reporting, and medical recordkeeping purposes ♦♦ The systems (dynamic and hybrid) that provide better control to the consultant pathologist appear to present better results in terms of both increased diagnostic accuracy and lowered deferral rates ♦♦ Developments in telepathology are likely to focus on three areas −− The first is the acceptance of open standards that will allow intersystem operability

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Fig. 9.2. Whole slide image of fine needle aspirate from a patient with adenocarcinoma, diagnosed by remote consultant.

Fig. 9.3. Biomedical informatics-driven workflow creates automation leading to increased efficiency and reduction in patient errors.

−− The second area is the incorporation of telepathology into the LIS to facilitate image database reporting and billing capabilities −− The third area is the development of whole slide imaging (WSI) for use in clinical practice

Whole Slide Imaging ♦♦ In the late 1990s, pathologists began to experiment with systems that imaged and permanently stored the entire slide at high resolutions

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Fig. 9.4. Automation and standardization of workflow. ♦♦ In 1997, a system in which a robotic microscope captured a large area of a slide, field by field, and a computer that “knitted” the individual fields together into a montage was developed ♦♦ This system had significant limitations; however, the most important one was the duration of prolonged time needed to capture a single extended field ♦♦ In late 1999, a prototype with a fully functional robot was developed ♦♦ It was based on traditional microscope optics, a strobe light connected to a precision stage, and a digital video camera ♦♦ Primary magnification of 20, a numerical aperture of 0.7 and square, 6.6 µm pixels; it had a spatial sampling period (pixel size/optical magnification – a measure of resolution) of 0.33 µm/pixel and could image a slide in 5–10 min depending on the size of the tissue section and the amount of image compression desired ♦♦ Image quality produced is generally of diagnostic quality and, with the viewing software, clinical annotations and clinical metadata presented with the image is made possible with potential resulting in a virtual microscope with all the clinical information needed to signout the case (Fig. 9.4) ♦♦ Today, a typical imaging robot can perform in batch mode (reading barcodes on slides) and can capture and compress an image of a slide with a 1.5 × 1.5  cm tissue section in approximately 6 min with spatial sampling periods between 0.3 and 0.5 µm/pixel ♦♦ Latest devices are implementing nontraditional optics, illumination, and sensors designed specifically for very high speed image capture, and should result in significant improvements in speed, throughput, and resolution in the months and years ahead, with different manufacturers eventually focusing on different aspects of the market

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♦♦ Recent studies have established the utility of WSI in teaching and assessment −− The high-speed WSI robot industry is becoming highly diverse with a broad range of optics, detectors, slide handling devices, and software resulting in an increasing range of capabilities and costs (Fig. 9.5)

Structured Data Entry (Synoptic Reporting) ♦♦ Gross and microscopic examination of surgical specimens, particularly large resections, produces detailed information with implication for ongoing and future medical and oncology care −− A significant proportion of use of prognostic information about patient care is obtained from pathology reports ♦♦ Narrative descriptive reports have been used traditionally in surgical pathology to provide valuable information to the patients and their health care teams −− This information allows great value in making treatment decisions such as adjuvant therapy, radiation, chemotherapy, prognosis and outcomes ♦♦ Data capturing in the LIS is usually carried out by dictation followed by transcription −− Result in the creation of a few large text fields correlating with specific parts of the surgical pathology report (e.g., gross description, microscopic description, diagnosis) −− The dictation is usually free form, with the pathologist speaking in continuous sentences, guided directly by the material at hand −− Traditional narrative and descriptive reports in free text format have significant variability because different pathologists use a multitude of different reporting styles to describe their findings, and variability results in pathology

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Fig. 9.5. Imaging robots are networked to storage.

reports missing important data elements such as margins, lymphatic invasion, etc ♦♦ Synoptic reporting provides uniform standardized data elements in forms of checklists to ensure that pathologists make note of these findings in their reports −− Structured data entry takes a different approach and holds the promise of specific benefits. This model can be used to drive synoptic reports supports data entry (a) The basic idea is that data is entered in many smaller specific text fields rather than in a few large ones −− This mode of entry leads to supported data-querying capabilities, automated analysis, decision support, and predefined comment generation −− LIS vendors are currently employing tools for synoptic reporting within their systems (a) These systems have not reached their full-fledged potential, and there remains an area for further ­development. −− Synoptic reports provide a great degree of freedom to the pathologist to use structured data; for anything other than synoptic reporting, it is difficult because of placement in one large text field −− The College of American Pathologist Cancer Protocols and Checklists were created with the objective of

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improving the quality and uniformity of information in pathology reports (a) http://www.cap.org/apps/docs/cancer_protocols/ protocols_index.html LIS does not maintain discrete data elements for synoptic data elements −− The pathology checklists provide unstructured text blocks, which are embedded in the pathology reports −− The latter arrangement results in the presentation of pertinent pathology data in a cumbersome and difficult-toaccess format Dictated with structured data, use a template that parses every single data element into its own predefined place in the database Synoptic report can either be placed at the end of the surgical pathology report or can replace the conventional-free textbased final diagnosis section Structured collection of data could allow great versatile queries because every discrete data element (e.g., 1.8  cm) is directly linked to its inherent context Structured data entry offers significant benefits for reporting as well −− The template could easily define a synopsis of diagnostic findings −− This provides a standard framework of findings for each broad category of disease

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♦♦ The clinician often appreciates such a framework because its familiarity promotes rapid comprehension −− It also forces a standardization of reporting by all of the pathologists within a given group ♦♦ Synoptics usually ensures completeness of the report while promoting brevity −− In more advanced systems, data in some fields could be used to autogenerate data in other fields (a) For example, by supplying depth of tumor invasion and lymph node status, the staging could be defined automatically (b) This should reduce the number of errors and ­decrease the turnaround time ♦♦ Automated insertion of “canned” comments, references, diagrams, or graphs based on data in a specific field, such as stage or tumor subtype −− For example, in a prostate needle biopsy report, the diagnosis of high grade prostatic intraepithelial neoplasia could result in the automatic insertion of a comment that states the clinical significance of this finding, lists an

appropriate reference, and suggests recommended clinical followup −− Such a comment, written once and updated as needed, could be made to autoinsert whenever the  diagnosis is given, greatly enhancing the value of the report and hence the contribution of the pathologist ♦♦ Automated “reasoning engine” complete with rigorous logic rules and access to clinical followup data −− Such a system may, on completion of the template and before signout, generate incidence data for the institution or the region, provide prognostic information based on stage and recent local experience, and suggest appropriate followup ♦♦ Disadvantages are the tremendous amount of upfront work that must be done to design the templates and compose appropriate comments, graphs, and the like −− Consequently, specialty and referral laboratories that concentrate on fewer organ systems and face stiff competition are the sites most likely to advance this approach −− Conversely, simply using dictation templates without employing advanced database designs can significantly decrease transcription costs and increase efficiencies

INFORMATICS CHALLENGES ♦♦ The large volume of data provided by these high-throughput methods poses numerous challenges including the areas of data management, data analysis, visualization, integration, and annotation

Data Management ♦♦ Typical microarray data output can comprise several different files per experiment and may total from 50 MG to over 1 G, depending on the platform −− For example, the high-density SNP arrays generate more than 1 G of data per sample ♦♦ It is not practical to store entire experiment sets on CDs or DVDs ♦♦ This creates data management challenges for storage, retrieval, and sharing with collaborators

Data Analysis ♦♦ Novel analytical methods have emerged for these large and complex data sets −− Development of robust analytical methods is a very active area of biomedical informatics research ♦♦ Specific data analysis strategies depend on platform and research objectives ♦♦ Analysis may be conducted using numerous open source or commercial software ♦♦ Open source packages such as R and Bioconductor (http://www.bioconductor.org/GettingStarted/) offer flexibility,

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extensibility, and are actively supported by the academic community −− Some popular academic analytical tools include the following (a) BRB Array tools (http://dctd.cancer.gov/ProgramPages/ brb/tools_arrayTools.htm) (b) Gene Pattern (http://genecruiser.broadinstitute.org/ cancer/software/genepattern/) ♦♦ A typical analytical strategy for mRNA expression data is outlined below

Class Discovery ♦♦ Discover groups that are similar based on gene expression ♦♦ Research objectives may include identification of subgroups of samples that can be distinguished by their gene ­expression profile −− One of the earliest examples is the identification of two subtypes in diffuse large B-cell lymphomas (DLBCL) ♦♦ Techniques for such analysis include multidimensional scaling, hierarchical clustering, and self-organizing maps

Class Comparison ♦♦ Class comparison is the application of statistical methods to find different molecular profiles between two or more experimental groups −− Examples include identification of genes that are up or down in tumors compared to normals or genes differentially expressed in invasive vs. ­organ-confined cancer

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−− Earliest uses of microarray are global gene profiling in the yeast S. cerevesia Numerous statistical methods including parametric tests such as the t test, nonparametric, and Bayesian methods have been applied to microarray data Statistical methods often include fold change calculations that give the ratio of expression of a particular gene in the two different conditions being compared, for example, cancer vs. normal Additional metrics that are included in the methods include confidence values such as a p value that ­estimates the probability of these genes being d­ ifferentially expressed For high-dimensional data where thousands of genes are evaluated simultaneously, additional statistical consideration includes, what is commonly referred to as “multiple comparison” corrections and estimates of false discovery; i.e., the proportion of genes that are most likely false identified as differentially expressed Genes identified by class comparison methods are often validated by other methods such as RT-PCR

Class Prediction ♦♦ Complex algorithms or rules are developed based on the molecular profiles of training data to predict the group of a test sample ♦♦ Examples include a 76 gene prognostic breast cancer signature and gene expression signature that predicts risk of recurrence in small-cell lung cancer ♦♦ In such a study, the prediction algorithm is built using training data consisting of, for example, recurrent and nonrecurrent samples

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♦♦ The performance, or sensitivity and specificity of the predictive molecular profile is validated using crossvalidation techniques ♦♦ Class prediction methods that have been utilized for biological data include Neural Networks, Support Vector Machines Decision Trees, K means, and Shrunken Centroid

Biological Pathway Analysis ♦♦ Molecular profiles generated from class discovery, comparison, or prediction are mined for involvement of biological pathways that may yield clues about the molecular mechanism of a particular disease and permit development of therapeutic targets

Integrative or Systems Biology Approaches ♦♦ Approaches to combine data from studies of different molecular processes such as integration of gene expression and SNP data or expression and methylation data pose considerable challenges, and they are the active area of research ♦♦ This is a rapidly changing landscape with emerging new technologies such as Next Gen sequencing, which have the potential to rapidly sequence entire genomes −− This will result in tremendous amounts of data, which will accelerate the biomedical informatics challenges of data management and analysis ♦♦ Studies are evolving from one-platform strategies to complex data integration from multiple platforms −− Examples include integration of proteomic and genomic data, integration of the microRNA, methylation, SNP, and expression data

ANALYSIS AND MANAGEMENT OF MOLECULAR DATA ♦♦ The rich molecular data from high-throughput studies create the opportunity to integrate molecular information with traditional histopathology, particularly in cancer tissues ♦♦ Of biomarker discovery studies, cancer biomarker studies comprise the largest proportion due to the availability of surgical pathology biospecimens ♦♦ These specimens are at the core of translational research, which as defined by the National Cancer Institute (NCI) is “research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity, and mortality”

Cancer Biomarker Studies ♦♦ Cancer biomarker studies involve high-throughput ­molecular techniques on cancer biospecimens ♦♦ These molecular studies have the potential to impact pathology where molecular diagnosis, i.e., the molecular profile of

a particular tissue or sample, may become as critical as morphological diagnosis ♦♦ The aim of these studies is to discover molecular signatures that can aid in early diagnosis, prediction of prognosis, and response to therapy and affect outcome ♦♦ Biospecimens may include frozen or paraffin embedded (FFPE) tissue, blood, serum or other sample types

Key Components of Biomarker Studies ♦♦ Cancer biomarker studies are data and informatics intensive and require a robust infrastructure ♦♦ Key components of this infrastructure include highly annotated, de-identified biospecimens outcome data, and a biomedical informatics infrastructure for data management, analysis, and sharing ♦♦ In spite of numerous cancer biomarker discovery studies, few have reached clinical use

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♦♦ Biomarkers identified in small discovery studies have generally not been validated successfully in larger studies ♦♦ Reasons include interstudy variation in study design, techniques, and inadequate quality control ♦♦ Additionally, discovery studies are conducted ­retrospectively on archival specimens with poor QC, and validation on large prospective cohorts is required to demonstrate the reliability of a particular molecular signature ♦♦ Optimization of QC must occur at all stages of a study from tissue procurement, annotation, laboratory procedures to data analysis

Tissue Resources ♦♦ Numerous studies have shown that variability in tissue handling leads to variability in expression profiles. For example, warm ischemia time can impact the quality or RNA in expression studies ♦♦ There are other examples of tissue variability that can impact biomarker analysis −− Whether sample is FFPE or frozen −− Media for freezing sample −− The cellular composition of tissue analyzed such as the percentage of stoma or epithelial cells in a sample or the percentage of normal contamination in a tumor sample −− Whether gross dissection or laser capture dissection is provided for analysis ♦♦ The tissue repository is a vital component of the informatics infrastructure for biomarker studies ♦♦ Standardization of tissue-handling procedures will result in high-quality tissue for discovery studies ♦♦ This highlights the need for tissue banking inventory and annotation systems

Clinical Annotation ♦♦ There are institutional differences in how clinical information is obtained for research studies and the quality and depth of available clinical annotations −− Similarly, the requirements and procedures for institutional review board compliance are not uniform between institutions ♦♦ There is a need for databases that warehouse or ­integrate clinical information from various sources such as cancer registry and electronic medical records and provide this information in a de-identified fashion to researchers

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Laboratory Procedures ♦♦ Laboratory procedures for high-throughput experiments can impact the output data quality ♦♦ This creates the need for a laboratory information management system (LIMS) for data management, and to track all steps of laboratory protocols including reagents, materials, and methods ♦♦ However, there are no current LIMS solutions that can adapt to the highly dynamic workflows within genomic and proteomic labs ♦♦ This is an active area of research and development within commercial and academic groups

Data Analysis ♦♦ Analytical methods differ from study to study and are not often statistically justified ♦♦ The same data set analyzed with different methods may produce different molecular signatures ♦♦ Analytical methods are often difficult to replicate due to inadequate details provided in publications ♦♦ There is a need for standardized data analysis methods that are modular, interoperable, and can be replicated ♦♦ National initiatives such as caBIG (https://cabig.nci.nih. gov/) are attempting to create a national biomedical informatics infrastructure of interoperable databases, software, and tools for facilitating translational research

Data Sharing ♦♦ For multi-institutional discovery or validation studies, researchers must agree upon standard vocabulary for all data including clinical annotation, biospecimen annotation and laboratory procedures, and data analysis ♦♦ The MIAME standard (http://www.mged.org/Workgroups/ MIAME/miame.html) for microarray data is intended to facilitate this process ♦♦ Many journals now require that publication data be submitted to GEO (http://www.ncbi.nlm.nih.gov/geo/) or other databases using MIAME compliant format ♦♦ caArray (http://caarray.nci.nih.gov/), the microarray repository, allows for standards-based annotation and sharing of cancer microarray data ♦♦ Development of disease-specific (cancer and noncancer) standard vocabulary and an informatics infrastructure is the critical need for translational research

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SUGGESTED READING Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503–511.

Hastie T, Tibshirani R, Friedman J. The elements of statistical learning: data ­mining, inference, and prediction. NY: Springer; 2001.

Aller R, Carey K. Anatomic pathology computer systems. CAP Today 1999;13:70–72, 74, 76 passim.

Henricks WH, Roumina K, Skilton BE, et  al. The utility and cost ­effectiveness of voice recognition technology in surgical pathology. Mod Pathol 2002;15:565–571.

Aller RD. Linking software making gains and foraying into new domains. CAP Today 2005;19:29–30, 32–34, 36–38 passim.

Kumar RK, Velan GM, Korell SO, et al. Virtual microscopy for learning and assessment in pathology. J Pathol 2004;204:613–618.

Allison DB, Cui X, Page GP, Sabripour M. Microarray data analysis: from disarray to consolidation and consensus. Nat Rev Genet 2006;7:55–65.

LaFramboise T. Single nucleotide polymorphism arrays: a decade of ­biological, computational and technological advances. Nucleic Acids Res 2009;37:4181–4193.

Altschul SF, Gish W, Miller W, et al. Basic local alignment search tool. J Mol Biol 1990;215:403–410. Amin MB, Srigley JR, Grignon DJ, et  al. Updated protocol for the ­examination of specimens from patients with carcinoma of the urinary bladder, ureter, and renal pelvis. Arch Pathol Lab Med 2003;127:1263–1279. Amin W, Parwani AV, Schmandt L, et al. National Mesothelioma Virtual Bank: a standard based biospecimen and clinical data resource to enhance translational research. BMC Cancer 2008;8:236. Barbareschi M, Demichelis F, Forti S, et al. Science Fiction? Int J Surg Pathol 2000;8:261–263 Becich MJ, Gilbertson JR, Gupta D, et al. Pathology and patient safety: the critical role of pathology informatics in error reduction and quality initiatives. Clin Lab Med 2004;24:913–943,VI.

Lamb J, Crawford ED, Peck D, et  al. The Connectivity Map: using ­gene-expression signatures to connect small molecules, genes, and ­disease. Science 2006;313:1929–1935. Lashkari DA, DeRisi JL, McCusker JH, et  al. Yeast microarrays for genome wide parallel genetic and gene expression analysis. Proc Natl Acad Sci U S A 1997;94:13057–13062. Leong AS. Synoptic/checklist reporting of breast biopsies: has the time come? Breast J 2001;7:271–274. Leslie KO, Rosai J. Standardization of the surgical pathology report: ­formats, templates, and synoptic reports. Semin Diagn Pathol 1994;11: 253–257.

Becich MJ. Information management: moving from test results to clinical information. Clin Leadersh Manag Rev 2000;14:296–300.

Liu CG, Calin GA, Meloon B, et  al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci U S A 2004;101:9740–9744.

Bhattacharyya AK, Davis JR, Halliday BE, et al. Case triage model for the practice of telepathology. Telemed J 1995;1:9–17.

Markel SF, Hirsch SD. Synoptic surgical pathology reporting. Hum Pathol 1991;22:807–810.

Brauchli K, Christen H, Haroske G, et al. Telemicroscopy by the Internet revisited. J Pathol 2002;196:238–243.

McDonald CJ, Huff SM, Suico JG, et al. LOINC, a universal standard for identifying laboratory observations: a 5-year update. Clin Chem 2003;49:624–633.

Demichelis F, Barbareschi M, Dalla Palma P, et  al. The virtual case: a new method to completely digitize cytological and histological slides. Virchows Arch 2002;441:159–164. Dupuy A, Simon RM. Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J Natl Cancer Inst 2007;99:147–157. Eisen MB, Spellman PT, Brown PO, et al. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998;95: 14863–14868. Friedman BA. Informatics as a separate section within a department of pathology. Am J Clin Pathol 1990;94:S2–S6. Fujita K, Crowley RS. The Virtual Slide Set – a curriculum development system for digital microscopy. AMIA Annu Symp Proc 2003;846. Gasch AP, Spellman PT, Kao CM, et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 2000;11:4241–4257. Gilbertson JR, Petal A, Yagi Y. Clinical slide digitization – whole slide imaging in clinical practice. In: Gu J and Ogilvie RW, eds. Virtual Microscopy and Virtual Slides in Teaching, Diagnosis and Research. Boca Raton: Taylor and Francis; 2005. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of ­cancer: class discovery and class prediction by gene expression monitoring. Science 1999;286:531–537. Gstaiger M, Aebersold R. Applying mass spectrometry-based­ proteomics to genetics, genomics and network biology. Nat Rev Genet 2009;10:617–627.

Network TCGAR. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455: 1061–1068. Oberholzer M, Christen H, Haroske G, et  al. Modern telepathology: a  distributed system with open standards. Curr Prob Dermatol 2003;32:102–114. Parmigiani G, Garrett, ES, Irizarry RA, et  al. The analysis of gene expression data. NY: Springer; 2003. Patel AA, Gilbertson JR, Parwani AV, et  al. An informatics model for tissue banks – lessons learned from the Cooperative Prostate Cancer Tissue Resource. BMC Cancer 2006;6:120. Potti A, Mukherjee S, Petersen R, et  al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570–580. Quackenbush J. Computational analysis of microarray data. Nat Rev Genet 2001;2:418–427. Qualman SJ, Bowen J, Amin MB, et al. Protocol for the examination of specimens from patients with Wilms tumor (nephroblastoma) or other renal tumors of childhood. Arch Pathol Lab Med 2003;127:1280–1289. Rashbass J. The impact of information technology on histopathology. Histopathology 2000;36:1–7. Rosai J. Standardized reporting of surgical pathology diagnoses for the major tumor types. A proposal. The Department of Pathology, Memorial Sloan-Kettering Cancer Center. Am J Clin Pathol 1993;100:240–255.

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Sauter G, Simon R, Hillan K. Tissue microarrays in drug discovery. Nat Rev Drug Discov 2003;2:962–972. Sawyers CL. The cancer biomarker problem. Nature 2008;452:548–552. Schubert E, Gross W, Siderits RH, et al. A pathologist-designed imaging system for anatomic pathology signout, teaching, and research. Semin Diagn Pathol 1994;11:263–273. Srigley JR, Amin MB, Bostwick DG, et  al. Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland: a basis for checklists. Cancer Committee. Arch Pathol Lab Med 2000;124:1034–1039.

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Thorne NMJ, Rakyan V, Ibrahim A, et  al. DNA methylation arrays: Methods and analysis. In: Hardiman G, ed. Microarray Innovations: Technology and Experimentation in Drug Discovery and Biomedical Research. Boca Raton, FL: CRC Press; 2009:Ch 13. Wang Y, Klijn JGM, Zhang Y, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. The Lancet 2005;365:671–679. Weinstein RS, Descour MR, Liang C, et al. An array microscope for ultrarapid virtual slide processing and telepathology. Design, fabrication, and validation study. Hum Pathol 2004;35:1303–1314.

Stoughton RB. Applications of DNA microarrays in biology. Annu Rev Biochem 2005;74:53–82.

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Tamayo P, Slonim D, Mesirov J, et  al. Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc Natl Acad Sci U S A 1999;96: 2907–2912.

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10 Quality Assurance and Regulations for Anatomic Pathology Maxwell L. Smith, md and Stephen S. Raab, md

Contents

I. Quality Assurance..............................10-2

Introduction......................................................10-2 Quality Control.................................................10-2 Quality Improvement.......................................10-2 Quality Improvement Methodologies.............10-3 Toyota Production System.....................10-3 Six-Sigma.................................................10-3 Total Quality Management....................10-3 Zero Defects............................................10-3

II. Medical Error.....................................10-4 Impact on Health Care....................................10-4 Definition...........................................................10-4 Classification.....................................................10-4 Error Detection Methods.................................10-4 Active Versus Passive..............................10-4 Prospective Versus Retrospective..........10-4 Examples of Traditional Error Detection Methods.............................10-4

III. Regulations........................................10-5 Laboratory Accreditation................................10-5

College of American Pathologists Accreditation......................................10-5 Phase I and Phase II Deficiencies.........................................10-5 Laboratory General Requirements.......10-5 Select Anatomic Pathology Requirements for CAP Accreditation......................................10-5 Select Cytopathology Requirements for CAP Accreditation.......................10-6 Select Autopsy Requirements for CAP Accreditation.............................10-7 Hospital Accreditation.....................................10-7 Health Insurance Portability and Accountability Act of 1996 (HIPAA)..............................................10-7 Occupations Safety and Health Administration (OSHA)....................10-7 US Centers for Disease Control and Prevention...................................10-7

IV. Suggested Reading.............................10-7

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_10, © Springer Science+Business Media, LLC 2002, 2006, 2011

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QUALITY ASSURANCE Introduction ♦♦ Quality assurance (QA) is a global system of control activities that promote higher level functioning of specific processes within the anatomic pathology laboratory ♦♦ Control activities include (1) quality control (QC) in individual areas of the anatomic pathology laboratory, (2) a global quality improvement (QI) plan for the organization, and (3) regulatory compliance activities including CAP laboratory inspection components ♦♦ The main goal of QA, QC, and QI is to prevent medical error ♦♦ Traditional measures of quality in anatomic pathology include the following: diagnostic accuracy, customer satisfaction, and specimen turnaround-time

Quality Control ♦♦ QC consists of activities designed to ensure particular steps or subprocesses within the laboratory that meet acceptable parameters ♦♦ Because there are several distinct areas through which a specimen passes (e.g., accessioning, gross room, histology, residents, transcription, pathologists), each area develops its own QC activities, which often have downstream impact on other lab processes ♦♦ Many QC activities are dictated by accreditation organizations such as the College of American Pathologists. See specific examples in the section below on accreditation ♦ ♦ Other QC activities are designed by the laboratory to meet the needs specific to the functioning of the laboratory

−− Asking the question “why?” five times is a simple way to perform root cause analysis −− Zarbo used a complex classification system as a tool for root cause analysis of why reports required amendments. Four major categories included interpretation errors, specimen errors, identification errors, and reporting errors, with each having a more detailed subclassification −− The Eindhoven Classification Model involves the classification of root causes into three domains: technical (equipment, forms, IT), organizational (procedures, policies, and protocols), and human (knowledge based, rule based, and skill based) (a) This method allows the analysis of the system as a whole rather than focusing on the human factors (b) Generally, emphasis is put on punishment of the individual who is perceived to be responsible for the error, rather than the process (both within the lab and outside the lab) that put the individual in the position to make the error −− Raab et al. designed the no blame box as a tool for root cause analysis in cytology–histology correlation (a) The no blame box has the quality of the specimen on the x-axis and the amount of tumor on the y-axis (Table 10.1) (b) Specimens can be charted into one of the four categories of cancer/no cancer and good/poor quality.

Table 10.1. The “No blame Box”

Quality Improvement ♦♦ Activities that involve analysis of QA and QC data and failures and seek to improve the quality of a specific product or service beyond its current state ♦♦ A documented QI plan is required by the CAP for accreditation −− The plan should reference the mission statement of the laboratory and be specific about goals and what metrics are to be measured by whom −− Both internal and external benchmarks should be included as goals ♦♦ Many different QI or error reduction styles exist ♦♦ Good QI programs use a variety of error detection methods to catch errors prospectively to prevent patient harm ♦♦ Once errors are detected, root cause analysis is undertaken to drive down to the true underlying cause of the error

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Specimen quality A Poor quality specimen No tumor identified C Poor quality specimen Tumor identified Amount of tumor

B Excellent quality specimen No tumor identified D Excellent quality specimen Tumor identified

Quality Assurance and Regulations for Anatomic Pathology

Table 10.2. Problem Solving with an A3 Problem/current condition •  Define the problem using data •  Describe the current condition Root cause analysis •  Perform a root cause analysis like 5 Whys? To get to the source of the problem

Action plan •  Develop an action plan with specific tasks assigned to different people with due dates

Metrics and time line •  Show what will be measured to evaluate success or failure of the action plan •  Develop a time line for task completion and success monitoring

This method often illustrates that errors are multifactorial and not based on interpretive defects alone −− A3 Problem-solving tool (Table 10.2) (a) Used by the Toyota Corporation to define, characterize, and solve problems (b) Single sheet of paper divided into four quadrants: Problem/Current condition, Root Cause Analysis, Action Plan, and Metrics and Time Line (c) Single page requires short, concise, and well-thoughtout responses in each box

Quality Improvement Methodologies ♦♦ Types of QI methodologies used to achieve quality goals. Many overlapping theories and philosophies

Toyota Production System ♦♦ Principle 1 – Base your management decisions on a longterm philosophy, even at the expense of short-term financial goals ♦♦ Principle 2 – Create a continuous process flow to bring problems to the surface −− Redesign work process to eliminate waste (muda) through continuous improvement (kaizen) −− Types of waste include overproduction, waiting, unnecessary transport or conveyance, overprocessing or incorrect processing, excess inventory, unnecessary movement, defects, and unused employee creativity ♦♦ Principle 3 – Use “pull” systems to avoid overproduction ♦♦ Principle 4 – Level out the workload (heijunka) ♦♦ Principle 5 – Build a culture of stopping to fix problems, to get quality right at the first time

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♦♦ Principle 6 – Standardized tasks and processes are the foundation for continuous improvement and employee empowerment ♦♦ Principle 7 – Use visual control so that no problems are hidden −− 5S Program – Sort, straighten, shine, standardize, and sustain ♦♦ Principle 8 – Use only reliable, thoroughly tested technology that serves your people and processes ♦♦ Principle 9 – Grow leaders who thoroughly understand the work, live the philosophy, and teach it to others ♦♦ Principle 10 – Develop exceptional people and teams who follow your company's philosophy ♦♦ Principle 11 – Respect your extended network of partners and suppliers by challenging them and helping them improve ♦♦ Principle 12 – Go and see for yourself to thoroughly understand the situation (Genchi Genbutsu) ♦♦ Principle 13 – Make decisions slowly by consensus, thoroughly considering all options; implement decisions rapidly (nemawashi) ♦♦ Principle 14 – Become a learning organization through relentless reflection (hansei) and continuous improvement (kaizen)

Six-Sigma ♦♦ Method to improve the quality in a process by identifying and eliminating the causes of defects or errors and variation −− Trains “Black Belts,” who are specific people embedded within the organization that specializes in six-sigma, in the process −− Depends on statistical and quality management methods −− Defects are defined as anything that leads to customer dissatisfaction −− Achieving 6 sigma is reaching 99.9997% efficiency or only 3.4 defects per million opportunities

Total Quality Management ♦♦ A business strategy that aims to increase overall awareness to quality throughout the organization

Zero Defects ♦♦ The philosophy that all services or products should be designed and produced to meet the immediate need of the downstream customer −− If the product or service does not meet the need of the customer it is defective −− Emphasis is on the prevention of errors rather than tracking and correcting defective products

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MEDICAL ERROR Impact on Health Care ♦♦ The Institute of Medicine estimated that between 44,000 and 98,000 patients die each year as a result of a medical error ♦♦ The total financial cost of medical error was estimated between $17 billion and $29 billion in the USA each year ♦♦ These estimates fail to include the number of patients who suffer increased morbidity and outpatient medical errors

♦♦ Laboratories that function under two domains of control (e.g., hospital-controlled laboratory processing control and pathologist medical group-controlled pathologist interpretation control) often dichotomize the analytic phase of testing into technical or processing related and pathologist interpretation related

Error Detection Methods

Definition

Active Versus Passive

♦♦ Defined by the Institute of Medicine as the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim. Specifically to anatomic pathology, an error is defined as the failure to correctly diagnose the disease process occurring in a patient ♦♦ It is important to note that patient harm is not a prerequisite for medical error. The determination of error is performed independently of patient outcome or root cause analysis ♦♦ Once an error is identified and the outcome is analyzed the error may then be classified as “harm,” “near-miss,” or “no-harm” ♦♦ The majority of medical errors are not associated with an adverse patient outcome ♦♦ Terminology is an important factor as error is often associated with a negative connotation and physician training poorly addresses medical error

♦♦ Passive error detection involves waiting for errors to surface, is the more common method, but drastically underestimates the number of errors ♦♦ Active error detection involves continuous scrutiny of patient material for all required elements in all phases of testing by all laboratory staff and comes much closer to the true error rate within the laboratory

Classification ♦♦ Errors in anatomic pathology may be classified based on the testing phase involved. Testing phases include the following −− Pre-preanalytic in which the decision to test is made and the specific test is chosen −− Preanalytic in which the test material is taken from the patient (biopsy performed) and is transported to the laboratory −− Analytic in which the sample is processed and interpreted. This is the domain over which the testing laboratories have the most control. Errors in each of these domains may lead to errors in the analytic phase (a) Accessioning (b) Grossing (c) Processing (d) Histology (e) Transcription (f) Pathologist interpretation (g) Additional testing (h) Sign-out −− Postanalytic in which the test results are reported to the clinician −− Post-postanalytic in which the clinician makes a decision and acts on the test result

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Prospective Versus Retrospective ♦♦ Retrospective error detection is the basis for the majority of QC/QI activities in anatomic pathology ♦♦ Usually involves secondary slide/report review after the case has been signed out and clinical decision making has occurred. See examples of traditional error detection below ♦♦ Prospective error detection is a more active from of error detection in which potential errors are reviewed and corrected prior to the case being verified and the clinical decision is made ♦♦ Secondary slide review of all new malignant diagnoses, a common policy present in approximately 50% of laboratories, is an example of prospective error detection

Examples of Traditional Error Detection Methods ♦♦ Clinician requested review ♦♦ Random selection of the CAP suggested 10% case review ♦♦ Correlation between frozen section and permanent section diagnosis ♦♦ Correlation between Pap testing and subsequent cervical biopsies ♦♦ Focused case review of potential difficult cases, as determined by the specific lab (e.g., negative prostate needle biopsies, transbronchial biopsies) ♦♦ Second opinion or consultation review ♦♦ Correlation between cytology and biopsy findings ♦♦ Amended case review Once errors are detected, regardless of the method, an improvement opportunity exists to analyze the error and put into place mechanisms to prevent the defect from recurring. This is the basis for QI activities

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REGULATIONS ♦♦ Several regulatory agencies are involved in the quality and ­management of the anatomic pathology laboratory

Select Anatomic Pathology Requirements for CAP Accreditation

Laboratory Accreditation

♦♦ A procedure manual, which has undergone annual review by the laboratory director, should be available in all work areas (II) ♦♦ All employees should be knowledgeable on the contents of the procedure manual in their work area (II) ♦♦ Retired procedures and policies should be retained for 2 years (II) ♦♦ The procedure manual should include a policy for handling slides, blocks, and specimens for medical legal cases (II) ♦♦ Infectious specimens must be disposed of properly, and formalin and xylene concentrations must be kept below acceptable limits (II) ♦♦ A surgical pathology quality management program must be in place (II) and include a list of specimens not required for submission to pathology (I), a list of specimens not required for microscopic examination (I), a policy regarding review of prior cases in conjunction with current cases (II), an intradepartmental consultation policy, an extradepartmental consultation policy, and a frozen/permanent discrepancies procedure ♦♦ When available, the laboratory should participate in peer educational programs (I) ♦♦ The quality control program should provide sufficient space and facilities for gross examination (I), refrigeration (I), lighting (I), storage (II), dictation (I), gross photography (I), and policies for handling radioactive material and suboptimal material (II) ♦♦ Specimen identity must be maintained throughout accessioning and gross examination (II) ♦♦ Gross examination must be done by a pathologist, pathology resident, or by high complexity testing personnel under direct or indirect pathologist supervision (II), with an available grossing manual (I) ♦♦ Nonpathologists/residents who perform gross examination must undergo periodic performance review, and the types of specimens they are qualified to do must be clearly documented (II) ♦♦ Frozen section should be prepared on slides with patient identification using labeled stain solutions (II) ♦♦ At the time of frozen section, pathologists should verbally communicate with the surgeon directly (II), after confirming patient identity (II), and the consultation should be documented both at the time of diagnosis and also in the final report (II) ♦♦ The remaining tissue from a frozen section should be processed (I), and the frozen slides should be retained with the rest of the case (II) ♦♦ Frozen section turnaround time should be evaluated and documented (II)

♦♦ The Clinical Laboratory Improvement Act (CLIA ’88) required ongoing inspections and surveys of pathology laboratories to ensure quality. Accreditation was made a requirement for federal and state-funded medical programs (reimbursement). The Centers for Medicare and Medicaid Services (CMS) is the organization responsible for laboratory accreditation and for approving other accrediting agencies

College of American Pathologists Accreditation ♦♦ Accrediting agencies include COLA and the College of American Pathologists (CAP), although the CAP is the most commonly used CMS approved accrediting agency for anatomic pathology laboratories ♦♦ CAP inspections are done every other year with a selfinspection being required in off years ♦♦ Inspections are unannounced but occur within 3 months prior to the laboratory anniversary date

Phase I and Phase II Deficiencies ♦♦ Deficiencies found by the inspectors (self-inspections included) are classified into two phases, Phase I and Phase II ♦♦ Deficiencies must be addressed, in writing, within 30 days of the inspection −− Phase 1 – Deficiencies that may not have a direct impact on patient care. Requires a written response from the medical director indicating the corrective action taken −− Phase 2 – Deficiencies that may have a direct impact on patient care. Requires a written response from the medical director indicating the corrective action taken and supporting documentation (new policies and procedures, new log sheets, photos, floor plans, employee signature of policy review, etc.) showing that the corrective action has been completed ♦♦ In the CAP accreditation system, the anatomic pathology laboratory is responsible for the Laboratory General Checklist, Anatomic Pathology Checklist, Autopsy Pathology Checklist, and the Cytopathology Checklist. Everything requires documentation. Below are select requirements for CAP accreditation for each of the areas of  the anatomic pathology laboratory. Associated phase deficiencies are included in parentheses. The reader is referred to the College American Pathology Laboratory Accreditation Anatomic Pathology Checklists (2) for complete requirements

Laboratory General Requirements ♦♦ Laboratory General Checklist requires policies and procedures general to any lab handling patient specimens (clinical lab, molecular lab, cytogenetics, etc.)

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♦♦ Reports should include a gross examination (II), slide key (II), CAP cancer protocols (if appropriate) (II), correlation of additional studies (II), Analyte Specific Reagent disclaimer (if appropriate) (II), be completed in 2 days for routine cases (II), and be reviewed and signed by a pathologist (II) ♦♦ Unexpected or significant findings should be communicated verbally and documented in the report (II) ♦♦ Material should be retained for the appropriate time: accession logs – 2 years; wet tissue – 2 weeks; paraffin blocks – 10 years; glass slides and reports – 10 years (II) ♦♦ Histology −− The identity of blocks and slides must be maintained throughout all operations (II) −− Histologic quality must be sufficient (II) −− Workload volumes must be maintained (I) −− Reagents must be properly labeled (II) and used before their expiration date (II) −− Positive controls are required during special stain procedures (II) −− Positive and negative controls are required for immunohistochemistry and immunofluorescence (II) −− All antibodies currently in use must be in the procedure manual (II) −− All control slides must be reviewed by laboratory director or designee (II) −− New antibodies must be evaluated prior to use for diagnostic purposes −− FISH analysis requires control loci (II) and retention of photographic or digitized images (I) −− Predictive immunohistochemistry requires the report to include information on specimen processing, antibody clone used, and acceptable scoring method use (II) −− HER2 immunohistochemical testing requires proficiency testing with ongoing evaluation of results (II), no crosslaboratory communication (II), and documented validation (I) −− Temperature of paraffin solutions and water baths should be checked and maintained (II) −− There must be sufficient space, utility, light, and equipment so that the work quality is not compromised (II) −− Tissue processors should be at least 5 feet from flammable material (II) −− Procedures for processing suspected Creutzfeldt–Jakob disease specimens are required (II)

Select Cytopathology Requirements for CAP Accreditation ♦♦ Laboratory and personnel must participate in a CMSapproved proficiency testing program for GYN pathology (II), and educational peer-review programs in GYN and nonGYN pathology (I) ♦♦ Discrepancies must be resolved in a confidential peerreviewed QM document (II)

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♦♦ Daily review of cytology preparation by supervisory level technologist or pathologist (II) ♦♦ Instructions for proper collection, fixation, identification, and storage of specimens (II) ♦♦ Fine needle aspirations require patient identifiers on slides at the time of procedure and a procedure to prevent errors (e.g., time-out) (II) ♦♦ Upon receipt, specimens are recorded and given an accession number (II) ♦♦ Criteria for rejection of specimens with notification from the submitting physician is required (II) ♦♦ Stains and working solutions are labeled (II), periodically assessed (I), stored appropriately (II), unexpired (II), covered (I), changed appropriately (I), and periodically checked (II) ♦♦ Reports should include all key elements including patient identification, test performed, date, etc. (II) ♦♦ Pathologist’s name should be included on report if they reviewed the case (II) ♦♦ Interpretation should use standard diagnostic categories (II) with space for comments (II) as well as morphologic findings (II) ♦♦ Index of cases must be maintained including a cross-index with histologic material (II) ♦♦ Must have a mechanism to correlate specialized studies with cytologic results (II) ♦♦ Original slides should be stored in an orderly manner (I) for an appropriate period (FNA slides = 10 years, others = 5 years) (II) ♦♦ Gynecologic specimen should be stained with the Papanicolaou stain, and documented criteria should be used for categorizing specimens as unsatisfactory (II) ♦♦ Any gynecologic slide interpreted as suspicious for malignant, dysplasia, cervical intraepithelial neoplasia, low and high grade squamous intraepithelial lesions, atypical cells, and reactive or repair should be interpreted by pathologist (II) ♦♦ There should be at least 10% rescreening rate for gynecologic specimens interpreted as negative by the cytotechnologists by a supervisory level technologist (II), and the diagnostic performance of each individual cytotechnologist should be compared with the laboratory diagnostic averages (II) ♦♦ If a new diagnosis of high grade dysplasia is made, any available prior negative preparations should be reviewed and if a discrepancy is encountered, a revised report should be issued (II) ♦♦ Any followup surgical pathology specimen should be compared with the prior gynecologic cytologic s­ pecimens (II) ♦♦ The atypical cells/squamous intraepithelial lesion ratio for gynecologic specimens should be between the 5th and 95th percentile as determined by data compiled by the CAP (II) ♦♦ All non-GYN slides should be reviewed by pathologist (II) ♦♦ Non-GYN cytology specimens should be correlated with histological and clinical findings (II)

Quality Assurance and Regulations for Anatomic Pathology

♦♦ Ninety percent of routine non-GYN cases should be completed within 48 h, with the exception of cases in which special procedures are ordered including FISH, cell blocks, and special stains (I) ♦♦ The laboratory must assure that the pathologist and cytotechnologists meet the qualification criteria for respective positions and have a general supervisor who fulfills the responsibilities of CLIA-88 (II) ♦♦ Personnel must be commiserate with the volume and complexity of cases (II) ♦♦ A workload policy is required, and all screening must occur within the laboratory facility (II)

Select Autopsy Requirements for CAP Accreditation ♦♦ Clinicopathologic correlation of findings to improve patient care is required (II) ♦♦ Autopsy findings should be incorporated into the hospital quality management program (I) ♦♦ Incidental findings should be reported (II) ♦♦ Procedures for obtaining autopsy consent, body handling, and release of body are required (II) ♦♦ Instructions for triaging autopsy cases to medical examiner or corner are required (I) ♦♦ A scale for weighing organs is required (II) ♦♦ Autopsy should be performed following clinical and radiographic review by pathologist or under direct supervision of a pathologist (II) ♦♦ A preliminary report should be issued within two working days (II) ♦♦ Final reports should be issued within 30 days (II) ♦♦ Diagnoses should be entered into a database for easy retrieval (I)

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♦♦ Procedures for handling infectious and suspected Creutzfeldt– Jakob disease specimens are required (II) ♦♦ Autopsy area should be cleaned and disinfected after each use (II)

Hospital Accreditation ♦♦ The majority of hospitals invest in voluntary accreditation by the Joint Commission on Accreditation of Healthcare Organizations (JACHO). Accreditation involves inspection, survey, and reporting of sentinel events. Accreditation is required for the hospital to be eligible for federal and state funding programs. The laboratory may be involved in JACHO inspections and tracer programs where a single patient, including their laboratory specimens, is followed through the hospital

Health Insurance Portability and Accountability Act of 1996 (HIPAA) ♦♦ HIPAA requires national standards for electronic health care transactions to keep protected health information that is private. The anatomic pathology laboratory must follow HIPAA rules to protect patient privacy

Occupations Safety and Health Administration (OSHA) ♦♦ OSHA is the regulatory agency responsible for enforcing rules and standards for work-place safety and health to prevent work-related injuries, illnesses, and deaths

US Centers for Disease Control and Prevention ♦♦ The anatomic pathology laboratory interacts with the CDC in the reporting of epidemiological risks such as infectious organisms and bioterrorism

SUGGESTED READING College American Pathology Laboratory Accreditation Anatomic Pathology Checklists, accessed June 2009. www.cap.org

Meier FA et al. Amended reports: development and validation of a taxonomy of defects. Am J Clin Pathol 2008;130:238–246.

College of American Pathologists, Valenstein PN, Raab SS, et al. Identification errors involving clinical laboratories: a College of American Pathologists Q-Probes study of patient and specimen identification errors at 120 institutions. Arch Pathol Lab Med 2006;130:1106–1113.

Nakhleh RE, Fitzgibbons PL. Quality Management in Anatomic Pathology. Northfield, IL: CAP Press; 2003.

Kohn LT, Corrigan JM, Donaldson MD, eds. To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press; 1999.

Raab SS, Grzybicki DM, Condel JL, et al. Effect of Lean method implementation in the histopathology section of an anatomical pathology laboratory. J Clin Pathol 2008;61:1193–1199.

Liker JK. The Toyota Way: 14 Management Principles from the World’s Greatest Manufacturer. New York, NY: McGraw-Hill; 2004.

Tennant G. Six Sigma: SPC and TQM in Manufacturing and Services. Burlington, VT: Gower Publishing, Ltd; 2001.

Raab SS, Grzybicki DM. Measuring quality in anatomic pathology. Clin Lab Med 2008;28:245–259.

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11 Molecular Diagnostic Pathology James Huang, md and Richard D. Press, md, phd

Contents

I. Molecular Diagnostic Methodologies...................................11-2

Karyotyping......................................................11-2 Fluorescence In Situ Hybridization................11-2 Southern Blot Assay.........................................11-3 Polymerase Chain Reaction Assay..................11-4 PCR-RFLP Assay.............................................11-5 PCR-FRET........................................................11-5 PCR-dHPLC Screening Assay........................11-6 Real-Time Quantitative Reverse Transcription PCR......................................11-6 DNA Sequencing...............................................11-7 New Molecular Genetic Technology...............11-9 Spectral Karyotyping.............................11-9 Comparative Genomic Hybridization....11-9 Gene Expression Profiling with Microarray.........................................11-9 MicroRNA Profiling...............................11-9

II. Molecular Diagnosis of Hematolymphoid Neoplasms.............11-9 Introduction......................................................11-9 General Guidelines for the Rational Use of Specific Molecular Pathology Assays.......................................11-10 Molecular Assessment of Clonality...............11-13 Antigen Receptor Gene Rearrangements as Markers of Clonality............................11-13 Clinical Utility of IgH and T-Cell Receptor Gene Rearrangement Studies..................11-15 Molecular Determination of Clonality of Nonlymphoid Maligancies........................11-15 Molecular Markers or Lesions Associated with Specific Diseases................................11-15 Mature B-Cell Neoplasms....................11-15

Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma......11-16 B-Cell Prolymphocytic Leukemia.......11-16 Lymphoplasmacytic Lymphoma.........11-16 Hairy Cell Leukemia............................11-16 Marginal Zone Lymphoma..................11-16 Follicular Lymphoma...........................11-16 Mantle-Cell Lymphoma.......................11-17 Diffuse Large Cell Lymphoma............11-17 Mediastinal (Thymic) Large B-Cell Lymphoma........................................11-17 Burkitt Lymphoma/Leukemia.............11-17 Plasma Cell Neoplasms........................11-18 Mature Peripheral T-Cell Lymphoma/Leukemia.....................11-18 Anaplastic Large Cell Lymphoma......11-18 NK Cell Neoplasms...............................11-19 Nodular Lymphocyte Predominant Hodgkin Lymphoma........................11-19 Classic Hodgkin Lymphoma................11-19 Myeloproliferative Neoplasms (MPNs)..............................................11-19 Myeloid Neoplasms Associated with Eosinophilia and Abnormalities of PDGFRa, PDGFRb, or FGFR1.....11-20 Myelodysplastic/Myeloproliferative Neoplasms.........................................11-21 Myeloid Dysplastic Syndrome.............11-21 Acute Myeloid (Nonlymphoblastic) Leukemia..........................................11-21 Acute Lymphoblastic Leukemia/ Lymphoma........................................11-23

III. Suggested Reading...........................11-24

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_11, © Springer Science+Business Media, LLC 2002, 2006, 2011

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MOLECULAR DIAGNOSTIC METHODOLOGIES Karyotyping Basic Technical Steps ♦♦ These culture-based assays are typically set up as soon as possible with fresh cells in order to minimize the loss of viability ♦♦ Goal is to assess the numerical and gross abnormalities of whole/partial chromosomes of the tumor using nonspecific “banding” stains of metaphase chromosome spreads

Benefits ♦♦ Requires fresh and viable cells to be able to grow and divide ♦♦ A routine diagnostic test for hereditary/congenital disease ♦♦ A routine test in the diagnostic workup of bone marrow cells when hematopoeitic maligancy is suspected ♦♦ Not currently routinely performed for common solid organ cancers (except sarcomas)

Limitations ♦♦ Low sensitivity for detection of abnormalities (5–10% clonal cells) ♦♦ Nonspecific: target genes determining biologic behavior not directly analyzed ♦♦ Tumor cell metaphase spreads typically of poor quality ♦♦ Slow turnaround time: at least 1 week (for cell growth and analysis)

Examples ♦♦ Trisomy (an extra chromosome is present): Trisomy 21 (47, XY, +21) ♦♦ Monosomy (a chromosome is missing): Turner syndrome (45, X) ♦♦ Translocation (a broken segment of one chromosome is translocated to a broken segment of another chromosome). Philadelphia chromosome t(9;22) ♦♦ Deletion (a portion of the chromosome is lost):5q♦♦ Inversion (a section of the chromosome is inverted (reversed) on the same chromosome): inv(16)

Fluorescence In Situ Hybridization (Fig. 11.1) Basic Technical Steps ♦♦ Fresh tissue, formalin-fixed paraffin-embedded tissue, cell suspension, smears, touch imprints, cytospins are all acceptable for FISH analysis ♦♦ Fixation of tissue with formalin for less than 48  hours is preferable ♦♦ FISH probes are typically a small DNA fragment cloned into yeast or bacterial artificial chromosomes. The probes are designed to hybridize to specific regions/genes or segments of chromosomes

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Fig. 11.1. Detection of the translocation t(14;18) by fluorescence in situ hybridization (FISH). Fluorescent probes specific for bcl-2 (red), IgH (green), and the chromosome 18 centromere (aqua = control) were hybridized to tumor cell spreads. Panel (A) depicts a “negative” sample, each cell showing two distinct signals of each color. Panel (B) is a follicular lymphoma sample with each cell showing two abnormal yellow (bcl-2/IgH) fusion signals. The yellow signal is the result of the juxtapositioning of the red (bcl-2), and green (IgH) signals as the result of the t(14;18).

−− When they are designed to hybridize to repetitive DNA sequences located near chromosome centromeres, they are used for chromosome identification and enumeration. A loss of a centromere generally indicates the loss of an entire chromosome −− To determine if specific genes are amplified, translocated, or deleted, probes should be designed to hybridize to unique sequences −− With locus/gene-specific probes, there are two ­fluorescent signals in a normal cell, corresponding to the chromosome pairs. The double dots represent the signals from each of the two aligned sister chromatids

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−− To study chromosome translocations, probes are typically designed as either dual color single fusion probes, dual color break apart probes or dual color dual fusion probes (descriptions below) −− Dual color single fusion probes are useful in detecting high percentages of cells possessing a specific chromosomal translocation. The DNA probe hybridization targets are located on one side of each of the two genetic breakpoints −− Dual color break apart probes are used in cases where there may be multiple translocation partners associated with a known genetic breakpoint. This labeling scheme features two differently colored probes that hybridize to targets on opposite sides of a breakpoint in one gene −− Chromosome enumeration probe and locus-specific indicator probes are often used together −− A mixed of probes (often with different colors) can be used to paint the entire length of 1 or more chromosomes

Benefits ♦♦ FISH is a molecular tool to evaluate intact cells for genetic changes using DNA or RNA probes labeled with a fluorochrome. Specific genetic changes can be visualized at the single-cell level, offering a great benefit in anatomic pathology ♦♦ FISH can be ordered based on clinical history but it is often performed as a reflex test based on the initial karyotyping result or pathology evaluation ♦♦ Pathologists can order FISH studies with an individual probe or a panel of probes based on their initial histopathology evaluation, a very cost-effective way of applying genetic/ molecular technology in diagnostic pathology ♦♦ Pathologists should select the tissue block for FISH analysis based on the lesion distribution identified morphologically, in order to achieve the highest possible sensitivity and to correlate the potential cytogenetic abnormality with the histopathology of diagnostic interest. FISH data can be analyzed coordinately with morphology ♦♦ FISH can offer quantitative correlation with flow cytometry, because both report abnormal cell percentages ♦♦ The quick turnaround time allows timely integrated diagnosis in the pathology reports

Limitation ♦♦ A low percentage of abnormal cells identified by FISH is not always diagnostic and should be interpreted with caution

Example ♦♦ BCR–ABL, for translocation (9;22). FISH can be used for both diagnosis and posttreatment disease monitoring

Southern Blot Assay (Fig. 11.2) Basic Technical Steps ♦♦ DNA is extracted from fresh or cryopreserved tissue or cells ♦♦ Genomic DNA is digested with one or more specific restriction enzymes which cut the DNA into various heterogeneously sized fragments

Fig.  11.2. Southern blot analysis. Fragmented genomic DNA is  separated by size on an agarose gel. DNA fragments are ­transferred to a membrane that is then hybridized to a probe from the gene of interest. Band sizes are compared to those of a normal control.

♦♦ Digested DNA fragments are separated in a size-­dependent manner via agarose gel electrophoresis, yielding a smear of DNA when visualized by ethidium bromide and UV light ♦♦ DNA is transferred from the gel to a nylon or nitrocellulose membrane, which is then hybridized to a labeled probe specific to the gene of interest ♦♦ When the membrane is exposed to film, only the DNA fragments which hybridize to the labeled probe are visualized (as a “band” of DNA) ♦♦ Differences in size between the patient’s band(s) and those of a normal control yield important information regarding the patient’s gene alteration

Benefits ♦♦ It is useful for detecting large scale deletions, insertions, or duplications in a gene or several genes in a region ♦♦ In the hands of very skilled technologists, it can be quantitative. The intensity of rearranged bands reflects the quantity of target DNA

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Limitations ♦♦ It requires microgram (mg) quantities of high quality, high molecular weight genomic DNA. Therefore, DNA must be extracted from adequate fresh or cryopreserved tissue or cells −− It typically requires >107 cells (>1 mg tissue). Fine needle aspiration usually does not generate adequate cells for Southern Blot Assay −− Formalin-fixed paraffin tissue is usually not suitable ♦♦ It offers a low sensitivity: tumor cell burden below ~5% may not be detected. Tumor cell load of <1% of total cells will yield false-negative signal ♦♦ It is unable to accurately detect point mutations, small deletions/insertions/duplications unless they disrupt a restriction enzyme site ♦♦ Entire process takes several days to complete ♦♦ Many clinical molecular diagnostic laboratories no longer offer this assay

Examples ♦♦ Detecting deletions in the dystrophin gene that cause Duchene and Becker muscular dystrophies ♦♦ Detecting deletions or duplications within the mitochondrial genome, which cause a variety of disorders

Polymerase Chain Reaction Assay (Fig. 11.3) Basic Technical Steps ♦♦ Genomic DNA or RNA is extracted from unfixed or fixed tissue or cells ♦♦ For RT-PCR, complementary DNA (cDNA) is made from RNA extracted from the tissue or cells ♦♦ Targeted DNA will be amplified via multiple rounds of reaction of a three-temperature cycle −− 95°C denatures the two DNA strands −− 55–65°C allows primers to anneal to template −− 72°C allows the polymerase to extend the primers into full length product ♦♦ Each cycle of polymerase chain reaction (PCR) theoretically doubles the amount of product amplicon ♦♦ PCR products are separated in a size-specific manner by agarose gel electrophoresis, stained with ethidium bromide, and visualized under UV light ♦♦ Alternatively, PCR products can be visualized by capillary gel electrophoresis or by fluorescence (in real-time PCR) ♦♦ The expected size of the PCR product is based on the targeted DNA fragment length between the two primers

Benefits ♦♦ It requires only nanogram (ng) quantities of intact or partially degraded genomic DNA (or RNA) derived from blood, fresh frozen tissue, or fixed tissue −− Requires only >102–105 cells −− Useful for smaller biopsies or fine need aspiration material

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Fig.  11.3. Schematic representation of the polymerase chain ­reaction (PCR). Through repeated cycles of heating and cooling, Taq polymerase makes multiple copies of a specific target sequence, using gene-specific primers and free nucleotides (dNTPs).

♦♦

♦♦ ♦♦ ♦♦

−− Tissues can be trimmed of “nontumor” tissue to increase diagnostic sensitivity The gene of interest is enzymatically amplified >108-fold over background using short target-specific oligonucleotide primers, dNTPs, and a thermostable DNA polymerase It is useful for detecting point mutations, small insertions, or deletions Differences in size between patient and control samples can be accurately measured Entire process can be completed in several hours. Rapid result – often same day as biopsy

Limitations ♦♦ It cannot detect large deletions or insertions within the gene region ♦♦ Due to its extreme sensitivity, false-positive results can occur (from contamination by previously generated amplification products)

Example ♦♦ Detection of a deleterious insertion mutation in the FLT3 gene in AML ♦♦ PCR is used in conjunction with several other methodologies, such as restriction fragment length polymorphism

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(RFLP), fluorescence resonance energy transfer (FRET), denaturing high pressure liquid chromatography (dHPLC), and sequencing (see following) ♦♦ Almost every molecular diagnostic approach (except Southern blot) utilizes PCR in some way

PCR-RFLP Assay Basic Technical Steps ♦♦ PCR products are digested with a specific restriction enzyme that detects a known stretch of sequence (wild type or mutant) within the gene of interest. If a mutation creates or destroys a restriction enzyme site, it can then be detected ♦♦ Digested PCR fragments are visualized by agarose gel electrophoresis, ethidium bromide staining, and UV light. The pattern (sizing) of fragment sizes indicates the presence or absence of the specific nucleotide change

Benefits ♦♦ Works well for detecting previously characterized single nucleotide changes ♦♦ It is technically simple to perform ♦♦ It requires common laboratory equipment

Fig.  11.4. Representative factor V leiden PCR-RFLP gel. Samples were PCR amplified and digested with the restriction enzyme MnlI. Fragments were separated by size via agarose gel electrophoresis. Un undigested PCR product, Nl homozygous normal, Ht heterozygous, Hm Leiden homozygous, L DNA ­ladder used for size comparison. Numbers on the left indicate fragment sizes in basepair.

Limitations ♦♦ It does not detect novel, uncharacterized alterations ♦♦ It is possible for a nonpathologic nucleotide change near the one of interest to similarly affect enzyme digestion patterns and result in a false positive

Example ♦♦ Detection of the Factor V Leiden R506Q mutation causing thrombophilia (Fig. 11.4)

PCR-FRET (Fig. 11.5) Basic Technical Steps ♦♦ Real-time PCR is performed in the presence of two fluorescently labeled oligonucleotide probes, one of which is specific for a well characterized single nucleotide polymorphism (SNP) of interest ♦♦ During the annealing phase of PCR, the two labeled probes hybridize to the site of the SNP and emit a fluorescent signal that is only possible when both probes are bound to the same DNA template ♦♦ After PCR cycling is completed, the samples are slowly heated and the temperature at which the allele-specific probe denatures from the target (and fluorescent signal is lost) is monitored and indicates the presence or absence of the SNP of interest. The allele discrimination is based on the principle that mis-matched hybrids will disassociate (melt) at a lower temperature than perfectly matched hybrids

Benefits ♦♦ The entire assay (PCR and mutation detection) can be completed in less than 2 hours

Fig. 11.5. PCR-FRET (fluorescence resonance energy transfer). After PCR amplification, a fluorescence signal is only detected when  the allele-specific probe and anchor probe are both annealed to the PCR product. As samples are slowly heated, the shorter allele-specific probe denatures, and signal is lost. The temperature at which this happens (the melting temperature) indicates either a perfect match between the probe and the target (wild type) or a single mismatch (mutation). The star represents the nucleotide of interest. ♦♦ The assay can be designed such that a neighboring nonpathologic alteration will not be confused with the SNP of interest

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Limitations

Limitations

♦♦ Fluorescently labeled probes are expensive ♦♦ Requires nonstandard, somewhat expensive equipment

♦♦ It is only a screening technique, suspicious samples must be sequenced ♦♦ Technical optimization is often necessary for each target ♦♦ It requires expensive, nonstandard laboratory equipment

Example ♦♦ Detection of the HFE C282Y and H63D mutations resulting in hereditary hemochromatosis (Fig. 11.6)

Example

PCR-dHPLC Screening Assay (Fig. 11.7)

♦♦ Screening for c-kit mutations predictive of an imatinib response in GI stromal tumors

Basic Technical Steps ♦♦ PCR products are heated to denature complimentary strands, and allowed to slowly reanneal. If the sample is heterozygous for the presence of a small nucleotide substitution/ insertion/deletion, four populations of double-stranded DNA molecules will result (two homoduplexes and two heteroduplexes) ♦♦ Samples are analyzed on an HPLC instrument that efficiently separates (by chromatography) homoduplexes and heteroduplexes. Any pattern of peaks that is different from the normal control (homoduplexes only) is indicative of a possible mutation. Followup DNA sequencing is used to confirm the presence of an alteration

Benefits ♦♦ It detects various single nucleotide changes, small deletions, and small insertions ♦♦ It saves time and money by indicating which samples should be sequenced

Real-Time Quantitative Reverse Transcription PCR Basic Technical Steps ♦♦ RNA is extracted from tissue or cells of interest ♦♦ cDNA is generated from RNA by traditional reverse transcription methods ♦♦ Real-time PCR is performed using two standard oligonucleotide primers plus one (or two) fluorescently labeled DNA probes ♦♦ With each cycle of annealing, the probes hybridize to newly synthesized PCR products and a measurable fluorescent signal is generated in a product-dependent manner ♦♦ The PCR cycle number at which the PCR product is first detectable (the so-called crossing point or cycle threshold) is directly proportional to the concentration (log) of the input DNA target

Fig. 11.6. Hemochromatosis (HFE gene) FRET data for three genotypes and a negative control. Melting curves (A) indicate that different genotypes lose fluorescent signal at different temperatures. The first derivative data yields melting peaks (B), which are more straightforward to interpret.

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Fig. 11.7. Schematic representation of dHPLC. PCR products are heated to denature sense and antisense strands, and allowed to cool. If the sample is heterozygous, four populations of double-stranded molecules will result, including a normal sense strand coupled with a mutant antisense strand, a mutant sense strand coupled with a normal antisense strand (heteroduplexes), and the two original homoduplex molecules (A). Samples are then analyzed on an HPLC instrument, which retains DNA molecules based upon size and composition. A homozygous sample has only one population of double-stranded molecules and will demonstrate a single peak. Heterozygous samples yield multiple peaks indicating the presence of heteroduplexes (B). The sample can then be sequenced to determine the exact nature and location of the mutation.

♦♦ An internal control gene (i.e., GAPDH) is often used to normalize results and control for varying amounts of cells or nucleic acid

Benefits ♦♦ It is highly sensitive for detecting and quantitating low levels of transcript ♦♦ Results are generated in a single day

Limitations ♦♦ Optimization can be tedious and difficult ♦♦ It can be difficult to work with RNA, which is highly susceptible to degradation

Example ♦♦ Quantitating BCR–ABL fusion transcripts in patients with chronic myelogenous leukemia undergoing imatinib therapy (Fig. 11.8)

DNA Sequencing Basic Technical Steps ♦♦ DNA from the gene of interest is first amplified by PCR −− After PCR, the amplicon is subjected to an enzymatic chain termination cycle sequencing reaction using a single primer (may be one of the PCR primers), DNA polymerase, the four deoxynucleotides (dATP, dCTP, dGTP, dTTP) and one fluorescently labeled dideoxynucleotide (i.e., ddTTP) at a much lower concentration −− One strand of the DNA is replicated. When a dideoxynucleotide (i.e., ddTTP) is added to the growing strand, chain elongation stops −− The reaction yields molecules of various sizes, each ending where a ddTTP has been added. Four reactions are performed, each with a different dideoxynucleotide. Collectively, the results yield the sequence of nucleotides within the region of interest – by a heterogeneous collection of fragments of varying sizes

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Fig. 11.8. Real-time RT-PCR for quantification of BCR–ABL transcripts for monitoring the molecular response of CML to imatinib therapy. The standard curve resulting from amplifying calibration controls with known amounts of transcripts are shown as raw amplification curves (A) and a resultant calibration curve (B). There is a linear relationship between the crossing point (PCR cycle at which the amplification curve rises above baseline) and the input copy number of original transcripts. For BCR–ABL, the specific fluorescent signal results from the ­presence of two fluor-labeled hybridization probes to ABL exon a3. (C) (BCR–ABL primers and probes) and (D) (G6PDH ­housekeeping gene primers and probes) show the amplification curves from a patient that is not responding to imatinib ­therapy – as assessed by the approximately equal crossing point (concentration) of BCR–ABL RNA compared to G6PDH RNA. A good imatinib response would be indicated by a significant right-shift of the BCR–ABL curve –indicative of a lower BCR–ABL ­transcript burden.

−− If the ddNTPs are fluorescently labeled, four reactions (TACG) can be performed in a single tube, with each nucleotide represented by a different color −− Samples are separated by capillary electrophoresis; each peak representing a single nucleotide −− Heterozygous samples are indicated by two different colored peaks at the same location (Fig. 11.9)

Benefits ♦♦ Visualization of each nucleotide makes sequencing the gold standard for mutation detection ♦♦ Reactions can be completed in a single day

Limitations ♦♦ Reagents can be expensive ♦♦ Sequencing an entire gene can be labor intensive ♦♦ Insertion or deletion mutations may be difficult to interpret

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Fig. 11.9. Results of fluorescent dideoxynucleotide sequencing and capillary electrophoresis. This patient is heterozygous at nucleotide 7; one allele has a G (black) at this location and the other has an A (green).

Example ♦♦ Sequencing the BRCA1 gene in patients with hereditary breast cancer

Molecular Diagnostic Pathology

New Molecular Genetic Technology ♦♦ Following are new technologies transitioning from the ­discovery stage into clinical diagnostics. They will need to be thoroughly researched, exhaustively validated, and carefully standardized for routine clinical use

Spectral Karyotyping ♦♦ 24 chromosome-specific (22 autosomes + X + Y) painting probes are used in just one FISH experiment to simultaneously visualize all the pairs of of metaphase chromosomes in different colors ♦♦ Although spectrally distinct fluorophores are limited, many different colors can be generated with a combinatorial labeling technique ♦♦ A fluorescence microscope attached with an ­interferometer is used to capture and analyze the spectral differences ♦♦ A pseudo color is assigned to each spectrally different combination with an image processing software, allowing the visualization of the individually colored chromosomes ♦♦ It can identify subtle karyotypic rearrangments or structural aberrations in cancer cells and other disease conditions when Giemsa banding or other techniques are not accurate or sensitive enough

Comparative Genomic Hybridization ♦♦ Assess the genomic DNA copy number gains or losses by evaluating the relative binding of different fluorescently labeled normal and tumor DNAs to normal chromosomes ♦♦ Traditional comparative genomic hybridization (CGH) to metaphase chromosome spreads can provide only limited resolution at the 5–10 Mb level ♦♦ High-density, submegabase, array-based CGH can detect nonrandom chromosome copy-number aberrations often masked under complex karyotypes ♦♦ The spotted DNAs (normal copy number) in a CGH-array contain sequence information that can be directly linked with the genome database. The copy-number aberrations of genes

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within these regions can be detected by differential hybridization of patient-derived DNA (fluorecently labeled) to the array spots ♦♦ The identification of disease-related genetic aberrations that have not yet been detected by existing ­technologies may be useful in diagnostic work up and risk stratification

Gene Expression Profiling with Microarray (Fig. 11.10) ♦♦ Assess the global gene expression profile or focused gene expression signatures by simultaneous hybridization of fluorescently labeled tumor RNA (or cDNA or cRNA) to thousands of “probes” immobilized as an array onto a miniaturized solid support ♦♦ Two platforms available: cDNA and oligonucleotide microarrays ♦♦ High throughput ♦♦ Requires fresh tissue or cells ♦♦ Genes expressed at low levels or genes with unstable mRNA may not be detected ♦♦ Interpretation is technically challenging, especially when the tissue samples contain admixed benign and malignant cells ♦♦ It has been validated and FDA-approved to identify the primary tumor site in patients with carcinoma of unknown primary

MicroRNA Profiling ♦♦ MicroRNAs (miRNA) are single-stranded RNA molecules of about 21–23 nucleotides in length ♦♦ miRNAs are not translated into protein ♦♦ miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules and their main function is to down-regulate gene expression ♦♦ miRNA signatures may enable classification of cancer. Research has shown that it can predict the prognosis of chronic lymphocytic leukemia

MOLECULAR DIAGNOSIS OF HEMATOLYMPHOID NEOPLASMS Introduction ♦♦ Consistent nonrandom genetic alterations are the hallmark of the majority of hematopoietic neoplasms (Tables 11.1–11.3) ♦♦ Morphological and immunophenotypic studies are not always sufficient for disease classification and prognostic stratification ♦♦ Molecular studies are sometimes necessary for −− Clonality assessment: monoclonal vs. polyclonal −− Lineage determination: B- vs. T-cell

−− Diagnostic/prognostic classification: Some molecularly defined abnormalities are associated with specific types of lymphoma/leukemia with prognostic and therapeutic implications −− Detection of minimal residual disease (MRD): Unique molecular markers are often useful for therapeutic response monitoring, early detection of relapse, and evaluation of effectiveness of the “purging” of therapeutic bone marrow prior to transplanation

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Fig. 11.10. Hierarchical clustering of 96 samples of normal and malignant lymphocytes; clustered based on the expression of 2,000 known genes as analyzed by microarray analysis. Each row represents a separate gene and each column a separate lymphocyte cell sample. Fluorescent cDNA probes prepared from each experimental RNA sample are hybridized to the array chip, each containing thousands of immobilized cDNA or oligonucleotide sequences. Shown are the relative ratios of hybridization of each lymphocyte sample to each reference gene. These ratios are a measure of relative gene expression in each experimental sample and are depicted according to the color scale shown at the bottom. As indicated, the scale extends from fluorescence ratios of 0.25–4 (−2 to +2 in log base 2 units). Red indicates overexpression. Green indicates underexpression. Grey indicates missing or excluded data. In this manner, the experimental lymphocyte samples can be classified into “clusters” (or groups), each with a similar pattern of global gene expression. For some tumors, this type of gene expression “clustering” analysis can subclassify morphologically indistinguishable tumors into biologically distinct prognostic categories.

General Guidelines for the Rational Use of Specific Molecular Pathology Assays ♦♦ The diagnosis of hematopoeitic malignancy can be made for a majority of cases without molecular studies ♦♦ A diagnosis of lymphoma should never be made using only the gene rearrangement data

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♦♦ Gene rearrangement data should always be interpreted along with the accompanying clinical, histologic, and immunophenotypic data ♦♦ Molecular studies can best be utilized to address the specific questions raised after morphological and immunological evaluations are performed ♦♦ It is always recommended that representitive fresh tissue or cells be archived whenever possible for possible molecular

Molecular Diagnostic Pathology

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Table 11.1. Commonly Used FISH Panels for Hematopoietic Malignancy Probe loci ALL PBX1/TCF3 TEL/AML1 BCR/ABL MLL p16/Cen9 Cen4/Cen10/Cen17 hypodiploid, unfavorable ABL/CAN (NUP214) AML PML/RARA MYH11/CBFB ETO/AML1 DEK/CAN RPN1/EVI1 Cen8/c-MYC MLL ET6/ARG MPN BCR/ABL ETV6/ABL ETV6/PDGFRb H4 (D10S170)/PDGFRb PDE4DIP/PDGFRb BCR/PDGFRa CHIC2 MDS D5S630/EGR1 D7S486/Cen7 Cen8/c-MYC D13S319/LAMP1 D20S108/20qter B-NHL c-MYC c-MYC/IGH bcl-2/IGH CCND1/IGH B-CLL D13S319/LAMP1 MDM2/Cen12 ATM/Cen11 p53/Cen17 c-MYB/Cen6 MM CCND1/IGH Rb1/LAMP1 Cen9/Cen15 Cen3/Cen7 IGH p53/Cen17

Chromosome anomalies

Disease association

t(1;19) t(12;21) t(9;22) 11q23 rearrangements −9/9p deletion or +9 Hyper- or hypodiploidy

More often in children than in adults Favorable Unfavorable Unfavorable Unfavorable Hyperdiploid (>50), favorable

ABL1/CAN coamplification

T-ALL, sensitive to imatinib

t(15;17) inv(16) or t(16;16) t(8;21) t(6;9) inv(3) +8 11q23 rearrangements t(1;12)

AML (M3), favorable AML (M4,Eos), favorable AML (M2), favorable AML (M2,M4) AML (M1,M2,M4,M6,M7) AML, M0-M7 AML, M0-M7 AML, imatinib responsive

t(9;22) Complex† t(5;12) t(5;10) t(1;5) t(4;22) −4q12 (F1P1L1/PDGFRa)

CML, imatinib responsive uCMPD imatinib responsive CMML, imatinib responsive CMPD, imatinib responsive CMPD, imatinib responsive CMPD, imatinib responsive SM-eos/CEL, imatinib responsive

−5/5q deletion −7/7q deletion +8 −13/13q deletion, inv(3) 20q-/ider(20q)

Isolated −5q with good prognosis Poor prognosis intermediate risk intermediate risk Isolated 20q- with good prognosis

8q24 rearrangement t(8;14) t(14;18) t (11;14)

Burkitt/DLBCL, aggressive Burkitt/DLBCL, aggressive FL, DLBCL MCL

−13/13q deletion +12 −11/11q deletion −17p deletion −6/6q deletion

Good prognosis Intermediate prognosis Poor prognosis Very poor prognosis Larger tumor mass but associated with no inferior outcome

t(11;14) −13/13q deletion +9 and +15 +3 and +7 14q32 rearrangements −17/17p deletion

Neutral/good prognosis Neutral/good prognosis Neutral/good prognosis Neutral/good prognosis Poor prognosis Very poor prognosis

studies since fresh tissue or cells is always better than fixed paraffin tissue for molecular studies ♦♦ Clonal gene rearrangement usually (not always) indicates malignancy; benign (reactive) lesions are usually (not always) nonclonal

−− Antigen receptor gene rearrangement PCR may give false positives due to a few clonal lymphocytes in the study samples −− Clonality of antigen receptor gene rearrangements, especially a pattern of oligoclones, is some times seen in the following conditions

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Table 11.2. Common PCR Assays for Hematological Malignancy Assay name

Other names

Clinical application

B-cell clonality (PCR)

B-cell gene rearrangement B-cell Ig heavy chain PCR Immunoglobulin gene rearrangement J-Heavy chain PCR (framework 1,2,3a) JH gene rearrangement

To detect B-cell clonality

T-cell clonality (PCR)

Gamma gene rearrangement T-cell receptor gamma chain PCR T-cell receptor gene rearrangement

To detect T-cell clonality

t(9;22) PCR for CML, qualitative

Philadelphia chromosome PCR, qualitative BCR/ABL: t(9;22) RNA PCR, qualitative (p210) BCR/ABL CML Breakpoint (p210)

To confirm the diagnosis of CML

t(9;22) PCR, quantitative

Philadelphia chromosome PCR, quantitative BCR/ABL: t(9;22) RNA PCR, quantitative (p210)

To monitoring residual CML

Table 11.3. Common Mutational Analyses in Hematological Malignancy Assay name JAK2 mutation MPL mutation FLT3 mutation NPM mutation IgH V somatic mutation c-kit D816V/F/Y mutation

Clinical application To diagnose BCR/ABL negative MPN To diagnose JAK mutation negative PMF or ET To define the prognosis of AML To define the prognosis of AML To define the prognosis of CLL To diagnose the mast cell disease, associated with imatinib resistance

(a) Autoimmune diseases (i.e., Sjögren syndrome and rheumatoid arthritis) (b) Infections (i.e., Helicobacter pylori gastritis, viral infections) (c) Dermatitis (d) Immune response to tumors (e) Immune reconsititution post bone marrow transplant ♦♦ Ultrasensitive qualitative PCR methods may rarely detect leukemia/lymphoma-associated translocations in normal individuals, i.e., t(14;18), t(9;22), t(2;5), t(12;21), and 11q23 ♦♦ A negative PCR for Ig gene rearrangement does not entirely rule out a clonal lymphoid population due to sample problems such as −− A small clonal B-cell population in a background of polyclonal B-cells −− DNA degradation or inadequate DNA extraction −− Using limited or inappropriate primers for DNA amplification

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−− Somatic hypermutation in mature B-cells, especially in follicular lymphoma −− IgH gene deletion (10%) −− Oligoclonal rearrangements and ongoing rearrangement in precursor B-cells ♦♦ Gene-specific translocation detection by PCR may be negative due to the heterogeneity of the breakpoints (i.e., DNA PCR for t(11;14) has a high false-negative rate). FISH may then be a better alternative method ♦♦ Selection of methods for antigen receptor gene rearragements −− PCR for IgH and TCRg or b is usually the first choice for evaluation of B- or T-cell clonality −− PCR for Igk may help when PCR for IgH is negative and suspicion for lymphoma remains ♦♦ Disease-specific considerations −− If follicular lymphoma or mantle-cell lymphoma are suspected, molecular studies for t(14;18) or t(11;14) may be considered if morphological and immuno­logical features are not diagnostic. FISH is usually better than PCR −− Differential diagnosis between Burkitt lymphoma/leukemia and large-cell lymphoma can be difficult in some cases, Molecular studies for c-MYC translocations are helpful. FISH is usually better than PCR −− For leukemia and myelodysplastic syndrome, peripheral blood or bone marrow are routinely studied by conventional karyotyping. Molecular studies for specific mole­ cular lesions are sometimes indicated in the following conditions (a) Confirm the diagnsosis, i.e., acute promyelocytic leukemia, chronic myeloid leukemia (b) Prognostic stratifications, i.e., acute leukemia and chronic lymphocytic leukemia (c) Post therapeutic evaluation for presence of minimal residual disease when leukemic molecular markers are available

Molecular Diagnostic Pathology

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Molecular Assessment of Clonality Immunoglobulin and T-Cell Receptor Gene Rearrangements ♦♦ Genetic rearrangements in the immunoglobulin and T-cell receptor genes determine the diversity of immune responses ♦♦ Cell-specific gene rearrangements can be used as a molecular “signature” of a clone of B- or T-cells ♦♦ Molecular methods to detect these gene rearrangements can  determine the presence of a “clone” of identical ­lymphocytes – a hallmark of neoplasia ♦♦ It is very useful for both primary diagnosis and posttherapy disease monitoring

Immunoglobin and T-Cell Receptor Gene ­Rearrangements in Normal Lymphocyte ­Development ♦♦ In the germline (unrearranged state), the Ig and TCR genes are composed of discontinuous coding regions (Table 11.4).

Immunoglobulin Heavy Chain (Fig. 11.11) and Light Chain Gene Rearrangements ♦♦ Unique V, D, and J region DNA rearrangements in each B cell generate the variable regions (antigen-binding domains) of the Ig light and heavy chains ♦♦ First rearrangement: DH to JH with insertion of random number of nucleotides (N) between DH and JH ♦♦ The VH gene then joins to the DHNJH segment with insertion of random number of nucleotides (N) between VH and DH ♦♦ The VHNDHNJH segment then joins with a CH constant region gene and its switch region to generate VHNDHNJHCH ♦♦ VDJC is transcribed and translated into an Ig heavy chain ♦♦ Failed rearrangements are followed by attempts at rearranging the second immunoglobulin heavy (IgH) allele ♦♦ k and l undergo VJC gene rearrangements similar to heavy chain genes (except no D regions for light chain genes)

Fig. 11.11. The process of B-cell receptor immunoglobulin heavy (IgH) chain gene rearrangement during the differentiation of the B cell. The DNA in the IgH chain gene locus is cut and recombined to make a rearranged gene that is able to produce one of millions of functionally active immunoglobulin heavy chains. This gene can then be transcribed into mRNA, which is, in turn, translated into the specific heavy polypeptide chain.

♦♦ Light chain genes rearrange after successful Ig heavy chain gene rearrangement. l light chain genes rearrange only after both k alleles fail to successfully rearrange ♦♦ Approximately 1014 different variable region configurations exist (for immune diversity)

T-Cell Receptor Gene Rearrangements ♦♦ Mechanism of TCR gene rearrangement very similar to IgH (above) ♦♦ TCR genes undergo VDJ or VJ rearrangments in the order: TCRd, TCRg, TCRb, and TCRa ♦♦ A majority of circulating T-cells express TCRa/b and they undergo the entire spectrum of rearrangements ♦♦ A small population of T-cells express TCRg/d and do not undergo TCRb and TCRa rearrangements ♦♦ TCR rearrangements do not occur in natural killer (NK) cells

Antigen Receptor Gene Rearrangements as Markers of Clonality Table 11.4. Immunoglobulin and T-Cell Receptor Gene Structure

Gene segments V (variable regions) D (diversity regions) J (joining regions)

IG (# available gene segments)

TCR (# available gene segments)

H

k

l

a

b

g

d

50

25

30

60

46

8

10

24

 0

 0

 0

 2

0

 3

 6

 5

 4

50

12

5

 3

♦♦ Principle: Each individual lymphocyte contains a uniquely rearranged DNA pattern within the IgH or TCR genes ♦♦ Routine molecular methods (Southern blot and/or PCR) are not sufficiently sensitive to detect VDJ genetic rearrangements in a single cell ♦♦ Molecular analysis of polyclonal lymphocyte populations (reactive lymph nodes) will then show a heterogeneous mixture of unique (each individually invisible) “single-cell” signals ♦♦ The gel electrophoresis pattern will reveal a very faint “smear” – consisting of many hundreds of heterogeneously sized DNA fragments ♦♦ The size heterogeneity in the VDJ DNA fragments of nonclonal lymphocytes results from

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−− Many differently sized V, D, J, or C genes being represented −− Insertion of a random number of N nucleotides between VD and DJ −− Imprecise exonuclease-mediated gene recombination ♦♦ Clonal lymphocyte populations (i.e., lymphoma) contain, by definition, thousands of cells with the identical IgH (B-cell) or TCR (T-cell) gene rearrangement −− Molecular analysis (Southern or PCR) will then show a single detectable nongermline VDJ rearrangement (from the predominant clone of cells) −− The gel electrophoresis pattern will reveal a distinct band (reflecting the predominant clone) often together with a faint “smear” (the background polyclonal lymphocyte population)

Southern Blot Detection of IgH (Fig. 11.12) and TCR Gene Rearrangements ♦♦ It typically uses 2–3 simultaneous restriction enzymes to increase diagnostic sensitivity ♦♦ IgH probe (for suspected B-cell lesions) or TCRb probe (for suspected T-cell lesion) is typically used ♦♦ It is quite often that both probes are used, especially when it is not clear that the lymphoma is of B- or T-cell lineage ♦♦ Distinct nongermline rearranged bands (not smears) imply rearrangement with IgH or TCRb (presence of a monoclonal

Fig. 11.12. Southern blot hybridization for IgH gene rearrangements. A positive (lymphoma) B-cell line control is shown in lanes 1 and 2, both showing clonally rearranged DNA bands in addition to the germline (unrearranged) band at ~4 kb. A negative control (polyclonal tonsil) in lanes 3, 7, and 11, shows only the germline (unrearranged) band and no additional clonally rearranged bands. Patient sample 1 (lanes 4 and 8) and patient sample 3 (lanes 6, 10, and 14) show clonally rearranged bands. Patient sample 2 (lanes 5, 9, and 13) shows no clonal rearrangement. Each DNA sample was digested with the restriction enzymes BamHI, Bal II or Xbal I as indicated. The digested IgH locus fragments are detected by hybridization with a radiolabeled probe from the joining region of the Immunoglobulin heavy chain gene.

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

population of B- or T-cells), usually (not always) suggesting a lymphoma of B-or T-cell origin Southern blot will detect rearranged band if lymphocyte clone represents >5% of the cells analyzed Tumor cell load of <5% of total cells will yield ­false-­negative signal Intensity of rearranged band reflects quantity of tumor cells. It may be useful for estimating tumor burden Southerns can also be probed with immunoglobulin light chain gene (k or l probes) Southern blots of the TCRb chain are not able to detect gene rearrangements in malignancies of g/d T-cells or NK cells

PCR-Based Detection of IgH and TCR Gene ­Rearrangements IgH PCR for B-Cell Clonality Determinations ♦♦ Sense PCR primers are designed to conserved sequences within VH region (frameworks I, II, or III) ♦♦ Antisense PCR primers are designed for conserved sequences within JH region ♦♦ Depending on primer pairs chosen, PCR product band from a clone of rearranged B-cells will be 70–380  bp in length ♦♦ Multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged Ig and TCR genes through a European BIOMED-2 collaborative study ♦♦ VH and JH regions in germline (unrearranged) cells are too distant for successful PCR amplification and yield no PCR product. Only rearranged cells (clones) yield detectable PCR bands ♦♦ A distinct (above background) PCR band between 70 and 380 bp suggests clonal B-cell population ♦♦ A clone of B-cells representing >0.1–10% of all cells is needed to yield a detectable PCR band which is also dependant on primers, tissue source, and PCR conditions ♦♦ Only ~70–90% of known lymphomas will yield detectable IgH PCR products ♦♦ Sequence heterogeneity in VH and JH regions may prevent primer binding in some clones −− False-negative results are more frequently seen in the follicular lymphomas and plasma cell malignancies due to somatic mutations of the immunoglobulin heavy chain gene which alter the sequence of the region to be amplified −− Most tests that employ consensus primers can detect only one clonal cell in 100 polyclonal cells ♦♦ PCR tests for rearrangement of the kappa light chain gene can detect clonality in up to 50% of B-cell lymphomas. It is particularly helpful in detecting a clonal population in plasma cell disorders that give false-negative results for the IgH PCR test due to somatic hypermutation of the immunoglobulin heavy chain gene

Molecular Diagnostic Pathology

T-Cell Receptor PCR for T-Cell Clonality ­Determinations ♦♦ Sense PCR primers: from conserved sequences within V or D regions ♦♦ Antisense PCR primers: from conserved sequences within J region ♦♦ Depending on primer pairs chosen, PCR product band from a clone of rearranged T-cells will be 55–100 bp in length ♦♦ V and J regions in germline (unrearranged) cells are too distant for successful PCR amplification and yield no PCR product ♦♦ Typically, a panel of multiple primer pairs is used, as any one primer pair will fail to bind to a significant minority of TCR genes ♦♦ Only rearranged cells (clones) yield detectable PCR bands ♦♦ Gel interpretation: detectable PCR band between 55 and 100 bp suggests clonal T-cell population ♦♦ Analytical sensitivity: clones of T-cells representing >0.05– 5% of all cells will yield detectable PCR band (dependant on primers, tissue source, PCR conditions) ♦♦ Diagnostic sensitivity: only ~70–90% of known T-cell lymphomas will yield detectable TCR PCR products (dependant on primers, tissue source, PCR conditions, tumor type) ♦♦ TCRb PCR requires a large number of primers (>30) due to the complexity of TCRb locus ♦♦ TCRg PCR may be preferred for diagnostic purposes −− TCRg region is less complex: the typical diagnostic PCR contains four primers against different V regions and a multiplex of J region primers and detects >90% of clonal T-cell neoplasms −− TCRg locus is consistently rearranged prior to TCRb locus −− g/d T-cell neoplasms show evidence of clonality by PCR for TCRg but not by Southern blotting for TCRb ♦♦ Consensus primers may fail to amplify some VDJ clones ♦♦ Oligoclonal cells of questionable clinical significance may generate specific bands

Clinical Utility of IgH and T-Cell Receptor Gene Rearrangement Studies Clonality and Lineage Determination ♦♦ Monoclonal rearrangements of IgH or TCR usually indicate monoclonal proliferations of B-cells or T-cells (usually “malignant”) ♦♦ AML: ~20% have clonal IgH or TCRb gene rearrangements (typically TdT positive cases) ♦♦ B-cell lymphoma and leukemia: Most have clonal IgH gene rearrangements and some may have clonal TCR gene rearrangements ♦♦ T-cell lymphoma and leukemia: Most have clonal TCR gene rearrangements, and some may have clonal IgH gene rearrangements

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♦♦ Hodgkin lymphomas have clonal IgH gene rearrangement but often not detectable unless tumor cells are enriched by microdissection ♦♦ Reactive T-cells in the tissue involved by a B-cell lymphoma may occasionally show clonal IgH gene rearragment ♦♦ Reactive B-cells in the tissue involved by a T-cell lymphoma may occsionally show clonal IgH gene rearragment ♦♦ NK-cell neoplasms typically do not show IgH or TCR gene rearrangement

Monitoring Disease Progress ♦♦ Once a clone of lymphocytes has been discovered, PCR and/ or Southern blotting can be used to continually track the tumor cell clone to evaluate response to therapy (minimal residual disease) ♦♦ Disappearance of the “tumor-specific” gel band may correlate with successful therapy ♦♦ Reappearance of the “tumor-specific” gel band may correlate with disease relapse ♦♦ PCR clearly more sensitive than Southern blotting for minimal residual disease determinations

Molecular Determination of Clonality of Nonlymphoid Maligancies ♦♦ One of the two X-chromosomes is randomly inactivated in the early embryonic development of all females ♦♦ In neoplasms, nonrandom inactivation of X-chromosome genes indicates monoclonality ♦♦ The human androgen receptor (HUMARA) locus (X-linked) has highly polymorphic trinucleotide (CAG) repeats. It is used to detect monoclonal nonrandom X-inactivation in nonlymphoid malignancies ♦♦ Evaluation of methylation sensitive restriction endonuclease sites or methylation-specific PCR primers can also be used, because methylation is a marker for inactivated regions of the X-chromosome ♦♦ Can only be applied to female patients

Molecular Markers or Lesions Nonrandom Associated with Specific Diseases Mature B-Cell Neoplasms ♦♦ Morphological and immunological features are adequate for the diagnosis and classification of the majority of mature B-cell lymphomas ♦♦ Some lesions show features overlapping with reactive lymphoid hyperplasia; molecular characterization then often indicated ♦♦ Residual disease could be submicroscopic, requiring sensitive techniques for detection ♦♦ Molecular assays are frequently performed for ­determining clonality (to establish the diagnosis of lymphoma), the presence of specific genetic lesions (to clarify the classification), and detection of minimal residual disease

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♦♦ Specific translocations are present in follicular lymphoma (FL), mantle-cell lymphoma (MCL), and a subset of marginal zone lymphoma (MZL). These translocations are defining genetic lesions with great diagnostic significance

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ♦♦ Two distinct types based on Ig VH gene mutation status −− Pregerminal center type (40–50%): Germline IgH, naïve B-cells, often CD38+, increased ZAP-70 expression and poor prognosis (median survival: three years) −− Postgerminal center type (50–60%): Mutated IgH, memory B-cells, often CD38−, decreased ZAP-70 expression (median survival: 7 years) ♦♦ CLL/SLL has a variety of nonspecific, recurrent genetic lesions of prognostic significance ♦♦ About 80% of the cases have abnormal karyotypes −− Trisomy 12 (20%), predominatly in pregerminal center type −− Deletions at 13q14(~50%), more often in postgerminal center type −− Deletions at 11q22-23(20%), often in postgerminal center group, associated with poor prognosis −− Deletions at 17p13(10%), associated with loss of TP53 and poor prognosis −− Deletions at 6q21(5%) ♦♦ Routine cytogenetic or FISH studies are the method of choice for evaluation of genetic lesions ♦♦ Molecular assays for IgH mutational status are not routinely performed

B-Cell Prolymphocytic Leukemia ♦♦ Ig H and L chain genes are clonally rearranged ♦♦ Abnormalities of TP53 gene occur in about 53% of cases ♦♦ Deletions at 11q23 and 13q14 are reported

Lymphoplasmacytic Lymphoma ♦♦ There is somatic mutation in VH genes ♦♦ ~50% of cases show t(9;14)(p13;q32) involving PAX5 gene −− PAX5 encodes a B-cell-specific activator protein (BSAP) −− Expression of BSAP is independent of the translocation

Hairy Cell Leukemia ♦♦ ♦♦ ♦♦ ♦♦

VH genes show somatic mutation No specific cytogenetic abnormalities are identified Cyclin D1 is overexpressed in about 50–75% of the cases There are no bcl-1 rearrangements or detectable t(11;14)

Marginal Zone Lymphoma ♦♦ Splenic marginal zone lymphoma (MZL) −− Most have somatic mutation with intraclonal variation in IgH gene −− 40% of cases show allelic loss of chromosome 7q21-32

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−− Trisomy 3 is uncommon −− No t(14;18) or t(11;18) detected ♦♦ MALT lymphomas −− Ig H and L chain genes are clonally rearranged −− About 60% of them have trisomy 3 −− About 25–50% of them have t(11;18), mainly detected in pulmonary, gastric, and intestinal tumors −− No association with t(14;18) or t(11;14) −− Gastric MALT lymphoma and t(11;18) (q21;q21) (a) Partner genes are API2 (chromosome 11) and MLT (chromosome 18) (b) Produce a API2-MLT chimera (c) Both involved in apoptosis regulation (d) Associated nuclear bcl-10 positive staining by IHC (e) Independent of H. Pylori infection (f) Do not respond to antibiotic treatment (g) Detection methods: IHC for bcl-10 protein, RT-PCR for fusion transcript, or FISH for translocation ♦♦ Nodal MZL −− Not well genetically characterized

Follicular Lymphoma ♦♦ Variable region genes show somatic mutations with intraclonal heterogeneity ♦♦ 100% of the cases show cytogenetic abnormalities ♦♦ 70–95% of them have t(14;18) involving bcl-2 gene −− It is not specific for follicular lymphoma, also present in ~20% of diffuse B-cell lymphomas −− It juxtaposes IgH gene with the bcl-2 gene on chromosome 18 (a) Lymphomas show two predominant breakpoint regions within bcl-2 (b) Major breakpoint region (MBR) is utilized in ~60– 70% of tumors (c) Minor cluster region (MCR) breakpoints is utilized in most of the other tumors −− bcl-2 coding regions left intact by translocations −− IgH regulatory controls stimulate inappropriate overproduction of bcl-2 protein −− bcl-2 normal function is suppression of apoptosis (programmed cell death) −− B-cell bcl-2 over-production suppresses cell death, promotes inappropriate cell survival, and thus increases the chances for secondary oncogenic genetic aberrations −− Southern blot with MBR and/or MCR bcl-2 probe will show “novel” rearranged bands, but insensitive for low tumor cell burdens −− PCR with primer for bcl-2 (MBR and/or MCR) and primer for JH (IgH) (a) Only cells with rearrangements (i.e., tumor cells) will show a PCR product

Molecular Diagnostic Pathology

(b) Highly sensitive: typical detection limit is one ­lymphoma cell in 104–105 background cells (c) Useful for monitoring for minimal residual disease after therapy (d) Useful for checking “purged” bone marrow prior to transplantation (e) May be overly sensitive, leading to false postive results (f) Some benign lymphoid tissue (tonsils, nodes) may contain rare cells with t(14:18), below the sensitivity limit of most PCR assays (g) Demonstration of t(14;18) or IgH gene rearrangement typically argues against follicular hypperplasia (FH). However a negative FISH for t(14;18) or negative PCR for IgH gene reaarangement does not completely rule out FL ♦♦ Other genetic and molecular abnormalities −− t(14;18) as a sole abnormality in only 10% −− Rare cases with t(2;18) (p12;q21) −− +7 (20%) −− +18 (20%) −− 3q27-28 (15%) −− 6q23-26 (15%), suggesting deletion of tumor supressor genes −− 17p (15%), alteration in TP53 gene, associated with a worse prognosis −− bcl-6 rearranged (15%) −− bcl-6 mutations (40%)

Mantle-Cell Lymphoma ♦♦ Variable region genes are unmutated in the majority of the cases ♦♦ Small proportion of cases show somatic mutation ♦♦ Virtually all cases carry characteristic t(11;14)(q13;q32) −− Partner genes are IgH (chromosome 14) and cyclin D1 (chromosome 11) −− Cyclin D1 gene is also known as CCND1, bcl-1, PRAD1 −− Juxtapositioning near IgH causes inappropriate overexpression of bcl-1 −− bcl-1 normally functions to inactivate (phosphorylate) the tumor-suppressing retinoblastoma protein RB, thus preventing its suppression of cell cycle progression −− Overexpressed cyclin D1 thus promotes inappropriate cell growth −− Immunohistochemistry for cyclin D1 protein is adequate in most cases −− When immunostains are equivocal, FISH or PCR can be considered −− FISH is more sensitive (~100%) than conventional cytogenetics (70–75%) −− Presence of t(11;14) essentially rules out the possibility of SLL/CLL

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−− Study for t(11;14) can help to differentiate blastic variant MCL from diffuse large B-cells lymphoma (DLBCL) ♦♦ Other genetic and molecular abnromalities −− ATM mutation or deletion (40~75%) −− Total or partial trisomy 12 (~25%) −− Frequent chromosomal imbalance ♦♦ No bcl-2 or c-MYC rearrangement ♦♦ c-MYC rearrangement rarely detected

Diffuse Large Cell Lymphoma ♦♦ A diverse group with different morphological subtypes and clinicopathological variants ♦♦ Gene expression profiling shows three different subtypes with different gene expression signatures: germinal center B-cell (GCB) like, activated B-cell (ABC) like, type III with overlapping features −− GCB-DLBCL: ~50%, CD10+, median survival of ~10 years −− ABC-DLBCL: ~35%, CD10-, median survival of ~2 years ♦♦ Variable region genes show somatic mutations ♦♦ 20–30% of cases show t(14;18) with translocation of bcl-2 gene ♦♦ ~30% of cases show 3q27 abnormalities involving bcl-6 gene −− bcl-6 gene on chromosome 3q27 is often translocated to a partner chromosome including IgH (chromosome 14); light chain gene (chromosome 22q11), and others −− bcl-6 encodes a likely transcription factor which may regulate B-cell growth when inappropriately overexpressed −− bcl-6 abnormalities are not specific for DLBCL ♦♦ MYC rearrangement is uncommon ♦♦ Morphological/immunostains are sufficient for routine diagnosis ♦♦ Genetic and molecular studies are typically not indicated

Mediastinal (Thymic) Large B-Cell Lymphoma ♦♦ Hyperdiploid karyotypes with gains of 9p and amplification of REL gene are often seen ♦♦ NAL gene overexpression is identified in a high proportion of the cases ♦♦ bcl-2, bcl-6, and c-MYC rearrangements are absent

Burkitt Lymphoma/Leukemia ♦♦ Variable region genes show somatic mutations ♦♦ All cases have a translocation of c-MYC (on chromosome 8) −− Most commonly as t(8;14) involving IgH gene ­(chromosome 14) −− Less commonly as t(2;8) or t(8;22) involving either of the light chain genes −− Deregulation of c-MYC promotes lymphomagenesis

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−− Diagnosis usually apparent by histology and immuno­ phenotype −− Molecular methods typically not required for clinical practice −− However, c-MYC translocation detection by cytogenetic or molecular methods denotes an aggressive high grade B cell lymphoma with a high proliferative rate −− The c-MYC translocations are not entirely specific for Burkitt Lymphoma/Leukemia (BL). Secondary B-acute lymphoblastic leukemia/lymphoma following follicular lymphoma is reported to also be positive −− BL and CD10-positive DLBCL may be difficult to tell apart when morphological and immunological features are atypical. Molecular studies, especially FISH for c-MYC or bcl-2 gene rearrangements, are very useful. Presence of c-MYC translocation only support the diagnosis of BL or its variants. Presence of bcl-2 gene rearrangement can be seen in either FL or DLBCL. Absence of c-MYC translocation argues against BL or it variants. Translocations involving c-MYC and bcl-2 in DLBCL are associated with an aggressive clinical course ♦♦ EBV genomes in tumor cells are detectable in almost all endemic cases, less than 30% of sporadic cases, and 25–40% of immunodeficiency cases ♦♦ Other genetic lesions include inactivation of TP53 in ~30% of cases

t(8;14)(q24;q32) ♦♦ Brings the c-MYC proto-oncogene (chromosome 8) under the regulation of the IgH enhancer (chromosome 14) ♦♦ Typically associated with Burkitt lymphoma/leukemia, one of the most rapidly dividing neoplasms, requiring intensive therapy in order to achieve better outcomes ♦♦ 75% of cases of Burkitt lymphoma/leukemia are positive for t(8;14), the remainder positive for t(2;8) or t(8;22) (with light chain partner genes) ♦♦ For t(8;14), long-distance PCR assays are required because the breakpoints in and around the c-MYC and IgH genes are widely dispersed ♦♦ FISH and Southern blot analysis with c-MYC probes are often the methods of choice ♦♦ Clinical, morphological and immunological features are quite well characterized. Ki-67 is positive in almost 100% of tumor cells, serving as a surrogate marker ♦♦ Commercial c-MYC FISH probes are available. A FISH study for the c-MYC translocation is the method of choice for quick confirmation of the diagnosis

Plasma Cell Neoplasms ♦♦ Clonal rearrangement of Ig genes commonly detected −− Most cases (~95%) show a single, monoclonal rearranged Ig band −− Some cases (~5%) show multiple rearranged Ig bands −− JH segments and/or parts or the entire chromosome 14 (where IgH gene is located) may be lost in light chain only disease

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♦♦ About 20–60% of plasma cell myelomas have structural and numerical chromosomal abnormalities −− More chromosomal aberrations are seen in cases with progressive disease than in newly diagnosed cases −− Most frequent changes are complex karyotypic abnormalities with multiple chromosomal gains or losses ♦♦ Translocations, deletions, and mutations are also present −− About 10% of cases have t(11;14)(q13;q32) involving cyclin D1 −− About 25% of cases have deletion of 17p13 associated with allelic loss of TP53 −− Expression of PAX5 gene (chromosome 9) is altered, resulting in loss of CD19. Normal plasma cells are CD19 positive while myeloma cells are CD19 negative −− Deletion of 7q is also seen, associated with multidrug resistance

Mature Peripheral T-Cell Lymphoma/ Leukemia ♦♦ A variety of translocations involving one of the T-cell receptors: a or d on chromosome 14 and b or g on ­chromosome 7. Partner genes are typically transcription factors whose expression is dysregulated due to translocation ♦♦ The t(2;5) is the most common cytogenetic abnormality in systemic anaplastic large cell lymphoma ♦♦ Clonal TCR gene rearrangement supports the diagnosis of T-cell lymphoma ♦♦ Detection of the t(2;5) helps to confirm the diagnosis of CD30+ anaplastic large cell lymphoma associated with a better prognosis ♦♦ Clinical and pathological correlation is always necessary for definitive diagnosis ♦♦ Monoclonality does not equal lymphoma ♦♦ Presence of t(2;5) does not equal CD30+ anaplastic large cell lymphoma

Anaplastic Large Cell Lymphoma ♦♦ The majority of cases express ALK protein, due to ALK translocation −− t(2;5)(p23;q35) (70–80%), resulting in the NPM–ALK fusion gene on 5q35 −− Variants (20–30%): TPM3 gene at 1p21, TFG at 3p21, ATIC at 2p35, CLTC at 17p23 and other genes −− Translocations result in expression of ALK protein which is not normally expressed in lymphocytes −− Patients with ALK-positive ALCL have better survival than ones with ALK-negative ALCL −− Rarely B-cell lymphomas have ALK translocations with ALK protein expression −− Translocations are detectable by cytogentics, FISH, and Southern blot −− Fusion transcripts are detectable by RT-PCR −− Abnormal expression of ALK proteins is detectable by immunohistochemistry

Molecular Diagnostic Pathology

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−− For routine diagnosis, ALK immunohistochemistry is the preferred test −− FISH is more sensitive than RT-PCR −− Not all ALK gene abnormalities are detectable by RT-PCR −− RT-PCR may be used in monitoring minimal residual disease. It can detect much lower levels (1 in 10,000) of the disease than the standard PCR test for TCR gene rearrangement (~1 in 100) ♦♦ ALK negative cases: genetic lesions not fully studied

−− 10–40% of nodular sclerosis HL −− Almost 100% in patients in developing regions and those with HIV infection ♦♦ Aneuploid and hypertetraploid karyotypes are common in HRS cells ♦♦ Recurrent gains of the chromosomal subregions of ­chromosomal arms 2p, 9p, and 12q and amplifications on chromosomal bands 4p16, 4q23-q24, and 9p23-p24 are revealed by CGH ♦♦ No t(14;18) and t(2;5) detected

NK Cell Neoplasms

Myeloproliferative Neoplasms (MPNs)

♦♦ TCR genes are in germline configuration ♦♦ Pattern of X-chromosome inactivation used for clonality evaluation (in females) ♦♦ A variety of nonspecific but recurrent and clonal cytogenetic abnormalities are reported with del(6)(q21q25) as the commonest one ♦♦ EBV genomes are present in the majority of cases

♦♦ Chromosomal translocation t(9;22) is positive in chronic myelogenous leukemia (CML) ♦♦ JAK2V617F mutations are present in about 90% patients with polycythemia vera (PV), and in approximately half of those with essential thrombocytosis (ET) and primary myelofibrosis (PMF) ♦♦ JAK2 V617F mutation test is a part of routine clinical workup to distinguish MPNs from the many benign and malignant disorders they mimic clinically ♦♦ JAK2 exon 12 mutations account for a significant number of JAK2V617F-negative PV cases. If a JAK2 V617F assay is negative and tobacco use, sleep apnea, or hepatic or renal abnormality is not evident, evaluation of mutations involving JAK2 exon 12 is indicated ♦♦ A small portion of patients with ET and PMF who lack a mutated JAK2 may have instead activating mutations in MPL (MPLW515L/K) ♦♦ A positive JAK2 mutation confirms the clinical impression of a myeloproliferative neoplasm ♦♦ A negative JAK2 mutation assay does not rule out a myeloproliferative neoplasm ♦♦ JAK2 mutations can be seen in some cases of myelodysplastic syndrome/myeloproliferative neoplasm, rare cases of acute myeloid leukemia, and occasionally in combination with BCR-ABL rearrangement ♦♦ JAK2 targeted therapies are currently in clinical trials and there is possible future need for quantitative V617F assays for monitoring minimal residual disease (MRD) ♦♦ Recurring genetic abnormalities including somatic point mutations of c-KIT, a tyrosine kinase receptor for stem cell factor (SCF or mast cell growth factor) in mastocytosis. Point mutation of c-KIT (D816V) is associated with resistance to Imatinib Mesylate

Nodular Lymphocyte Predominant Hodgkin Lymphoma ♦♦ L&H cells have clonally rearranged Ig genes. However, rearrangements not detectable in whole tissue but detectable in enriched single L&H cells ♦♦ VH genes have a high load of somatic mutation with ongoing mutation ♦♦ EBV infection is consistently absent in the L&H cells

Classic Hodgkin Lymphoma ♦♦ Ig gene rearrangements are present in Hodgkin Reed– Sternberg (HRS) cells in >98% of cases ♦♦ Rare cases show clonal TCR rearrangements ♦♦ Rearrangements not detectable in whole tissue but ­detectable in enriched single HRS cells ♦♦ VH genes have a high load of somatic mutation without ongoing mutation ♦♦ No detectable Ig mRNA and protein due to a lack of the octamer-dependent transcription factor Oct-2 and or its coactivator BOB.1 −− Other B-cell lymphomas and nodular lymphocyte predominant hodgkin lymphoma (NLPHL) have detectable Oct-2 and/or BOB.1 ♦♦ There is persistent activation of NFkB, preventing apoptosis in HRS cells. This may be caused by −− Defects of the natural inhibitors of NFkB −− Aberrant activation of IkB kinase (IKK) −− Overexpression of TNF receptor associated factor (TRAF) 1 molecule −− EBV infection, producing LMP1 ♦♦ EBV infection in HRS cells is common −− Characterized as latency type II EBV infection, ­producing LMP1 and EBNA-1 but not EBNA-2 −− About 75% of mixed cellularity HL

Translocation t(9;22)(q34;q11) (Philadelphia Chromosome) (Ph) ♦♦ Most CML cases are cytogenetically positive for t(9;22) (q34;q11) ♦♦ About 2.5% of CML cases are only positive at the ­molecular level ♦♦ Cases with clinical and morphological features of CML without detectable t(9;22)(q34;q11) are classified as atypical CML under the current WHO category of ­myelodysplastic/myeloproliferative diseases that often show dysplastic features

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♦♦ Also present in ~25% of adult B lineage ALL and 5% of childhood ALL. The presence of t(9;22) in ALL predicts poor prognosis ♦♦ The translocation involves the ABL tyrosine kinase protooncogene on 9q34 and the BCR gene (breakpoint cluster region) on 22q11 ♦♦ It results in aberrant expression of a BCR–ABL fusion protein with enhanced tyrosine kinase (and transforming) activity ♦♦ There are two predominant breakpoint regions within BCR −− Major breakpoint cluster region (M-BCR) in most CML cases and approximately half of ALL cases; resulting in synthesis of a 210 kD BCR-ABL kinase −− Minor breakpoint cluster region (m-BCR) (further upstream in BCR) in most pediatric ALL cases and approximately half of adult ALL cases; resulting in synthesis of shorter 190 kD BCR–ABL kinase ♦♦ The breakpoint occurs rarely in the µ-BCR region, resulting in a large fusion protein, p230. Patients with this fusion may have prominent neutrophilic maturation ♦♦ Detection methods −− Routine cytogenetics (a) Typically performed at diagnosis and during the course of the disease for monitoring clonal ­evolution or emergence of Ph-negative clones (b) Major cytogenetic response is typically categorized complete (0% Ph-positive cells in metaphase in a bone marrow sample) or partial (1–35% Ph-positive cells in metaphase) (c) Loss of major cytogenetic response is typically defined as an increase in Ph-positive cells in ­metaphase by at least 30% of points −− FISH (a) Very helpful to confirm the diagnosis when cytogenetic karyotyping is not done or not available (b) Due to the high variation of BCR–ABL-negative lymphoid cells in the samples, FISH results show a high degree of variation and do not provide any additional information for the management of patients with complete cytogenetic response achieved by imatinib −− RT-PCR (Fig. 11.13) (a) RT-PCR with an ABL primer and a BCR primer (M-BCR and/or m-BCR) (b) Only tumor cells (with juxtaposed BCR and ABL) yield PCR signal (c) Extremely sensitive in tumor cell detection; quantitative with real-time PCR technology (d) Useful for monitoring minimal residual disease, particularly after targeted imatinib (or other tyrosine kinase inhibitor) therapy * Molecular response is usually measured every 3 months throughout therapy and is an excellent surrogate marker for disease status * Greater than 3 log reduction of BCR–ABL RNA levels is ­predictive of sustained remission

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Fig.  11.13. Qualitative RT-PCR analysis for the detection of BCR–ABL fusion transcripts in CML. (a) Depicts the locations of the two sense PCR primers (in bcr exon b2 or e1) and the common antisense primer (in abl exon a4). (b) Shows RT-PCR for BCR–ABL with exon e1 BCR primer. (c) Shows RT-PCR for BCR–ABL with exon b2 BCR primer. (d) Shows RT-PCR for Beta 2 microglobulin as a house keeping gene control. Lane 1 depicts a patient sample (and lane 3 a positive control sample) with an e1a2 fusion gene. Lane 2 depicts a patient sample (and lane 4 a positive control sample) with a b3a2 fusion gene. Lane 5 shows a negative control. MW molecular weight ladder. * BCR–ABL reappearance (or increased amount) after therapy predicts clinical relapse (and increased risk of a kinase domain point mutation) * RT-PCR is inable to detect clonal evolution * There is a high concordance between peripheral blood and bone marrow RT-PCR ­testing * RT-PCR positivity 6 months after stem cell ­transplantation predicts a high risk of relapse * RT-PCR positivity (or increasing levels) precedes cytogenetic and hematologic relapse by several months

Myeloid Neoplasms Associated with Eosinophilia and Abnormalities of PDGFRa, PDGFRb, or FGFR1 ♦♦ These diseases have myeloproliferative features and eosinophilia ♦♦ They are caused by activating mutations or translocations involoving platelet-derived growth factor receptors (PDGFR, a and b) or fibroblast growth factor receptor (FGFR). These patients often respond to therapy with imatinib mesylate ♦♦ t(5;12) involves ETV6 (TEL) and PDGFb −− Marked leukocytosis with variable monocytosis and eosinophilia −− Variably classified as chronic myelomonocytic leukemia (CMML), chronic eosinophilic leukemia (CEL), Atypical CML (a-CML), etc −− Possible frequent evolution to AML ♦♦ Cytogenetically cryptic interstitial deletion on 4q12 producing FIP1L1/PDGFRa −− Dramatic response to low-dose imatinib

Molecular Diagnostic Pathology

♦♦ t(8;13) −− Involves FGFR1 on 8p11 and ZNF198 on 13q12 −− Bilineal presentation as T-lymphoblastic lymphoma or myeloproliferative disorder, and frequent progression to AML

Myelodysplastic/Myeloproliferative Neoplasms ♦♦ All negative for t(9;22)(q34;q11) (Philadelphia chromosome): BCR–ABL ♦♦ Cytogenetic and molecular studies are often necessary to rule out CML ♦♦ Nonspecific and recurrent genetic abnormalities are frequently detected: +8, +13, −7/del(7q), del(20q), i(17q), del (12p), or structural abnormalities of 12p ♦♦ Ras mutation in about 40% of patients with chronic myelomonocytic leukemia (CMML) and 20% of juvenile myelomonocytic leukemias (JMML) ♦♦ Cytogenetic studies are helpful for establishing the diagnosis in the right clinicopathological setting ♦♦ FISH is helpful for monitoring disease status ♦♦ Absence of genetic abnormalities does not rule out myeloproliferative/myelodysplastic syndrome

Myeloid Dysplastic Syndrome ♦♦ Common nonspecific, recurrent cytogenetic abnormalities include +8, −5, del(5q), −7, del (7q), and del(20q) as well as complex karyotypes ♦♦ Present in about 25% of cases with refractory anemia (RA), less than 10% of refractory anemia with ringed sideroblasts (RARS), up to 50% of cases with refractory cytopenia with multilineage dysplasia (RCMD), 30–50% of cases with refractory anemia with excess blasts (RAEB) ♦♦ Deletion between bands q31 and 33 of chromsome 5 is the sole cytogenetic abnormality in 5q-syndrome, associated with a long survival ♦♦ Although most changes are not specific, the presence of cytogenetic abnormalities helps to establish the diagnosis and to define the prognosis ♦♦ Three major risk categories are based on cytogenetic findings −− Good risk: Normal cytogenetics, isolated (5q), isolated del(20), and –Y −− Poor risk: complex abnormalities, i.e. >3 recurring abnormalities, or abnormalities of chromosome 7 −− Intermediate risk: all other abnormalities

Acute Myeloid (Nonlymphoblastic) Leukemia ♦♦ Acute myeloid leukemia (AML) with t(8;21)(q22;q22) (AML1-ETO) −− It constitutes about 5–12% of AML, and about one-third of AML with maturation −− Bone marrow may have less than 20% of blasts. Do not classify them as RAEB

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−− t(8;21) fuses AML1 (chromosome 21) with ETO (chromosome 8) to create AML1–ETO fusion protein, an aberrant transcription factor −− It is most characterically associated with AML with maturation (FAB AML M2); however, seen in only about 40% of AML with maturation −− Greater than 90% of t(8;21) positive cases have M2 morphology −− AML with t(8;21) have a particular sensitivity to ­therapeutic regimens containing high dose cytosine arabinoside −− Association with a good prognosis (good response to therapy) is well established in adult AML −− Detectable by cytogenetics, FISH, or RT-PCR ♦♦ AML with inv(16)(p13;q22) or t(16;16)(p13;q22) (CBFbMYH11) −− It constitutes about 10–12% of AML −− It usually shows monocytic and granulocytic differentiation and abnormal eosinophils (FAB, AML M4Eo), associated with a high rate of complete remission, and favorable prognosis −− Inv(16) fuses CBFb gene (q22) (a transcription factor) with MYH11 (p13) (smooth muscle myosin heavy chain) −− The inv(16) or t(16;16) can be detected by cytogenetics, FISH, or RT-PCR −− The inv(16) can sometimes be quite subtle and may be missed occasionally if the metaphase preparations are suboptimal −− The break points in the two genes are quite ­heterogeneous with at least ten different fusion transcripts generated ♦♦ AML with t(15;17)(q22;q11-22) (PML-RARa) and variants −− t(15;17) is the hallmark of acute promyelocytic leukemia (APL or FAB AML M3) including both classic ­hypergranular form and microgranular variant −− It constitute about 5–8% of AML, associated with a high rate of complete remission and favorable prognosis −− Timely confirmation with FISH or RT-PCR very important so the patient can be effectively treated with all-trans retinoic acid (ATRA) −− About 99% of APL have t(15;17)(q22;q21), resulting in a fusion between the retinoic acid receptor alpha (RARa) (chromosome 17q12) (a retinoid regulated transcription factor) and the promyelocytic leukemia (PML or MYL) gene (chromosome 15q22) −− The remaining 1% of APLs have variant translocations with disruption of RARa gene at 17q21: t(11;17)(q23;q21) resulting in a fusion gene PLZF-RARa; t(11;17)(q13;q21) resulting in a fusion gene NUMA-RARa; t(5;17)(q35;q21) resulting in a fusion gene NPM-RARa; der(17) resulting in a fusion gene STAT5-RARa −− The RARa fusion transcription factors have altered activity and promote leukemogenesis −− All APL except the t(11;17)(q23;q21) variant can be effectively treated with retinoic acid. Treatment with his-

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♦♦

♦♦ ♦♦

♦♦

tone deacetylase (HDAC) inhibitors is required to induce differentiation in APL with t(11;17)(q23;q21) −− Cytogenetics (typically) and FISH are often the primary diagnostic choice. About 15% have been reported to be cytogenetically negative due to cryptic lesions and technical failures −− In the common t(15;17) translocation, the breakpoints in RARa are well conserved in intron 2, while there are two major breakpoints in the PML gene. A single down stream RAR primer and two upstream PML primers are required for the detection of most (greater than 90%) PML-RARa fusion transcripts −− Molecular methods are available for detection, but falsenegative studies may occur −− RT-PCR is useful for detecting minimal residual disease after all-trans retinoic acid therapy −− Persistent PCR positivity after treatment predicts relapse −− Persistent PCR negativity predicts continued remission AML with 11q23 (MLL) abnormalities −− The MLL (stands for mixed lineage leukemia, or myeloid lymphoid leukemia) gene is located on ­chromosome 11q23 −− The gene has also been named ALL1, htrx or HRX −− The most common translocations include t(9;11) (q21;q23); t(11;19)(q23;p13.1); t(11;19)(q23;p13.3) −− Partial tandem duplication is also reported −− It is associated with intermediate survival −− 11q23 (MLL) abnormalities are seen in myeloid dysplastic syndrome (MDS) and in ~80% of ALL cases in infants −− AML with 11q23 translocations often show monocytic differentiation (M4 or M5), or prior therapy with topoisomerase II inhibitors −− MLL translocations involve at least 80 different translocation partner genes including FEL (AF4) on 4q21 in the t(4;11), AF9 on 9q21 in the t (9;11) and one of three different genes ENL, ELL, and EEN on 19p13 in the different t(11;19) translocations −− MLL regulates the expression of genes via chromatin remodeling. Many of the fusion partners are putative transcription factors −− It predicts poor response to standard therapies −− Commercial FISH probes are available to detect the break apart of the MLL gene −− Molecular studies are confounded by the many different partner genes involved in the translocations −− Breakpoints in MLL cluster in an 8.3 kb region and may be detected by Southern Blot analysis AML with t(6;9) (DEK-CAN) is associated with basophilia, multilineage dysplasia, and poor prognosis AML with inv 3(q21;q26.2) or t(3;3) (RPN1-EVI1) is associated with thrombocytosis, increased hypolobated megakayocytes and multilineage dyplasia and poor prognosis AML with t(1;22) (RMB15- MKL1) is associated with infantile acute megakaryoblastic leukemia

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♦♦ Genetic abnormalities are common but nonspecific in other types of AML −− AML with multilineage dysplasia (a) Chromsome abnormalities are similar to those seen in MDS (b) Gain or loss of major segments of certain chromoses are common: −7/del(7q), −5/del(5q), del(9q), –13/del(13q), i(17q), +(17p), del(11q), del(12p), del(12p)/t(12p) (c) Less often: translocations ­involving 3q21, 3q26 regions, and 5q32-33 −− AML, therapy related (a) Balanced translocations often involves 11q23 (b) Other abnormalities include t(8;21), t(3;21), inv(16), t(8;16) and t(6;9) −− Acute leukemia of ambiguous lineage (a) About one-third of them have the Philadelphia ­chromosome (b) Some are associated with 11q23 abnormalities (c) Substantial cases show rearrangement or deletion of the Ig heavy chain gene or TCR chain genes −− AML not otherwise categorized, mainly based on morphological features and lineage differentiation

♦♦

♦♦

♦♦

♦♦ ♦♦

(a) No unique chromosomal abnormalities have been identified (b) Nonspecific and recurrent cytogenetic lesions are often observed Prognostic stratification of AML based on genetic abnormalities −− Favorable prognosis with higher rate of complete remission (70–85%) and better 5-year survival ­(35–60%): t(8;21), t(15;17), inv (16), or t(16;16) −− Unfavorable prognosis with lower rate complete remission (25–60%) and worse 5-year survival (2–15%): −5, −7, 3q abnormality or complex −− Intermediate prognosis: Normal, +8, +21, or 11q23 abnormality Cytogenetically normal AML −− Certain genotypes are associated with clinically significant differences in response to therapy and in survival The genotype of mutant NPM1 without FLT3-ITD is associated with a complete remission after conventional anthracycline and cytarabine-based induction therapy and with 4-year overall survival of 60%. These patients might not benefit from stem cell transplantation as a first-line treatment The mutant CEBPA genotype is also associated with a complete remission and with 4-year overall survival of 62% The genotype of FLT3-ITD and the triple-negative genotype of wild-type NPM1 and CEBPA without FLT3-ITD had poor outcomes with 4-year overall survival of 24–33%. Only these two groups benefited from an allogeneic transplant performed during the first complete remission

FLT3 Abnormalities ♦♦ FLT3 is a receptor tyrosine kinase expressed by hematopoietic progenitor cells and downregulated during differentiation

Molecular Diagnostic Pathology

♦♦ Abnormalities of FLT3 have been described as an internal tandem duplication (ITD) of the juxtamembraneous domain and a missense mutation at codons D835 or I836 ♦♦ The ITD occurs in about 23% of AML cases with the point mutation in about 7% of cases ♦♦ FLT3 abnormalities result in the constitutive activation of the tyrosine kinase domains via autophosphorylation, leading to a persistent “on” signal in the leukemic cells ♦♦ Molecularly targeted therapy with FLT3 inhibitors are under active investigation ♦♦ Detection of FLT3 abnormalities is helpful to select a subset of AML patients for clinical trials with these new agents ♦♦ FLT3 abnormalities are associated with poor prognosis in AML less than 60 years old, independent of karyotype ♦♦ PCR (both DNA and RT) assays targeting the ITD or D835/ I836 regions are available for diagnosis

NPM Mutations ♦♦ Nucleophosmin (NPM1, also known as nucleolar ­phosphoprotein B23 or numatrin) is a ubiquitously expressed nucleolar phosphoprotein that continuously shuttles between the nucleus and cytoplasm with prominent nucleolar localization. Mutations in NPM usually result in abnormal cytoplasmic localization of the protein (which can be detected by immunohistochemistry) ♦♦ NPM1 regulates the stability and transcriptional activity of p53 after different types of stress ♦♦ Mutation of NPM gene has been reported as the most frequent mutation in AML, especially in the presence of a normal karyotype ♦♦ NPM mutations (usually insertions or deletions near the C-terminus) are associated with AML with a high white blood cell count and monocytic lineage (M4/M5) ♦♦ NPM1 mutations predicts for better response to induction therapy and for favorable overall survival in the absence of FLT3 ITD

CEBPA Mutation ♦♦ The transcription factor CCAAT/enhancer-binding protein a, encoded by the CEBPA, is crucial for the differentiation of immature granulocytes. Mutation of the CEBPA may play an important role in leukemogenesis and prognosis ♦♦ Most AML with CEBPA mutations are associated with an immunophenotype of HLA-DR+CD7+CD13+CD14–CD15+ CD33+CD34+ ♦♦ The mutant CEBPA genotype (in the absence of a FLT3 mutation) predicts a relatively good prognosis in AML

Acute Lymphoblastic Leukemia/Lymphoma ♦♦ Classification is mainly based on morphological and immunological features ♦♦ B-acute lymphoblastic leukemia/lymphoma (B-ALL/LBL) −− The cytogenetic findings are prognostically important and used to modify the treatment in pediatric disease −− Recurrent cytogenetic abnormalities used to define the subtypes include

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(a) t(9;22); BCR-ABL (b) t(v;11q23); MLL rearranged (c) t(12:21); TEL-AML1 (ETV6-RUNX1) (d) Hyperdiploidy (e) Hypodiploidy (f) t(5;14); IL3-IGH (g) t(1;19); E2A-PBX1 (TCF3-PBX1) −− Favorable prognostic group with higher rate of complete remission (70–85%) and better 5-year survival (35– 60%): t(12;21) or hyperdiploid (51–65) −− Unfavorable prognostic group with lower rate of complete remission (25–60%) and worse 5-year survival (2–15%): t(9;22), t(4;11), t(1;19), or hypodiploidy −− Intermediate prognostic group: del(6q), del(9p), del(12p), hyperdiploidy (less than 51), near triploidy or near tetraploidy −− There are specific associations with morphological and immunological features (a) MLL rearranged: often CD10−, CD24−, and CD15+ (b) t(1;19): often CD10+,CD34−, and CD20− or dim, cytoplasmic mu+ (c) t(12;21): often show high density of CD10 and HLADR but no expression of CD9 or CD20 ♦♦ T-ALL/LBL −− Translocations often involve the TCR loci at 14q11.2 (alpha and delta), 7q35 (beta), and 7p14-15 (gamma), present in about one-third of the cases −− Partner chromosomes include 8q24.1 (MYC), 1p32(TAL1), 11p15(RBTN1), 11p13(RBTN2), 10q24(HOX11), and 1p34.3-35 (LCK) −− Microdeletion of 5¢ regulatory region of TAL1 locus is present in about 25% of cases −− Deletion del(9p) (loss of CDKN2A) is present in about 30% of cases −− Specific clinical significance is not evident

t(1;19)(q23;p13): E2A-PBX1 ♦♦ t(1;19) occurs in ~25% of ALL with pre-B (cytoplasmic Ig) immunophenotype ♦♦ Predicts poor prognosis and need for more aggressive treatment ♦♦ t(1;19) fuses the E2A transcription factor (chromosome19) with the PBX1 transcription factor (chromosome 1), creating a E2A–PBX1 fusion protein, a transcription factor with direct transforming activity ♦♦ It is detected by cytogenetics (less sensitive) or RT-PCR ♦♦ Some cases have t(1;19) by cytogenetics but no E2A–PBX1 (by RT-PCR), associated with a good response to standard therapies

t(9:22)(q34;q11) ♦♦ It is the most common translocation in adult ALL (25–35% of cases) ♦♦ 5% of children with ALL, 1% of AML-M1 ♦♦ It occurs almost exclusively in the precursor B-cell ALLs (CD10+) with frequent aberrant coexpression of myeloid antigen CD13 and CD33

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♦♦ It is associated with uniform poor prognosis ♦♦ The breakpoints in the ABL gene are usually consistent in both CML and ALL, but they vary in the BCR gene ♦♦ RT-PCR detects a BCR–ABL fusion in up to 10% of ALL cases with normal karyotypes ♦♦ Commercial FISH probes are available

t(12;21)(p13;q22) ♦♦ The translocation results in a fusion between AML1 (RUNX1, CBFa2 chromosome 21) and TEL (ETV6, chromosome 12) ♦♦ The normal TEL allele is deleted in most cases ♦♦ It is the most common translocation in pediatric ALL, and present in about 20% of pediatric ALL. 3% of adult ALL are positive for t(12;21) ♦♦ Precursor B-lymphoblasts with t(12;21) often express myeloid antigen, associated with good prognosis, but with increased risk for late relapse

♦♦ It is rarely detectable by conventional cytogenetics (submicroscopic). FISH or molecular methods (PCR and/or Southern) are required for detection

t(4;11)(q11;q23) ♦♦ It is present in about 70% of infantile ALL and about 5% of adult and pediatric ALL ♦♦ It results in a fusion between MLL (chromosome 11) and AF4 (FEL, chromosome 4) ♦♦ Leukemic blasts are often early precursor B-cells, negative for CD10, but with aberrant expression of CD15 and CD65 ♦♦ It is associated with an adverse prognosis in both infants and adults ♦♦ It is detectable by conventional cytogenetics or FISH ♦♦ RT-PCR with a single exon 8 MLL primer and a single exon 7 AF4 primer is sufficient in the detection of all known fusion transcripts

SUGGESTED READING Arber DA. Molecular diagnostic approach to non-Hodgkin’s lymphoma. J Mol Diagn 2000;2:178–190.

Hartmann EM, Ott G, Rosenwald A. Molecular biology and genetics of lymphomas. Hematol Oncol Clin North Am 2008;22:807–823.

Bagg A. Clinical applications of molecular genetic testing in hematologic malignancies: advantages and limitations. Hum Pathol 2003;34:352–358.

Jennings L, Van Deerlin VM, Gulley ML. College of American Pathologists Molecular Pathology Resource Committee. Recommended principles and practices for validating clinical molecular pathology tests. Arch Pathol Lab Med 2009;133:743–755.

Bäsecke J, Griesinger F, Trümper L, et  al. Leukemia- and lymphomaassociated genetic aberrations in healthy individuals. Ann Hematol 2002; 81:64–75. Bench AJ, Erber WN, Follows GA, et al. Molecular genetic analysis of haematological malignancies II: Mature lymphoid neoplasms. Int J Lab Hematol 2007;29:229–260. Bejjani BA, Shaffer LG. Clinical utility of contemporary molecular ­cytogenetics. Annu Rev Genomics Hum Genet 2008;9:71–86. Bernard PS, Wittwer CT. Real-time PCR technology for cancer diagnostics. Clin Chem 2002;48:1178–1185. Cherian S, Bagg A. The genetics of the myelodysplastic syndromes: classical cytogenetics and recent molecular insights. Hematology 2006;11:1–13. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003;348:1764–1775.

Jevremovic D, Viswanatha DS. Molecular diagnosis of hematopoietic and lymphoid neoplasms. Hematol Oncol Clin North Am 2009;23:903–933. Jones D, Kamel-Reid S, Bahler D, et al. Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia: a report of the Association for Molecular Pathology. J Mol Diagn 2009; 11:4–11. Liehr T, Starke H, Weise A, et al. Multicolor FISH probe sets and their applications. Histol Histopathol 2004;19:229–237. Liu H, Bench AJ, Bacon CM et al. Practical strategy for the routine use of BIOMED-2 PCR assays for detection of B- and T-cell clonality in ­diagnostic haematopathology. Br J Haematol 2007;138:31–43. Osaki M, Takeshita F, Ochiya T. MicroRNAs as biomarkers and therapeutic drugs in human cancer. Biomarkers 2008;13:658–670.

Espinet B, Bellosillo B, Melero C, et al. FISH is better than BIOMED-2 PCR to detect IgH/BCL2 translocation in follicular lymphoma at diagnosis using paraffin-embedded tissue sections. Leuk Res 2008;32:737–742.

Ou J, Vergilio JA, Bagg A. Molecular diagnosis and monitoring in the clinical management of patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. Am J Hematol 2008;83:296–302.

Gabert J, Beillard E, van der Velden VH, et  al. Standardization and ­quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe against cancer program. Leukemia 2003;17:2318–2357.

Schiffer CA. Molecular characterization of AML: a significant advance or just another prognostic factor? Best Pract Res Clin Haematol 2008; 21:621–628.

Gulley ML, Shea TC, Fedoriw Y. Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. J Mol Diagn 2010;12:3–16.

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Molecular Diagnostic Pathology

Staudt LM. Molecular diagnosis of the hematologic cancers. N Engl J Med 2003;348:1777–1785. Swerdlow SH, Campo E, Harris NL. et  al. (eds). World Health Organization Classification of Tumours of Hematopoietic and Lymphoid Tissues. 4th edn. IARC Press: Lyon, 2008 Tefferi A. JAK and MPL mutations in myeloid malignancies. Leuk Lymphoma 2008;49:388–397. Tefferi A. Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDFRB and FGFR. J Cell Mol Med 2009;13:215–237

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Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and ­point-of-care diagnostic algorithms. Leukemia 2008;22:14–22. van Krieken JH, Langerak AW, Macintyre EA et  al. Improved reliability of lymphoma diagnostics via PCR-based clonality testing:report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007;21:201–206. Vladareanu AM, Müller-Tidow C, Bumbea H, Radesi S. Molecular markers guide diagnosis and treatment in Philadelphia chromosome-negative myeloproliferative disorders (Review). Oncol Rep 2010;23:595–604.

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12 Molecular Pathology of Solid Tumors Franklin R. Moore, md, phd and Richard D. Press, md, phd

Contents

I. Sarcomas...........................................12-3

General Considerations...................................12-3 Ewing Sarcoma/Primitive Neuroectodermal Tumor.............................12-4 Desmoplastic Small Round Cell Tumor.........12-4 Alveolar Rhabdomyosarcoma.........................12-4 Synovial Sarcoma.............................................12-5 Dermatofibrosarcoma Protuberans and Giant Cell Fibroblastoma...........................12-5 Low Grade Fibromyxoid Sarcoma.................12-5 Congenital/Infantile Fibrosarcoma................12-5 Myxoid/Round Cell Liposarcoma...................12-6 Clear Cell Sarcoma..........................................12-6 Extraskeletal Myxoid Chondrosarcoma........12-6 Alveolar Soft-Part Sarcoma............................12-6 Gastrointestinal Stromal Tumor.....................12-6

II. Multistep Carcinogenesis: The Colorectal Cancer Paradigm..............12-7 General Considerations...................................12-7 Microsatellite Instability..................................12-8 APC (FPC, DP2) and CTNNB1 (B-Catenin Gene).........................................12-8 KRAS and Epidermal Growth Factor Receptor...........................................12-8 DCC (Deleted in Colorectal Carcinoma), SMAD2, and SMAD4................................12-10 TP53 (Also Known as p53)............................12-10

III. Breast Adenocarcinoma...................12-10 HER2/neu Overexpression in Breast Cancer: Predicting Response to Molecularly Targeted Therapy................12-10

FGF1/FGF4.....................................................12-11 CSRC...............................................................12-11 TP53.................................................................12-12 CCND1 (Cyclin D1)........................................12-12 CDH1 (E-Cadherin).......................................12-12 Matrix Metalloproteinases............................12-12 Molecular Analysis of Sentinel Lymph Nodes.............................................12-12 Gene Expression Profiling.............................12-13

IV. Thyroid Cancer................................12-13 Papillary: RET/PTC, NTRK1, and BRAF...................................................12-13 Follicular: PAX8/PPAR..................................12-14

V. Melanoma........................................12-14 RAS/RAF/MEK/ERK Pathway......................................................12-14

VI. Prostate Adenocarcinoma................12-14 TMPRSS2/ERG Fusion.........................................................12-14

VII. Lung Cancer.....................................12-14 Nonsmall Cell Lung Cancer..........................12-14 RAS........................................................12-14 EGFR.....................................................12-14 Small Cell Lung Cancer.................................12-15 Malignant Mesothelioma...............................12-15

VIII. Oligodendroglioma..........................12-15

1p-/19q-............................................................12-15 IDH1 and IDH2..............................................12-15

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_12, © Springer Science+Business Media, LLC 2002, 2006, 2011

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IX. Neuroblastoma................................12-15 XII. Renal Cell Carcinoma......................12-17 NMYC.............................................................12-15

VHL.................................................................12-17 TFE3................................................................12-17

X. Pancreatic Ductal Adenocarcinoma.............................12-16 XIII. Head and Neck Cancer....................12-18 General Considerations.................................12-16 KRAS...............................................................12-16 HER1/EDFR and HER2/neu.........................12-16

Squamous Cell Carcinoma............................12-18 Pleomorphic Adenoma...................................12-18 Mucoepidermoid Carcinoma........................12-18

XI. Bladder Adenocarcinoma.................12-16 XIV. Tumors of Unknown Origin.............12-18 General Considerations.................................12-16 UroVysion.......................................................12-17

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XV. Suggested Reading...........................12-19

Molecular Pathology of Solid Tumors

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SARCOMAS General Considerations ♦♦ Specific chromosomal translocations are the characteristic genetic alteration in a variety of sarcomas ♦♦ Eleven different sarcomas (see Table  12.1) have had specific chromosomal translocation breakpoints molecularly characterized −− The resulting fusion gene (or transcript) is present in the majority of cases of each of these categories of sarcomas – i.e., the presence of these genetic alterations is a sensitive diagnostic test −− The specific fusion gene (or transcript) for each tumor type is typically not associated with any other type of tumor – i.e., the presence of these genetic alterations is a specific diagnostic test ♦♦ The detection of these chromosomal translocations is often very helpful for primary diagnosis, particularly given the similar morphology of many of these tumors ♦♦ Polymerase chain reaction (PCR)-based diagnostic methods are becoming routine – with one primer directed at each specific fusion partner −− Only tumor cells with the specific translocation will yield a PCR-positive signal −− Nontumor cells (or tumor cells of a different “type”) will be PCR-negative

−− Due to the heterogeneity of translocation breakpoints within introns, reverse transcriptase PCR (RT-PCR) using RNA (not DNA) as the typical PCR-based diagnostic target is typically employed (a) RT-PCR is also a powerful tool for minimal residual disease detection and monitoring the efficacy of therapy ♦♦ Fluorescence in situ hybridization (FISH) is a very useful technique for detecting chromosomal translocations, especially since the use of a break-apart probe strategy allows for detection of a rearrangement regardless of its translocation partner, unlike PCR, which requires a separate probe for each alternate partner −− FISH can usually detect an abnormality when present in as few as 5% of the sampled cells −− FISH is best performed on touch preparations or smears rather than paraffin-embedded tissue, if possible. But paraffin-derived tissue usually yields satisfactory results ♦♦ In most of these sarcomas, the fusion genes created by these specific chromosomal translocations encode transcription factors aberrantly regulating gene expression −− The novel chimeric fusion proteins formed by the translocation often obtain novel biochemical functions –

Table 12.1. Chromosomal translocations and fusion genes in sarcomas Tumor Alveolar rhabdomyosarcoma Alveolar rhabdomyosarcoma Alveolar soft-part sarcoma Clear cell sarcoma Dermatofibrosarcoma protuberans Desmoplastic small round cell tumor Ewing sarcoma/primitive neuroectodermal tumor Ewing sarcoma/primitive neuroectodermal tumor Ewing sarcoma/primitive neuroectodermal tumor Ewing sarcoma/primitive neuroectodermal tumor Ewing sarcoma/primitive neuroectodermal tumor Infantile (congenital) fibrosarcoma Inflammatory myofibroblastic tumor Inflammatory myofibroblastic tumor Myxoid chondrosarcoma Myxoid chondrosarcoma Myxoid liposarcoma Myxoid liposarcoma Synovial sarcoma Synovial sarcoma Synovial sarcoma

Cytogenetic translocation

Fusion genes

t(2;13)(q35;q14) t(1;13)(p36;q14) t(X;17)(p11;q25) t(12;22)(q13;q12) t(17;22)(q22;q13) t(11;22)(p13;q12) t(11;22)(q24;q12) t(21;22)(q22;q12) t(7;22)(p22;q12) t(2;22)(q33;q12) t(17;22)(q12;q12) t(12;15)(p13;q25) t(1;2)(q22;p23) t(2;19)(p23;p13) t(9;22)(q22;q12) t(9;17)(q22;q11) t(12;16)(q13;p11) t(12;22)(q13;q12) t(X;18)(p11;q11) t(X;18)(p11;q11) t(X;18)(p11;q11)

PAX3–FKHR PAX7–FKHR TFE3–ASPL EWS–ATF1 COL1A1–PDGFB EWS–WT1 EWS–FLI1 EWS–ERG EWS–ETV1 (rare) EWS–E1AF (rare) EWS–FEV (rare) ETV6–NTRK3 TPM3–ALK TPM4–ALK EWS–CHN TAF2N–CHN (rare) TLS–CHOP EWS–CHOP (rare) SYT–SSX1 SYT–SSX2 SYT–SSX4 (rare)

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typically as a “new” transcription factor with altered activity −− The novel biochemical activities induced by these chimeric fusion proteins include enhanced proliferative capability, inhibition of apoptosis, inhibition of differentiation, and facilitation of lineage commitment – all specific properties of tumor cells

Ewing Sarcoma/Primitive Neuroectodermal Tumor ♦♦ t(11;22)(q24;q12) EWS–FLI1 ♦♦ t(21;22)(q22;q12) EWS–ERG ♦♦ Ewing sarcoma/primitive neuroectodermal tumor (EWS/ PNET) is a tumor that typically arises in the soft tissue of children/young adults −− However, the tumor has been documented in all ages and many different anatomic sites ♦♦ Genetically, the tumor is characterized by a balanced chromosomal translocation that results in a chimeric protein containing the EWS gene product and a member of the ETS transcription factor family −− Over 90% of these translocations are t(11;22)(q24;q12) but occasionally t(21;22)(q22;q12) and rarely other translocations are involved −− These translocations have a variable breakpoint resulting in many structurally distinct fusion proteins −− All fusion products are highly expressed and transcriptionally active, contributing to tumorigenesis ♦♦ Multiplex RT-PCR (with a primer directed at each specific fusion partner) has been used for the detection of chimeric genes in clinical testing with a sensitivity of 90–95% −− Alternatively, FISH using break-apart probes has also been successful (Fig. 12.1) −− Furthermore, these highly sensitive techniques have been used in detection of minimal disease, with prognostic implications

Desmoplastic Small Round Cell Tumor ♦♦ t(11;22)(p13q12) EWS–WT1 ♦♦ Desmoplastic small round cell tumor (DSRCT) is a sarcoma that typically occurs in young males but has been reported in both sexes of all ages ♦♦ Similar to EWS/PNET, DSRCT is characterized by a translocation involving the EWS gene on chromosome 22 −− However the fusion partner gene in this case is the Wilms tumor gene (WT1) on chromosome 11 −− Like EWS/PNET, there is variation as to the exact breakpoint ♦♦ By using multiplex RT-PCR, with a primer directed at each specific fusion partner, a detection sensitivity of approximately 80% has been reported in clinical samples, with a specificity of near 100%

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Fig. 12.1. A reciprocal translocation [t(11;22)(q24;q12)] resulting in a EWS/FLI1 gene fusion in a Ewing sarcoma. (A) Shows a G-banded metaphase chromosome analysis. (B) Shows a FISH image (with a metaphase cell on the left and an interphase cell on the right). The EWS “break-apart” FISH probe consists of separate green- and red-labeled probes that hybridize to a contiguous region of the EWS gene on chromosome 22. In a normal cell, both probe spots are contiguous, yielding a yellow fusion signal. In a Ewing tumor cell with an EWS translocation, the two probes migrate to different chromosomes (i.e., break-apart), and yield separate red and green signals. Note that this type of FISH strategy does not identify the exact partner gene involved with EWS in the translocation.

Alveolar Rhabdomyosarcoma ♦♦ t(2;13)(q35;q14) PAX3–FKHR ♦♦ t(1;13)(p36;q14) PAX7–FKHR ♦♦ Alveolar rhabdomyosarcoma is a round cell tumor that exhibits skeletal muscle differentiation typically occurring in young people, but also less commonly in older patients ♦♦ Approximately 75% of cases have a t(2;13)(q35;q14) translocation involving the PAX3 and FKHR genes −− Another 10% harbor the t(1;13)(p36;q14) translocation (PAX7–FKHR)

Molecular Pathology of Solid Tumors

−− The breakpoint always occurs in intron 1 of FKHR and intron 7 of PAX3/7 −− However, since all of these introns contain many kilobases of DNA, the exact breakpoints in a given tumor can vary over large genomic regions −− The PAX3 and 7 gene products are involved in the regulation of normal embryonal development, and the PAX3/7– FKHR fusion genes appear to act as aberrant transcriptional activators ♦♦ Primer pairs specific for homologous regions of the PAX3/7 and FKHR genes have been used in PCR reactions that allow amplification of the fusion gene regardless of whether or not it involves PAX 3 or 7 −− FISH has also been used successfully with excellent concordance with PCR

Synovial Sarcoma ♦♦ t(X;18)(p11;q11) SYT–SSX1 ♦♦ t(X;18)(p11;q11) SYT–SSX2 ♦♦ Synovial sarcoma is a spindle cell tumor predominantly occurring in deep soft tissues of the extremities in young adults ♦♦ Almost all cases have an t(x;18) translocation that fuses the SYT gene with a member of the SSX gene family, SSX1 or SSX2 −− Tumors other than synovial sarcomas that bear this translocation have only rarely been reported −− Two morphologic variants exists, a biphasic form (i.e., spindled and epithelioid components) that usually involves the SSX1 gene and a monophasic form (usually spindled component only, but occasionally epithelioid only) that usually involves the SSX2 gene −− The translocation creates a chimeric protein that has the transactivation domain of SYT placed in juxtaposition to a repressor domain of SSX −− The resulting aberrant regulation of transcription is thought to contribute to oncogenesis −− Other complex chromosomal rearrangements occur in up to two-thirds of synovial sarcomas ♦♦ RT-PCR using primers that can detect both SSX1 and SSX2 involvement are commonly used. Alternatively, FISH can be used to detect the t(X;18) translocation. Since patients with the SYT–SSX2 fusion have a better clinical outcome that those with the SYT–SSX1, it is important when using either PCR or FISH to distinguish between them

Dermatofibrosarcoma Protuberans and Giant Cell Fibroblastoma ♦♦ t(17;22)(q22;q13) COLIA1–PDGFB ♦♦ Dermatofibrosarcoma protuberans (DFSP) is a low to intermediate grade fibrohistiocytic tumor of adults −− Giant cell fibroblastoma is a similar tumor occurring in children

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♦♦ While both tumors are characterized by a t(17;22) ­translocation, they also commonly have supernumerary ring chromosomes that result from the translocation −− The translocation and the ring chromosomes produces a fusion gene consisting of the collagen type I alpha1 gene from chromosome 17 and the platelet-derived growth factor beta-chain gene from chromosome 22 −− The net result of the fusion is to replace the normally strong negative regulators upstream of the PDGFB gene with the COLIA1 promoter, leading to increased unregulated production of PDGFB −− PDGFB is a tyrosine kinase whose activation contributes to oncogenesis −− In fact, the tyrosine kinase inhibitor, imatinib, has shown some promise in treating the tumor ♦♦ RT-PCR can be used to detect the fusion gene, but the heterogeneity in the breakpoint locations in the COLIA1 gene necessitates the use of multiple primer pairs −− It is prudent to sequence the amplicon after a successful PCR since the sequence similarity between various COLIA1 exons can give rise to spurious products

Low Grade Fibromyxoid Sarcoma ♦♦ t(7;16)(q34;p11) TLS–CREB3L2 ♦♦ Low grade fibromyxoid sarcoma is a cytologically bland spindle cell tumor typically occurring in deep soft tissues of young to middle-aged adults ♦♦ The hallmark translocation, t(7;16)(q34;p11), juxtaposes the 5¢ region of TLS (encodes a transcriptional activation domain) to the 3¢ region of CREB3L2 (encodes a leucine zipper motif DNA-binding domain) −− The resulting chimeric protein leads to unregulated transcriptional control and oncogenesis −− This same translocation is also observed in hyalinizing spindle cell tumor with giant rosettes ♦♦ The breakpoints in the TLS and CREB3L2 genes occur in a relatively small region and can be identified by either conventional cytogenetics, FISH or RT-PCR

Congenital/Infantile Fibrosarcoma ♦♦ t(12;15)(p13;q25) ETV6–NTRK3 ♦♦ Congenital/Infantile fibrosarcoma, also known as juvenile fibrosarcoma, is typically diagnosed in newborns in the soft tissue of the extremities, though it can occur in the head, neck, and trunk as well ♦♦ The t(12;15)(p13;q25) translocation juxtaposes the ETV6 transcriptional factor to the tyrosine kinase domain of NTRK3, which results in constitutive activation of the tyrosine kinase activity in the chimeric protein ♦♦ Though the translocation can be detected with conventional cytogenetics, the similar size and banding patterns of the involved segments render diagnosis difficult −− FISH and RT-PCR have both shown good sensitivity in detecting the lesion

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−− Immunohistochemistry has also been used to detect overexpression of the NTRK3 protein, though RT-PCR is both more sensitive and specific −− It should be noted that the ETV6–NTRK3 fusion gene has also been detected in congenital mesoblastic nephroma as well as other spindle cell lesions

Myxoid/Round Cell Liposarcoma ♦♦ t(12;16)(q13;p11) TLS–CHOP ♦♦ t(12;22)(q13;q12) EWS–CHOP ♦♦ Most myxoid liposarcomas occur in the deep soft tissue of the extremities, especially the thigh ♦♦ The large majority of cases harbor the t(12;16)(q13;p11) translocation creating a fusion gene containing TLS gene (usually exons 4 and 5 or 4–7) and the CHOP gene (usually at intron 1) −− The resulting chimeric protein includes the transcriptional activation domain of TLS and the leucine zipper transcriptional activation domain of CHOP −− This chimeric protein is strongly and constitutively expressed and inhibits differentiation of adipocytes −− A minority (5%) of myxoid liposarcomas possess a t(12;22)(q13;q12) translocation fusing the EWS gene to the CHOP gene with a similar mechanism of action ♦♦ FISH or RT-PCR is used to detect the gene fusions −− Round cell liposarcoma is characterized by the same translocations

Clear Cell Sarcoma ♦♦ t(12;22)(q13;q12) EWS–ATF1 ♦♦ Clear cell sarcoma occurs in deep soft tissues of young adults ♦♦ The hallmark t(12;22)(q13;q12) translocation fuses the ATF1 gene on chromosome 12 with the EWS gene on chromosome 22, usually at intron 3 −− The chimeric protein is a constitutively expressed transcriptional activator of unknown target genes −− FISH and RT-PCR have been used to detect the gene fusions

Extraskeletal Myxoid Chondrosarcoma ♦♦ ♦♦ ♦♦ ♦♦

t(9;22)(q22;q12) EWS–CHN t(9;17)(q22;q11) TAF2N–CHN t(9;15)(q22;q21) TCF12–CHN Most extraskeletal myxoid chondrosarcomas occur in the deep soft tissues of the extremities ♦♦ The t(9;22)(q22;q12) translocation is present in approximately 75% of cases, with t(9;17)(q22;q11) translocation in 15–20% of cases, and the t(9;15)(q22;q21) rearrangement in most of the remaining cases −− The predominant rearrangement fuses the EWS gene to the CHN gene forming a chimeric protein that possesses

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the strong transactivation domain of EWS and a fulllength CHN −− The t(9;17) rearrangement fuses the TAF2N gene, which is highly homologous to EWS, to CHN −− The t(9;15) translocation fuses the TCF12 gene to the CHN gene −− All three resulting chimeric proteins are specific to extraskeletal myxoid chondrosarcomas and are thought to promote oncogenesis through the abnormal activation of unknown genes ♦♦ The three rearrangements can be readily detected with conventional cytogenetics −− Molecular techniques, such as RT-PCR can also be used, with the caveat that primer sets for all three rearrangements would need to be included in the reaction mixes

Alveolar Soft-Part Sarcoma ♦♦ der(17)(X;17)(p11;q25) ASPL–TFE3 ♦♦ Alveolar soft-part sarcoma occurs mainly in the head and neck region of children but can also occur in deep soft tissues, especially the thigh, of adults ♦♦ The hallmark rearrangement is a nonreciprocal der(17) (X;17)(p11;q25) translocation resulting in a ASPL–TFE3 fusion gene −− Since the rearrangement is nonreciprocal, there is a concomitant loss of 17q25 sequences telomeric to ASPL and a gain of Xp11 sequences telomeric to TFE3, which may contribute to oncogenesis −− The ASPL–TFE3 chimeric protein is constitutively expressed and thought to lead to transcriptional deregulation of target genes ♦♦ Most rearrangements can be detected with conventional cytogenetics, but FISH or RT-PCR may be needed in difficult cases −− Interestingly, the ASPL–TFE3 fusion gene is also found in a childhood variant of renal cell carcinoma as a result of a balanced t(X;17)(p11;q25) translocation

Gastrointestinal Stromal Tumor ♦♦ Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal gut neoplasms. Over 90% of GISTs have mutations in either c-kit or platelet-derived growth factor receptor-alpha (PDGFRA) ♦♦ C-kit and PDGFRA are members of a subfamily of transmembrane tyrosine kinases −− Most GISTs have detectable gain of function mutations in c-kit −− Mutated c-kit has constitutively activated kinase activity that drives cell proliferation and inhibits apoptosis −− GISTs are insensitive to standard chemotherapy but are sensitive to targeted therapy with imatinib (Gleevec), a small molecule inhibitor of activated tyrosine kinases

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♦♦ Identifying the type and location of c-kit mutations has significant clinical relevance −− GIST patients with exon 11 c-kit point mutations or deletions (75% of all GISTs) are more sensitive to imatinib and carry a better prognosis than tumors with other (or no) c-kit mutations −− Determining the c-kit mutation status is becoming routine to predict responses to imatinib ♦♦ Of GIST patients not carrying c-kit mutations, about 10% harbor mutations in PDGFRA −− These tumors tend to occur in the stomach and have an epithelioid morphology −− GISTs with PDGFRA mutations are sensitive to imatinib except for those carrying the D842V mutation, which is the most common alteration in this gene ♦♦ As with chronic myelogenous leukemia patients, many GIST patients on imatinib will eventually develop secondary mutations in c-kit that render them resistant to the drug −− Periodic molecular monitoring of these patients is warranted −− Other second- and third-generation tyrosine kinase inhibitors (under development) may circumvent this resistance ♦♦ C-kit and PDGFR mutations in GIST are typically detected by a two-tiered methodologic approach (due to the heterogeneity of the mutations) −− This typically involves an initial PCR-based mutation screening method (denaturing high performance liquid chromatography or high resolution melting) to nonspecifically assess the presence or absence of a mutation (any mutation) −− If the mutation-screen is positive, then direct DNA sequencing is typically used to identify the exact mutation site (Fig. 12.2) −− If the mutation-screen is negative (a highly sensitive procedure), laborious DNA sequencing is obviated

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Fig. 12.2. Electropherograms (DNA sequence tracings) from a gastrointestinal stromal tumor showing mutations in exon 11 of c-kit. (A) Shows a GTT to GAT point mutation. Note the double peak that shows both a T (red) and an A (green) sequencing signal. (B) Shows a two base pair c-kit gene deletion. Note the emergence of double peaks after position 119, indicative of an “out of frame” DNA sequence downstream from the deletion.

MULTISTEP CARCINOGENESIS: THE COLORECTAL CANCER PARADIGM General Considerations ♦♦ All colorectal cancers (CRCs) (and their adenomatous precursor lesions) contain discrete genetic alterations ♦♦ The sequence and timing of these mutations is predictable during the usual progression from hyperplasia to adenoma to carcinoma ♦♦ The specific gene alterations found in specific stages of CRC confirms the “multi-hit” model of carcinogenesis ♦♦ Carcinogenesis requires the sequential accumulation of multiple genetic alterations in a single target cell, the sum total of which create the full cancer cell phenotype

♦♦ “Early” CRC lesions (hyperplasia and adenoma) include loss or mutation of either “gatekeeper” genes or “caretaker” genes −− “Gatekeeper” genes normally function to regulate cell growth and differentiation (a) These genes are often “tumor suppressor” genes, such as APC – commonly lost or mutated in early precancerous lesions (hyperplasia and early adenoma) (b) APC mutation is the earliest observable genetic alteration in cells destined to become CRC

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−− “Caretaker” genes normally function to maintain genomic stability (a) These gene mutations in early colonic precursor lesions include mismatch repair genes such as MSH2, MLH1, PMS1, and PMS2 ♦♦ Later stages of CRC multistage tumorigenesis associated with −− Methylation abnormalities (typically hypomethylation) – as another mechanism to inactivate tumor suppressor genes (a) Often first apparent in early adenomas −− Proto-oncogene activation: typically a ras family member in CRC (a) Often first apparent in intermediate adenomas −− Loss of other tumor suppressor genes: typically p53 or loss of chromosome segment 18q (the DCC gene) in CRC (a) Often first apparent in late adenomas or early ­carcinomas ♦♦ Inherited alterations in the same “gatekeeper” or “caretaker” genes (often mutated in “sporadic” cancers) are often found in patients with familial cancer syndromes −− Familial adenomatous polyposis (FAP) patients often have APC “gatekeeper” gene mutations −− Hereditary nonpolyposis colon carcinoma (HNPCC) patients often have “caretaker” mismatch repair gene mutations −− Retinoblastoma patients often have “gatekeeper” Rb gene mutations −− Breast cancer patients often have “carekeeper” BRCA-1 or BRCA-2 mutations −− von Hippel–Lindau syndrome patients (renal cell carcinomas and others) often have “gatekeeper” VHL gene mutations −− Li–Fraumeni syndrome patients (multiple tumor types) often have “gatekeeper” p53 gene mutations

Microsatellite Instability ♦♦ Altered mismatch repair (MMR) genes confer the phenotype of “microsatellite instability” (MSI) that is often measured in the lab by either an immunohistochemistry stain or a PCRbased assay −− Microsatellites are short DNA stretches (typically 1–5 nucleotides) repeated several times in tandem (a) These repeats are numerous, comprising 3% of the human DNA, and distributed randomly throughout the genome (b) The most common example is a repeat of the dinucleotide CA, though mononucleotide repeats are also common −− Gain or loss of repeat units (in tumor DNA vs. normal DNA), as assessed by the size of microsatellite-specific PCR products, is designated as MSI (a) MSI (indicative of an underlying deficiency in MMR genes) is seen in ~15% of all CRCs and confers a relatively good prognosis compared to tumors without MSI

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−− High levels of MSI can be due to germ-line mutations in MMR genes, as in hereditary nonpolyposis colon cancer (HNPCC), or may be secondary to acquired hypermethylation and subsequent silencing of their promoter regions as in sporadic colon cancer −− Also correlated with MMR gene promoter hypermethylation and sporadic colon cancer are activating mutations in BRAF, notably a V600E point mutation −− MSI can be assessed with an immunohistochemistry stain showing reduced expression of proteins involved in MMR (Fig. 12.3A) −− Alternatively, a PCR-based assay using probes specific for known mono- and dinucleotide repeats (e.g., BAT26 and D2S123) detects changes in repeat length in tumor tissue relative to normal tissue that occur as a result of defects in MMR genes (Fig. 12.3B)

APC (FPC, DP2) and CTNNB1 (B-Catenin Gene) ♦♦ The adenomatosis polyposis coli (APC) gene resides on chromosome 5q21–22 and is mutated in the germ-line of patients with FAP ♦♦ In sporadic colonic adenocarcinoma, the APC gene is commonly mutated −− The gene encodes a multifunctional protein that is involved in cell adhesion, migration, signal transduction, microtubule assembly, and chromosome segregation −− Its main role in cancer development, however, is its capacity to regulate intracellular B-catenin (CTNNB1) levels, itself a part of the highly conserved Wnt pathway −− When activated, B-catenin shuttles to the nucleus and serves as an activator of transcription, involving Myc and cyclin D1 among other targets ♦♦ The importance of this pathway in colon cancer is underscored by the fact that in sporadic cancers that do not harbor APC mutations, activating mutations in the CTNNB1 gene are likely found

KRAS and Epidermal Growth Factor Receptor ♦♦ Although epidermal growth factor receptor (EGFR) is overexpressed (as measured by immunohistochemistry; IHC) in up to 80% of colorectal carcinomas, mutations in the EGFR gene are rare −− Furthermore, neither overexpression of EGFR protein nor mutations in the EGFR gene have been shown to predict clinical outcome −− However, mutations in KRAS, a small G-protein essential in the downstream EGFR signaling cascade, do have important clinical implications −− Most KRAS mutations, found in approximately 40–50% of sporadic colon cancers, are activating missense mutations in codons 12 and 13 that lead to constitutive activation of the EGFR pathway

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Fig. 12.3. Microsatellite instability in a colonic adenocarcinoma. (A) Shows an immunohistochemical stain for PMS2 in a colon tumor sample. Note the relative lack of nuclear staining (indicative of loss of PMS2 expression) in the malignant cells compared to the normal colonic epithelium in the upper right hand corner. (B) Shows a capillary electrophoresis tracing of PCR products generated with primers for three different microsatellite regions from the tumor sample (bottom panel) vs. a normal control tissue from the same patient (top panel). The tumor shows microsatellite instability (MSI-high) in at least two of these three loci as judged by a different pattern of peaks in the NR-21 and BAT-25 loci than in the normal tissue.

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♦♦ Cetuximab and Panitumumab, EGFR inhibitors that are commonly used to treat metastatic colon cancer, are ineffective in tumors with these KRAS mutations −− Thus, all metastatic colon cancer patients being considered for anti-EGFR therapy should be screened for these mutations before this therapy is instituted −− If a KRAS mutation in codon 12 or 13 is detected, then the patient should not receive anti-EGFR antibody therapy ♦♦ Detection of KRAS mutations generally involves DNA sequencing of the exon 12 and 13 “hot spot” regions that have been shown to commonly harbor mutations −− Other diverse genotyping methods can also be used, and some, like allele-specific PCR, afford increased analytic sensitivity for the detection of low-level mutations – which may not be as clinically relevant −− More recently, pyrosequencing has been used to detect KRAS mutations with a high degree of sensitivity and specificity

DCC (Deleted in Colorectal Carcinoma), SMAD2, and SMAD4 ♦♦ The chromosomal region 18q21.3 is commonly deleted in colon cancer resulting in loss of heterozygosity (LOH) at this site ♦♦ The DCC gene, SMAD2 and SMAD4 are all located at this region and their loss is thought to be important in cancer development −− The DCC protein is a receptor for neptin-1 and is thought to act as a tumor suppressor by having pro-

apoptotic activity, but its role in carcinogenesis is still unclear ♦♦ Two other genes in the 18q21 region, SMAD2 and SMAD4, are also currently thought to be important in colon cancer −− These two proteins mediate the TGF-B signaling pathway which acts as a tumor suppressor pathway in colon cancer −− Additionally, SMAD2 and SMAD4 have been found to be mutated in cancers, even when they are not deleted

TP53 (Also Known as p53) ♦♦ Mutations in TP53 are found in up to 50% of colorectal carcinomas, being more prevalent in distal and rectal tumors than proximal ones ♦♦ Most mutations are missense mutations occurring at five hotspots in highly conserved regions of exons 5–8 −− The TP53 protein, often referred to as “the guardian of the genome,” is a multifunctional transcriptional activator that is involved in regulating apoptosis and the cell cycle −− It is highly responsive to DNA damage and can initiate DNA repair or induce apoptosis under these conditions ♦♦ Some studies have shown a better response of patients to fluorouracil-based chemotherapy when TP53 mutations are absent

BREAST ADENOCARCINOMA HER2/neu Overexpression in Breast Cancer: Predicting Response to Molecularly Targeted Therapy ♦♦ Human epidermal growth factor receptor 2 (HER2) (also known as neu or c-erbB-2) is an oncogene that is overexpressed in ~30% of invasive breast cancers −− Encodes a tyrosine kinase receptor that transduces intracellular growth-promoting (oncogenic) signals −− Mechanism of overexpression is typically gene amplification ♦♦ HER2 overexpression is an important predictive and prognostic biomarker −− HER2 overexpression predicts an aggressive natural course of the tumor but an enhanced benefit from anthracycline (doxorubicin)-based adjuvant chemotherapy −− For metastatic breast cancer, HER2 overexpression also predicts benefit from treatment with targeted anti-HER2 monoclonal antibody therapy (trastuzumab) −− Determining HER2 oncogene expression status is now an integral part of the routine clinicopathologic evaluation of breast cancer to assess the likely effectiveness of trastuzumab

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−− However, HER2 overexpression is associated with a lack of expression of estrogen and progesterone receptors and a lack of response to therapeutic agents directed against these receptors ♦♦ Common lab methods for determining HER2 overexpression include semiquantitative immunohistochemistry (protein target) and/or FISH (DNA target) −− Both routinely performed on usual formalin-fixed paraffin-embedded tissue section −− HER2 overexpression assessed by immunohistochemistry is determined by assigning a score of 0, 1+, 2+, or 3+ to each slide after staining (a) Patients with a 0 or 1+ score are not considered candidates for anti-HER2 therapy while those with a 3+ score are candidates (Fig. 12.4A) (b) A 2+ score is considered indeterminate and these cases are often reflexed to FISH −− Two FDA-approved tests are available for scoring HER2 amplification using FISH, PathVysion, and Inform (a) For PathVysion, a probe specific for HER2 and a probe specific for the centromere of chromosome 17 are hybridized to interphase nuclei

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(b) A ratio of HER2 signal to centromere signal of 2.0 or greater is considered positive (Fig. 12.4B, C) (c) For Inform, only a HER2 probe is employed and an absolute gene copy number >4.0 is ­considered positive −− When performed with appropriate quality assurance measures, HER2 FISH and immunohistochemistry methods almost always yield concordant results −− As compared to immunohistochemistry, FISH has a higher failure rate, higher reagent cost, and longer turnaround time −− FISH methods, however, may be better predictors of clinical outcomes, particularly in cases with indeterminate (i.e., 2+) immunohistochemistry

FGF1/FGF4 ♦♦ FGF1 and FGF4 are receptor tyrosine kinases that are members of the fibroblast growth factor family −− These proteins function in cell survival, mitogenesis, tissue repair, and angiogenesis ♦♦ Both FGF1 and FGF4 are commonly amplified or undergo missense mutations in breast cancer −− These mutations lead to activation of the downstream signal transduction processes regulated by these receptors, including the Ras/MAPK and the PI-3 kinase/Akt pathways −− In vitro evidence suggests that ER + breast cancer cells with FGF-activating mutations are able to bypass estrogen dependence for growth, possibly explaining the lack of response of some women to endocrine therapy ♦♦ Clinical trials with women with advanced stage breast cancer are underway testing the efficacy of FGFR inhibitors as therapeutic agents

CSRC

Fig.  12.4. HER2/neu overexpression in an infiltrating ductal carcinoma of the breast. (A) Shows a HER2/neu immunohistochemistry stain scored as 3+. (B) Shows a HER2/neu FISH scored as “negative” with an approximately equal number of signal spots from the red HER2 probe as compared to the green control probe (centromere of chromosome 17). In comparison, (C) shows a strongly positive breast tumor FISH with a HER2 to CEP17 signal ratio of >4.

♦♦ CSRC nonreceptor tyrosine kinase is overexpressed and activated in a large number of breast cancers −− CSRC is known to interact with a diverse array of molecules, including growth factor receptors and cell-to-cell adhesion receptors, integrins and steroid receptors including the ER, promoting tumor cell proliferation, survival, differentiation, migration, and invasion ♦♦ Recent in vitro studies have shown the overexpression and over activity of CSRC during the acquisition of tamoxifen resistance in ER-positive cell lines −− CSRC inhibition has also been shown to significantly reduce the invasiveness of these cells −− Furthermore, inhibition of CSRC has been shown to reduce the incidence of breast cancer metastases and increase survival in mice ♦♦ CSRC kinase inhibition is currently being investigated as a therapeutic target for anti-invasive therapies in breast cancer, showing promise for treating triple-negative (ER−, PR−, HER2/neu−) cancers

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TP53

♦♦ In general, retention of normal E-cadherin levels correlates with well-differentiated, noninvasive cancers and loss of expression is linked to the development of metastases ♦♦ Interestingly, it is thought that initial loss of E-cadherin leads to the invasive phenotype and that regaining expression later in tumor evolution favors survival and reattachment of metastases −− Also, estrogen has been proposed to regulate E-cadherin expression such that ER-negative status is linked to loss of E-cadherin and a poorer prognosis −− It should be noted that a related protein, P-cadherin, is critical for the adhesion of myoepithelial cells to one another and its loss is also implicated in breast tumorigenesis

♦♦ TP53 is mutated in 20–40% of breast cancers −− Its importance in breast cancer development is underscored by the increased incidence of breast cancer in patients with germ-line TP53 mutations (Li–Fraumeni Syndrome) ♦♦ Its status has been probed using either molecular techniques or IHC −− Most TP53 alterations found in breast carcinomas are point mutations leading to the synthesis of a stable, malfunctional, and nondegradable protein that accumulates in tumor cells, and thus can be detected by IHC −− Thus, even though TP53 “overexpression” can be detected, its contribution to carcinogenesis is actually a result of loss of function −− At the molecular level, not all mutations lead to nondegradable proteins – some result in truncated species that may not be detectable with IHC (a) As previously discussed, TP53 is involved in regulating many cell processes, including apoptosis and DNA repair −− The presence of TP53 mutations in in situ breast carcinoma suggest that these mutations occur early in carcinogenesis. Patients with TP53 mutations have been shown to have a worse prognosis

CCND1 (Cyclin D1) ♦♦ Cyclin D1 is overexpressed in up to 50% of ductal carcinomas and up to 100% of lobular carcinomas ♦♦ The CCND1 gene is located on chromosome 11q13 and this region is amplified in up to 15% of breast cancers, with the remaining cancers showing molecular alterations resulting in CCND1 overexpression ♦♦ Cyclin D1 plays a critical role in cell cycle progression through the formation of active enzyme complexes with Cdk4 and Cdk6 which then phosphorylate pRB −− Cyclin D1 appears to play an especially important role in estrogen-induced mitogenesis

CDH1 (E-Cadherin) ♦♦ E-cadherin is normally expressed in breast ductal epithelial cells ♦♦ The E-cadherin gene, located on chromosome 16q22.1, codes for a transmembrane glycoprotein that mediates calcium-dependent intercellular adhesion and is specifically involved in epithelial cell-to-cell adhesion ♦♦ Over 85% of invasive lobular carcinomas (ILC) have reduced E-cadherin expression, either through LOH of the 16q region, mutation, or epigenetic silencing of the CDH1 gene −− The remaining ILCs show dysfunctional adhesion of the E-cadherin protein −− LOH also occurs in about 50% of ductal carcinomas −− Mutations in the remaining 50% are rare but epigenetic silencing is seen

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Matrix Metalloproteinases ♦♦ Matrix metalloproteinases (MMPs) encompass a large family of zinc-binding endopeptidases that can degrade almost all components of the extracellular matrix ♦♦ Their expression is controlled at the transcriptional and translational level and once switched on, can be degraded by tissue inhibitors of metalloproteinases (TIMPs) −− MMPs have been shown to be important in tumor growth, angiogenesis, and metastasis ♦♦ In breast cancer, MMPs are commonly overexpressed, their level generally correlating with poor outcome. MMP levels have also been used as clinical markers for prediction of metastasis ♦♦ Interestingly, breast cancer cells do not secrete MMPs themselves but rather induce production by stromal fibroblasts through paracrine stimulation

Molecular Analysis of Sentinel Lymph Nodes ♦♦ The presence or absence of metastases to lymph nodes in breast cancer patients is the single most important predictor of survival ♦♦ Molecular techniques have been utilized to increase the sensitivity of detecting small numbers (i.e., micrometastases) of metastatic breast cells in sentinel lymph nodes −− The most common assay has been RT-PCR using mRNA markers for cytokeratins, with the caveat that lymph node interstitial reticulum cells express small amounts of cytokeratin −− Thus, the most reliable results have been obtained using the two-gene combination of cytokeratin (CK19) and a cancer-specific marker (mammoglobin) ♦♦ The RT-PCR analysis has yielded positive results in 16–43% of cancer-negative nodes as assessed by histology alone −− RT-PCR can also be used for the intraoperative detection of metastases as the entire assay can be completed in under 35 min −− However, the clinical importance of these findings is under investigation

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Gene Expression Profiling ♦♦ Routine gene expression profiling was made possible by the introduction of DNA microarray technology in the mid-1990s −− Expression profiling allows the quantitative expression analysis of anywhere from dozens to tens of thousands of genes concurrently in one tissue sample −− The resulting molecular portraits have been used in many settings – generation of research hypotheses, determining prognosis, predicting response to treatment, identifying targets for therapy, and identifying tissues of unknown origin, among others ♦♦ The basic technique involves using reverse transcriptase to obtain fluorescently-labeled cDNA from mRNA isolated from the tissue of interest −− The cDNA is then hybridized to an array of many different target DNA oligonucleotides (attached to a solid support as tiny “spots” in specific locations on the microarray chip) −− After hybridization, a fluorimeter quantitates the relative hybridization signal of each individual “spot” (representing a gene or gene fraction), and software compares the extent of hybridization (expression) of the experimental tissue as compared to control “normal” tissue and generates an expression profile – detailing the relative expression level of each of the individual genes on the chip ♦♦ Breast carcinoma has probably been the most studies of all solid tumors using gene expression profiling technology −− Several commercial tests are available for expression profiling of breast cancers ♦♦ Oncotype Dx is one example of an RT-PCR-based assay that cumulatively analyzes a panel of 21 expressed genes within a tumor (16 cancer-related genes and 5 reference genes) −− The cumulative expression pattern (amount of expressed RNA) of these multiple genes defines a “gene expression

♦♦

♦♦

♦♦

♦♦

profile” that is reported as a ­cumulative “Recurrence Score” −− The Recurrence Score is a number between 0 and 100 that corresponds to the specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis −− This score strongly correlates with long-term recurrencefree survival, and helps predict which patients may benefit from adjuvant chemotherapy The assay uses formalin-fixed, paraffin-embedded tissue from a mastectomy, lumpectomy, or needle-core biopsy −− Though both tumor blocks and unstained slides can be submitted for analysis, blocks are preferred since microdissection is frequently required It should be noted that Oncotype Dx is only intended for women with early-stage invasive breast cancer who are ER + and whose lymph nodes are negative MammaPrint is another commercially available expression test that is based on a published 70-gene breast cancer signature profile −− The test is FDA-cleared for use in lymph node negative patients under 61 years of age with tumors less than 5 cm in greatest dimension −− Like Oncotype Dx, MammaPrint results in a score that measures risk of cancer recurrence −− However, unlike Oncotype Dx, it requires fresh tissue for analysis −− Interestingly, Oncotype Dx and MammaPrint have only one gene in common (SCUBE2, a member of the ER pathway) Other expression profiling tests are also either currently available or under active evaluation, including one designed for diagnostic screening using peripheral blood instead of breast tissue (DiaGenic), one that yields a “metastasis score” (Celera), and one that predicts response to treatment (NuvoSelect)

THYROID CANCER Papillary: RET/PTC, NTRK1, and BRAF ♦♦ The RET tyrosine kinase gene has been found to be juxtaposed to various genes, dubbed PTC genes, through chromosomal translocations in about 40% of papillary thyroid carcinomas ♦♦ Of the numerous PTC genes partnered to RET, only PTC1, PTC2, and PTC3 have been found in nonradiation-induced tumors −− All of the RET/PTC fusion proteins result in constitutive activation of the tyrosine kinase function of RET −− Less commonly, translocations involving the NTRK1 gene have been identified −− Like RET, NTRK1 encodes a tyrosine kinase that is constitutively activated by the translocations

♦♦ Lastly, a V600E (formerly called V599E) point mutation in the BRAF gene (a T to A transversion at nucleotide 1799 of codon 600 in exon 15), which encodes for a serine/threonine kinase, have been found in up to 60% of papillary thyroid carcinomas −− BRAF mutations have been associated with a worse prognosis, but importantly, therapies that target the gene are becoming available ♦♦ The RET and NTRK1 translocations are readily detected with FISH or RT-PCR techniques −− Direct sequencing or other genotyping methods can be used for BRAF mutation detection ♦♦ RAS mutations have been identified in papillary thyroid carcinoma but are not diagnostically useful since they are also seen in other malignant and benign conditions

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Follicular: PAX8/PPAR ♦♦ The characteristic genetic feature of follicular thyroid carcinoma, present in 30–50% of cases, is a t(2;3)(q13;p25) translocation that produces a PAX8–PPARalpha1 fusion gene ♦♦ The fusion encodes a chimeric protein in which the homeobox DNA-binding domains of PAX8 are fused with virtually the entire length of PPARalpha1

−− The resulting protein is a dominant negative suppressor of wild-type PPARalpha1 function, altering its transcriptional activity −− No prognostic significance is currently ascribed to the translocation ♦♦ Conventional cytogenetics, FISH, or RT-PCR have been used to detect the translocation ♦♦ As with papillary cancers, RAS mutations are common in follicular cancers but are not specific

MELANOMA RAS/RAF/MEK/ERK Pathway ♦♦ The MAPK (mitogen-activated protein kinase) pathway (Ras/ Raf/Mek/Erk) is a critical pathway in numerous cell types that operates by regulating proliferation and cell survival ♦♦ The MAPK pathway is mutated in up to 90% of sporadic melanomas −− Activating mutations may occur in any of the constituents of the pathway though mutations of NRAS and BRAF appear to be mutually exclusive −− RAS missense mutations have been found in 10–20% of melanomas, almost entirely in NRAS, leading to constitutive activation of its GTPase activity

−− Activating point mutations in BRAF (notably V600E), found in up to two-thirds of melanomas, lead to activation of its serine-threonine kinase function ♦♦ C-kit, a tyrosine kinase, has also been shown to have activating mutations in 30–40% of melanomas, being more common in the rarer types (e.g., acral and mucosal melanomas) ♦♦ Knowledge of the common disruption of the MAPK pathway has led to the introduction of targeted therapies, such as the BRAF inhibitor sorafenib, and the MEK inhibitors, CI-1040 and PD0325901

PROSTATE ADENOCARCINOMA TMPRSS2/ERG Fusion ♦♦ The TMPRSS2/ERG fusion has been detected in high grade prostatic intraepithelial neoplasia and in up to 60% of prostate adenocarcinomas ♦♦ The TMPRSS2 gene is an androgen-regulated gene, and when fused to the ERG gene, an ETS transcription factor with mitogenic activity, results in the overexpression of ERG in prostate cancer cells

−− The fusion arises from the joining of the promoter portion of the TMPRSS2 gene (21q22.3) with the coding sequence of the ERG gene (21q22.2), by either intrachromosomal deletion or translocation ♦♦ The fact that reduced expression of the fusion gene in vitro leads to cell growth inhibition has led to ongoing research into the TMPRSS2/ERG gene fusion as a potential therapeutic target

LUNG CANCER Nonsmall Cell Lung Cancer RAS ♦♦ Mutations in the RAS gene are found in 15–20% of nonsmall cell lung cancers and 30–50% of pulmonary adenocarcinomas ♦♦ Approximately 80% of these alterations are point mutations in codon 12 of KRAS ♦♦ The prognostic significance of RAS mutations in lung cancer is currently being assessed

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EGFR ♦♦ Epidermal growth factor receptor (EGFR, also known as c-Erb-B1 and HER1) is a cell membrane receptor closely related to HER2/neu ♦♦ Most documented mutations have been found in the tyrosine kinase domain, and are more frequent in adenocarcinomas, women, and never-smokers −− The majority of mutations are deletions in exon 19 and point mutations in exon 21

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♦♦ In addition to mutation analysis using molecular techniques, EGFR overexpression can often be detected in lung carcinomas by immunohistochemistry, and amplification of the gene has been detected with FISH −− Targeted EGFR inhibitors, notably the tyrosine kinase inhibitors gefinitib and erlotinib, are currently under evaluation for efficacy in treating lung cancer patients ♦♦ Patients with nonsmall cell lung cancer with a documented mutation in the EGFR appear, more likely, to respond to targeted anti-EGFR therapy −− Testing for these mutations may then be indicated before considering these therapies ♦♦ However, not all patients with EGFR mutations respond to tyrosine kinase inhibitors −− Certain clinical characteristics predict response to the agents – female gender, nonsmoker, and adenocarcinoma histology −− These characteristics are associated with specific mutations in the EGFR gene, notably exon 19 deletion and an exon 21 L858R substitution ♦♦ Other mutations in the tyrosine kinase domain of EGFR, especially T790M, are associated with an acquired resistance to ant-EGFR therapy −− Screening patients for this mutation can allow for earlier detection of a developing resistance

♦♦ The possibility that genetic polymorphisms in the EGFR gene may contribute to variability in response to anti-EGFR therapy is currently under study

Small Cell Lung Cancer ♦♦ Downregulation of the tumor suppressor genes TP53 and RB are considered crucial for the development of small cell lung carcinoma ♦♦ Additionally, overexpression of CMYC and members of the E2F family of transcriptional activators is common

Malignant Mesothelioma ♦♦ In contrast to many other solid tumors, including those of the lung, mutations in TP53 and RB are uncommon in mesothelioma ♦♦ However, deletions at 9p21 are frequent, and since this location contains the genes for P16 and P14, two key upstream regulators of RB and TP53, respectively, it is thought that these two tumor suppressor pathways are nonetheless important in mesothelioma pathogenesis ♦♦ Mutations in the NF2 gene are fairly unique to mesothelioma among epithelial tumors, present in approximately 50% of cases ♦♦ Attempts to use this feature to help distinguish mesothelioma from other lung cancers have been thwarted by the widespread localization of the mutations across the 17 exons of the gene

OLIGODENDROGLIOMA 1p-/19q-

IDH1 and IDH2

♦♦ The codeletion of segments of chromosomes 1p and 19q in oligodendrogliomas has been correlated with an enhanced response to chemotherapy and radiotherapy and an improved prognosis ♦♦ The missing areas in these deletions are relatively large and the exact deleted genes responsible for the improved clinical outcome are not currently known ♦♦ The deletions are now routinely screened for in oligodendrogliomas by either FISH or PCR-based loss of heterozygosity analysis

♦♦ Recently, mutations in the IDH1 gene have been detected in 55–80% of grade II and III oligodendrogliomas and astrocytomas. Less common are mutations in the IDH2 gene ♦♦ IDH1 mutations are often found in tumors that also have codeletion of chromosomes 1p and 19q ♦♦ The IDH1 mutations occur in residue R132 which is in the active site of the enzyme, and mostly consist of point mutations resulting in an Arg to His amino acid substitution. Similarly, mutations of IDH2 occur in the corresponding codon 172 ♦♦ Retrospective studies have shown a favorable prognostic outcome in patients with IDH1 and IDH2 mutations

NEUROBLASTOMA NMYC ♦♦ Neuroblastoma is the most common solid tumor of childhood −− As part of the staging process in all new diagnoses, the DNA index and NMYC amplification status is determined by molecular testing

♦♦ Amplification of the NMYC gene (from 3–1,500 copies) on chromosome 2p24 is present in about 25% of neuroblastomas and is associated with an aggressive clinical course ♦♦ Though NMYC amplification can be detected cytogenetically as double minutes or homogenously staining areas,

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molecular techniques such as Southern blotting, PCR, or FISH are usually performed −− The NMYC gene product is a DNA-binding transcriptional regulator that is important in cell survival ♦♦ Also important in prognostication of neuroblastomas is the determination of the DNA index, which is a measure of ploidy

−− Diploid tumors have a high proliferative activity and relatively worse outcome while hyperdiploid tumors tend to be associated with a better prognosis −− Diploid tumors are more likely to have NMYC amplification

PANCREATIC DUCTAL ADENOCARCINOMA General Considerations ♦♦ Pancreatic ductal adenocarcinoma is the most common pancreatic neoplasm and the cause of most pancreatic cancerrelated deaths in the United States ♦♦ Loss of expression or inactivation of several tumor suppressor genes is commonly identified in pancreatic adenocarcinomas −− These genes include p53, SMAD4/DPC4, and CDKN2A/ p16 and their inactivation can occur through mutations or deletions, and through epigenetic events such as promoter methylation and histone modification −− Germ-line mutations in BRCA2 are associated with a predisposition to pancreatic cancer ♦♦ Frequently, telomere shortening, activating mutations, and chromosomal losses of the regions of tumor suppressor genes are seen not only in infiltrative adenocarcinomas, but in pancreatic intraepithelial neoplasms as well, supporting a stepwise progression model of pancreatic adenocarcinomas

KRAS ♦♦ Activating mutations in KRAS are one of the earliest events in the tumorigenesis of pancreatic adenocarcinoma,

with the best characterized being point mutations in codon 12 ♦♦ These point mutations have been identified in over 90% of pancreatic adenocarcinomas and intraepithelial neopla­sias ♦♦ However, use of KRAS mutations as a screening tool is hampered by the fact that these mutations are also frequently detected in nonneoplastic pancreatic lesions

HER1/EDFR and HER2/neu ♦♦ HER1/EGFR and HER2/neu, members of the epidermal growth factor receptor family, are also commonly overexpressed in carcinoma of the pancreas, which can be detected with molecular techniques or by immunohistochemistry −− This finding has led to ongoing clinical trials with specific receptor tyrosine kinase inhibitors in an effort to improve the outcome of pancreatic cancer patients ♦♦ Recently, microRNAs, small RNA molecules that regulate the translational activity of target mRNAs, have been found to have a distinct expression profile in pancreatic adenocarcinomas which may lead to better identification and stratification of these cancers

BLADDER ADENOCARCINOMA General Considerations ♦♦ Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a tyrosine kinase receptor, have been shown to strongly correlate with low tumor grade and stage −− One study demonstrated FGFR3 mutations in 86% of papillary urothelial neoplasms of low malignant potential and low grade papillary urothelial carcinomas −− Approximately two-thirds of these alterations are S249C mutations in exon 7 −− All of the mutations result in constitutive activation of the intracellular tyrosine kinase domain of the FGFR3 protein and downstream activation of the RAS-MAPK pathway

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−− This finding has led to recent efforts to develop a tyrosine kinase inhibitor as a means of targeted therapy for bladder tumors ♦♦ Several other gene alterations are commonly found in epithelial cancers of the bladder, including mutations in HRAS and cyclin-dependent kinases, and loss of tumor suppressors TP53 and RB1 −− However, molecular genetic analysis is not generally performed in the diagnosis of these tumors since genetic alterations have not been found to correlate with tumor grade or stage ♦♦ Genomic approaches such as microarray studies to identify relevant diagnostic marker genes in bladder cancer show promise, but remain challenging due to lack of standardization among platforms and the heterogeneity of the results

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UroVysion ♦♦ Molecular genetic testing has found a role in the followup screening of urine from patients with previously biopsyproven urothelial carcinoma ♦♦ The most commonly employed of these methods is UroVysion, which is a proprietary FDA-approved FISH assay using four probes −− These probes include probes for the pericentromeric regions of chromosome 3, 7, and 17, and the chromosome region 9p21

♦♦ Scoring criteria for positivity is based on the number of cells that show a gain of two or more different chromosomes based on the chromosome 3, 7, and 17 probes, gain of a single chromosome, or loss of the 9p21 region ♦♦ The assay has been shown to have an overall sensitivity of approxi­mately 85% and an overall specificity of approximately 95% ♦♦ Most studies comparing FISH to cytology alone have shown that FISH outperforms cytology across all stages and grades ♦♦ A further advantage of FISH is that it is unaffected by BCG treatment

RENAL CELL CARCINOMA VHL ♦♦ Mutations in the VHL gene on chromosome 3p25 are the hallmark of conventional clear cell renal cell carcinoma (RCC), which accounts for approximately 85% of all renal malignancies ♦♦ The VHL alterations (all loss of function) include single base pair substitutions resulting in missense mutations, single base pair insertions/deletions resulting in-frame shift mutations, in-frame deletions, and intronic mutations −− These mutations can occur almost anywhere within the gene ♦♦ About 20% of RCC do not show VHL mutations but do show reduced expression of the VHL gene, suggesting that aberrant methylation is present −− The VHL protein is a tumor suppressor that functions in the regulation of various genes, some of which are involved in the cellular response to oxygen tension −− At normal oxygen tensions, the VHL protein mediates the destruction of proteins that upregulate angiogenesis and erythropoietin production −− Thus, the effect of a nonfunctional VHL is the net promotion of these processes even under normoxic conditions, which helps promote tumorigenesis ♦♦ Mutational analysis of the VHL gene in RCC is cumbersome due to the widespread nature of the mutations −− Rather than directly sequencing all tumors, many investigators use a mutation prescreening technique such as dHPLC to first identify cells harboring detectable mutations followed by direct sequencing −− Alternatively, LOH analysis can be used to detect inactivation of the gene (a) LOH analysis can be performed with FISH, Southern blotting, or PCR-based systems

(b) The combination of interphase FISH and PCR-based microsatellite analysis seems to provide the highest sensitivity for detecting LOH

TFE3 ♦♦ A subset of RCC is defined by rearrangements of the TFE3 gene at Xp11.2 −− This subset primarily affects children and young adults (24–41% of RCC in this category) but has been reported in older adults ♦♦ Most alterations involving the TFE3 gene are balanced translocations involving chromosome X and either 1 or 17, though one variant is caused by an inversion in X −− Depending on the translocation, a different partner gene is fused with TFE3 −− The TFE3 protein is a leucine zipper transcriptional factor whose function is fully retained in most TFE3 gene fusions −− Since all translocations result in the overexpression of the TFE3 gene, they are thought to contribute to tumorigenesis by the deregulation of the target genes ♦♦ Though the balanced translocation in this variant of RCC was originally discovered by conventional cytogenetics, RT-PCR is more sensitive, especially if the exact fusion is known through the initial use of a panel of primers specific for all known transcript types −− FISH using probe-fusion and probe-splitting technologies has also been used to detect the translocations and the inversion ♦♦ As with other cancers, research with renal cancers is ongoing using expression profiles gleaned from microarray studies in an effort to identify diagnostically and prognostically relevant biomarkers

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HEAD AND NECK CANCER Squamous Cell Carcinoma ♦♦ Squamous cell carcinoma (SCC) of the head and neck is thought to arise from the multistep accumulation of mutations progressing from dysplasia to invasive carcinoma to metastasis ♦♦ It is the accumulation of the mutations and not necessarily the order in which they occur that is important −− Furthermore, no single alteration appears to be necessary for any particular stage in tumorigenesis, thus no single locus has the sensitivity or specificity to be of clinical usefulness −− Nonetheless, some generalizations can be made −− For instance, tumor suppressor genes such as TP53, RB1 and p16 are commonly mutated, as are oncogenes such as CCND1 (cyclin D1 gene), p21 and EGFR −− Loss of heterozygosity at multiple loci and numerous gross chromosomal deletions and gains are also prevalent ♦♦ One potential use of molecular analysis of SCC is to screen for mutations in tissue from surgical margins once the mutation profile of a particular tumor is known −− Recent data show that tumor recurrence is much more likely when the mutations are detectable in the margin tissue than when the tissue is negative −− Molecular detection of mutations has also been used to detect metastatic burden in lymph nodes and serum, though these practices are fraught with technical and biologic issues that limit their clinical utility ♦♦ A distinction between HPV-associated (comprising 26% of SCCs worldwide) and HPV-negative (often tobacco-related) head and neck SCCs should be made since these two entities have different genetic profiles

Pleomorphic Adenoma ♦♦ Pleomorphic adenoma (PA) is the most common benign neoplasm of the salivary glands ♦♦ Over half of PAs have been shown to harbor chromosomal abnormalities, with approximately 40% showing 8q12 rearrangements and approximately 10% showing 12q15 rearrangements

−− The PLAG1 gene appears to be the consistent target with the 8q12 rearrangement −− In the majority of cases, a t(3;8) translocation results in a CTNNB1–PLAG1 fusion gene −− PLAG1 is a transcription factor whose overexpression resulting from the translocation is thought to contribute to PA development −− Interestingly, PLAG1 is also commonly overexpressed in PAs without the t(3;8) translocation −− The HMGA2 gene, which codes for a nonhistone chromatin-associated protein, is overexpressed in the alterations involving 12q15. A t(3;12), an ins(9;12) and complex rearrangements including t(1;12) have all been described in PA ♦♦ Conventional cytogenetics, FISH, and PCR-based techniques have all been used to detect the rearrangements involving the PLAG1 and HMGA2 genes

Mucoepidermoid Carcinoma ♦♦ Mucoepidermoid carcinoma (MEC) is the most common malignant neoplasm of the salivary gland ♦♦ Regardless of its anatomic site of origin, the hallmark genetic feature of MEC are rearrangements involving 11q21 and 19p13 −− The rearrangements produce a fusion between MECT1 on chromosome 19p13 and the MAML2 gene on 11q21 in which exon 1 of MECT1 is fused to exons 2 through 5 of MAML2 −− The resultant chimeric protein likely acts as an activator of genes regulated by cAMP response elements and genes involved in the Notch pathway, two signaling pathways involved in tumorigenesis ♦♦ The exact rearrangement, while structurally diverse, has been detected with conventional cytogenetics, FISH, and PCRbased assays, with RT-PCR having the highest sensitivity −− Interestingly, a t(11;19) translocation resulting in a MECT1–MAML2 fusion gene has been detected in a subset of cases of Warthin tumor

TUMORS OF UNKNOWN ORIGIN ♦♦ Molecular techniques have recently been employed in the identification of tumors of an unknown primary, which comprise approximately 5% of cancers diagnosed in the United States −− Identification of the site of origin is critical, since without it these patients will not be able to receive the benefits of targeted therapy ♦♦ Molecular approaches to identify tissue of origin in these tumors include the use of microarray or RT-PCR to classify

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tissue type based on gene expression profiling, which, in general, remains similar between primary and metastatic tumor cells −− Several commercial kits are available that have a success rate of 80–90% in determining tumor origin −− Alternatively, assays to detect the tissue-specific expression of microRNAs are also being used with a similar success rate

Molecular Pathology of Solid Tumors

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SUGGESTED READING Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 2009;27:2091–2096.

Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev 2010;29: 37–48.

Andreoiu M, Cheng L. Multifocal prostate cancer: biological, prognostic, and therapeutic implications. Hum Pathol 2010;41:781–793.

Gulley ML, Kaiser-Rogers KA. A rational approach to genetic testing for sarcoma. Diagn Mol Path 2009;18:1–10.

Arsanious A, Bjarnson GA, Yousef GM. From bench to bedside: current and future applications of molecular profiling in renal cell carcinoma. Mol Cancer 2009;8:20–31.

Hunt JL. Molecular testing in solid tumors: an overview. Arch Pathol Lab Med 2008;132:164–167.

Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol 2010;28:1254–1261. Borczuk AC, Toonkel RL, Powell CA. Genomics of lung cancer. Proc Am Thorac Soc 2009;6:152–158. Bosch A, Eroles P, Zaragoza R, et al. Triple-negative breast cancer: molecular features, pathogenesis, treatment and current lines of research. Cancer Treat Rev 2010;36:206–215. Bromberg JE, van den Bent MJ. Oligodendrogliomas: molecular biology and treatment. Oncologist 2009;14:155–163. Castel V, Grau E, Noguera R, Martinez F. Molecular biology of neuroblastoma. Clin Transl Oncol 2007;9:478–483. Cheng L, Davidson DD, MacLennan GT, et al. The origins of urothelial carcinoma. Exp Rev Anticancer Ther 2010;10:865–880. Cheng L, Williamson SR, Zhang S, et al. Understanding the molecular genetics of renal cell neoplasia: implications for diagnosis, prognosis and therapy. Exp Rev Anticancer Ther 2010;10:843–864. Cheng L, Zhang D. Molecular Genetic Pathology. New York, New York: Humana Press/Springer; 2008. Cheng L, Zhang S, Davidson DD, et al. Molecular determinants of tumor recurrence in the urinary bladder. Future Oncol 2009;5: 843–857. Cheng L, Zhang S, MacLennan GT, et al. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnosis, and prognosis of renal epithelial neoplasms. Hum Pathol 2009;40: 10–29.

Gold KA, Kim ES. Role of molecular markers and gene profiling in head and neck cancers. Curr Opin Oncol 2009;21:206–211.

Hunt JL. Molecular alterations in hereditary and sporadic thyroid and parathyroid diseases. Adv Anat Pathol 2009;16:23–32. Kumar-Sinha C, Tomlins SA, Chinnaiyan, AM. Recurrent gene fusions in prostate cancer. Nature Reviews/Cancer 2008;8:497–511. Lazar AJ, Trent JC, Lev D. Sarcoma molecular testing: diagnosis and prognosis. Curr Oncol Rep 2007;9:309–315. Monzon FA, Koen TJ. Diagnosis of metastatic neoplasms: molecular approaches for identification of tissue of origin. Arch Pathol Lab Med 2010;134:216–224. Plesac TP, Hunt JL. KRAS mutation testing in colorectal cancer. Adv Anat Pathol 2009;16:196–203. Ranganathan P, Harsha HC, Pandey A. Molecular alterations in exocrine neoplasms of the pancreas. Arch Pathol Lab Med 2009;133:405–412. Ross JS. Multigene classifiers, prognostic factors, and predictors of breast cancer clinical outcome. Adv Anat Pathol 2009;16:204–215. Shankaran V, Obel J, Benson AB. Predicting response to EGFR inhibitors in metastatic colorectal cancer: current practice and future directions. The Oncologist 2010;15:157–167. Singh M, Lin J, Hocker, TL, Tsao, H. Genetics of melanoma tumorigenesis. Br J Dermatol 2008;158:15–21. Vrooman OP, Witjes JA. Molecular markers for detection, surveillance, and prognostication of bladder cancer. Int J Urol 2009;16:234–243. Wang HL, Lopategui J, Amin MB, et al. KRAS mutation testing in human cancers: the pathologist’s role in the era of personalized medicine. Adv Anat Pathol 2010;17:23–32.

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13 Human Genetic Disorders Teresa M. Kruisselbrink, Noralane M. Lindor, md, Elyse B. Mitchell, Brittany C. Thomas, Cassandra K. Runke, Katrina E. Kotzer, Rajiv K. Pruthi, mbbs, Devin Oglesbee, phd, Elyse M. Grycki, and Ralitza H. Gavrilova, md

Contents

I. Chromosomal Disorders....................13-3

Chromosomal Aneuploidy...............................13-3 Trisomy 21 (Down Syndrome)..............13-3 Trisomy 13 (Patau Syndrome)..............13-3 Trisomy 18 (Edward Syndrome)...........13-4 Klinefelter Syndrome (XXY)................13-4 Turner Syndrome (45,X)........................13-5 Microdeletion Syndromes................................13-5 Angelman Syndrome..............................13-5 Prader–Willi Syndrome.........................13-6 1p36 Microdeletion Syndrome..............13-7 Cri du Chat Syndrome...........................13-7 22q Deletion Syndrome (DiGeorge/ Velo-Cardio-Facial Syndrome)........13-7 Smith–Magenis Syndrome.....................13-7 Miller–Dieker Syndrome.......................13-8 Williams Syndrome................................13-8 Wolf–Hirschhorn Syndrome.................13-8 Chromosome Breakage Syndromes................13-8 Fanconi Anemia......................................13-8 Bloom Syndrome....................................13-9 Ataxia Telangiectasia.............................13-9 Xeroderma Pigmentosum......................13-9

II. Trinucleotide Repeat Disorders........13-10 Fragile X Syndrome.......................................13-11 Myotonic Dystrophy Type 1..........................13-11 Myotonic Dystrophy Type 2 (Proximal Myotonic Myopathy)...............13-12 Friedreich Ataxia............................................13-12 Huntington Disease........................................13-13

Spinal Cerebellar Ataxia...............................13-13 Spinal and Bulbar Muscular Atrophy (Kennedy Disease).....................................13-14

III. Neuromuscular Disorders................13-14 Duchenne/Becker Muscular Dystrophy.......13-14 Spinal Muscular Atrophy, Types I–IV.........13-15 Charcot–Marie–Tooth Disease......................13-16 Hereditary Neuropathy with Liability to Pressure Palsies.....................................13-17

IV. Skeletal Disorders............................13-17 Craniosynostosis.............................................13-17 Apert Syndrome...................................13-17 Crouzon Syndrome..............................13-17 Pfeiffer Syndrome (Types I–III).........13-18 Saethre–Chotzen Syndrome................13-18 Achondroplasia...............................................13-19 Osteogenesis Imperfecta (Types I–VII)........13-19

V. Connective Tissue Disorders............13-20 Marfan Syndrome..........................................13-20 Loeys–Dietz Syndrome..................................13-21 Thoracic Aortic Aneurysm and Dissection............................................13-21 Ehlers–Danlos Syndrome..............................13-22 Stickler Syndrome..........................................13-22 Alport Syndrome............................................13-23

VI. Hematologic Disorders....................13-23 Alpha Thalassemia.........................................13-23 Beta Thalassemia............................................13-24

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_13, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Sickle Cell Anemia.........................................13-25 Hemophilia A..................................................13-26 Hemophilia B..................................................13-26 von Willebrand Disease.................................13-27 Factor V Leiden..............................................13-28 Prothrombin 20210G>A Mutation...............13-29

VII. Other Genetic Disorders.................13-30 Cystic Fibrosis................................................13-30 Albinism (Oculocutaneous Albinism Type 1)........................................................13-30 Neurofibromatosis Type 1 (von Recklinghausen)................................13-30 Neurofibromatosis Type 2..............................13-31 Tuberous Sclerosis Complex..........................13-32 Beckwith–Wiedemann Syndrome.................13-33

VIII. Metabolic Disorders: Inborn Errors of Metabolism.......................13-33 Amino Acid Disorders....................................13-33 Phenylketonuria...................................13-33 Tyrosinemia (Type 1 Most Prevalent).........................................13-34 Maple Syrup Urine Disease.................13-34 Homocystinuria....................................13-35 Urea Cycle Disorders.....................................13-35 Organic Acidemias.........................................13-36 Isovaleric Acidemia..............................13-36 Propionic Acidemia..............................13-36 Methylmalonic Acidemia (Methylmalonyl-CoA Mutase).......13-37 Mitochondrial Fatty Acid Oxidation Disorders....................................................13-37 Medium-Chain Acetyl-CoA Dehydrogenase Deficiency..............13-38 Very Long-Chain Acetyl-CoA Dehydrogenase Deficiency..............13-38 Long-Chain 3-Hydroxylacetyl-CoA Dehydrogenase/Mitochondrial Trifunctional Protein Deficiency....13-39 Short-Chain Acetyl-CoA Dehydrogenase Deficiency..............13-39 Carbohydrate Metabolism Disorders...........13-40 Glycogen Storage Disease (Type I).....13-40 Galactosemia.........................................13-41 Galactokinase Deficiency.....................13-41 Transport Disorders.......................................13-41 Familial Hypophosphatemic Rickets..............................................13-41 Cystinuria.............................................13-42 Hartnup Disease...................................13-42 Cystinosis..............................................13-42 Metal Metabolism Disorders.........................13-43 Wilson Disease......................................13-43 Acrodermatitis Enteropathica............13-43

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Menkes Disease.....................................13-44 Hemochromatosis.................................13-44 Purine Metabolism Disorders.......................13-45 Lesch–Nyhan Syndrome......................13-45 Adenosine Deaminase..........................13-45 Peroxisomal Disease.......................................13-45 Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease................13-45 Adrenoleukodystrophy (X-linked)......13-46

IX. Lysosomal Storage Disorders............13-46 Mucopolysaccharidoses.................................13-46 Mucolipidoses.................................................13-48 I-Cell Disease (Mucolipidosis II Alpha/Beta)......................................13-48 Pseudo-Hurler Polydystrophy (Mucolipidosis III Alpha/Beta)......13-48 Sphingolipidoses.............................................13-48 GM1 Gangliosidosis.............................13-48 GM2 Gangliosidoses (Tay–Sachs Disease and Sandhoff Disease).......13-49 Tay–Sachs Disease................................13-49 Sandhoff Disease..................................13-50 Niemann–Pick Disease, Types A and B.............................................13-50 Niemann–Pick Disease Type C...........13-50 Gaucher Disease...................................13-51 Krabbe Disease.....................................13-51 Metachromatic Leukodystrophy........13-52 Fabry Disease........................................13-53

X. Familial Cancer Syndromes..............13-53 Familial Adenomatous Polyposis..................13-53 MYH Associated Polyposis.............................13-54 Basal Cell Nevus Syndrome (Gorlin Syndrome)..................................................13-54 Birt–Hogg–Dube Syndrome..........................13-55 Breast/Ovarian Cancer..................................13-55 Lynch Syndrome.............................................13-56 Cowden Syndrome (Multiple Hamartoma Syndrome)............................13-57 Li–Fraumeni Syndrome.................................13-57 Multiple Endocrine Neoplasia Type 1..........13-58 Multiple Endocrine Neoplasia Types 2A, 2B and Familial Medullary Thyroid Carcinoma...................................13-58 Peutz–Jeghers Syndrome...............................13-59 Retinoblastoma...............................................13-59 von Hippel–Lindau.........................................13-60 Wilms Tumor..................................................13-60

XI. Mitochondrial Disorders..................13-61 XII. Suggested Reading...........................13-62

Human Genetic Disorders

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CHROMOSOMAL DISORDERS Chromosomal Aneuploidy Trisomy 21 (Down Syndrome) Chromosome and Gene Location ♦♦ Additional chromosome 21 ♦♦ Critical region at 21q22

Inheritance ♦♦ 95% meiotic nondisjunction (47 chromosomes present) −− 80–90% maternal, increases with maternal age −− 10–20% paternal ♦♦ 3–4% unbalanced translocation (46 chromosomes with an extra chromosome 21 fused to another acrocentric chromosome) −− 66% sporadic (not inherited) −− 33% balanced translocation in one parent ♦♦ 1–2% mosaicism (at least two different cell lines) −− Results from postzygotic nondisjunction or loss of the extra 21 in one cell line

Incidence ♦♦ 1/800 live births

Clinical Manifestations ♦♦ Flat facial profile, thick nuchal fold, upward slanting palpebral fissures, depressed nasal bridge, epicanthal folds, Brushfield spots of iris, (Fig. 13.1A), single transverse palmar crease (Fig.  13.1B), gap between first and second toe (Fig. 13.1C), low set c-shaped ears ♦♦ Developmental delay learning disabled (IQ = 40–80), poor Moro reflex, infantile hypotonia, joint hyperflexibility, increased risk for Alzheimer disease ♦♦ Congenital heart defects (endocardial cushion defects including atrioventricular canal defect and ventricular septal defects), increased risk for childhood acute leukemia, hypothyroidism, obesity, short stature, increased incidence of pulmonary hypoplasia, duodenal atresia ♦♦ Ultrasound findings may include increased nuchal translucency, thickened nuchal fold, congenital heart defects, duo-

denal atresia, short humerus and femur, short middle phalanx of fifth finger, echogenic bowel ♦♦ Seventy-five percent spontaneously abort in first trimester. Of those live born, 80% survival at age 30

Laboratory ♦♦ Chromosome analysis identifies extra chromosome 21 ♦♦ Prenatal diagnosis through chromosome analysis of chorionic villi or amniocentesis ♦♦ Altered prenatal maternal serum markers in the first trimester, (increased human chorionic gonadotrophin [hCG], decreased pregnancy associated plasma protein A [PAPPA]) and second trimester (decreased alpha fetoprotein and unconjugated estriol, increased hCG and inhibin A)

Treatment ♦♦ Not curable, supportive/symptomatic

Trisomy 13 (Patau Syndrome) Chromosome and Gene Location ♦♦ Additional chromosome 13

Inheritance ♦♦ 80% meiotic nondisjunction (47 chromosomes present) −− 80–90% maternal, increases with maternal age −− 10–20% paternal ♦♦ 20% unbalanced translocation (46 chromosomes with an extra chromosome 13 fused to another acrocentric chromosome)

Incidence ♦♦ 1/10,000 births

Clinical Manifestations ♦♦ Midline abnormalities ranging from simple ocular hypotelorism to cyclopia to complete absence of eyes, prominent occiput, microcephaly, malformed low set ears, cleft lip and palate, polydactyly, transverse palmar crease (Fig. 13.2) ♦♦ Complete or incomplete holoprosencephaly, severe mental retardation, seizures, deafness, hypotonia, apneic spells

Fig. 13.1. Down syndrome – brushfield spots on irides (A). Single transverse palmar creases and fifth finger clinodactyly (B). Gap between first and second toe (C).

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Fig. 13.3. Trisomy 18 – clenched hand and overlapping fingers.

Incidence ♦♦ 1/5,000–1/10,000 births

Clinical Manifestations

Fig.  13.2. Trisomy 13 – showing hypertelorism and tube-like nasal structure. Polydactyly on foot.

♦♦ Congenital heart defects (hypoplastic left heart and ventricular septal defects), urogenital defects, cryptorchidism, bicornuate uterus and hypoplastic ovaries, polycystic kidneys, umbilical hernia, omphalocele ♦♦ Ultrasound findings may include holoprosencephaly, cleft lip and palate, cystic hygroma, polydactyly, congenital heart defects, cystic kidneys, omphalocele ♦♦ 95% spontaneously abort. Of those live born, 90% die within first year of life

Laboratory ♦♦ Chromosome analysis identifies extra chromosome 13 ♦♦ Prenatal diagnosis through chromosome analysis of chorionic villi or amniocentesis ♦♦ Altered prenatal first trimester serum analytes

Treatment ♦♦ Not curable, supportive/symptomatic

Trisomy 18 (Edward Syndrome) Chromosome and Gene Location ♦♦ Additional chromosome 18

Inheritance ♦♦ Meiotic nondisjunction −− 95% maternal, increases with maternal age −− 5% paternal

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♦♦ Microcephaly with prominent occiput, micrognathia, malformed ears, clenched hands, second and fifth digits overlapping third and fourth (Fig. 13.3), rocker bottom feet, single transverse palmar crease, hypoplastic nails ♦♦ Severe mental retardation, seizures, hypertonia ♦♦ Severe intrauterine growth retardation, congenital heart defects (ventricular septal defects), urogenital defects, ­cryptorchidism, horseshoe kidney, diaphragmatic hernia, omphalocele ♦♦ Ultrasound findings may include clenched hands, club and rocker-bottom feet, micrognathia, congenital heart defects, omphalocele, diaphragmatic hernia, neural tube defects, choroid plexus cysts, cystic hygroma

Life expectancy ♦♦ 95% spontaneously abort. Of those live born, 90% die within first year of life

Laboratory ♦♦ Chromosome analysis identifies extra chromosome 18 ♦♦ Prenatal diagnosis through chromosome analysis of chorionic villi or amniocentesis ♦♦ Altered prenatal maternal serum markers in the first trimester (decreased hCG and PAPPA) and second trimester (decreased alpha fetoprotein, unconjugated estriol, and hCG)

Treatment ♦♦ Not curable, supportive/symptomatic

Klinefelter Syndrome (XXY) Chromosome and Gene Location ♦♦ Extra X chromosome in a male

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Inheritance ♦♦ Meiotic nondisjunction −− 55% maternal nondisjunction −− 45% paternal nondisjunction ♦♦ Also may be mosaic XY/XXY or rarely XX/XXY

Incidence ♦♦ 1/800 males

Clinical Manifestations ♦♦ Tall habitus, undervirilized, small testes, gynecomastia, poor musculature ♦♦ Mild delay, behavioral immaturity, shyness, learning disabilities (reading) speech delay ♦♦ Infertility ♦♦ Normal life expectancy

Laboratory ♦♦ Chromosome analysis identifies XXY ♦♦ Prenatal diagnosis through chromosome analysis of chorionic villi or amniocentesis ♦♦ Maternal serum screening and ultrasound findings are not useful

Treatment ♦♦ Testosterone supplementation for development of secondary sexual characteristics

Turner Syndrome (45,X) Chromosome and Gene Location ♦♦ Missing or structurally abnormal X chromosome

Inheritance ♦♦ 55% 45,X −− 80% loss of paternal X chromosome −− 20% loss of maternal X (no maternal age effect) ♦♦ 25% 46,XX −− Structural alteration in one X chromosome ♦♦ 15% mosaic −− 45X with 46XX, 46XY or other

Incidence ♦♦ 1/2,000–1/5,000 female births ♦♦ Most common chromosome finding in spontaneous abortions

Clinical Manifestations ♦♦ Short stature, webbed neck (Fig.  13.4), lymphedema of hands and feet, high arched palate, cystic hygroma, low posterior hairline, hypoplastic widely-spaced nipples ♦♦ Normal or near normal intelligence; may have delay in speech, neuromotor skills, and learning abilities ♦♦ Gonadal dysgenesis (infertility, primary amenorrhea), renal malformations (horseshoe kidney), cardiovascular malformations (coarctation of aorta, hypoplastic left heart),

Fig.  13.4. Turner syndrome – webbing of the neck and low posterior hairline. increased risk for gonadoblastoma if mosaic for some Y chromatin ♦♦ Ultrasound findings include cystic hygroma (detectable after 10 weeks), lymph collections (ascites, pleural effusion), congenital heart disease, renal anomalies ♦♦ 99% spontaneously abort; those who survive infancy usually reach adulthood

Laboratory ♦♦ Chromosome analysis indicates monosomy X or other variant ♦♦ Prenatal diagnosis through chromosome analysis of chorionic villi or amniocentesis ♦♦ Elevated prenatal maternal serum alpha fetoprotein (only in cases of cystic hygroma and hydrops)

Treatment ♦♦ Estrogen, thyroid, and growth hormone replacement therapy for development of secondary sexual characteristics and growth

Microdeletion Syndromes ♦♦ See Table 13.1

Angelman Syndrome Chromosome and Gene Location ♦♦ 15q11.2

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Table 13.1. Microdeletion Syndromes Syndrome

Features

Location

Angelman

Ataxia, seizures, happy demeanor, severe mental retardation

15q11–q13

Chromosome 1p36 deletion

Mental retardation, dysmorphic, hypotonia, seizures

1p36

Chromosome 22q11.2 deletion (DiGeorge, Velocardiofacial)

Cleft palate, heart defect, developmental delay, thymic and parathyroid hypoplasia

22q11.2

Cri du chat

“Cat-like” cry as newborn, microcephaly, mental retardation

5p15.2

Miller–Dieker

Lissencephaly, mental retardation

17p13.3

Prader–Willi

Hyperphagia, obesity, mental retardation, hypogonadism, small hands and feet

15q11–q13

Smith–Magenis

Sleep disturbances, self-injurious behaviors, mental retardation

17p11.2

Williams

Supravalvular aortic stenosis, mental retardation, hypercalcemia, social personality

7q11.2

Wolf–Hirschhorn

High, broad nasal bridge, microcephaly, growth deficiency, clefting, hypertelorism, mental retardation

4p16

Inheritance ♦♦ Angelman syndrome results from the loss of the maternally imprinted region at chromosome 15q11.2. Loss can occur via numerous mechanisms. Recurrence is dependent on mechanism of loss −− 60–70% deletion of maternal 15q11.2 −− 5% paternal uniparental disomy (UPD) (two copies of the paternal chromosome) −− 3% imprinting defect −− 11% Ubiquitinprotein-ligase E3A (UBE3A) mutation −− 11% unknown

Incidence ♦♦ 1/20,000

Clinical Manifestations ♦♦ Prominent mandible, open-mouthed expression, hyperflexia, microcephaly, brachycephaly, optic atrophy ♦♦ Ataxia, severe mental retardation, seizures, gross motor developmental delay ♦♦ Absent speech, inappropriate laughter, arm flapping, feeding difficulties ♦♦ Most survive into adulthood

Laboratory ♦♦ First-tier testing −− Molecular methylation analysis identifies missing maternal allele −− Methylation-sensitive Multiple Ligation-Dependent Probe Amplification (MLPA) detects missing maternal allele or deletion ♦♦ Second-tier testing −− Fluorescent in situ hybridization (FISH) detects deletion −− Molecular UPD studies identify two copies of paternal allele

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−− Sequence analysis identifies mutations in UBE3A gene −− Mutation analysis of imprinting center

Treatment ♦♦ Not curable, supportive/symptomatic

Prader–Willi Syndrome Chromosome and Gene Location ♦♦ 15q11.2

Inheritance ♦♦ Prader–Willi Syndrome results from the loss of the paternally imprinted region at chromosome 15q11.2. Loss can occur via numerous mechanisms. Recurrence is dependent on mechanism of loss. −− 75% deletion of paternal 15q11.2 −− 20–25% maternal UPD (two copies of maternal chromosome 15) −− Remainder is thought to be due to imprinting defects

Incidence ♦♦ 1/10,000–1/25,000

Clinical Manifestations ♦♦ Hypotonia, hypogonadism, obesity, small hands and feet, almond shaped eyes, short stature ♦♦ Mild to moderate mental retardation ♦♦ Failure to thrive, hyperphagia ♦♦ Most survive into adulthood

Laboratory ♦♦ First-tier testing −− Molecular methylation analysis identifies missing paternal allele −− Methylation-sensitive MLPA detects missing paternal allele or deletion

Human Genetic Disorders

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♦♦ Second-tier testing −− FISH detects deletion −− Molecular UPD studies identify two copies of maternal allele if either first-tier test is abnormal −− Mutation analysis of imprinting center

Laboratory

Treatment

Treatment

♦♦ Not curable, supportive/symptomatic

♦♦ Not curable, supportive/symptomatic

1p36 Microdeletion Syndrome Chromosome and Gene Location

22q Deletion Syndrome (DiGeorge/ Velo-Cardio-Facial Syndrome) Chromosome and Gene Location

♦♦ 1p36

Inheritance ♦♦ 90–95% sporadic ♦♦ 5–10% familial translocations

♦♦ Deletion may or may not be detected on chromosome analysis depending upon resolution of the study and size of the deletion ♦♦ FISH and/or aCGH identifies deletion at 5p15

♦♦ 22q11.2

Inheritance

Incidence

♦♦ 90% are deletions involving multiple genes ♦♦ Approximately 10–15% are familial (autosomal dominant)

♦♦ 1/5,000-10,000

Incidence

Clinical Manifestations ♦♦ Microcephaly, deep-set eyes, flat nasal bridge, cardiac malformations, hypotonia ♦♦ Mental retardation, seizures ♦♦ Growth retardation ♦♦ Most survive into adulthood

Laboratory ♦♦ Deletion may or may not be detected on chromosome analysis depending upon resolution of the study and size of the deletion ♦♦ FISH and/or array comparative genomic hybridization (aCGH) identifies deletion at abnormality of 1p36

Treatment ♦♦ Not curable, supportive/symptomatic

Cri du Chat Syndrome Chromosome and Gene Location ♦♦ 5p15

Inheritance ♦♦ 85–90% sporadic (85% deletion, 4% mosaics, 3% ring chromosomes, 4% translocations) ♦♦ 10–15% familial translocations, inversions and parental mosaicism

Incidence ♦♦ 1/50,000

Clinical Manifestations ♦♦ “Cat-like” cry, microcephaly, hypertelorism, micrognathia, transverse palmar crease, hypotonia ♦♦ Mental retardation ♦♦ 50% no speech, growth failure ♦♦ Most survive into adulthood

♦♦ 1/4,000

Clinical Manifestations ♦♦ The disturbance of neural crest migration of pharyngeal pouches is thought to cause clinical features ♦♦ Interpatient variability may be dependent on extent of deletion ♦♦ Hypertelorism, down slanting eyes, high arched palate, micrognathia, low set ears, bulbous nose, square nasal tip, cleft palate (Velo-Cardio-Facial (VCF)), small open mouth, retrognathia, microcephaly, slender hands and digits ♦♦ Cardiac manifestations include tetralogy of Fallot, outflow tract defect, right sided aortic arch, interrupted aortic arch, ventricular septal defect ♦♦ Mild-moderate learning difficulties, seizures, tetany, emotional, and behavioral problems ♦♦ Hypoparathyroidism, neonatal hypocalcemia (DiGeorge (DGS)), immune/T-cell deficit (DGS), hypernasal speech, hypospadius, short stature ♦♦ Most reach adulthood if cardiac lesion is not life threatening

Laboratory ♦♦ Hypocalcemia, decreased T-cells ♦♦ Deletion of 22q11 is usually not visible on chromosome analysis ♦♦ FISH and/or aCGH identifies deletion at 22q11

Treatment ♦♦ Cardiac surgery, calcium supplements, supportive care

Smith–Magenis Syndrome Chromosome and Gene Location ♦♦ 17p11.2

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Inheritance

Incidence

♦♦ Most are sporadic interstitial deletions ♦♦ A few cases of pericentric inversions with breakpoints in 17p11

♦♦ 1/20,000 live births

Incidence ♦♦ 1/50,000

Clinical Manifestations ♦♦ Brachycephaly, flat, broad mid-face, prominent forehead ♦♦ Seizures, mental retardation ♦♦ Hyperactivity, sleep disturbances, behavioral problems including screaming outbursts and self-mutilation behaviors, speech delay ♦♦ Most survive into adulthood

Laboratory ♦♦ Chromosome analysis detects deletion in most cases ♦♦ FISH and/or aCGH identifies deletion at 17p11.2

Treatment ♦♦ Not curable, supportive/symptomatic

Miller–Dieker Syndrome Chromosome and Gene Location ♦♦ 17p13.3

Inheritance ♦♦ 90% are sporadic deletions ♦♦ Approximately 10–15% are familial

Incidence

Clinical Manifestations ♦♦ Elfin facies, broad forehead, bitemporal narrowness, periorbital fullness, wide mouth, broad nasal tip, long philtrum, micrognathia, growth retardation, small widely spaced teeth ♦♦ Cardiac manifestations include supravalvular aortic stenosis, peripheral pulmonary stenosis ♦♦ Mental retardation ♦♦ Gregarious personality, joint limitations, hypercalcemia ♦♦ Most survive into adulthood

Laboratory ♦♦ Elevated serum calcium ♦♦ Deletion is usually not visible on chromosome analysis ♦♦ FISH and/or aCGH identifies deletion at 7q11.23

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Elimination of vitamin D and calcium from the diet

Wolf–Hirschhorn Syndrome Chromosome and Gene Location ♦♦ 4p16.3

Inheritance

♦♦ 1/100,000

♦♦ 85–90% sporadic ♦♦ 10–15% familial translocations

Clinical Manifestations

Incidence

♦♦ Lissencephaly, microcephaly, anteverted nostrils, carp mouth, agenesis of corpus callosum ♦♦ Seizures, mental retardation ♦♦ Failure to thrive, absent speech ♦♦ Life expectancy is variable, but most die in childhood

♦♦ 1/50,000

Laboratory ♦♦ Deletion may or may not be detected on chromosome analysis depending upon resolution of the study and size of the deletion ♦♦ FISH and/or aCGH identifies deletion at 17p13.3

Treatment ♦♦ Not curable, supportive/symptomatic

Williams Syndrome Chromosome and Gene Location ♦♦ 7q11.23

Inheritance ♦♦ Mostly sporadic ♦♦ Few cases of autosomal dominant inheritance have been reported

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Clinical Manifestations ♦♦ Microcephaly, hypertelorism, micrognathia, hypotonia ♦♦ Seizures, mental retardation ♦♦ Congenital heart defects, renal malformations, genital malformations ♦♦ Most survive into adulthood

Laboratory ♦♦ Deletion may or may not be detected on chromosome analysis depending upon resolution of the study and size of  the deletion ♦♦ FISH and/or aCGH identifies deletion at 4p16

Treatment ♦♦ Not curable, supportive/symptomatic

Chromosome Breakage Syndromes Fanconi Anemia Chromosome and Gene Location ♦♦ Genetically heterogeneous (multiple gene loci involved)

Human Genetic Disorders

13-9

Inheritance

Treatment

♦♦ Autosomal recessive

♦♦ Not curable, supportive/symptomatic ♦♦ Minimize exposure to radiation/mutagenic agents

Incidence ♦♦ 1/22,000

Clinical Manifestations ♦♦ Short stature, absent or hypoplastic radii and thumbs, brown skin pigmentation, cryptorchidism, renal anomalies ♦♦ Pancytopenia, anemia, increased incidence of leukemia and solid tumors

Molecular Basis of Disease ♦♦ Multiple complementation groups have been identified and appear to be involved in the formation of a protein complex that participates in a DNA-damage response pathway. The exact molecular mechanism that leads to impaired genomic stability has not been elucidated

Laboratory ♦♦ Increased chromosomal breakage, gaps, and rearrangements after exposure to diepoxybutane or mitomycin C (DNA alkylating agents) ♦♦ Mutation analysis is available on limited basis for specific mutations

Treatment ♦♦ Transfusions, bone marrow transplantation ♦♦ Not curable, supportive/symptomatic

Bloom Syndrome Chromosome and Gene Location

Ataxia Telangiectasia Chromosome and Gene Location ♦♦ 11q22–q23, ATM gene

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/40,000–1/100,000

Clinical Manifestations ♦♦ Cerebellar ataxia, conjunctival telangiectasia, deficiency ♦♦ Predisposition to malignancy ♦♦ Increased infections ♦♦ Growth failure, onset first 2 years of life

IgA

Molecular Basis of Disease ♦♦ Defect in DNA repair mechanisms leading to chromosomal breakage, increased intrachromosomal recombination, sensitivity to ionizing radiation (IR), and abnormal resistance to inhibition of DNA synthesis by IR

Laboratory

♦♦ Autosomal recessive

♦♦ Increased chromosomal breakage and X-radiation sensitivity; especially with breakpoints at sites of immunoglobulin genes or receptors ♦♦ 7;14 chromosomal translocation is identified in 5–15% of cells ♦♦ Molecular analysis of ATM gene identifies mutation in approximately 95% of patients

Incidence

Treatment

♦♦ Rare

♦♦ Not curable, supportive/symptomatic ♦♦ Treatment of infections and neoplasms, avoidance of radiation

♦♦ 15q26.1

Inheritance

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Short stature Facial erythema Increased susceptibility to infections Increase incidence of leukemia High pitched voice

Molecular Basis of Disease ♦♦ Decreased activity of DNA ligase I leads to genomic instability and multisystem anomalies

Laboratory ♦♦ Increased sister chromatid exchange (12× normal) ♦♦ Quadrilateral formation is increased as are random breaks and translocations between nonhomologous chromosomes

Xeroderma Pigmentosum Chromosome and Gene Location ♦♦ Multiple loci

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/250,000

Clinical Manifestations ♦♦ Sensitivity to sunlight (blistering and freckling with little exposure, beginning in childhood) ♦♦ Predisposition to malignancy (especially skin cancer) ♦♦ Mental deterioration in some

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Molecular Basis of Disease ♦♦ Defect in ultraviolet-induced DNA repair mechanisms ♦♦ Skin cells unable to repair sunlight induced DNA damage

Laboratory ♦♦ Diagnosis is based on clinical criteria, no routine clinical laboratory abnormality is observed in patients with XP

♦♦ Cytogenetic analysis can identify clones of cells with chromosome abnormalities, increased ultraviolet induced chromosome breaks and sister chromatin exchanges ♦♦ Fibroblasts show UV hypersensitivity and abnormal unscheduled DNA synthesis

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Avoidance of ultraviolet light

TRINUCLEOTIDE REPEAT DISORDERS ♦♦ A growing number of inherited disease syndromes (primarily neurologic) are known to be caused by the abnormal presence of an expanded tract of trinucleotide repeats within disease-specific genes (Table 13.2) ♦♦ Typically, the clinical hallmark of these trinucleotide repeat diseases is anticipation. Anticipation is defined as the clini-

cal observance of an earlier age of onset and increased rate of disease progression due to amplification in the number of expanded repeats in successive generations ♦♦ The diagnosis is made by determining the number of trinucleotide repeats within a specific disease-causing expandable allele (within the proper clinical context). The normal allele

Table 13.2. Trinucleotide Repeat Disorders

Disease Fragile X syndrome Myotonic dystrophy type 1 Myotonic dystrophy type 2 Friedreich ataxia Huntington disease Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 Spinocerebellar ataxia type 6 Spinocerebellar ataxia type 7 Spinocerebellar ataxia type 8

Gene FMR1

Xq

CGG

DMPK

19q

CTG

CNBP (ZNF9) FXN HHT

3q

CCTG

9q 4p

GAA CAG

ATXN1

6p

CAG

ATXN2

12q

CAG

ATXN3

14q

CAG

CACNA1A

19p

CAG

ATXN7

3p

CAG

ATXN8OS and ATXN8a

13q

(CTA·TAG)n (CTG·CAG)n

Xq

CAG

Spinal and bulbar AR muscular atrophy a

Gene Repeat location sequence

Repeat location, type of region

Normal allele Expanded mutant allele (fully size (no. of penetrant) repeats)

Exon 1, 5¢ untranslated region Exon 15, 3¢ untranslated region Intron 1

5–40

200–4,000

5–34

50–>2,000

11–26

75–11,000

Intron 1 Exon 1, polyglutamine coding Exon 8, polyglutamine coding Exon 1, polyglutamine coding Exon 10, polyglutamine coding 3¢ End of gene, polyglutamine coding Exon 1, polyglutamine coding 3¢ Untranslated region of the ATXN8OS gene and a short polyglutamine ORF in a newly identified overlapping ATXN8 Exon 1, polyglutamine coding

5–33 10–26

66–1,700 ³36

19–39

39–91

14–31

32–57

12–47

53–86

4–18

20–33

4–19

36–³200

15–50

80–250

11–34

>38

SCA8 is associated with a (CTA·TAG)n (CTG·CAG)n repeat in two overlapping genes: ATXN8OS and ATXN8

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Human Genetic Disorders

will have a “normal range” of trinucleotide repeats, whereas the disease-associated (expanded) allele will contain an increased number of repeats (in the hundreds and thousands, for some diseases)

Fragile X Syndrome Chromosome and Gene Location ♦♦ Xq27.3

Inheritance ♦♦ X-linked dominant

Incidence ♦♦ 1/1,500 males (accounts for up to 5% of male mental retardation) ♦♦ 1/2,500 females

Clinical Manifestations ♦♦ Mental retardation (IQ 50–60) ♦♦ Large narrow face, prominent jaw, with moderately increased head circumference, large ears ♦♦ Macroorchidism (80%)

Molecular Basis of Disease ♦♦ Expanded CGG repetitive element within FMR-1 gene −− 5–40 Normal −− 41–58 Indeterminate (minimal expansion, one to two repeats, meiotic instability of alleles that are >50 repeats), no associated phenotype −− 59–200 Premutation (meiotic instability with potential to expand to full mutation), fragile X-associated tremor/ ataxia syndrome (FXTAS) characterized by cerebellar ataxia and intentional tremor is observed in both males and females with almost half of all male premutation carriers affected by age 79; premature ovarian failure (POF) is also observed in an average 21% of female premutation carriers; however, penetrance is inversely correlated with the number of repeats in the indeterminate and premutation carrier ranges −− 200–4,000 full mutation, leads to abnormal methylation and transcriptional suppression of FMR-1 gene and absence of FMRP (RNA binding protein) −− CGG repeat expansion is through female germline (males transmit premutation repeat without much change) ♦♦ Sherman paradox −− Describes apparent deviation from traditional Mendelian inheritance and varies according to whether the causative gene is transmitted through a male or female −− In fragile X, this is the result of expansion from premutation to full mutation through the female germline only

Laboratory ♦♦ Molecular analysis detects expanded CGG repeat and is now the test of choice as expanded CGG repeats account for ~99% of disease-causing mutations

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♦♦ Molecular analysis by sequencing and dosage analysis detects the remaining 1% of FMR-1 mutations ♦♦ Chromosomal fragile site may be apparent when cultured in folate deficient/thymidine inhibiting media

Treatment ♦♦ Not curable ♦♦ Supportive/symptomatic

Myotonic Dystrophy Type 1 Chromosome and Gene Location ♦♦ 19q13.2–q13.3

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ 1/8,000 (accounts for myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2); together they represent the most common muscular dystrophy in adults)

Clinical Manifestations ♦♦ Myotonia (sustained muscle contraction), muscle wasting, facial weakness ♦♦ Cataracts ♦♦ Hypogonadism ♦♦ Frontal balding ♦♦ Cardiac conduction disturbances ♦♦ Diabetes mellitus (5%) ♦♦ Swallowing and speech disability ♦♦ Neonatal hypotonia ♦♦ Delayed motor development ♦♦ Wide phenotypic range and age of onset from severely affected infants (congenital DM1) to classically affected adults (classic DM1) to minimally symptomatic elderly individuals (mild DM1) whose symptoms may include any of those listed above

Molecular Basis of Disease ♦♦ Expansion of a trinucleotide CTG repeat in the myotonic dystrophy protein kinase (DMPK) gene −− 5–34 normal allele size −− 35–49 mutable normal (premutation) allele; not associated with disease −− >50 full penetrance allele, severity of phenotype increases as repeat size increases −− >2,000 full penetrance allele, severely affected (congenital form) −− Expansion occurs preferentially through maternal transmission

Laboratory ♦♦ Molecular analysis identifies expanded repeat in nearly 100% of cases ♦♦ Electromyogram shows slow nerve conduction velocities

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♦♦ Muscle biopsy may show marked proliferation of fibers within the central nuclei, sacroplasmic masses, and hypotrophy of type 1 muscle fibers (70%)

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Monitor for cataracts, cardiac conduction disturbances, ­diabetes, sleep apnea, hypogonadism, and other endocrine problems

Myotonic Dystrophy Type 2 (Proximal Myotonic Myopathy) Chromosome and Gene Location ♦♦ 3q13.3–q24

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ 1/8,000 (DM1 and DM2)

Essentials of Anatomic Pathology, 3rd Ed.

Laboratory ♦♦ Molecular analysis identifies expanded repeat in 99% of cases ♦♦ Electromyogram shows slow nerve conduction velocities ♦♦ Muscle biopsy may show marked proliferation of fibers within the central nuclei and type 2 fiber atrophy

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Monitor for cataracts, cardiac conduction disturbances, diabetes, and hypogonadism ♦♦ Treat with assistive devices for weakness, testosterone replacement therapy for hypogonadism in males, medications for pain management

Friedreich Ataxia Chromosome and Gene Location

Clinical Manifestations

♦♦ 9q13

♦♦ Myotonia (sustained muscle contraction), proximal weakness primarily in the thighs, facial weakness, muscle pain ♦♦ Cataracts ♦♦ Cardiac conduction disturbances ♦♦ Insulin insensitivity predisposing to hyperglycemia and diabetes mellitus ♦♦ Hypogonadism ♦♦ Onset typically occurs in the third decade of life; anticipation does not appear to be a feature of DM2

Inheritance

Molecular Basis of Disease ♦♦ Expansion of a trinucleotide CCTG repeat in intron 1 of the CNBP/ZNF9 gene −− Reported allele sizes usually include the total number of repeats in the TG TCTG, and CCTG repeat tracts all present at the DM2 locus −− Tetranucleotides (TCTG or GCTG) commonly interrupt the CCTG repeats in the normal range; however, these sequence interruptions are not found in fully expanded pathogenic alleles −− 11–26 CCTG repeats (104–176 total allele length) normal allele −− 27–74 CCTG repeats (177–372 total allele length) intermediate normal (intermediate alleles of unclear significance) allele; never been reported −− 74–11,000 CCTG repeats (372–44,000 total allele length) full penetrance allele −− CCGT repeat size typically contracts through either maternal or paternal transmission and somatic instability causes CCGT repeat sizes to increase as the affected individual ages −− Phenotype and age of onset cannot be predicted by CCGT repeat size as there is no correlation between repeat size and severity of disease

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♦♦ Autosomal recessive

Incidence ♦♦ 2/100,000–4/100,000

Clinical Manifestations ♦♦ Progressive ataxia, muscle weakness, dysarthria ♦♦ Absent deep tendon reflexes, decreased vibration and/or joint-position sense ♦♦ Optic nerve atrophy (10–25%) ♦♦ Deafness (13%) ♦♦ Scoliosis ♦♦ Hypertrophic cardiomyopathy (66%) ♦♦ Bladder dysfunction (urinary frequency and urgency) ♦♦ Hammer toes, pes cavus (foot deformity marked by high arch) ♦♦ Diabetes (30%) or glucose intolerance ♦♦ Normal intelligence ♦♦ Age of onset is approximately 10–15 years for classic Friedreich ataxia (FRDA); however, ~15% of cases are associated with delayed onset (late-onset FRDA, LOFA; and very late-onset FRDA, VLOFA) and ~12% are associated with delayed onset and intact tendon reflexes (FRDA with retained reflexes, FARR)

Molecular Basis of Disease ♦♦ Expansion of a trinucleotide GAA repeat in intron 1 of the frataxin (FXN) gene −− 5–33 normal allele −− 34–65 premutation (meiotic instability with potential to expand to full penetrance allele) allele −− 66–1,700 full penetrance allele

Human Genetic Disorders

−− Expansion occurs through both maternal and paternal transmission −− Statistically significant correlations have been observed between the size of the smaller of the two expanded alleles and age of onset, presence of leg muscle weakness, duration of wheelchair use, and presence of other clinical manifestations

Laboratory ♦♦ Molecular analysis identifies two expanded repeat sizes in 96% of cases ♦♦ Molecular analysis by sequencing and dosage analysis detects the remaining 4% of FXN mutations ♦♦ Electromyogram shows slow nerve conduction velocities

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♦♦ Late −− Inability to walk and speak −− Dysphagia −− Rigidity and dystonia −− Total dependence on others ♦♦ Juvenile Huntington disease (onset prior to age 21 years) is characterized by motor, cognitive, and psychiatric changes; however, the clinical presentation differs and is much more severe than in adults; epileptic seizures are also common

Molecular Basis of Disease

♦♦ Autosomal dominant

♦♦ Disease results from an expansion of a trinucleotide CAG repeat in the Huntington (HD) gene −− 10–26 normal allele −− 27–35 intermediate allele (meiotic instability, expansion to full penetrance allele may occur with transmission); not associated with disease −− 36–39 reduced penetrance allele (at-risk but not certain to develop symptoms of disease) −− >40 full penetrance allele −− >60 full penetrance allele is associated with juvenile onset Huntington disease −− Expansion can occur through both maternal and paternal transmission; however, large expansions are more frequently observed through paternal transmission −− Inverse correlation between number of CAG repeats and age of onset

Incidence

Laboratory

♦♦ 3/100,000–7/100,000 (Western European ancestry) ♦♦ 0.1/100,000–15/100,000 (range, all ethnicities)

♦♦ Molecular analysis identifies expanded repeat in 100% of cases ♦♦ Computed tomography, positron emission tomography, and magnetic resonance imaging identifies atrophy of the caudate nucleus and putamen

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Monitor for hypertrophic cardiomyopathy (by echocardio­ graphy and electrocardiogram), diabetes, and deafness ♦♦ Treat with assistive devices for weakness, antispasmodic agents for bladder dysfunction, and speech therapy to maximize communication

Huntington Disease Chromosome and Gene Location ♦♦ 4p16.3

Inheritance

Clinical Manifestations ♦♦ Slowly progressive fatal disorder with onset of neurologic or psychiatric changes usually in mid-life (35–44 years) ♦♦ Life expectancy is approximately 50–60 years or about 15–18 years after initial onset of disease ♦♦ Early (preclinical) −− Behavioral/mood changes and personality changes (72%) −− Depression −− Anxiety −− Delusions, hallucinations −− Abnormal eye movements ♦♦ Middle (clinical) −− Chorea (90%) −− Involuntary movements −− Difficulty with voluntary movements (slow, difficult to initiate or control, impaired reaction time, trouble with balance and walking) −− Weakness −− Dysarthria −− Cognitive decline

Treatment ♦♦ Not curable, supportive/symptomatic

Spinal Cerebellar Ataxia Chromosome and Gene Location ♦♦ Numerous loci have been identified and more than 30 subtypes have been delineated

Inheritance ♦♦ Majority are autosomal dominant, although autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms exist

Incidence ♦♦ Varies by subtype and ethnicity

Clinical Manifestations ♦♦ Adult onset gait ataxia, dysarthria, dysphagia, ophthalmoplegia, deafness ♦♦ Decreased vibrations sense and sphincter disturbances

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♦♦ Peripheral neuropathy ♦♦ Death usually occurs 10–20 years following age of onset

Molecular Basis of Disease ♦♦ Many subtypes of spinal cerebellar ataxia (SCA) result from expansion of trinucleotide CAG repeat (see Table  13.2), although some (e.g., SCA5) result from nonrepeat mutations

Laboratory ♦♦ Molecular analysis identifies expanded trinucleotide repeat in most subtypes ♦♦ Neuroimaging may be necessary to distinguish hereditary forms of ataxia from acquired forms

Treatment ♦♦ Not curable, supportive/symptomatic

Spinal and Bulbar Muscular Atrophy (Kennedy Disease) Chromosome and Gene Location

♦♦ Slowly progressive proximal muscle weakness, muscle atrophy and fasciculations with bulbar involvement, dysarthria, and dysphagia ♦♦ Androgen insensitivity (gynecomastia, reduced fertility, testicular atrophy) ♦♦ Normal life expectancy

Molecular Basis of Disease ♦♦ Expansion of trinucleotide CAG repeat in the human androgen receptor (AR) gene −− 11–34 normal allele size −− 35 unknown clinical significance −− 36–37 reduced penetrance allele (at-risk but not certain to develop symptoms of disease) −− >38 full penetrance allele, severity of phenotype increases as repeat size increases −− The larger the expansion, the earlier the age at onset of disease and the more rapid the disease progression

♦♦ Xq11–q12

Laboratory

Inheritance

♦♦ Molecular analysis identifies expanded repeat in 100% of cases

♦♦ X-linked recessive

Treatment

Incidence ♦♦ 1/50,000 males

Clinical Manifestations ♦♦ Teen to adult onset, usually in the third to fifth decade of life

♦♦ Not curable, supportive/symptomatic ♦♦ Hormone replacement as needed ♦♦ Monitor with annual strength testing and pulmonary function

NEUROMUSCULAR DISORDERS Duchenne/Becker Muscular Dystrophy Chromosome and Gene Location ♦♦ Xp21.2

Inheritance ♦♦ X-linked recessive

Incidence ♦♦ 1/3,500 (male) 1/1,500 (female carriers) −− 30% of cases are new mutations −− 5–15% of sporadic cases are result of gonadal mosaicism (mother carries a subpopulation of oocytes with the mutation)

Clinical Manifestations ♦♦ Duchenne muscular dystrophy −− Proximal muscle weakness leading to difficulties involving gait, jumping, and climbing stairs −− Positive for Gower sign (use of arms to push oneself into standing position by moving hands up one’s thighs, indicative of hip weakness)

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−− Pseudohypertrophy of the calf muscles, muscle weakness −− Rapidly progressive with loss of ability to walk before age 13 −− Dilated cardiomyopathy (100% by age 18) −− Gastrointestinal dilation −− Mental retardation (25–35%) −− Death usually occurs in the second decade ♦♦ Becker muscular dystrophy −− Milder course of muscle involvement with later-onset skeletal muscle weakness −− Slower progression −− Survival age 30-40, with dilated cardiomyopathy being the most common cause of death −− Cognitive problems are rare ♦♦ Female carriers of Duchenne/Becker muscular dystrophy (DMD or BMD) −− Muscle weakness (19% DMD carriers, 14% BMD carriers) −− Myalgia cramps (5%)

Human Genetic Disorders

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−− Left ventricle dilation (19% DMD carriers, 16% BMD carriers) −− Dilated cardiomyopathy (8% of DMD carriers only)

Molecular Basis of Disease ♦♦ Dystrophin is a protein found in the sarcolemma of normal muscle. It is thought to be involved in the anchoring of the cytoskeleton of the muscle cell to extracellular proteins ♦♦ DMD and BMD result from alterations within the dystrophin (DMD) gene ♦♦ Deletions in 60–65% of DMD and 85% of BMD −− Deletions that disrupt the reading frame of the triplet code (frameshift mutations) lead to DMD −− Deletions that do not disrupt the reading frame of the triplet code (in-frame mutations) most often lead to BMD ♦♦ Duplications in 5–10% of DMD and BMD ♦♦ Point mutations in 30–35% of DMD and 5–10% of BMD

♦♦ Genetics −− Deletions and duplications detected directly by molecular analysis −− Linkage analysis is available when deletion/duplication analysis negative

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Treatment of dilated cardiomyopathy with medication and transplantation in rare cases ♦♦ Corticosteroid therapy (prednisone) in affected individuals to improve strength and function

Spinal Muscular Atrophy, Types I–IV Chromosome and Gene Location ♦♦ 5q12.2–q13.3

Inheritance

Laboratory

♦♦ Autosomal recessive

♦♦ Pathology −− Variability in size of muscle fibers, degeneration, atrophy of individual fibers and proliferation of endomysial and perimysial connective tissue ♦♦ Antidystrophin antibodies detect −− <3% of normal dystrophin in DMD −− 3–10% in mild DMD or severe BMD −− >20% normal dystrophin correlates with BMD ♦♦ Serum creatinine phosphokinase (CK) concentration −− >5–10× the normal range (100% of affected individuals) −− 1/2 of DMD carriers and 1/3 of BMD carriers have elevated CK levels (2–10× normal) −− Caution must be used as CK levels vary with age, pregnancy, and activity

Incidence ♦♦ 1/25,000

Clinical Manifestations ♦♦ See Table 13.3

Molecular Basis of Disease ♦♦ Survival Motor Neuron (SMN1) is homozygously deleted in nearly all of type I and II and about 80% of type III Spinal Muscular Atrophy (SMA) ♦♦ 2–5% of type I SMA is caused by compound heterozygosity for an SMN1 deletion and point mutation ♦♦ The presence of three or more copies of SMN2, a gene just adjacent to SMN1, is associated with a milder SMA phenotype in individuals with two SMN1 deletions and/or point mutations

Table 13.3. Spinal Muscular Atrophy (SMA) Subtypes Type I (Werdnig–Hoffmann)

Type II (Dubowitz disease)

Type III (Kugelberg–Welander)

Onset 0–6 months

Onset after 6 months

Onset after 10 months

Reduced fetal movements General muscle weakness Low muscle tone Respiratory muscle weakness Arthrogryposis Tongue fasciculations

Mild/arrested type 1 Low muscle tone Nonambulatory Finger trembling Absence tendon reflexes Increased life span when respiratory function preserved

Ambulation feasible Waddling gait Muscle weakness Fasciculations Contractures

Type IV Onset second or third decade of life Muscle weakness Independent ambulation

Contractures Lack of motor development Absence of tendon reflexes Death often by 1 year

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Laboratory ♦♦ Molecular analysis for deletions in exon 7 and/or exon 8 of SMN1 gene; this is the primary test used to diagnose individuals with SMA ♦♦ Muscle biopsy can assess atrophy of anterior horn cells

Treatment ♦♦ Not curable, supportive/symptomatic

Charcot–Marie–Tooth Disease Chromosome and Gene Location ♦♦ Numerous loci have been identified

Inheritance ♦♦ Autosomal dominant, recessive and X-linked forms; see Table 13.4

Incidence ♦♦ 1/3,300 (The most common genetic cause of neuropathy)

Clinical Manifestations ♦♦ Progressive muscular atrophy and weakness of arms and legs (during first two decades) and later on of the feet and hands ♦♦ Pes cavus ♦♦ Central nervous system involvement includes optic and cochlear nerve ♦♦ CMT1 – Charcot–Marie–Tooth type 1 (50%) −− Demyelinating peripheral neuropathy −− Distal muscle weakness and atrophy −− Decreased nerve conduction velocities −− Absent deep tendon reflexes −− Onset 5–25 years −− Six subtypes (CMT1A–CMT1F) are distinguishable only by molecular analysis −− Autosomal dominant inheritance

♦♦ CMT2 – Charcot–Marie–Tooth type 2 (20–40%) −− Axonal (non-demyelinating) neuropathy −− Distal muscle weakness and atrophy −− Normal or slightly decreased nerve conduction velocities −− Deep tendon reflexes are preserved −− Milder phenotype than CMT1 −− 15 subtypes distinguishable by molecular analysis −− Autosomal dominant inheritance ♦♦ Autosomal dominant intermediate CMT −− Abnormal myelin and axonal neuropathy −− Decreased nerve conduction velocities ♦♦ CMT4 – Charcot–Marie–Tooth type 4 −− Demyelinating and axonal neuropathy −− Distal muscle weakness and atrophy −− Pes cavus −− Autosomal recessive inheritance ♦♦ CMTX – X-linked Charcot–Marie–Tooth (10–20%) −− Motor and sensory neuropathy in males, mental retardation, deafness, spasticity −− Five subtypes

Molecular Basis of Disease ♦♦ Multiple genes at different loci are involved. See Table 13.4. Molecular analysis is available for many subtypes. Some subtypes are clinically indistinguishable and are designated solely on molecular findings

Laboratory ♦♦ Molecular testing is available for many of the CMT subtypes. ♦♦ Electrophysiological studies and nerve biopsy may be helpful in distinguishing it from other acquired and hereditary forms of peripheral neuropathy and in establishing a diagnosis of CMT

Treatment ♦♦ Not curable, supportive/symptomatic

Table 13.4. Charcot–Marie–Tooth (CMT) Subtypes CMT1 (50%)

Disorder (% of CMT)

CMT1A (70–80%)

CMT1B (5–10%)

CMT2 (20–40%)

Gene location Gene name

17p PMP22

1q MPZ

Multiple loci Multiple genes

Multiple loci Multiple genes

Inheritance

Autosomal dominant

Autosomal dominant

Autosomal recessive

Molecular genetics

1.5 kb duplication of PMP22, point mutations in PMP22

Point mutations in MPZ

Autosomal dominant Point mutation in NFL and HSPB1

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CMT4 (rare)

Point mutations in GDAP1, EGR2, or PDX

X-linked CMT (10–20%) X GJB1 (90%), PRPS1, other unknown genes X-linked dominant point mutations in GJB1

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Hereditary Neuropathy with Liability to Pressure Palsies Chromosome and Gene Location

Molecular Basis of Disease

Incidence

♦♦ Deletion at 17p11.2 involving the peripheral myelin protein 22 (PMP22) gene (80%) or point mutations in the PMP22 gene (20%) ♦♦ Unequal crossing over between misaligned repetitive elements leads to the hereditary neuropathy with liability to pressure palsies (HNPP) deletion and the CMT1A duplication syndromes ♦♦ De novo mutations are most often paternally derived

♦♦ Unknown

Laboratory

Clinical Manifestations

♦♦ Cytogenetics using FISH or molecular genetics analysis identifies deletion at 17p11.2 involving the PMP22 gene or a point mutation ♦♦ Nerve biopsy reveals sausage shaped swellings of myelin sheath (tomacula) ♦♦ Increase in distal motor latency of the median nerve at the wrist in both symptomatic and asymptomatic individuals ♦♦ Reduced motor and sensory nerve conduction velocity

♦♦ 17p11.2

Inheritance ♦♦ Autosomal dominant

♦♦ Recurrent transient palsies (i.e., carpel tunnel syndrome and foot drop) ♦♦ Sensory dysfunction (result of compression to peripheral nerve) ♦♦ Pes cavus (20%) ♦♦ Absent ankle reflexes (50–80%) and reduced tendon reflexes (15–30%) ♦♦ Scoliosis

Treatment ♦♦ Not curable, supportive/symptomatic

SKELETAL DISORDERS Craniosynostosis Apert Syndrome Chromosome and Gene Location

Laboratory ♦♦ Molecular testing for common FGFR2 mutations is available

♦♦ 10q24 (FGFR2)

Treatment

Inheritance

♦♦ Not curable, supportive/symptomatic and surgical management ♦♦ Early surgical consultation and correction is important to reduce the risk of intracranial pressure

♦♦ Autosomal dominant, vast majority due to new mutation

Incidence ♦♦ 1/65,000–1/100,000

Clinical Manifestations ♦♦ Brachycephaly due to coronal craniosynostosis ♦♦ Hypoplasia of midface, hypertelorism ♦♦ “Mitten hand” deformity; symmetric and severe osseous or cutaneous syndactyly affecting hands and feet, broad thumbs and great toes ♦♦ Fused cervical vertebrae, typically C5–C6 ♦♦ Genitourinary anomalies in 10% ♦♦ Cardiac anomalies in 10% ♦♦ Mental retardation

Molecular Basis of Disease ♦♦ Mutation in fibroblast growth factor receptor 2 (FGFR2), tyrosine kinase receptor involved in regulation of osteogenesis ♦♦ Two common gain-of-function mutations account for >98% of cases

Crouzon Syndrome Chromosome and Gene Location ♦♦ 10q24 (FGFR2)

Inheritance ♦♦ Autosomal dominant with variable expressivity

Incidence ♦♦ 1/25,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Coronal, lamdoid, or sagittal craniosynostosis Hypoplasia of midface Hypertelorism Proptosis Beaked nose Normal intelligence

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Molecular Basis of Disease

Treatment

♦♦ Mutation in FGFR2, tyrosine kinase receptor involved in regulation of osteogenesis

♦♦ Not curable, supportive/symptomatic and surgical management ♦♦ Types II and III are typically more severe and have an increased risk for early death but early and aggressive surgical and medical treatment may increase the possibility of a positive outcome

Laboratory ♦♦ Molecular testing for FGFR2 mutations is available

Treatment ♦♦ Not curable, supportive/symptomatic and surgical management

Pfeiffer Syndrome (Types I–III) Chromosome and Gene Location

Saethre–Chotzen Syndrome Chromosome and Gene Location ♦♦ 7p21.1 (TWIST1)

Inheritance

♦♦ 8p11.2 (FGFR1) type I ♦♦ 10q24 (FGFR2) types I–III

♦♦ Autosomal dominant

Incidence

Inheritance

♦♦ 1/25,000–1/50,000

♦♦ Autosomal dominant with variable expressivity

Clinical Manifestations

Incidence

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ 1/100,000

Clinical Manifestations ♦♦ See Table 13.5

Molecular Basis of Disease ♦♦ Type I: mutation in fibroblast growth factor receptor (FGFR) 1 or 2, tyrosine kinase receptors involved in regulation of osteogenesis ♦♦ Type II or III: mutation in FGFR2, tyrosine kinase receptor involved in regulation of osteogenesis

Laboratory ♦♦ Molecular testing for FGFR1 and FGFR2 mutations are available

Brachycephaly due to coronal craniosynostosis Ptosis Maxillary hypoplasia Small ears with prominent crus Cutaneous syndactyly Normal intelligence typically, patients with microdeletions may have developmental delay

Molecular Basis of Disease ♦♦ Typically loss of function mutations in TWIST1 gene, which negatively regulates FGFR and osteogenic transcription factors

Laboratory ♦♦ Molecular testing for TWIST1 mutations is available

Table 13.5. Clinical Findings of Pfeiffer Syndrome

Type I Type II

Type III

Craniofacial

Extremities

Intellect

Other

Brachycephaly (premature synostosis of coronal and often sagittal sutures) Cloverleaf skull (premature synostosis of all but metopic and squamosal sutures), extreme proptosis Turribrachycephaly (premature synostosis of bicoronal, sagittal, and metopic sutures), extreme proptosis

Broad, medially deviated thumbs and great toes, variable syndactyly

Typically normal

Hearing loss, hydrocephalus occasionally

Broad, medially deviated thumbs and great toes, elbow ankylosis/ synostosis

Developmental delay/ mental retardation commonly

Choanal stenosis/atresia, laryngotracheal anomalies, hydrocephalus, seizures

Broad, medially deviated thumbs and great toes

Developmental delay/ mental retardation commonly

Choanal stenosis/atresia, laryngotracheal anomalies, hydrocephalus, seizures

Adapted from Robin NH, Falk MJ, Haldeman-Englert CR. (Updated [09/27/2007]). FGFR-Related Craniosynostosis Syndromes. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed [04/09/2009]

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Treatment

♦♦ >99% caused by same mutation

♦♦ Not curable, supportive/symptomatic and surgical management

Laboratory ♦♦ X-ray implicates skeletal involvement ♦♦ Molecular testing for FGFR-3 mutation is available

Achondroplasia Chromosome and Gene Location

Treatment

♦♦ 4p16.3

♦♦ Not curable, supportive/symptomatic

Inheritance

Osteogenesis Imperfecta (Types I–VII) Chromosome and Gene Location

♦♦ Autosomal dominant; 80% result from a new mutation

Incidence

♦♦ COL1A1 gene (chromosome 17q21.3) ♦♦ COL1A2 gene (chromosome 7q22.1) ♦♦ CRTAP gene (chromosome 3p22)

♦♦ 1/25,000

Clinical Manifestations ♦♦ Short stature, proximal shortening of long bones, disproportionate shortening of limbs, genu varum ♦♦ Large head, frontal bossing, hypoplasia of mid-face ♦♦ Infantile hypotonia ♦♦ Gross motor developmental delay ♦♦ Normal intelligence ♦♦ Normal life expectancy ♦♦ Also at risk for cord compression due to odontoid hypoplasia

Inheritance

Molecular Basis of Disease

♦♦ Collagen is the major protein of the white fibers of connective tissue, cartilage, and bone ♦♦ There have been numerous types of collagen identified

♦♦ Mutation in transmembrane domain of fibroblast growth factor transmembrane receptor (FGFR3)

♦♦ Autosomal dominant, often due to new mutation

Incidence ♦♦ 1/20,000–30,000

Clinical Manifestations ♦♦ See Table 13.6

Molecular Basis of Disease

Table 13.6. Clinical Findings of Osteogenesis Imperfecta Inheritance

Clinical findings

Gene

  Abnormal collagen chains

Type I

Autosomal dominant

Bone fragility, blue sclera, hearing loss

COL1A1

Pro-a1(I)

Type II

Autosomal dominant, but usually new germline mutation, 6-7% recurrence risk due to parental gonadal mosaicism

Perinatal lethal, calvarial under-mineralization, beaded ribs, compressed long bones, dark blue sclera

COL1A1 COL1A2

Pro-a1(I) Pro-a2(I)

Type III

Autosomal dominant Autosomal recessive (rarely)

Multiple prenatal bone fractures, limb shortening, limb deformities, deafness, blue sclera

COL1A1 COL1A2

Pro-a1(I) Pro-a2(I)

Type IV

Autosomal dominant

Mild short stature, mild deformity, dentinogenesis imperfecta, normal/gray sclera

COL1A1 COL1A2

Pro-a1(I) Pro-a2(I)

Type V

Autosomal dominant

Variable stature, multiple fractures, moderate bone deformities, normal sclera

Unknown

Type VI

Uncertain

Mild short stature, multiple fractures, rhizomelic shortening, normal sclera

Unknown

Type VII

Autosomal recessive

Mild short stature, multiple fractures, bone deformity, normal sclera

CRTAP

Adapted from: Steiner RD, Pepin MG, Byers PH. (Updated [01/28/2005]). Osteogenesis Imperfecta. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2009. Available at http://www.genetests.org. Accessed [04/09/2009]

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♦♦ Mutations in the procollagen genes, whose products make up the triple helix of type 1 collagen, lead to the various types of osteogenesis imperfecta ♦♦ Clinical presentation is dependent on the extent to which the mutation alters the protein product

♦♦ Direct molecular analysis of procollagen and CRTAP genes available ♦♦ Collagen testing on cultured fibroblasts available

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Surgical intervention when indicated

Laboratory ♦♦ X-ray implicates skeletal involvement

CONNECTIVE TISSUE DISORDERS Marfan Syndrome Chromosome and Gene Location

♦♦ Mitral valve prolapse, aortic dilation (Fig.  13.5C), aortic aneurysm ♦♦ Without treatment, life expectancy is reduced to about twothird normal life span. With proper management of cardiovascular manifestations, life expectancy approximates that of the general population

♦♦ FBN1, 15q

Inheritance ♦♦ Autosomal dominant ♦♦ 15–30% result from a new mutation

Molecular Basis of Disease ♦♦ Mutations in FBN1 gene for fibrillin, a structural protein, which is the major constituent of microfibrils

Incidence ♦♦ 1/10,000

Laboratory

Clinical Manifestations ♦♦ Diagnosis based on clinical criteria ♦♦ Tall, thin habitus, long extremities, (Fig. 13.5A) ♦♦ Pectus deformity (Fig. 13.5B), scoliosis ♦♦ Ectopia lentis, retinal detachment

arachnodactyly

♦♦ Molecular linkage analysis to 15q for familial cases is available ♦♦ Direct molecular analysis is available for FBN1

Treatment ♦♦ Surgical intervention when indicated

Fig. 13.5. Marfan syndrome – arachnodactyly, wrist sign (A). Pectus deformity and striae on shoulders (B). Intraoperative view of dilated aortic root (C).

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♦♦ Close monitoring of heart defects as they can lead to sudden death ♦♦ Use of beta adrenergic blockade ♦♦ Clinical trials underway to assess the potential benefits of angiotensin II receptor antagonist drugs (Losartan) on slowing aneurysm progression

Loeys–Dietz Syndrome Chromosome and Gene Location ♦♦ TGFBR1, 9q22, and TGFBR2, 3p22

Inheritance

13-21

Thoracic Aortic Aneurysm and Dissection Chromosome and Gene Location ♦♦ Four genes and two loci have been associated with thoracic aortic aneurysm and dissection (TAAD) −− TGFBR2 on 3p22 −− TGFBR1 on 9q33–q34 −− MYH11 on 16p13.13–p13, 12 −− ACTA2 on 10q22–q24 −− TAAD1 locus on 5q13–q14 (causative gene unknown) −− FAA1 locus on 11q23.3–q24 (causative gene unknown)

♦♦ Autosomal dominant ♦♦ ~75% result from new mutation

Inheritance

Incidence

Incidence

♦♦ Unknown, no apparent enrichment in any ethnic group

♦♦ Aortic aneurysms account for approximately 1–2% of deaths in industrialized society ♦♦ It is estimated that 20% of TAAD results from a genetic predisposition

Clinical Manifestations ♦♦ Minimal clinical diagnostic criteria not established ♦♦ Two clinical phenotypes described. LDS type I has vascular, skeletal, and craniofacial findings. LDS type II has vascular, skeletal, and cutaneous findings ♦♦ Dilatation or dissection of the aorta. Aortic dilatation present in >95% of probands. Arterial aneurysms tend to be more aggressive and dissect at smaller aortic dimensions than in Marfan syndrome ♦♦ Other arterial aneurysms and tortuosity throughout the arterial tree ♦♦ Pectus excavatum or pectus carinatum, scoliosis ♦♦ Joint laxity ♦♦ Arachnodactyly ♦♦ Talipes equinovarus ♦♦ Ocular hypertelorism, bifid uvula/cleft palate, and craniosynostosis (most commonly sagittal, but also coronal and metopic) in LDS type I ♦♦ Translucent skin, easy bruising, and dystrophic scars in LDS type II

Molecular Basis of Disease ♦♦ Mutations in genes coding for transforming growth factor beta receptors 1 and 2, which regulate a variety of cellular processes, including proliferation, differentiation, cell cycle arrest, apoptosis, and formation of the extracellular matrix

Laboratory ♦♦ Direct mutation analysis for TGFBR1 and TGFBR2 is available

Treatment ♦♦ Echocardiography at frequent intervals to monitor ascending aorta, MRA, or CT as indicated ♦♦ Early and aggressive surgical intervention ♦♦ Use of beta adrenergic blockade

♦♦ Autosomal dominant

Clinical Manifestations ♦♦ Major diagnostic criteria for TAAD are the following ♦♦ Presence of dilatation and/or dissection of the ascending thoracic aorta or dissection of the descending aorta just distal to the origin of the subclavian artery ♦♦ Exclusion of Marfan syndrome, Loeys–Dietz syndrome, and other connective tissue abnormalities ♦♦ Other occasional manifestations include inguinal hernia, scoliosis, aneurysms in other portions of the aorta, cerebral aneurysms, livedo reticularis (ACTA2), iris floculli (ACTA2), bicuspid aortic valve (ACTA2), and patent ductus arteriosus (MYH11)

Molecular Basis of Disease ♦♦ TGFBR1 and TGFBR2 regulate a variety of cellular processes, including proliferation, differentiation, cell cycle arrest, apoptosis, and formation of the extracellular matrix. Mutations in TAAD families are most often found in the kinase domain of these proteins, though rarely other mutations have been reported ♦♦ MYH11 is the smooth muscle heavy chain. Smooth muscle myosin is the major contractile protein of smooth muscle and is composed of a MYH11 dimer and two pairs of nonidentical light chains ♦♦ ACTA2 is the smooth muscle cell alpha-actin, a major contractile protein in smooth muscle cells

Laboratory ♦♦ Direct mutation analysis available for TGFBR1, TGFBR2, MYH11, and ACTA2

Treatment ♦♦ Echocardiography to monitor aortic root, consider imaging entire aorta and other vasculature

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♦♦ Prophylactic surgical repair of the aorta (timing depends on rate of progression, causative gene, other) ♦♦ Medications that reduce hemodynamic stress, such as beta andrenergic blockade ♦♦ Aggressive treatment of hypertension ♦♦ Assessment and standard treatment for hernias and scoliosis

Molecular Basis of Disease

Ehlers–Danlos Syndrome Chromosome and Gene Location

Laboratory

♦♦ Classic type: COL5A1, 9q34 and COL5A2, 2q31 ♦♦ Vascular type: COL3A1, 2q31 ♦♦ Others −− Hypermobility type: causative gene is mostly unknown; some cases of TNXB mutations (6p21) −− Kyphoscoliotic type: PLOD1, 1p36 −− Arthrochalasia type: COL1A1, 17q21–q22 and COL1A2, 7q22

Inheritance ♦♦ Most autosomal dominant ♦♦ Kyphoscoliotic form is autosomal recessive ♦♦ Mutations in TNXB can be inherited in an autosomal dominant or autosomal recessive manner

Incidence ♦♦ Classic type: estimated 1/20,000 ♦♦ Vascular type: estimated 1/250,000

Clinical Manifestations ♦♦ Classic type −− Skin hyperextensibility −− Smooth, velvety skin −− Widened atrophic scarring −− Abnormal, delayed wound healing −− Joint hypermobility −− Joint dislocations −− Easy bruising −− Generalized tissue fragility −− Less commonly, mitral and tricuspid valve prolapse, aortic root dilatation, spontaneous rupture of large arteries ♦♦ Vascular type −− Thin, translucent skin −− Characteristic facial appearance (thin nose and lips, ­emaciated face with prominent cheekbones, eyes appear sunken or bulging, often with coloring around them and thin telangiectasia on the eyelids) −− Easy bruising −− Arterial, intestinal, and/or uterine fragility −− Vascular rupture or dissection −− GI perforation −− Organ rupture

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♦♦ Collagen is the major protein of the white fibers of connective tissue, cartilage, and bone ♦♦ Mutations in collagen genes lead to decreased synthesis, altered secretion, and instability of collagen ♦♦ The defect for some types is unknown

♦♦ Protein analysis is available for some subtypes ♦♦ Histological features are nondiagnostic ♦♦ Direct molecular analysis is available for COL5A1, COL5A2, COL3A1, PLOD1, COL1A1, and COL1A2

Treatment ♦♦ Not curable, supportive/symptomatic

Stickler Syndrome Chromosome and Gene Location ♦♦ COL2A1, 12q13, COL11A1, 1p21, and COL11A 2, 6p21.3

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ Unknown

Clinical Manifestations ♦♦ Progressive myopia, retinal detachment, blindness ♦♦ Pierre Robin syndrome (micrognathia and abnormal smallness of the tongue, often with cleft palate) ♦♦ Severe myopia, congenital glaucoma, and retinal detachment, cataracts ♦♦ Premature degenerative changes in various joints with abnormal epiphyseal development ♦♦ Mitral valve prolapse

Molecular Basis of Disease ♦♦ The COL2A1 gene encodes the chains of type II collagen, a major structural component of cartilaginous tissues ♦♦ The COL11A1 gene encodes the alpha 1 chain of type XI collagen, thought to play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils ♦♦ The COL11A2 gene encodes the alpha 2 chain of type XI collagen expressed in cartilage but not in adult liver, skin, tendon, or vitreous

Laboratory ♦♦ Skeletal X-rays show changes of a skeletal dysplasia ♦♦ Direct molecular analysis available for COL2A1, COL11A1, and COL11A2

Treatment ♦♦ Not curable, supportive/symptomatic

Human Genetic Disorders

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Alport Syndrome Chromosome and Gene Location

Molecular Basis of Disease

♦♦ Xq22.3 (collagen alpha 5(IV) chain), 2q36–q37 (collagen alpha 3(IV) and 4(IV) chains)

Inheritance ♦♦ X-linked (80%) ♦♦ Autosomal recessive (15%) ♦♦ Autosomal dominant (5%)

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Incidence ♦♦ Unknown

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Mutations in the type IV collagen genes result in abnormalities in expression of the collagen chains and absent or defective structure and function in the collagen networks of the basement membranes ♦♦ Molecular testing on clinical basis

Renal failure Sensorineural deafness Lenticonus Macular changes

Microscopic hematuria Urinary red cell casts Proteinuria Leukocyturia Abnormal glomerular basement membrane on electron microscopy

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Kidney transplant as indicated

HEMATOLOGIC DISORDERS Alpha Thalassemia ♦♦ The normal adult hemoglobin is a tetramer of 2 alpha and 2 beta globin chains, the alpha thalassemias are a group of inherited conditions characterized by decreased synthesis of alpha globin chains resulting in an imbalance of globin chains for the formation of the hemoglobin (Hb) tetramer

Chromosome and Gene Location ♦♦ 16p13.1–pter (there are two alpha globin genes present on each chromosome at this locus)

Inheritance ♦♦ Complex: individuals with alpha thalassemia may have alterations in two, three, or four alpha globin genes

Incidence ♦♦ Varies by population, most common in African American, Southeast Asian, Mediterranean, and Indian populations ♦♦ Severe forms occur predominantly in Asians

Clinical Manifestations ♦♦ An individual with one altered alpha gene is a silent carrier and does not have any clinical symptoms (a+-thalassemia) ♦♦ Individuals with two altered alpha globin genes on the same chromosome (in cis), have alpha-thalassemia trait (a0-thalassemia), which is manifested by minimal anemia with microcytosis ♦♦ Hemoglobin H (HbH) disease results when three alpha globin genes are altered. HbH is a tetramer of four beta chains and is unstable. Thus, HbH disease is a form of hemolytic anemia. This is characterized by moderate ­anemia,

enlarged liver and spleen, and erythroid hyperplasia in the bone marrow ♦♦ Bart hydrops fetalis results when all four alpha globin genes are not functional. Hb Bart is a tetramer of four gamma chains. The oxygen affinity of hemoglobin Bart is so high that it cannot release oxygen to the tissues. Onset is in the fetal period and includes severe hypochromic anemia, extramedullary erythropoiesis, generalized edema, pleural and pericardial effusions, hepatosplenomagaly, and hydrocephalus. This condition is not compatible with life; death occurs from anoxia in utero

Molecular Basis of Disease ♦♦ Alpha thalassemia results from mutations in the HBA1 gene and HBA2 that encode a1-globin and a2-globin, respectively. Mutations result in reduced production of the a-globin chains. The clinical severity is determined by the degree of a-globin chain deficiency relative to B-globin production. Numerous mutations have been found ♦♦ The most common types of mutations are deletions of one or both alpha globin genes, which results from the misalignment and subsequent recombination of the alpha globin genes

Laboratory ♦♦ Red blood cell morphology reveals microcytic anemia in HbH and a-thalassemia trait. Silent carriers generally have normal red blood cell indices. Hb Bart syndrome shows macrocytic red blood cells ♦♦ Peripheral blood smear demonstrates hypochromic red cells and anisopiokilocytosis in Hb Bart syndrome. In HbH ­disease, microcytosis, hypochromia, anisocytosis, poikilocytosis are

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apparent. Carriers have morphologic changes that are less severe than affected individuals, and may also show reduced MCV and MCH ♦♦ Inclusion bodies can be shown in HbH disease using supravital stain, carriers and those with alpha thalassemia trait can also show small amounts of inclusions ♦♦ Hemoglobin analysis (electrophoresis, HPLC, isoelectric focusing) detects the presence of HbH (four B-globin chains) in adults, and Hb Bart (four g-globin chains) in infants ♦♦ Molecular genetic analysis is available

Treatment ♦♦ Hemolytic or aplastic crisis caused by HbH disease can be treated with red blood cell transfusions ♦♦ Splenectomy may be performed in cases of massive splenomegaly ♦♦ Iron chelation therapy is used if chronic blood transfusions are necessary ♦♦ Surveillance includes hematologic evaluation and growth and development assessment. Iron overload should be monitored in individuals requiring transfusions ♦♦ No treatment is available for Hb Bart hydrops fetalis

Beta Thalassemia Chromosome and Gene Location ♦♦ 11p15.5

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Most commonly found in Mediterranean and Southeast Asian populations but also in Middle Eastern and Africans, and African Americans

Clinical Manifestations ♦♦ The clinical presentation and classification of Beta thalassemia is dependant on the extent to which beta chain production is decreased and the resulting imbalance of globin alpha chain to non-globin alpha chain ♦♦ Beta thalassemia becomes clinically evident as the fetal hemoglobin production decreases and adult hemoglobin is supposed to replace it (around 6 months of age) ♦♦ Beta thalassemia major (results from the homozygous or compound heterozygous state of alleles resulting in severe disturbances of beta chain production) −− Onset between 6 and 24 months −− Characterized by microcytic anemia, failure to thrive, fever, diarrhea, liver and spleen enlargement, progressive pale color −− Complications from iron overload include growth retardation, failure of sexual maturation, dilated cardiomyopathy, pericarditis, liver fibrosis and cirrhosis, diabetes, parathyroid, thyroid, and pituitary insufficiency

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−− Death often occurs in second or third decade due to cardiac complications −− Untreated individuals exhibit severe failure to thrive, jaundice, increased skin pigmentation, liver and spleen enlargement, poor musculature, chipmunk face, skeletal deformities, stunted growth, and have a shortened life expectancy ♦♦ Beta thalassemia intermedia has milder phenotype and results from homozygosity or compound heterozygosity of alleles with a reduced beta chain production (may result from coinheritance of alpha and beta thalassemia) −− Variable presentation includes milder anemia, liver and spleen enlargement, moderate skeletal features, pallor, jaundice, cholelithiasis, osteopenia and osteoporosis, extramedullary erythropoietic masses −− Increased risk for iron overload due to increased absorption of iron in the intestine −− Transfusions on an as needed basis ♦♦ Beta thalassemia minor or thalassemia trait refers to the heterozygous carrier state. Carriers generally do not exhibit clinical symptoms other than possible mild anemia

Molecular Basis of Disease ♦♦ Beta thalassemia results from mutations in the HBB gene, which encodes for the hemoglobin subunit beta ♦♦ The clinical presentation of beta thalassemia is dependant on the extent to which the genetic alteration disrupts beta chain production (ranging from complete absence of production to silent/mild production disturbances) and the subsequent imbalance in the alpha to non-alpha globin chain ratio ♦♦ Normally, both alpha and beta globin chains are produced in roughly equal amounts. When beta globin synthesis is decreased, alpha globin synthesis increases. Free alpha chains are very unstable and precipitate in the red cell. Erythropoiesis is ineffective and results in anemia. Subsequently, there is a phenomenal increase in erythropoiesis with ­marrow expansion and persistence of erythropoiesis in the liver and spleen ♦♦ More than 200 genetic alterations have been described including −− Nucleotide substitutions −− Deletions −− Transcriptional mutations −− RNA processing mutations ♦♦ Molecular analysis may be helpful in determining clinical phenotype and identifying at risk relatives

Laboratory ♦♦ Red blood cell indices reveal microcytic anemia ♦♦ Peripheral blood smear shows nucleated red blood cells, microcytosis, hypochromia, anisocytosis, poikilocytosis −− Carriers have reduced MCV, MCH, and RBC morphology less severe than affected individuals. Nucleated red blood cells are generally not seen in carriers

Human Genetic Disorders

♦♦ Elevated iron ♦♦ Hyperplastic marrow with hyperplasia of red cell precursors ♦♦ Hemoglobin analysis shows reduced amounts of hemoglobin A and increases in minor hemoglobins ♦♦ Molecular analysis is available on a clinical basis

Treatment ♦♦ Thalassemia major −− Regular transfusions to correct anemia, suppress erythropoiesis, and inhibit gastrointestinal absorption of iron −− Iron chelation to prevent iron overload −− Bone marrow transplantation from HLA identical sib or cord blood transplantation from related donor −− Ongoing surveillance is necessary to monitor effectiveness of transfusion and chelation therapy (a) Regular physical exams including growth and development assessment (b) Liver function tests, serum ferritin (c) Ophthalmologic, audiologic, and cardiac exams (d) Endocrine function and liver ultrasound (e) In adults, bone densitometry, serum AFP, and gallbladder echography are also assessed ♦♦ Thalassemia intermedia −− Symptomatic therapy −− Splenectomy −− Folic acid supplementation −− Sporadic red cell transfusions −− Radiotherapy, transfusions, hydroxyurea for treatment of extramedullary erythropoietic masses −− Chelation therapy if iron overload develops

Sickle Cell Anemia Chromosome and Gene Location ♦♦ 11p15.5

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/500 African American births

Clinical Manifestations ♦♦ Severe anemia ♦♦ Painful swelling and crisis due to vasoocclusive episodes usually affecting the limbs, back, abdomen, and chest ♦♦ Pneumococcal sepsis ♦♦ Leg ulcerations ♦♦ Enlarged spleen ♦♦ Pallor ♦♦ Acute chest syndrome (presence of infiltrate on chest radiograph, may include lower respiratory tract symptoms, fever, and hypoxemia)

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♦♦ Autosplenectomy (reduction in spleen size as a result of continual stasis and infarctions from trapping of abnormal red blood cells) ♦♦ Chronic organ damage (renal, hepatic, retinopathy) ♦♦ Delayed growth and sexual development ♦♦ Repeated infections

Molecular Basis of Disease ♦♦ Sickle cell disease most commonly results from inheritance of a glutamic acid to valine substitution in the HBB gene encoding the hemoglobin subunit beta ♦♦ This mutation leads to the formation of hemoglobin S (Hb S), which alters the configuration of the hemoglobin molecule and causes the cells to sickle and obstruct blood flow in small vessels leading to ischemia of tissues and organs. Variable degrees of hemolysis also occur ♦♦ When inherited in a homozygous fashion, the condition is referred to as homozygous sickle cell disease or Hb SS ♦♦ Other forms of sickle cell disease result from inheritance of one Hb S allele along with another abnormal beta chain variant

Laboratory ♦♦ Significant quantities of Hb S are identified by HPLC, isoelectric focusing, or electrophoresis ♦♦ Sickling and reduced oxygen tension of red cells and nucleated red blood cells are apparent in peripheral blood smear ♦♦ There is also an increase in neutrophils and platelets ♦♦ All 50 of the United States provide newborn screening for sickle cell disease ♦♦ Direct molecular testing for nucleotide substitution is clinically available and can be used for confirmatory testing, carrier testing for at risk relatives, and prenatal diagnosis

Treatment ♦♦ Vasoocclusive pain is treated with oral hydration and analgesics ♦♦ Transfusion is used during splenic or hepatic sequestration crises ♦♦ Acute chest syndrome is treated with oxygen, spirometry, analgesics, antibiotics, and transfusions ♦♦ Pulmonary hypertension is treated with transfusions, oxygen, hydroxyurea, and hypertension – specific investigational agents ♦♦ Preventative measures include hydration, prophylactic antibiotics, and immunizations ♦♦ Stem cell transplantation has been used on a limited basis ♦♦ A number of investigative therapies including gene therapy, nitric oxide (and its precursor l-arginine), therapies that increase the percentage of fetal hemoglobin, and therapies involved in transport systems are being studied ♦♦ Regular surveillance is necessary to assess development, early detection, and treatment of organ damage, risk of stroke, cardiac, and pulmonary manifestations

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Hemophilia A Chromosome and Gene Location ♦♦ Xq28

Inheritance ♦♦ X-linked recessive

Incidence ♦♦ 1 in 10,000 live male births, among all ethnic populations ♦♦ About 30% of cases result from new mutations occurring in families in whom there is no apparent family history of hemophilia A (HA)

Clinical Manifestations ♦♦ HA predominantly affects males ♦♦ Bleeding is main manifestation, occurs spontaneously in severe hemophilia, but only after major trauma or surgery in mild to moderate hemophilia ♦♦ Some female carriers have reduced FVIII levels and may have clinically significant bleeding. For example, lyonization of the normal X chromosome, Turner syndrome (XO karyotype)

Molecular Basis of Disease ♦♦ Reported deleterious mutations and polymorphisms are cataloged in an International database available on the Internet and updated periodically: (http://www.europium.csc.mrc.ac. uk/usr/WWW/WebPages/main.dir/main.htm) ♦♦ The most common deleterious mutation is an inversion within Intron 22 found in approximately 40% of severe HA patients ♦♦ An additional inversion of exon 1 of the FVIII gene affecting up to 5% of patients with severe HA has also been described ♦♦ Deletions are common and account for about 5% of characterized mutations ♦♦ The remaining patients typically have single base pair changes (resulting in missense, frameshift splice junction mutations), insertions, or duplications spread throughout the factor VIII gene ♦♦ X-autosome translocation involving a breakpoint within the factor VIII gene, and uniparental isodisomy have been implicated

Laboratory ♦♦ The diagnosis of HA in males is established by assaying plasma FVIII coagulant activity (FVIII:C) for reduced or absent activity ♦♦ Classification (based on FVIII:C) −− Severe FVIII:C <1% −− Moderate FVIII:C 1–5% −− Mild FVIII:C >5–40% −− Estimated prevalence of severe, moderate, and mild are 43, 26, and 31%, respectively

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♦♦ For carrier testing of at risk females, initially performing FVIII:C is reasonable, if it is reduced, carrier status is established; however, in the large majority of carriers FVIII:C is normal, thus carrier status is established by genetic testing ♦♦ Other laboratory findings include normal prothrombin time (PT), variably prolonged activated partial thromboplastin time (APTT), normal von Willebrand factor (VWF) levels

Treatment ♦♦ Plasma derived or recombinant FVIII concentrate is infused intravenously for prevention or treatment of bleeding episodes ♦♦ Current standard practice for severe hemophilia is to provide prophylactic clotting factor concentrate two to three times a week from childhood, so these patients currently lead relatively normal lives ♦♦ Patients with large deletions, nonsense mutations, and ­inversion mutations are susceptible to formation of FVIII inhibitor (antibodies) in response to therapy with FVIII concentrates

Hemophilia B Chromosome and Gene Location ♦♦ Long arm of X chromosome (Xq27.1)

Inheritance ♦♦ X-linked recessive

Incidence ♦♦ Approximately 1 in 30,000 live male births across all ethnic groups ♦♦ Up to 30% of hemophilia B (HB) cases occur in families with no prior family history of HB

Clinical Manifestations ♦♦ HB is a bleeding disorder due to a deficiency in factor IX (FIX) and is clinically indistinguishable from HA ♦♦ HB predominantly affects males ♦♦ Bleeding is main manifestation, occurs spontaneously in severe hemophilia, but only after major trauma or surgery in mild to moderate hemophilia ♦♦ Some female carriers have reduced FIX levels and may have clinically significant bleeding, e.g., lyonization of the normal X chromosome, Turner syndrome (XO karyotype)

Molecular Basis of Disease ♦♦ Reported deleterious mutations and polymorphisms are cataloged in an International database available on the Internet and updated periodically: (http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html) ♦♦ The majority of the mutations are missense, frameshift, or nonsense mutations. Short deletions (<30 nucleotides) account for ~7%, larger deletions ~3%, and insertions ~2% of mutations

Human Genetic Disorders

♦♦ Mutations have been detected in all regions including the poly(A) signal ♦♦ An unusual FIX variant, due to mutation at Ala-10, is characterized by normal baseline FIX activity. However, warfarin therapy results in a severe and disproportionate reduction in FIX activity (typically <1%) and causes bleeding in patients being treated with warfarin who have an apparently therapeutic International Normalized Ratio (INR). An indication of such a situation is a disproportionate prolongation of the APTT, which should prompt clotting factor assays

13-27

♦♦ ♦♦ ♦♦ ♦♦

Laboratory ♦♦ The diagnosis of HB in males is established by assaying plasma FIX coagulant activity (FIX:C) for reduced or absent activity ♦♦ Classification (based on FIX:C) −− Severe FIX:C <1% −− Moderate FIX:C 1–5% −− Mild FIX:C >5–40% ♦♦ For carrier testing of at risk females, initially performing FIX:C is reasonable, if it is reduced, carrier status is established; however, in the large majority of carriers FIX:C is normal thus carrier status is established by genetic testing ♦♦ Other laboratory findings include normal PT, variably prolonged APTT, normal VWF levels

Treatment ♦♦ Plasma derived or recombinant FIX concentrate is infused intravenously for prevention or treatment of bleeding episodes ♦♦ Current standard practice for severe hemophilia is to provide prophylactic clotting factor concentrate two to three times a week from childhood, so these patients currently need relatively normal lives ♦♦ Patients with large deletions are susceptible to formation of FIX inhibitors (antibodies) in response to therapy with FIX concentrates and may experience anaphylactic reactions in response to factor IX concentrate infusions

von Willebrand Disease Chromosome and Gene Location ♦♦ 12p ♦♦ A pseudogene is located on chromosome 22q11.2

Inheritance ♦♦ Autosomal dominant and autosomal recessive

Incidence ♦♦ von Willebrand disease (VWD) is the most commonly ­recognized congenital bleeding disorder, with a prevalence varying from 0.82 to 2%

Clinical Manifestations ♦♦ Diagnosis is established based on a personal and family history of abnormal clinical bleeding and reduced plasma VWF

♦♦

antigen levels and/or functional activity (ristocetin cofactor activity), and analysis of distribution of the VWF multimers VWD is classified into quantitative (types 1 and 3) or qualitative (type 2) abnormalities of plasma VWF Quantitative abnormalities include a mild reduction of qualitatively normal VWF (type 1) or absent VWF (type 3) Qualitative abnormalities (type 2 VWD) types 2A, B, M, and N VWD Mild reductions in VWF do not typically resulted in spontaneous bleeding; however, patient will bleed after trauma or surgery Type 3 VWD patients have a severe reduction in a VWF ­levels, thus may bleed spontaneously

Molecular Basis of Disease ♦♦ Reported deleterious mutations and polymorphisms are cataloged in an International database available on the Internet and updated periodically: http://www.sheffield.ac.uk/VWF/ ♦♦ Type 1 VWD −− Autosomal dominant with variable penetrance −− In the large majority of patients, mutations are not found, implying locus heterogeneity as an explanation for the mild quantitative deficiency of VWF associated with type 1 VWD e.g., defects in glycosylation of the VWF protein −− However, selected patients with type 1 VWD had missense mutations spread throughout VWF gene ♦♦ Type 3 VWD −− Autosomal recessive −− Deleterious mutations currently characterized include frameshifts, deletions, or nonsense mutations −− Although most patients are typically compound heterozygous for such VWF mutations, homozygosity has been demonstrated in a few consanguineous families ♦♦ Type 2A VWD −− Autosomal dominant, accounts for ~75% of all type 2 VWD −− Missense mutations resulting in type 2A VWD occur predominantly in the A2 domain ♦♦ Type 2B VWD −− Autosomal dominant, accounts ~20% of all type 2 VWD −− This variant is distinguished from type 2A VWD by the presence of mild to moderate thrombocytopenia in type 2B −− Causative missense mutations are found in the A domain and result in a dominant gain-of-function phenotype ♦♦ Type 2M VWD −− Mutations in A1 domain can result in decreased binding affinity for platelet GPIb ♦♦ Type 2N (Normandy) VWD −− Mutations in the FVIII binding domain of VWF result in suboptimal binding of FVIII to VWF. This binding defect

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−−

−− −−

−−

Essentials of Anatomic Pathology, 3rd Ed.

results in a shorter half life of plasma FVIII and thus plasma FVIII activity is reduced This subtype mimics mild HA; however, it is distinguished by its autosomal recessive pattern of inheritance rather than the X-linked recessive pattern of HA Three VWF gene mutations Thr791Met, Arg816Trp, and Arg854Gln accounted for 96% of type 2N patients Type 2N VWD should be considered in patients with a diagnosis of “mild HA” with a non-X-linked inheritance Typically, heterozygotes have normal FVIII levels and homozygotes have reduced FVIII activity. However, apparent heterozygotes with low FVIII levels typically have inherited a second allele resulting in VWD type 1 (compound heterozygotes)

Laboratory ♦♦ See Table 13.7 −− Currently, the most significant impact on clinical management and genetic counseling is the differentiation of VWD type 2N and mild HA. Both have a mild to moderate reduction in FVIII and normal levels of VWF antigen and ristocetin cofactor activity. The autosomal inheritance pattern and the need for use of VWF concentrates rather than pure FVIII concentrates make this an important distinction −− Differentiation of VWD types 2 A and B provides useful information that would alter clinical management. Although patients with type 2B are characterized by the presence of variable degrees of thrombocytopenia, such a clear ­distinction is not always possible. The importance of such a distinction affects management given that the therapeutic use of vasopressin (DDAVP) is contraindicated in patients with type 2B given the potential for worsening the thrombocytopenia

Treatment ♦♦ Intravenous infusion of plasma-derived VWF concentrate is used for prevention and treatment of bleeding ♦♦ Occasionally, patients with type 1 VWD are treated with intravenous infusion of desmopressin (DDAVP) if they have had a documented response at a DDAVP trial

Factor V Leiden Chromosome and Gene Location ♦♦ 1q21–25

Inheritance ♦♦ Autosomal dominant with variable penetrance

Incidence ♦♦ Factor V Leiden is a considered to be a founder mutation ♦♦ Prevalence of the mutation varies with ethnic population and ranges from 2% in southern Europe to 15% in southern Sweden ♦♦ In US approximately 3–7% of asymptomatic white populations of northern European or Scandinavian ancestry are heterozygous carriers ♦♦ Prevalence varies from 1.2% in African Americans, 2.2% in Hispanics, 1.2% in Native Americans, and 0.45% in Asian Americans

Clinical Manifestations ♦♦ Large majority of patients are asymptomatic ♦♦ Patients may develop venous thromboembolism or pregnancy related complications ♦♦ The large majority of asymptomatic carriers may never develop any clinical manifestations attributable to the presence of factor V Leiden mutation

Table 13.7. Typical laboratory Values in von Willebrand Disease VWD Subtype

VWF: RCO

VWF: Ag

FVIII:C

VWF: CBA

VWF: FVIIIB

Plt count

LD RIPA

Multimers

↓

↓

↓/N

↓/N

N

N

Absent

Decreased production of all multimeric forms

2A

↓

↓

↓/N

↓

N

N

Absent

↓ HMWH

2B

↓

↓

↓/N

↓

N

↓

Present

↓ HMWH

2M

↓

N/↓

N

↓

N

N

Absent

Normal

2N

N

N

↓

↓

↓

N

Absent

Normal

Type 3

↓↓↓/Absent

↓↓↓/Absent

↓↓↓

↓↓↓

N

Absent

Absent

Type 1 Type 2

VWD von Willebrand disease, VWF von Willebrand factor, RCO ristocetin cofactor, Ag antigen, FVIII:C factor VIII coagulant activity, VWF:CBA VWF collagen binding assay, VWF:FVIIIB VWF FVIII binding assay, LD RIPA low dose ristocetin induced platelet aggregation (0.5 mg/dL), HMWM high molecular weight multimers, N normal, Plt platelet, ↓ decreased, ↓↓↓ markedly decreased

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Human Genetic Disorders

♦♦ Selective patients may develop clinical manifestations of venous thromboembolism, especially when exposed to other acquired risk factors for venous thrombosis ♦♦ The incidence of recurrent venous thromboembolism attributable to heterozygous factor V Leiden mutation is debated; however, homozygotes are higher risk for recurrent venous thromboembolism

Molecular Basis of Disease ♦♦ The Factor V Leiden mutation encodes for a single ­nucleotide substitution 1,691G > A within exon 10 of the factor V gene. This results in a missense mutation of a glutamine (Q) for arginine (R) at amino acid position 506 (506R > Q)

Laboratory ♦♦ Laboratory testing is used to evaluate for inherited risk factors for patients with venous thromboembolism (deep vein thrombosis and pulmonary embolism), recurrent fetal loss, and complications of pregnancy ♦♦ Initial screening test consists of a clot-based functional assay to detect activated protein C resistance (APC-R) ♦♦ If patient plasma is found to be resistant to activated protein C, reflexive molecular testing for the factor V Leiden mutation could be performed to determine genotype ♦♦ Alternatively, direct DNA-based testing could be considered

Treatment ♦♦ Carriers of the factor V Leiden mutation who have not had any venous thromboembolism are counseled regarding risks of venous thrombosis, and empiric anticoagulation is not indicated ♦♦ Heterozygous carriers of the factor V Leiden who have had venous thrombosis typically are treated with anticoagulants for 3–6 months ♦♦ Homozygous carriers of the factor V Leiden mutation who have had venous thrombosis are typically treated with longterm anticoagulation ♦♦ Patients who experience pregnancy-related complica­ tions attributable to the presence of the factor V Leiden ­typically receive heparin anticoagulation during subsequent pregnancies

Prothrombin 20210G>A Mutation Chromosome and Gene Location ♦♦ Chromosome 11p

Inheritance ♦♦ Autosomal dominant with variable penetrance

Incidence ♦♦ Overall prevalence in Europe is approximately 2%, (1.7% in northern Europe to 3.0% in southern Europe) ♦♦ Prevalence among US Caucasians is 1–2%

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♦♦ The prothrombin 20210G > A mutation is uncommon among African Americans, Asian Americans, and Native Americans

Clinical Manifestations ♦♦ Large majority of patients are asymptomatic ♦♦ Patients may develop venous thromboembolism or pregnancyrelated complications ♦♦ Young women on estrogen-based oral contraceptives who carried the prothrombin G20210A mutation are at higher risk for cerebral venous sinus thrombosis ♦♦ The large majority of asymptomatic carriers may never develop any clinical manifestations attributable to the presence of prothrombin 20210G > A ♦♦ Selective patients may develop clinical manifestations of venous thromboembolism, especially when exposed to other acquired risk factors for venous thrombosis ♦♦ The incidence of recurrent venous thromboembolism attributable to heterozygous prothrombin 20210G > A mutation is debated; however, homozygotes are at higher risk for recurrent venous thromboembolism

Molecular Basis of Disease ♦♦ Prothrombin 20210G>A Mutation is a common mutation in the gene encoding prothrombin (FII gene) ♦♦ The prothrombin 20210G > A mutation is located at 3¢-untranslated region ♦♦ Presence of this mutation increases recognition of the polyadenylation cleavage signal, 3¢ end RNA processing, and mRNA accumulation, thus increasing protein synthesis

Laboratory ♦♦ Direct DNA-based testing for the specific mutation is required for diagnosis ♦♦ Testing allows evaluation of inherited risk factors for patients with venous thromboembolism (deep vein thrombosis and pulmonary embolism), recurrent fetal loss, and complications of pregnancy

Treatment ♦♦ Carriers of the PT20210A mutation who have not had any venous thromboembolism are counseled regarding risks of venous thrombosis, and empiric anticoagulation is not indicated ♦♦ Heterozygous carriers of the PT20210A who have had venous thrombosis typically are treated with anticoagulants for 3–6 months ♦♦ Homozygous carriers of the PT20210A mutation who have had venous thrombosis are typically treated with long-term anticoagulation ♦♦ Patients who experience pregnancy-related complications attributable to the presence of the PT20210A typically receive heparin anticoagulation during subsequent pregnancies

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OTHER GENETIC DISORDERS Cystic Fibrosis Chromosome and Gene Location ♦♦ 7q31.2

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/2,500 in the Caucasian population, lower in other ethnic groups

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦

Chronic pulmonary disease (inflammation and infection) Pancreatic insufficiency, failure to thrive Hepatobilliary disease Male infertility due to congenital absence of the vas deferens (CAVD) ♦♦ Meconium ileus in neonate (15–20%) ♦♦ Median survival age for classic CF is about 35 years ♦♦ Other CFTR-related disorders include isolated CAVD, CFTR-related pancreatitis, bronchiectasis, allergic bronchopulmonary aspergillosis, and chronic rhinosinusitis

Molecular Basis of Disease ♦♦ Point mutations and large deletions in the cystic fibrosis transmembrane conductance regulator (CFTR) gene ♦♦ Over 1,000 mutations described are associated with a wide range of clinical severity ♦♦ DeltaF508 most common in Caucasian (75% of carriers) ♦♦ W1282X most common in Ashkenazi Jews (60% of carriers) ♦♦ Polymorphic poly T tract in intron 8 of the CFTR gene modifies the phenotype associated with certain CFTR genotypes ♦♦ 5T allele is associated with abnormal splicing of exon 9 ♦♦ R117H in trans with 5T allele causes CAVD

Laboratory ♦♦ ♦♦ ♦♦ ♦♦

Molecular analysis identifies mutations in CFTR gene Elevated sweat chloride (>60 mEql/L) Abnormal transepithelial nasal potential difference Semen analysis to evaluate for azoospermia

Treatment ♦♦ ♦♦ ♦♦ ♦♦

Antibiotics for control of respiratory infections Postural drainage and inhalation therapy Chest physiotherapy for airway clearance Pancreatic enzyme-replacement therapy and supplemental feedings ♦♦ Oral ursodial for biliary build-up/obstruction ♦♦ Assisted reproductive technologies for infertility

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♦♦ Lung transplant for end-stage lung disease ♦♦ Surveillance −− Blood glucose testing for diabetes −− Chest radiograph and pulmonary function testing −− Cultures of respiratory tract secretions to evaluate for the presence of Pseudomonas aeruginosa −− Bone density

Albinism (Oculocutaneous Albinism Type 1) Chromosome and Gene Location ♦♦ 11q14–q21 (Oculocutaneous Albinism type 1 (OCA1)) ♦♦ There are numerous other types of albinism

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/30,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hypopigmented skin and hair Nystagmus Reduced iris and retinal pigment Foveal hypoplasia with significantly reduced visual acuity Two subtypes −− OCA1A – no melanin synthesis in any tissue −− OCA1B – variable amounts of melanin synthesis in some tissues

Molecular Basis of Disease ♦♦ Mutations in the tyrosinase gene (TYR) alter melanin production ♦♦ Mutations in other genes involved in melanocyte production, transportation, or proliferation lead to various other types of albinism

Laboratory ♦♦ Molecular genetic analysis identifies mutations in the TYR gene ♦♦ Deficient tyrosinase activity in hair bulb

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Avoidance of direct sunlight ♦♦ Ophthalmologic care and correction

Neurofibromatosis Type 1 (von Recklinghausen) Chromosome and Gene Location ♦♦ 17q11.2

Human Genetic Disorders

13-31

Inheritance

Laboratory

♦♦ Autosomal dominant −− 50% are new mutations (de novo) −− 50% inherited from a parent

♦♦ FISH, cytogenetic analysis, and molecular analysis identifies mutation involving the NF1 gene in approximately 95% of individuals

Incidence ♦♦ 1/3,500

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Diagnosis based on established clinical criteria Neurofibromas Café au lait spots (Fig. 13.6A) Axillary and inguinal freckling (Fig. 13.6A) Lisch nodules (Fig. 13.6B) Optic gliomas Bony complications Learning disabilities (50%) Peripheral nerve sheath tumors Osseous lesions Hypertension Noonan syndrome phenotype (12%) −− Ocular hypertelorism, down-slanting palpebral fissures, low-set ears, webbed neck, and pulmonary stenosis

Molecular Basis of Disease ♦♦ Mutations in the NF1 gene cause NF1 and include point mutations, small insertions and deletions, splicing mutations, large gene deletions and duplications, whole gene deletions, and large chromosomal rearrangements ♦♦ Homozygous or compound heterozygous mutations in the four mismatch repair genes, MLH1, MSH2, MSH6, and PMS2 result in childhood malignancies and features of NF1

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Surgical intervention when indicated ♦♦ Monitor by ophthalmologic examination and blood pressure measurements

Neurofibromatosis Type 2 Chromosome and Gene Location ♦♦ 22q12.2

Inheritance ♦♦ Autosomal dominant −− 50% are new mutations (de novo) −− 50% inherited from a parent

Incidence ♦♦ 1/50,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Diagnosis based on established clinical criteria Vestibular schwannomas (bilateral acoustic neuromas) Spinal tumors (schwannoma, astrocytoma, ependymoma) Meningiomas (50%) Loss of hearing Balance disturbance Subcapsular lens opacities that may progress to cataract Childhood mononeuropathy, adult polyneuropathy Mental retardation (associated with large deletions)

Fig. 13.6. Neurofibromatosis type 1 – Café au lait macule and axillary freckling (A). Lisch nodules (B).

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Molecular Basis of Disease ♦♦ Mutations in the NF2 cause NF2 ♦♦ Point mutations, small insertions and deletions, splicing mutations ♦♦ Submicroscopic (10–600 kb) deletions (10–16%) ♦♦ Large gene deletions and duplications ♦♦ Ring chromosome 22 (NF2 phenotype) ♦♦ Chromosomal translocations involving NF2 gene

Laboratory ♦♦ Molecular and cytogenetic analysis for abnormalities involving the NF2 gene is available

Treatment ♦♦ ♦♦ ♦♦ ♦♦

Not curable, supportive/symptomatic Surgical intervention when indicated Radiation therapy can induce or accelerate tumors Monitor by MRI for presence of tumors

Tuberous Sclerosis Complex Chromosome and Gene Location ♦♦ 9q34 (TSC1) ♦♦ 16p13.3 (TSC2)

Inheritance ♦♦ Autosomal dominant −− 60–75% are new mutations (de novo) −− 25–40% inherited from a parent

Incidence ♦♦ 1/6,000

Clinical Manifestations ♦♦ Diagnosis based on established clinical criteria ♦♦ Highly variable

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Skin abnormalities (~100%) −− Facial angiofibromas (Fig. 13.7A) −− Hypopigmented leaf shaped spots (by Wood lamp) (Fig. 13.7B) −− Ungual fibroma −− Shagreen patches ♦♦ Central nervous system abnormalities −− Cortical tubers −− Subependymal nodules −− Subependymal giant-cell astrocytomas −− Cerebral white matter radial migration lines −− Seizures and epilepsy −− Mental retardation/learning difficulties (50%) −− Behavioral and psychiatric disorders ♦♦ Renal abnormalities −− Renal lesions (angiomyolipomas) −− Renal cysts −− Polycystic renal disease −− Renal cancer ♦♦ Cardiac rhabdomyomas, retinal hamartomas, hamartomatous rectal polyps, or nonrenal hamartoma ♦♦ Bone cysts ♦♦ Lymphangiomyomatosis ♦♦ Dental enamel pits

Molecular Basis of Disease ♦♦ Mutations involving TSC1 and TSC2 cause tuberous sclerosis complex (TSC) ♦♦ In general, TSC1 mutations are associated with a milder phenotype than TSC2 mutations, with the exception of missense mutations in TSC2 ♦♦ Small insertions and deletions, point mutations (nonsense mutations only), splice mutations, and large deletions (1%) have been described in TSC1

Fig. 13.7. Tuberous sclerosis – facial angiofibromas (A). Hypopigmented macule (B).

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Human Genetic Disorders

♦♦ Small insertions and deletions: Missense mutations, nonsense mutations, splice mutations, large deletions (1–7%) have been described in TSC2 ♦♦ Contiguous gene syndrome involving large gene deletions and rearrangements of both the TSC1 and PKD1 (associated with autosomal dominant polycystic kidney disease) genes

Laboratory ♦♦ Molecular analysis for mutations involving the TSC1 and TSC2 genes is clinically available

Treatment ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Not curable, supportive/symptomatic Surgical removal of tumors Monitor for renal abnormalities by renal ultrasound Monitor for brain abnormalities by CT/MRI Chest CT for adult females to monitor for lymphangiomyo­ matosis

Beckwith–Wiedemann Syndrome Chromosome and Gene Location ♦♦ 11p15.5 (includes multiple genes: IGF2, LIT1/KCNQ1OT1, H19, and CDKN1C)

Inheritance ♦♦ 85% sporadic ♦♦ 10–15% autosomal dominant (inherited from a parent)

Incidence ♦♦ 1/14,000

Clinical Manifestations ♦♦ Overgrowth syndrome: macroglossia, macrosomia, nephromegaly, splenomegaly ♦♦ Hemihyperplasia, mid-face hypoplasia ♦♦ Cryptorchidism ♦♦ Seizures ♦♦ Developmental delay ♦♦ Omphalocele observed by fetal ultrasound ♦♦ Neonatal hypoglycemia ♦♦ Increased risk for embryonic tumors (Wilms tumor, adrenal cortical carcinoma, hepatoblastoma, rhabdomysosarcoma, neuroblastoma)

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Molecular Basis of Disease ♦♦ Beckwith–Wiedemann Syndrome (BWS) is due to dysregulation of imprinted genes at 11p15 ♦♦ Imprinting refers to the difference in gene expression based on parent of origin ♦♦ Imprinted genes are usually regulated by methylation, which prevents a gene from being expressed ♦♦ Imprinted genes associated with BWS −− IGF2 (paternally expressed) −− LIT1/KCNQ1OT1 (paternally expressed) −− H19 (maternally expressed) −− CDKN1C/p57(KIP2) (maternally expressed) ♦♦ Molecular etiology of sporadic cases of BWS −− Hypomethylation of LIT1 (50%) −− Paternal UPD of chromosome 11 (10%) −− Hypermethylation of H19 (10%) −− Point mutation in CDKN1C (5–10%) −− Cytogenetic abnormality (1–2%) −− Unknown (10%) ♦♦ Molecular etiology of inherited cases of BWS −− Point mutations in CDKN1C (40%) −− Unknown

Laboratory ♦♦ Methylation analysis to detect methylation abnormalities of LIT1 and H19 ♦♦ UPD analysis of chromosome 11 ♦♦ Molecular analysis of CDKN1C for point mutations ♦♦ Cytogenetic analysis identifies paternal duplications, translocations, or inversions of 11p15

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Abdominal wall repair for abdominal wall defects in neonates ♦♦ Treatment of hypoglycemia ♦♦ Monitor for embryonic tumors by ultrasound and serum alpha fetoprotein measurement

METABOLIC DISORDERS: INBORN ERRORS OF METABOLISM Amino Acid Disorders Phenylketonuria Chromosome and Gene Location

Incidence

♦♦ 12q24

Clinical Manifestations

Inheritance

♦♦ Mental retardation ♦♦ Seizures

♦♦ Autosomal recessive

♦♦ 1/10,000–1/25,000 (lower in African Americans and Ashkenazi Jews)

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hyperactivity Eczema Hypopigmentation “Mousey” odor Maternal PKU – children born to mothers with PKU have a high risk (90%) of having mental retardation, microcephaly, impaired growth and cardiac malformations, if mothers have not received dietary restriction of phenylalanine during pregnancy

Molecular Basis of Disease ♦♦ Mutations in phenylalanine hydroxylase (PAH) gene cause −− Inactivation of enzyme (more than 500 described) −− Disrupting the conversion of phenylalanine to tyrosine with subsequent hyperphenylalaninemia

Laboratory ♦♦ Newborn screening detects blood phenylalanine (>0.13– 1.2  mM) and phenylalanine/tyrosine ratio (>2.5) using tandem mass spectrometry. Fluorometric or Guthrie bacterial inhibition assay also useful for measuring phenylalanine ♦♦ Molecular genetic analysis available for positive screens

Treatment ♦♦ Low phenylalanine diet supplemented with tyrosine throughout life

Essentials of Anatomic Pathology, 3rd Ed.

ALA-dehydratase (PBG synthase) activity in erythrocytes due to inhibition by succinylacetone. Plasma or serum tyrosine is not 100% sensitive or specific ♦♦ Newborn screening detects succinylacetone by tandem mass spectrometry (an analyte not widely included in all newborn screening laboratories) ♦♦ Decreased fumarylacetoacetate hydrolase activity in liver biopsy specimens or cultured fibroblasts or chorionic villi sample ♦♦ Molecular analysis for targeted mutations and entire coding region is commercially available

Treatment ♦♦ Low phenylalanine, tyrosine, and methionine diet delays but does not stop progression of disease ♦♦ NTBC (2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohex­ anedione; (Nitisinone) treatment reduces the accumulation of toxic metabolites by blocking the second step in the tyrosine degradation pathway and ameliorates the severe clinical manifestations

Maple Syrup Urine Disease Chromosome and Gene Location

Tyrosinemia (Type 1 Most Prevalent) Chromosome and Gene Location

♦♦ ♦♦ ♦♦ ♦♦

♦♦ 15q23–q25

Inheritance

Inheritance

♦♦ Autosomal recessive

♦♦ Autosomal recessive

Incidence

Incidence

♦♦ 1/125,000–1/300,000

♦♦ Varies by population, highest incidence along the St. Laurence waterway in Canada (1/1,846)

Clinical Manifestations

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Vomiting, acidosis, diarrhea, failure to thrive Rickets Hepatic cirrhosis Fanconi renotubular syndrome Urine odor of boiled cabbage (caused from methionine metabolites) ♦♦ Increased risk for hepatocellular carcinoma

Molecular Basis of Disease ♦♦ Mutations in the gene for Tyrosinemia inactivate the enzyme fumarylacetoacetate hydrolase (FAH), which results in the accumulation of tyrosine and its metabolites (succinylacetoacetate, succinylacetone, and fumarylacetone) in the liver and kidney ♦♦ Numerous mutations have been found in the FAH gene and are generally population-specific

Laboratory ♦♦ Increased urine tyrosine metabolites, serum alpha-fetoprotein concentration, and succinylacetone excretion. Reduced delta-

568

19q13.1–q13.2, (type 1-E1a subunit) 1p31 (type 2-E2 subunit) 6p14 (type 3-E1b subunit) 7q31–q32 (E3 subunit)

♦♦ Variable based on type, level of enzyme deficiency, and management of acute episodes ♦♦ Features include −− Apnea −− Hypoglycemia −− Cerebral edema −− Poor feeding, vomiting, lethargy −− Maple syrup odor of urine and cerumen −− Hypertonicity/hypotonicity −− Muscle rigidity −− Seizures

Molecular Basis of Disease ♦♦ The branched chain alpha ketoacid dehydrogenase is a mitochondrial enzyme consisting of four subunits: E1a, E1b, E2, and E3 (each subunit is located on a different chromosome, see above) ♦♦ The enzyme system is responsible for the decarboxylation of the branched-chain amino acids: leucine, isoleucine, and valine ♦♦ Mutations in the genes encoding the various subunits result in defective expression and build up of the branched chain

Human Genetic Disorders

13-35

♦♦ Deficiency of branched chain alpha ketoacid dehydrogenase activity in leukocytes and cultured skin fibroblasts (prenatal diagnosis also available) ♦♦ Elevation of leucine, isoleucine, valine, and alloisoleucine in plasma or serum. Elevation of branch-chain ketoacids in urine, serum or plasma

♦♦ Folic acid permits response to pyridoxine and optimizes conversion of homocysteine to methionine ♦♦ Betaine is used in pyroxidine unresponsive patients to lower plasma homocysteine levels by allowing conversion to methionine ♦♦ Low methionine diets reduce accumulation of methionine and homocysteine and their metabolites ♦♦ Patients treated from newborn period have had fewer complications than those treated late or untreated

Treatment

Urea Cycle Disorders

♦♦ Thyamine for B1 responsive form ♦♦ Not curable, supportive/symptomatic, manage acute episodes ♦♦ Reduce intake of branched chain amino acids by using special formulas and reducing protein intake

♦♦ The urea cycle functions to prevent the accumulation of toxic nitrogenous compounds and also contain several reactions required for the synthesis of arginine. The urea cycle consists of five biochemical reactions. Defects in the biosynthesis or function of any of the five enzymes in this pathway lead to disease

amino acids and their metabolites in the blood, urine, and cerebral spinal fluid

Laboratory

Homocystinuria Chromosome and Gene Location

Chromosome and Gene Location

♦♦ 21q22.3

♦♦ See Table 13.8

Inheritance

Inheritance

♦♦ Autosomal recessive

♦♦ See Table 13.8

Incidence

Incidence

♦♦ 1/100,000 ♦♦ Clinical Manifestations ♦♦ Dislocation of ocular lens, myopia, strabismus, cataracts, glaucoma ♦♦ Thinning and lengthening of the long bones, osteoporosis, scoliosis ♦♦ High arched palate, pes cavus, genu valgum, biconcave vertebrae ♦♦ Thromboembolism ♦♦ Bluish mottling of the skin on legs and hands ♦♦ Developmental delay and seizures

♦♦ See Table 13.8

Molecular Basis of Disease ♦♦ The enzyme, cystathionine-B-synthase (CBS), converts homocysteine to serine and cystathionine ♦♦ Mutations in the CBS gene result in inactivation of enzyme function, which leads to elevated methionine and homocysteine levels

Laboratory ♦♦ Increased levels of homocysteine in urine or plasma ♦♦ Hyperhomocystinemia with increased methionine in plasma or serum. Decreased enzyme activity in fibroblasts, liver biopsy specimens, or PHA stimulated lymphocytes (prenatal diagnosis available) ♦♦ Molecular analysis available for mutation detection

Treatment ♦♦ High doses of pyridoxine (vitamin B6), which is a cofactor of CBS, are given to decrease homocysteine levels (increases conversion of homocysteine to cysteine)

Clinical Manifestations ♦♦ All defects with the exception of arginase deficiency result in a similar clinical phenotype which includes −− Lethargy, persistent vomiting, poor feeding coma −− Hypotonia −− Seizures −− Hepatomegaly ♦♦ The onset usually occurs after feeding in newborn period or after infections or protein overload ♦♦ In arginase deficiency, children are often asymptomatic for the first few months to years of life ♦♦ Clinical features include −− Loss of developmental milestones −− Increased clumsiness −− Spastic quadriplegia with loss of ambulation −− Loss of speech −− Seizures −− Progressive mental retardation

Molecular Basis of Disease ♦♦ See Table 13.8 for enzyme involved. Enzyme defects lead to the accumulation of ammonia and alter levels of other amino acids ♦♦ Ammonia is a neurotoxin that adversely affects the CNS

Laboratory ♦♦ Hyperammonia, altered amino acids levels in plasma, which are specific to each reaction

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Table 13.8. Urea Cycle Disorders Chromosome

Enzyme

Inheritance

Incidence

Carbamyl phosphate synthetase deficiency

2q35

Carbamyl phosphate synthetase

Autosomal recessive

1/60,000

Orithine transcarbamylase deficiency

Xp21.1

Orithine transcarbamylase

X-linked recessive

1/30,000

Citrullinemia

9q34

Argininosuccinate synthetase

Autosomal recessive

Rare

Arginosuccinic aciduria

7cen–q11.2

Argininosuccinate lyase

Autosomal recessive

1/70,000

Argininemia

6q23

Arginase

Autosomal recessive

Rare

♦♦ Deficient enzyme activity, molecular testing available for carrier and prenatal testing

Treatment ♦♦ Control of and avoidance of acute attacks, including supportive care during symptomatic episodes ♦♦ Restrict protein, high caloric diet to minimize breakdown of protein ♦♦ Prognosis is better if disorder is treated promptly

Organic Acidemias Isovaleric Acidemia Chromosome and Gene Location ♦♦ 15q14–q15

Inheritance ♦♦ Autosomal recessive

♦♦ Deficient isovaleryl CoA dehydrogenase results in the accumulation of isovaleric acid and its metabolites, which are toxic to the body ♦♦ A recurring mutation, A282V, is frequently found in asymptomatic and relatively mild IVA cases detected by newborn screening with tandem mass spectrometry

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Elevated isovaleric acid Hyperammonemia Hypocalcemia pancytopenia Neutropenia Thrombocytopenia Anemia Elevated urine isovalerylglycine during an acute attack Deficiency of isovaleryl CoA dehydrogenase in leukocytes or cultured skin fibroblasts (prenatal diagnosis available)

Incidence

Treatment

♦♦ Rare

♦♦ Not curable, supportive/symptomatic ♦♦ Avoidance of, and symptomatic control of, acute episodes ♦♦ Correct dehydration, electrolyte disturbances, and metabolic acidosis ♦♦ Reduce protein intake ♦♦ Remove excess isovalerylic acid by use of glycine and carnitine, which allows for urinary excretion

Clinical Manifestations ♦♦ Usually presents within the first few days of life, symptoms include −− Acute attacks of vomiting, lethargy −− Acidosis −− Ataxia −− Coma −− Seizures −− Mental retardation ♦♦ Attacks are usually triggered by stresses such as infections or surgery

Molecular Basis of Disease ♦♦ Isovaleryl CoA dehydrogenase catalyzes the conversion of isovaleric acid to 3-methylcrotonic acid in the branch-chain amino acid, leucine, degradation pathway

570

Propionic Acidemia Chromosome and Gene Location ♦♦ 13q32 ♦♦ 3q21–q22

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Rare

Human Genetic Disorders

Clinical Manifestations ♦♦ Onset may occur within the first few weeks of life ♦♦ Symptoms include −− Apnea −− Hypoglycemia −− Poor feeding, vomiting, lethargy −− Coma −− Hypotonia −− Seizures −− Frequent infections −− Osteoporosis −− Mental retardation ♦♦ Symptoms may be triggered by infections, constipation, and protein overload

Molecular Basis of Disease ♦♦ Propionyl-CoA-Carboxylase (PCC) is a multimeric, mitochondrial enzyme consisting of alpha subunits, encoded by PCCA, and beta subunits, encoded by PCCB ♦♦ The gene for each subunit is located on different chromosomes: chromosome 13 (alpha) and chromosome 3 (beta) ♦♦ Propionic acidemia can arise from mutations in either the alpha or beta subunit ♦♦ PCC is involved in the catabolic pathway for the odd chain length fatty acids: threonine, methionine, isoleucine, and valine ♦♦ Deficiencies of PCC lead to the accumulation of propionic acid, which results in the inhibition of citric acid cycle enzymes, acetylglutamate synthetase, granulocytes, and Tand B-cell development ♦♦ Numerous mutations have been described in the beta and alpha subunits

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Metabolic acidosis Hypoglycemia Hyperammonemia Carnitine deficiency Elevated glycine Elevated propionic and methylcitric acids Neutropenia Thrombocytopenia Deficiency of PCC activity in leukocytes or cultured skin fibroblasts (prenatal diagnosis available)

Treatment ♦♦ Not curative. Avoidance of, and symptomatic control of, acute episodes ♦♦ Correct dehydration, electrolytes disturbances, and metabolic acidosis (bicarbonate) ♦♦ Decrease protein intake ♦♦ Antibiotics prevent production of propionic acid by intestinal bacteria

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♦♦ Some individuals respond to biotin treatment, as it is a cofactor for PCC

Methylmalonic Acidemia (Methylmalonyl-CoA Mutase) Chromosome and Gene Location ♦♦ 6p21

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/50,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Lethargy, failure to thrive, recurrent vomiting, dehydration Respiratory distress Muscular hypotonia Growth retardation Psychomotor retardation Impairment of renal function Neurological abnormalities

Molecular Basis of Disease ♦♦ Methylmalonic acid is derived from propionic acid as part of the catabolic pathway of isoleucine, valine, threonine, methionine, cholesterol, and odd-chain fatty acids ♦♦ Methylmalonic acid is converted to succinic acid by methylmalonyl-CoA mutase and cobalamine (vitamin B12), which is a cofactor ♦♦ Defects in the mutase or reduced levels of its cofactor result in the accumulation of methylmalonic acid and its precursors ♦♦ The number of different genes involved in cobalamine metabolism and methylmalonic acidemia is uncertain; however, six complementation groups have been identified indicating multiple alleles ♦♦ Numerous mutations within the mutase gene on chromosome 6 have been reported

Laboratory ♦♦ Ketosis, acidosis, anemia, elevated urinary and serum methylmalonic acid ♦♦ Decreased or absent mutase activity in cultured fibroblasts ♦♦ Prenatal diagnosis available

Treatment ♦♦ Restricted protein ♦♦ Vitamin B12 supplements to lower MMA levels

Mitochondrial Fatty Acid Oxidation Disorders ♦♦ Mitochondrial fatty acid oxidation fuels ketogenesis in the liver and energy production during an unfed state, or during activities requiring a high energetic demand. Thus, many disorders of mitochondrial fatty acid oxidation present with sudden death that is often triggered by an acute illness or other episode. In addition, several of these disorders affect liver function and may also be complicated by cardiac dysfunction

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♦♦ Mitochondrial fatty acid oxidation consists of multiple biochemical reactions. Defects in the function of several of the enzymes in this pathway lead to disease

Medium-Chain Acetyl-CoA Dehydrogenase Deficiency Chromosome and Gene Location ♦♦ 1p31

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/15,000

Clinical Manifestations ♦♦ Onset may occur within the first few days of life if triggered by an illness or fasting ♦♦ Symptoms include −− Sudden, unexplained death −− Hypoketotic hypoglycemia −− Vomiting, lethargy −− Seizures −− Coma −− Reye-like syndrome −− Hepatomegaly and acute liver disease

Molecular Basis of Disease ♦♦ Medium-chain acetyl-CoA dehydrogenase (MCAD) is an enzyme encoded by ACADM on chromosome 1, and it is required for the beta oxidation of medium-chain fatty acids in the mitochondria ♦♦ A defect in MCAD results in the reduction of acetyl-CoA levels and in the accumulation of medium-chain fatty acids, which are further conjugated to glycine and carnitine-esters, or metabolized to dicarboxylic acids ♦♦ The accumulation of medium-chain fats and their conjugates can be detected in the blood, urine, and tissue of patients with MCAD deficiency. The medium-chain, carnitine–ester conjugates are used as biomarkers for newborn screening of this disorder by tandem mass spectrometry ♦♦ A frequent cause of MCAD deficiency is homozygosity for the 985A > G mutation in exon 11 of ACADM, a mutation that has an estimated carrier frequency of 1/40 in peoples of Northern European descent ♦♦ Numerous mutations within the ACADM gene have been identified and several may lead to a mild biochemical phenotype

Laboratory ♦♦ ♦♦ ♦♦ ♦♦

Hypoketotic hypoglycemia Hyperammonemia Carnitine deficiency Elevated medium-chain acylcarnitines with prominent octanoylcarnitine

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♦♦ Elevated medium-chain acylglycines with prominent hexanoylglycine and suberylglycine ♦♦ Deficiency of MCAD activity in cultured skin fibroblasts ♦♦ ACADM mutations, such as 985A > G

Treatment ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Avoidance of fasting for more than 12 h Control of acute illnesses by intravenous glucose Uncooked cornstarch for toddlers at bedtime l-Carnitine supplementation (100 mg/kg/day) Low-fat diet

Very Long-Chain Acetyl-CoA Dehydrogenase Deficiency Chromosome and Gene Location ♦♦ 17p13

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/40,000

Clinical Manifestations ♦♦ Onset often occurs during infancy where it can present with cardiomyopathy and hepatic dysfunction. It also occurs in childhood where it presents with hepatic symptoms and hypoglycemia. A few adult patients have been described with muscle symptoms and without hepatic or cardiac involvement ♦♦ Symptoms include −− Sudden, unexplained death −− Hypoketotic hypoglycemia −− Vomiting, lethargy −− Seizures −− Rhabdomyolysis −− Myoglobinuria −− Dilated or hypertrophic cardiomyopathy −− Hepatomegaly and acute liver disease

Molecular Basis of Disease ♦♦ Very long-chain acetyl-CoA dehydrogenase (VLCAD) is an enzyme encoded by ACADVL on chromosome 17 that is essential for the beta oxidation of long-chain fatty acids in the mitochondria ♦♦ VLCAD leads to the accumulation of long-chain fatty acids, particularly the unsaturated C12–C14 chain-length fats, which are further conjugated to carnitine–esters or metabolized to dicarboxylic acids ♦♦ Accumulation of long-chain fats (unsaturated C12–C14) are found in VLCAD patient tissues and their carnitine–ester conjugates are used as biomarkers for newborn screening of this disorder by tandem mass spectrometry ♦♦ Numerous private mutations within the VLCAD gene account for this disorder

Human Genetic Disorders

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hypoketotic hypoglycemia Hyperammonemia Carnitine deficiency Elevated very long-chain plasma acylcarnitines with prominent unsaturated C14 species Elevated hepatic enzymes and creatine kinase (CK) Myoglobinuria Deficiency of VLCAD activity in cultured skin fibroblasts ACADVL mutation analysis is available for confirmation and prenatal diagnosis

Treatment ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Avoidance of fasting or prolonged exercise Control of acute illnesses by intravenous fluids High-carbohydrate and low-fat diet Supplementation with MCT-oil l-Carnitine supplementation is controversial

Long-Chain 3-Hydroxylacetyl-CoA Dehydrogenase/Mitochondrial Trifunctional Protein Deficiency Chromosome and Gene Location ♦♦ 2p23

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Rare

Clinical Manifestations ♦♦ This presents as neonatal hypoglycemia, lactic acidosis, and sudden, unexplained death. It also occurs in childhood where it presents with additional symptoms, such as progressive neuropathy, myopathy, and ophthalmologic abnormalities. It is also associated with maternal, acute fatty liver of pregnancy or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome in mothers of affected children ♦♦ Symptoms include −− Sudden, unexplained death −− Hypoketotic hypoglycemia −− Coma −− Lactic academia −− Hypotonia −− Seizures −− Progressive retinopathy −− Peripheral neuropathy −− Cardiomyopathy −− Hepatic dysfunction

Molecular Basis of Disease ♦♦ Long-chain 3-hydroxylacetyl-CoA dehydrogenase/mitochondrial trifunctional protein deficiency (LCHAD/MTP) is

13-39

caused by the deficiency of proteins encoded by HADHA and HADHB. Both genes are located in tandem on chromosome 2p23 and their protein products form a heteromer that is essential for the beta oxidation of long-chain fatty acids in the mitochondria. The heteromer functions as a long-chain 3-hydroxylacetyl-CoA dehydrogenase (LCHAD, encoded by HADHA), a long-chain enoyl-CoA hydratase, and a longchain thiolase, hence the name, mitochondrial trifunctional protein (MTP) ♦♦ LCHAD/MTP leads to the accumulation of 3-hydroxyl longchain fatty acids, particularly the hydroxylated C14–C18 chain-length fats, which are further conjugated to carnitine– esters or metabolized to dicarboxylic acids ♦♦ Accumulation of long-chain (hydroxylated C14–C18), ­fatty-acid, carnitine–ester conjugates are used as biomarkers for newborn screening of this disorder by tandem mass spectrometry ♦♦ Private mutations are frequent within HADHA and HADHB genes

Laboratory ♦♦ ♦♦ ♦♦ ♦♦

Hypoketotic hypoglycemia Hyperammonemia and lactic acidemia Carnitine deficiency Elevated, long-chain, hydroxylated plasma acylcarnitines with prominent C14–C18 species ♦♦ Elevated hepatic enzymes and CK ♦♦ Deficiency of LCHAD/MTP activity in cultured skin fibroblasts ♦♦ HADHA and HADHB mutation analysis is available for confirmation and prenatal diagnosis

Treatment ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Avoidance of fasting or prolonged exercise Control of acute illnesses by intravenous fluids High-carbohydrate and low-fat diet Supplementation of diet with MCT-oil DHA supplementation is also commonplace with the aim to stabilize the retinopathy ♦♦ l-Carnitine supplementation is controversial

Short-Chain Acetyl-CoA Dehydrogenase Deficiency Chromosome and Gene Location ♦♦ 12q22–qter

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/50,000

Clinical Manifestations ♦♦ Clinical heterogeneity of this disorder has complicated a complete understanding of its natural history. Several case reports have associated short-chain acetyl-CoA ­dehydrogenase (SCAD) deficiency with neonatal hypotonia, developmental

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delay, with or without seizures. However, with the advent of newborn screening by tandem mass spectrometry, of which SCAD deficiency is a secondary target, numerous SCADdeficient patients have been found to be asymptomatic exclusive of persistent ethylmalonic aciduria. The presence of two common SCAD gene variants may account for the biochemical and clinical variability of this disorder ♦♦ Reported symptoms include −− Hypotonia −− Seizures −− Developmental and speech delay −− Lethargy −− Failure to thrive −− Ethylmalonic aciduria without other symptoms

♦♦ l-Carnitine supplementation (100 mg/kg/day) ♦♦ Low-fat diet

Molecular Basis of Disease

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Short-chain acetyl-CoA dehydrogenase (SCAD) is an enzyme encoded by ACADS on chromosome 12 and is required for the last chain-shortening step of mitochondrial fatty acid oxidation ♦♦ Reduction of SCAD function leads to the accumulation of short-chain fatty acids (of the C4 chain-length), which are further conjugated to glycine and carnitine–esters, or meta­ bolized to dicarboxylic acids, ethylmalonic acid, and methylsuccinic acid ♦♦ Accumulation of short-chain fats and their conjugates can be detected in the blood and urine of patients with SCAD deficiency and the carnitine–ester conjugate (C4 acylcarnitine) is used as a biomarker for newborn screening of this disorder by tandem mass spectrometry ♦♦ Two common SCAD gene variants, 625G > A and 511C > T, are frequently found in the normal population, lead to mild ethylmalonic aciduria, but do not confer disease ♦♦ Numerous SCAD-deficient patients who are compound heterozygous for an SCAD gene variant and a single mutation have been identified by newborn screening. It does not appear that compound heterozygosity for a mutation and a variant will lead to a clinical phenotype. However, additional studies are needed to understand the possible complex multifactorial components that lead to a phenotype

Laboratory ♦♦ Hypoglycemia ♦♦ Elevated short-chain plasma acylcarnitines with prominent butyrylcarnitine ♦♦ Elevated ethylmalonic acid excretion detectable by urine organic acids or acylglycines ♦♦ Deficiency of SCAD activity in cultured skin fibroblasts ♦♦ SCAD gene sequence analysis is commercially available and will detect gene variants and most missense mutations

Treatment ♦♦ Avoidance of fasting ♦♦ Control of acute illnesses by intravenous fluids

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Carbohydrate Metabolism Disorders Glycogen Storage Disease (Type I) Chromosome and Gene Location ♦♦ 17q21

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/100,000

Clinical Manifestations Hypoglycemia Hypertension Excessive perspiration Bruising, nose bleeds Short stature Delayed puberty Protuberant abdomen Liver adenomas, hepatomegaly, hepatoblastoma, hepatocellular carcinoma ♦♦ Chronic pancreatitis ♦♦ Renal insufficiency

Molecular Basis of Disease ♦♦ The enzyme glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose ♦♦ Mutations in the gene encoding glucose-6-phosphatase result in a deficiency of this enzyme and the subsequent inability to free glucose for use in the body ♦♦ Mutations in the glucose-6-phosphatase gene (G6PC) have been found in about 80% of patients studied ♦♦ There are various types of glycogen storage diseases, which result from deficiencies of other enzymes involved in the glycogen metabolism pathway

Laboratory ♦♦ Deficiency of glucose-6-phosphatase in liver biopsy (enzyme not present in skin fibroblasts) ♦♦ Lipidemia ♦♦ Hyperuricemia ♦♦ Lactic acidemia ♦♦ Ketonemia ♦♦ Molecular analysis available

Treatment ♦♦ Maintenance of normal blood glucose concentration, by supplementation of glucose, pancreatic enzymes, and cornstarch ♦♦ Limit intake of fructose and galactose ♦♦ Low fat diet ♦♦ Liver transplantation if necessary

Human Genetic Disorders

Galactosemia Chromosome and Gene Location ♦♦ 9p13

Inheritance

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Treatment ♦♦ Eliminate lactose and galactose from the diet, special formula is necessary ♦♦ Even with good dietary control there may be poor intellectual function, speech problems, and ovarian dysfunction

♦♦ Autosomal recessive ♦♦ 1/30,000

Galactokinase Deficiency Chromosome and Gene Location

Clinical Manifestations

♦♦ 17q24

♦♦ Babies with galactosemia may appear normal at birth −− Symptoms begin soon after milk feedings have begun ♦♦ Symptoms include −− Lethargy, irritability, vomiting, feeding difficulties, poor weight gain, failure to thrive −− Seizures −− Jaundice −− Hepatomegaly, hepatic cirrhosis, splenomegaly −− Hypoglycemia −− Ascites −− Lens opacities −− Increased susceptibility to infections ♦♦ Long-term complications include −− Speech deficits −− Ataxia −− Dysmetria −− Diminished bone density −− Premature ovarian failure

Inheritance

Incidence

Molecular Basis of Disease ♦♦ Galactose-1-P uridyl transferase (GALT) catalyzes the conversion of galactose-1-phosphate to glucose-1-phosphate ♦♦ Deficiency of GALT results in the accumulation of galactose-1-phosphate, which causes injury to the parenchymal cells of the kidney, liver, brain, ovaries, and eyes ♦♦ A single mutation (Q188R) accounts for about 70% of galactosemia alleles in northern Europeans ♦♦ 12% carry the Duarte variant, which decreases enzyme activity, but does not result in phenotypic consequence

Laboratory ♦♦ Newborn screening uses dot enzyme fluorescent assay and/ or measurement of galactose-1-phosphate in the blood ♦♦ Classic and variant alleles can be detected with isoelectric focusing ♦♦ Molecular analysis is used in conjunction with biochemical testing for prognostication, heterozygote detection, and prenatal diagnosis ♦♦ Serum in affected individual shows elevated transaminase, hyperbilirubinemia, follicular stimulating hormone, and leutenizing hormone, decreased estrogen, and anemia ♦♦ E. coli septicemia occurs frequently

♦♦ Autosomal recessive

Incidence ♦♦ 1/40,000

Clinical Manifestations ♦♦ Cataracts ♦♦ Neonatal jaundice ♦♦ Normal intelligence

Molecular Basis of Disease ♦♦ Galactokinase catalyzes the conversion of galactose to ­galactose-1-phosphate ♦♦ Galactokinase deficiency results in the accumulation of galactose ♦♦ Some galactose is converted to galacticol, which may be responsible for the cataract formation

Laboratory ♦♦ Deficiency of galactokinase activity in red blood cells

Treatment ♦♦ Elimination of lactose and galactose from the diet

Transport Disorders Familial Hypophosphatemic Rickets Chromosome and Gene Location ♦♦ Xp22.2–p22.1

Inheritance ♦♦ X-linked dominant (also autosomal recessive and sporadic forms)

Incidence ♦♦ 1/1,000,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Bowing of lower extremities Waddling gait Short stature Decreased femur/shaft angle Dolichocephaly Tooth deformities

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Molecular Basis of Disease ♦♦ Deficiency interferes with phosphate reabsorption in kidney and conversion of 25-hydroxy-D to 1,25-hydroxy-2D

Laboratory ♦♦ Hyperphosphaturia ♦♦ Normal amino acids ♦♦ X-rays show metaphyseal widening and fraying, cupping of metaphyses at tibia, femur, radius, and ulna ♦♦ Molecular analysis of the PHEX gene is available

Treatment ♦♦ Phosphate supplements, surgery for limb deformities

Cystinuria Chromosome and Gene Location ♦♦ 2p16.3 and 19q13.1

Inheritance ♦♦ Complex inheritance that is mostly autosomal recessive with genetic components from multiple alleles producing three clinical types

Essentials of Anatomic Pathology, 3rd Ed.

Hartnup Disease Chromosome and Gene Location ♦♦ 5p15

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/30,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Cerebellar ataxia Emotional instability, psychosis Delayed development Severe retardation Photosensitive skin

Molecular Basis of Disease ♦♦ Caused by mutations in SLC6A19, which leads to a defect in neutral amino acid transport across the brush-border membrane of the renal and intestinal epithelium

Laboratory

♦♦ 1/2,000 in England to 1/100,000 in Sweden ♦♦ Overall approximately 1/7,000

♦♦ Characteristic pattern of increased secretion of the monoaminomonocarboxylic acids (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine, glutamine, and asparagine)

Clinical Manifestations

Treatment

Incidence

♦♦ Urinary tract calculus ♦♦ Cystine stones are formed and crystals appear in the urine ♦♦ Increased risk for impaired cerebral function

♦♦ Nicotinic acid or nicotinamide for deficiency of this vitamin, reduces rash, ataxia, and psychotic behavior ♦♦ High protein diet or supplementation

Molecular Basis of Disease

Cystinosis Chromosome and Gene Location

♦♦ Mutations in the SLC3A1 gene on chromosome 2p are responsible for type I, which is recessive; mutations in SLC7A9 are responsible for types II and III, which show incomplete penetrance ♦♦ The relationship between SLC3A1 and SLC7A9 gene products and their influence on the complex inheritance of cystinuria is not completely understood

Laboratory ♦♦ Dibasic aminoaciduria (excess excretion of cystine) and increased urinary lysine, arginine, and ornithine ♦♦ Molecular analysis of SLC3A1 and SLC7A is available

Treatment ♦♦ Dietary therapy to reduce cystine excretion and increase solubility ♦♦ Decreased methionine ♦♦ Low-sodium diets ♦♦ High fluid intake ♦♦ Alkanization of urine by sodium bicarbonate or sodium citrate to increase solubility of cystine ♦♦ Surgery to remove stones ♦♦ Penicillamine treatment for dissolving stones

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♦♦ 17p13

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/100,000–1/200,000

Clinical Manifestations ♦♦ There appears to be three types of cystinosis with varying degrees of involvement −− Nephrotic-classic renal and systemic disease in which children develop dehydration, acidosis, vomiting, electrolyte imbalances, hypophosphatemic rickets, failure to grow, photophobia, corneal crystals, hypothyroidism, myopathy, decreased ability to sweat and renal failure by age 9–10 −− Intermediate late-onset of nephrotic cystinosis −− Nonnephrotic, clinically affecting only the corneas

Molecular Basis of Disease ♦♦ Defective carrier mediated transport of cystine causes accumulation of cystine and formation of crystals in the lysosomes of most tissues

Human Genetic Disorders

♦♦ Mutations in the CTNS gene are responsible for all three types of cystinosis

Laboratory ♦♦ ♦♦ ♦♦ ♦♦

Generalized aminoaciduria Glucosuria with normal blood glucose Elevated leukocyte cystine Cystine crystals in tissue biopsy of bone marrow, conjunctiva, kidney, liver, intestine, and other tissues (not present in skin biopsy), cystine storage in pancreatic islet cells, aorta, atrophic ovaries, and brain ♦♦ Molecular mutation analysis and prenatal diagnosis is available

Treatment ♦♦ ♦♦ ♦♦ ♦♦

Management of electrolyte imbalance Renal allografts Growth hormones Therapy with cysteamine averts the otherwise inevitable renal failure, but systemic therapy does not improve the ­corneal keratopathy; cysteamine eye drops may prevent photophobia

Metal Metabolism Disorders Wilson Disease Chromosome and Gene Location

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♦♦ Copper accumulates in the liver and other tissues and inhibits various enzymatic reactions ♦♦ Numerous mutations in ATP7B have been identified

Laboratory ♦♦ Reduced serum copper level and ceruloplasmin, increased urinary copper excretion ♦♦ Elevated copper in liver biopsy ♦♦ Diagnosis by quantitating hepatic copper stores which are increased ♦♦ Molecular analysis clinically available

Treatment ♦♦ Zinc acetate, which inhibits intestinal absorption of copper ♦♦ Penicillamine, tetrathiomolybdate, or trientine (which may have fewer side effects) increase urinary copper excretion ♦♦ Liver transplantation when necessary

Acrodermatitis Enteropathica Chromosome and Gene Location ♦♦ 8q24.3

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Rare

♦♦ 13q14

Clinical Manifestations

Inheritance

♦♦ Symptoms most often occur early in infancy after transition from breast milk to cow milk ♦♦ Features include −− Dry, scaly, reddish skin lesions on face, knees, elbows, and perineal areas −− Reddish hair −− Hair loss −− Photophobia −− Conjunctivitis −− Corneal dystrophy −− Chronic diarrhea −− Growth retardation −− Delayed wound healing −− Immune defects

♦♦ Autosomal recessive

Incidence ♦♦ 1/30,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Liver disease Neurologic disturbance Acute jaundice Hemolysis Dysarthria Involuntary movement Renal tubular acidosis Osteoarthropathy Cardiomyopathy Golden-brown granular pigmentation is seen in the outer crescent of the iris (“Kayser Fleischer” rings)

Molecular Basis of Disease ♦♦ Wilson disease is caused by mutations in the ATP7B gene, which encodes a copper-binding P-type ATPase ♦♦ Expression occurs primarily in the liver, kidney, and placenta ♦♦ Defects in the gene lead to defective liver-specific copper transport and defective copper excretion into the bile

Molecular Basis of Disease ♦♦ Impaired zinc absorption due to an absent or defective zincspecific transporter, which is encoded by SLC39A4 and ­facilitates zinc absorption ♦♦ Variety of clinical features is likely because zinc plays a role in numerous metabolic pathways ♦♦ Without therapy, plasma zinc concentration and serum alkaline phosphatase, as well as urinary excretion of zinc, are very low

Treatment ♦♦ Oral zinc compounds abolish the manifestations of the disease

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Menkes Disease Chromosome and Gene Location ♦♦ Xq13

Inheritance ♦♦ X-linked recessive

Incidence ♦♦ 1/40,000–1/350,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hypothermia Hypotonia Myoclonic seizures Chubby, rosy cheeks Kinky, colorless friable hair (Fig. 13.8) Failure to thrive Severe mental retardation Optic atrophy Osteopenia with pathologic fractures (may be mistaken for child abuse)

Molecular Basis of Disease ♦♦ Caused by mutations in the copper-transporting ATPase, ATP7A ♦♦ Mutations in ATP7A result in defective copper absorption and transport ♦♦ A wide spectrum of mutations have been identified

Laboratory ♦♦ Low serum copper and ceruloplasmin levels ♦♦ Intracellular accumulation of copper in cultured cells

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Molecular analysis of ATP7A is available, prenatal diagnosis also available

Treatment ♦♦ Copper histidine treatment has had limited success. Many patients deteriorate and die of complications from seizures before 2 years of age

Hemochromatosis Chromosome and Gene Location ♦♦ 6p21.3

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Varies by population ♦♦ 1/200–1/300 in northern European populations ♦♦ Lower in others

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Fatigue Palpitations Premature arthritis Impotence in males Amenorrhea in females Cardiac arrhythmias Congestive heart failure due to cardiomyopathy Cirrhosis with hepatosplenomegaly Ascites Hyperpigmentation Onset is generally between ages 40 and 60 Females have later onset due to menses/child birthing

Molecular Basis of Disease ♦♦ A gene called HLA-H or HFE has been shown to be altered in the majority of hemochromatosis patients ♦♦ The most common mutation causes an amino acid substitution at codon 282 (C282Y) ♦♦ Approximately 85% of hemochromatosis patients of northern European descent are homozygous, 5–10% are heterozygous, and an additional 5–10% do not carry the C282Y mutation ♦♦ A second less frequent alteration is an amino acid sub­ stitution at codon 63 (H63D), its role in this disease is ­controversial, but may increase ones risk for developing hemochromatosis ♦♦ It has been hypothesized that the C282Y mutation results in an abnormal protein trafficking or cell surface expression of the HFE gene

Laboratory

Fig. 13.8. Menkes disease – magnified image of pili torte of hair.

578

♦♦ Elevated serum transferrin saturation and concentration ♦♦ Elevated hepatic iron concentration on liver biopsy ♦♦ Molecular mutation analysis available

Human Genetic Disorders

Treatment ♦♦ Phlebotomy reduces iron stores to normal ♦♦ Chelating agents remove smaller amounts of iron but are not as effective as phlebotomy

Purine Metabolism Disorders Lesch–Nyhan Syndrome Chromosome and Gene Location ♦♦ Xq26–q27

Inheritance ♦♦ X-linked recessive

Incidence ♦♦ 1/300,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hypotonia Delayed motor development Choreoathetosis Spastic movements Hyper-reflexia Self-injurious behavior Gouty arthritis Kidney stones composed of uric acid Carrier females develop gout in later years

Molecular Basis of Disease ♦♦ The enzyme, hypoxanthine–guanine phosphoribosyltransferase, converts hypoxanthine and xanthine to nucleotides, inosinic acid, and guanylic acid ♦♦ Deficiency in enzyme activity results in accelerated purine production de novo and increased uric acid ♦♦ Deficiencies may also result in decreased synthesis of nucleotides

Laboratory ♦♦ Elevated serum uric acid concentration ♦♦ Elevated urate to creatinine ratio in urine ♦♦ Marked increases in the production and excretion of uric acid ♦♦ Absence of hypoxanthine–guanine phosphoribosyl-transferase activity in erythrocytes and fibroblasts (prenatal diagnosis available) ♦♦ Molecular mutation analysis available, including prenatal diagnosis

Treatment ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Avoidance of dehydration Adequate nutrition Behavior control and modification Allopurinol to prevent damage to kidneys Experimental gene therapy

13-45

Adenosine Deaminase Chromosome and Gene Location ♦♦ 20q13

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/200,000–1,000,000

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦

Severe immunodeficiency Complete impairment of T-cell function Rib cage abnormalities Chondroosseous dysplasia

Molecular Basis of Disease ♦♦ Mutations in the ADA gene encoding the enzyme, adenosine deaminase, result in the accumulation of adenosine, 2¢ deoxyadenosine and 2¢-O-methyladenosine, which leads to lymphocyte toxicity and subsequent immunodeficiency

Laboratory ♦♦ Absence of adenosine deaminase in red-blood cells, or cultured fibroblasts

Treatment ♦♦ Enzyme replacement therapy has resulted in clinical and immunologic improvement in some patients ♦♦ Bone marrow transplantation

Peroxisomal Disease Zellweger Syndrome, Neonatal Adrenoleukodystrophy, and Infantile Refsum Disease Chromosome and Gene Location ♦♦ 7q11.23 (also chromosomes 1, 2, 6, 8, 11, 12, 17, and 22)

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/25,000–1/50,000

Clinical Manifestations ♦♦ Clinical spectrum with Zellweger syndrome representing the most severe presentation, infantile Refsum disease is the least severe phenotype ♦♦ High forehead ♦♦ Upslanting palpebral fissures ♦♦ Hypoplastic supraorbital ridges ♦♦ Epicanthal folds ♦♦ Severe weakness ♦♦ Hypotonia ♦♦ Seizures

579

13-46

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Essentials of Anatomic Pathology, 3rd Ed.

Incidence

Eye abnormalities Profound mental retardation Early lethality Liver cysts Chondrodysplasia punctata Hearing loss and visual impairment

♦♦ 1/42,000

Clinical Manifestations

Molecular Basis of Disease ♦♦ Peroxisome biogenesis disorders are caused by mutations in several different genes involved in peroxisome biogenesis ♦♦ Mutations have been identified in numerous peroxisome biogenesis factor (PEX) genes as well as the peroxisomal membrane protein-3 gene

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Reduced or absent peroxisomes Catalase in cytosol Reduced plasmalogens Accumulation of very long chain fatty acids Increased phytanic acid Bile acid intermediates Increased l-pipecolic acid Increased urinary excretion of dicarboxylic acids Molecular mutation analysis available

Treatment ♦♦ Not curable, supportive/symptomatic

Adrenoleukodystrophy (X-linked) Chromosome and Gene Location

♦♦ Learning deficits (attention deficit disorder, hyperactivity), followed by regression of academic performance ♦♦ Leg weakness, loss of sphincter control, and sexual dysfunction ♦♦ Progressive spastic paresis ♦♦ Loss of hearing and vision ♦♦ Dementia ♦♦ Demyelination of cerebral hemispheres

Molecular Basis of Disease ♦♦ Mutations in the ABCD1 gene result in defective peroxisomal beta oxidation of very long chain fatty acids (VLCFAs), the protein is an ATP-binding cassette (ABC) protein transporter ♦♦ Deficiency results in the accumulation of VLCFAs in the adrenal cortex and brain gangliosides, plasma, blood cells, and cultured fibroblasts ♦♦ Numerous mutations have been identified in the ABCD1 gene

Laboratory ♦♦ Accumulation of unbranched saturated fatty acids with a chain length of 24–30 carbons in plasma, cultured skin fibroblasts, prenatal diagnosis available ♦♦ Molecular mutation analysis is available

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ VLCFA-restricted diet, bone marrow transplantation ♦♦ Corticosteroid replacement therapy for adrenal in-sufficiency

♦♦ Xq28

Inheritance ♦♦ X-linked recessive

LYSOSOMAL STORAGE DISORDERS Mucopolysaccharidoses Chromosome and Gene Location ♦♦ See Table 13.9

Inheritance ♦♦ See Table 13.9

Incidence ♦♦ See Table 13.9

Clinical Manifestations ♦♦ Onset typically by 2 years ♦♦ Coarse facial features ♦♦ Corneal clouding

580

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Organomegaly Skeletal dysplasia (dysostosis multiplex) Mental retardation (not observed in MPS IV or MPS VI) Loss of developmental milestones Behavioral problems (MPS III) Hearing loss Decreased range of motion in joints Heart valve abnormalities Inguinal or umbilical hernias

Molecular Basis of Disease ♦♦ The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by the deficiency of any of the

Keratan sulfate, chondroitin 6-sulfate Keratan sulfate

Galactose-6-sulfatase Beta galactosidase

17q25.3

MPS IVA: 16q24.3 MPS IVB: 3p21.33

X-linked

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Hunter syndrome (MPS II)

Sanfilippo syndrome (MPS III)

Morquio syndrome (MPS IVA and MPS IVB)

Maroteaux–Lamy syndrome (MPS VI)

Sly syndrome (MPS VII)

Hyaluronidase deficiency (MPS IX)

3p21.3–p21.2

7q21.11

5q11–q13

Xq28

4p16.3

Hyaluronidase

Beta glucuronidase

N-acetylgalactosamine-4-sulfatase (arylsulfatase B)

Sanfilippo A – Heparan N-sulfatase Sanfilippo B – Alpha-N-acetylglucosaminidase Sanfilippo C – Acetyl-CoA: alpha glucosaminide N-acetyltransferase Sanfilippo D – Nacetylglucosamine-6-sulfatase

Iduronate sulfatase

Alpha-l-iduronidase

Dysostosis multiplex, corneal clouding, normal intelligence

Hyaluronan

Short stature, periarticular soft tissue masses

Dysostosis multiplex, Dermatan sulfate, hepatosplenomegaly heparan sulfate, chondroitin 4-,6-sulfates

Dermatan sulfate

Profound mental deterioration, hyperactivity

Heparan sulfate

Skeletal abnormalities, corneal clouding, odontoid hypoplasia

Dysostosis multiplex, organomegaly, mental retardation, death typically before 15 years

Corneal clouding, stiff joints, normal intelligence, normal life span

Corneal clouding, dysostosis multiplex, organomegaly, heart disease, mental retardation, death in childhood

Clinical features

Dermatan sulfate, heparan sulfate

Dermatan sulfate, heparan sulfate

Dermatan sulfate, heparan sulfate

Autosomal recessive

Alpha-l-iduronidase

Scheie syndrome (MPS IS)

4p16.3

Autosomal recessive

Excess excretion

Hurler syndrome (MPS IH)

Enzyme deficiency

Inheritance Gene location

Name

Table 13.9. Mucopolysaccharidoses

Unknown

1/800,000–1/1,300,000

1/800,000–1/1,300,000

Unknown

1/75,000–1/300,000

1/75,000–1/300,000

1/100,000–1/170,000 male births

1/500,000

1/100,000

Incidence

Human Genetic Disorders 13-47

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enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans) ♦♦ Accumulation of glycosaminoglycans (previously called mucopolysaccharides) in the lysosomes interferes with the normal functioning of cells, tissues, and organs

Laboratory ♦♦ Increased urinary excretion of glycosaminoglycans ♦♦ Decreased enzyme activity in cultured fibroblasts, leukocytes, serum, or plasma ♦♦ Radiographs show skeletal abnormalities ♦♦ Molecular sequencing is available for most types ♦♦ Prenatal diagnosis available

Treatment ♦♦ Hematopoietic stem cell transplantation (bone marrow or cord blood) can improve somatic features for some patients with severe forms of MPS I and MPS VI; neurological outcomes still being investigated ♦♦ Enzyme replacement therapy is available for patients with MPS I, MPS II, MPS VI, and in clinical trials for other MPS disorders ♦♦ Treatment remains primarily supportive/symptomatic ♦♦ Bacterial endocarditis prophylaxis for patients with cardiac abnormalities ♦♦ Orthopedic surgery for skeletal complications

Mucolipidoses ♦♦ Mucolipidoses are a group of disorders, which result from abnormal lysosomal enzyme transport

I-Cell Disease (Mucolipidosis II Alpha/Beta) Chromosome and Gene Location ♦♦ 12q23.3

Inheritance

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ ♦♦ ♦♦ ♦♦

beta-d-glucuronidase, beta-d-galactosidase, alpha-l-fucosidase, and arylsulfatase A); diagnosis cannot be made in leukocytes Increased urinary excretion of oligosaccharides Cytoplasmic granular inclusions in skin fibroblasts (swollen lysosomes called I cells) Molecular sequencing of the GNPTAB gene is available. Prenatal diagnosis available

Treatment ♦♦ Not curable, supportive/symptomatic

Pseudo-Hurler Polydystrophy (Mucolipidosis III Alpha/Beta) Chromosome and Gene Location ♦♦ 12q23.3

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Rare

Clinical Manifestations ♦♦ Onset is typically between 2 and 4 years. Clinical presentation resembles the mucopolysaccharidoses

Molecular Basis of Disease ♦♦ GNPTAB (N-acetylglucosamine-1-phosphotransferase, alpha/ beta subunits gene) is the only gene known to be associated with ML III alpha/beta ♦♦ Mutations within the gene disrupt interactions and recognition of the phosphotransferase, resulting in secretion of lysosomal enzymes into the extracellular medium instead of being targeted correctly to the lysosomes ♦♦ A milder variant of I-cell disease (ML II alpha/beta) caused by the same enzyme deficiency

♦♦ Autosomal recessive

Laboratory

Incidence

♦♦ Increased activity of lysosomal hydrolases in plasma and other body fluids (in particular: beta-d-hexosaminidase, beta-d-glucuronidase, beta-d-galactosidase, and beta-dmannosidase); the diagnosis cannot be made in leukocytes ♦♦ Increased urinary excretion of oligosaccharides ♦♦ Cytoplasmic granular inclusions in skin fibroblasts (swollen lysosomes) ♦♦ Molecular sequencing of the GNPTAB gene is available ♦♦ Prenatal diagnosis available

♦♦ Rare

Clinical Manifestations ♦♦ Mucolipidosis II is a severe type of mucolipidosis. Presentation is similar to the mucopolysaccharidoses

Molecular Basis of Disease ♦♦ GNPTAB (N-acetylglucosamine-1-phosphotransferase, alpha/ beta subunits gene) is the only gene known to be associated with ML II alpha/beta ♦♦ Mutations in the GNPTAB gene disrupt interactions and recognition of the phosphotransferase, resulting in secretion of lysosomal enzymes into the extracellular medium instead of being correctly targeted to the lysosomes

Laboratory ♦♦ Increased activity of lysosomal hydrolases in plasma and other body fluids (in particular: beta-d-hexosaminidase,

582

Treatment ♦♦ Not curable, supportive/symptomatic

Sphingolipidoses GM1 Gangliosidosis Chromosome and Gene Location ♦♦ 3p21.33

Human Genetic Disorders

Inheritance

13-49

♦♦ Autosomal recessive

Tay–Sachs Disease Chromosome and Gene Location

Incidence

♦♦ 15q23–q24

♦♦ 1 in 100,000–200,000

Inheritance

Clinical Manifestations ♦♦ Onset −− Type 1 (Infantile) – between birth and 6 months −− Type 2 (Late infantile or juvenile) – between 7 months and 3 years −− Type 3 (Adult or late-onset) – between 3 and 30 years ♦♦ Psychomotor deterioration ♦♦ Hepatosplenomegaly ♦♦ Skeletal abnormalities (widening of the long bones and ribs, broad short stubby fingers, contractures) ♦♦ Coarse facial features ♦♦ Failure to thrive ♦♦ Gum hypertrophy ♦♦ Macroglossia ♦♦ Macrocephaly ♦♦ Protuberant abdomen ♦♦ Frontal bossing ♦♦ Depressed nasal bridge ♦♦ Hypertelorism ♦♦ Cherry red spot on macula ♦♦ Cardiomyopathy ♦♦ Exaggerated startle response

Molecular Basis of Disease ♦♦ GLB1 is the only gene known to be associated with GM1 gangliosidosis ♦♦ Mutations in the GLB1 gene lead to a deficiency of beta galactosidase enzyme activity and subsequently results in an accumulation of GM1gangliosides, oligosaccharides, and keratan sulfate derivatives

Laboratory ♦♦ Deficient beta galactosidase in leukocytes or cultured fibroblasts ♦♦ Empty-appearing vacuoles on electron microscopy ♦♦ Large foam cells in bone marrow ♦♦ Radiographs show skeletal abnormalities ♦♦ Molecular sequencing of the GLB1 gene is available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Not curable, supportive/symptomatic

GM2 Gangliosidoses (Tay–Sachs Disease and Sandhoff Disease) ♦♦ The GM2 gangliosidoses are a group of disorders caused by excessive accumulation of GM2 ganglioside and other glycolipids in the lysosomes, particularly in neuronal cells

♦♦ Autosomal recessive

Incidence ♦♦ The incidence of Tay–Sachs has been substantially reduced in the Ashkenazi Jewish population in North America as a result of population-based carrier screening programs, education, counseling, and subsequent monitoring and testing of at-risk pregnancies ♦♦ Carrier frequency in Ashkenazi Jewish population: 1 in 30 ♦♦ Carrier frequency in non-Ashkenazi Jewish population: ~1 in 300

Clinical Manifestations ♦♦ Onset typically between 3 and 6 months ♦♦ Other forms may present with later onset (through adulthood) and have a more mild and varied clinical presentation ♦♦ Progressive mental and motor deterioration ♦♦ Exaggerated startle response ♦♦ Cherry red spot on macula ♦♦ Macrocephaly ♦♦ Decreased attentiveness ♦♦ Convulsions ♦♦ Blindness ♦♦ Usually fatal by 4 years of age

Molecular Basis of Disease ♦♦ HEXA, the gene encoding the alpha subunit of the HEX A enzyme, is the only gene associated with hexosaminidase A deficiency ♦♦ Hexosaminidase A is made up of one alpha subunit (encoded by HEXA) and one beta subunit (encoded by HEXB) ♦♦ Mutations in the alpha chain lead to a deficiency of hexosamidase A and mutations in the beta chain lead to Sandhoff disease (see below). Six common mutations include four deleterious mutations, (three null alleles (+TATC1278, +1IVS12, and +1IVS9), one adult-onset  allele (G269S)), and two pseudodeficiency alleles; R247W and R249W. Pseudodeficiency alleles result in low enzyme level on biochemical testing but are not true deficiency alleles ♦♦ Hexosaminidase A deficiency results in the accumulation of GM2-gangliosides in the brain, nervous system, liver, spleen, and heart, leading to the disruption of cell function and cell death

Laboratory ♦♦ Decreased hexosaminidase A in serum, leukocytes, or cultured fibroblasts ♦♦ Pseudodeficiency alleles account for approximately 35% of non-Ashkenazi Jewish individuals and 2% of Ashkenazi

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Jewish individuals identified as carriers through enzymebased testing and may falsely indicate carrier status ♦♦ Carrier screening can be performed by molecular analysis, biochemical analysis, or both ♦♦ Targeted mutation analysis for common mutations and sequence analysis are available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Not curable, supportive/symptomatic ♦♦ Hematopoietic stem cell transplantation (bone marrow or cord blood) is investigational

Sandhoff Disease Chromosome and Gene Location ♦♦ 5q13

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ ~1/300,000 (non-Ashkenazi Jewish) ♦♦ ~1/1,000,000 (Ashkenazi Jewish)

Clinical Manifestations ♦♦ Neurological presentation and clinical course similar to Tay– Sachs (note: Sandhoff does not demonstrate increased incidence in the Ashkenazi Jewish population) ♦♦ Hepatosplenomegaly ♦♦ Skeletal abnormalities ♦♦ Macrocephaly

Molecular Basis of Disease ♦♦ Mutations in HEXB, the gene encoding the beta subunit of the HEX B enzyme, results in deficiencies of both hexosaminidase A and B enzymes ♦♦ Deficiency results in the accumulation of GM2-gangliosides in the brain, nervous system, liver, spleen, and heart, leading to the disruption of cell function and cell death

Laboratory ♦♦ Deficient hexosaminidase A and hexosaminidase B in serum, leukocytes, or cultured fibroblasts ♦♦ Molecular sequence analysis is available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Not curable, supportive/symptomatic

Niemann–Pick Disease, Types A and B Chromosome and Gene Location

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Carrier frequency for type A is increased in the Ashkenazi Jewish population (1/80–1/100), although carrier screening and subsequent prenatal diagnosis have resulted in a decreased incidence in this population

Clinical Manifestations ♦♦ Type A −− Onset typically by 3 months −− Hepatosplenomegaly −− Progressive neurodegeneration −− Interstitial lung disease −− Cherry red spot on macula −− Usually fatal by 3 years of age ♦♦ Type B −− Typically later onset with milder presentation −− Hepatosplenomegaly −− Respiratory insufficiency −− A minority have neurologic involvement −− Life expectancy may extend into adolescence or adulthood

Molecular Basis of Disease ♦♦ Mutations in the SMPD1 gene coding for acid sphingomyelinase result in an accumulation of sphingomyelin in cells and tissues ♦♦ Three common mutations causing type A have been described in the Ashkenazi Jewish population (L302P, R496L, and fsP330) and account for >90% of the mutations in this population ♦♦ Only one common mutation for type B has been described (R608del) and is more common in individuals of North African background

Laboratory ♦♦ Deficiency of acid sphingomyelinase in leukocytes (or lymphocytes) or cultured fibroblasts ♦♦ Targeted mutation analysis for common mutations and sequence analysis are available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Bone marrow transplantation may be able to improve blood counts and reduce liver and spleen volumes. Improvement in neurologic features has not been reported

Niemann–Pick Disease Type C Chromosome and Gene Location

♦♦ 11p15.4–p15.1

♦♦ 18q11–q12 (Niemann–Pick disease type C [NPC1]), 14q24.3 (NPC2)

Inheritance

Inheritance

♦♦ Autosomal recessive

♦♦ Autosomal recessive

Incidence

Incidence

♦♦ 1/250,000

♦♦ 1/150,000

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Human Genetic Disorders

Clinical Manifestations ♦♦ Typically late infantile or juvenile onset (ranges from infantile to adult) ♦♦ Neonatal jaundice ♦♦ Sea-blue histiocytes in marrow ♦♦ Hepatosplenomegaly ♦♦ Progressive neurological deterioration: ataxia, dysarthria, dystonia, dementia, seizures ♦♦ Vertical supranuclear gaze palsy

Molecular Basis of Disease ♦♦ Mutations in two genes (NPC1 and NPC2) result in a complex defect involving cellular lipid trafficking and subsequent cholesterol and glycosphingolipid accumulation in the lysosomes ♦♦ Most patients (~90%) have mutations in the NPC1 gene

Laboratory ♦♦ Delayed induction of cholesterol esterification following LDL uptake ♦♦ Increased filipin staining of accumulated cholesterol in fibroblasts ♦♦ Molecular sequencing of the NPC1 and NPC2 genes is available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Not curable, supportive/symptomatic

Gaucher Disease Chromosome and Gene Location ♦♦ 1q21

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ Type 1: 1/855 (Ashkenazi Jewish) ♦♦ The prevalence is difficult to ascertain in non-Ashkenazi Jewish populations and for types 2 and 3

Clinical Manifestations ♦♦ Type 1 −− Adult onset is most common, though can present at any age −− Disease severity is variable −− Bone disease (osteopenia, bone pain, pathologic fractures) −− Hepatosplenomegaly −− Anemia −− Thromobocytopenia −− Acquired coagulation deficiencies of factor IX, XI, and von Willebrand ♦♦ Type 2 −− Onset is typically within first few months of life −− Strabismus

13-51

−− Hypertonia of neck muscles results in extreme arching of the neck −− Loss of head control −− Hepatosplenomegaly −− Poor sucking and swallowing −− Failure to thrive −− Spasticity −− Seizures −− Usually fatal by 2 years of age ♦♦ Type 3 – Clinically heterogeneous −− Onset typically in adolescence or early adulthood −− Strabismus −− Myoclonus −− Ataxia −− Seizures −− Hepatosplenomegaly −− Life expectancy is extremely variable (5–50 years) and dependent on severity of clinical manifestations

Molecular Basis of Disease ♦♦ Mutations in the GBA gene result in the deficiency of glucocerebrosidase (glucosylceramidase or acid b-glucosidase) and subsequent accumulation of glucocerebroside (glucosylceramide) in the lysosomes ♦♦ There are four common mutations: N370S, L444P, 84GG, IVS2(+1G > A), which account for >90% of the mutations in the Ashkenazi Jewish population ♦♦ Individuals with at least one N370S allele are not predicted to have central nervous system involvement (it is not found in types 2 or 3) and are thought to confer a less severe phenotype when compounded with other mutations

Laboratory ♦♦ Deficiency of glucocerebrosidase activity in leukocytes or cultured fibroblasts (not accurate for carrier determination) ♦♦ Presence of Gaucher storage cells in bone marrow ♦♦ Targeted mutation analysis for common mutations and sequence analysis are available

Treatment ♦♦ Enzyme replacement therapy available since l994 (effective for somatic symptoms but not CNS) ♦♦ Skeletal problems may be treated with limitation of physical activity, prostheses, analgesics, and surgical intervention

Krabbe Disease Chromosome and Gene Location ♦♦ 14q31

Inheritance ♦♦ Autosomal recessive

Incidence ♦♦ 1/100,000

585

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Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Onset typically within first 6 months Extreme irritability and hypersensitivity to external stimuli Feeding difficulties Spasticity Progressive neurologic deterioration Cortical blindness with optic atrophy Deafness Usually fatal by 2 years of age Also late onset variants

Molecular Basis of Disease ♦♦ The GALC gene codes for galactosylceramidase (galactocerebrosidase), a lysosomal enzyme, which degrades galactocerebroside to ceramide and galactose ♦♦ Mutations in the gene cause deficient enzyme activity resulting in an accumulation of enzyme substrates and early destruction of oligodendroglia (type of glial cell that forms the myelin sheath of nerve fibers in the central nervous system)

Laboratory ♦♦ Deficient galactosylceramide beta galactosidase activity in leukocytes or cultured fibroblasts ♦♦ Elevated protein in cerebral spinal fluid ♦♦ Neuroimaging demonstrates progressive, diffuse, and symmetrical, cerebral atrophy ♦♦ Targeted mutation analysis for common mutations and sequence analysis are available ♦♦ Prenatal diagnosis available ♦♦ Newborn screening has been instituted in some states despite lack of effective treatment

Treatment

Essentials of Anatomic Pathology, 3rd Ed.

−− −− −− −−

Slurred speech Blindness Unaware of surroundings Death typically occurs approximately 5 years after the onset of symptoms ♦♦ Juvenile (20–30% of cases) −− Onset typically between 4 and 14 years −− Decline in school performance, behavioral problems −− Clumsiness, gait problems −− Slurred speech −− Seizures −− Death typically by 20 years of age ♦♦ Adult (15–20% of cases) −− Onset typically after puberty and into the sixth decade of life −− Problems in school or job performance, personality changes −− Weakness, loss of coordination, peripheral neuropathy −− Seizures −− Duration of disease may range from a few years to several decades before the patient reaches a vegetative state, and ultimately, death

Molecular Basis of Disease ♦♦ The ARSA (arylsulfatase A) gene is the only known gene associated with MLD ♦♦ Mutations in this gene lead to a deficiency in the enzymatic hydrolysis of sulfatide and subsequent accumulation of sulfatides, mainly within the lysosomes

Laboratory

Incidence

♦♦ Deficient arylsulfatase A enzyme activity in leukocytes or cultured fibroblasts ♦♦ The presence of individuals with pseudodeficiency (unaffected individuals whose ARSA activity in leukocytes is 5–20% of controls) makes establishing a diagnosis of true ARSA deficiency difficult by biochemical analysis alone ♦♦ Increased protein in the cerebrospinal fluid ♦♦ Metachromatic lipid deposits in a nerve or brain biopsy ♦♦ Increased urinary sulfatide excretion ♦♦ Targeted mutation analysis for common mutations and sequence analysis are available ♦♦ Prenatal diagnosis available

♦♦ 1/40,000–1/160,000

Treatment

Clinical Manifestations

♦♦ Not curable, supportive/symptomatic ♦♦ Bone marrow transplantation may be able to slow disease progression when performed prior to symptoms occurring in juvenile and adult onset forms. BMT does not appear to alleviate peripheral nervous system manifestations and has not been shown to be effective in symptomatic patients with the late infantile form. BMT remains controversial due to risks and uncertain long-term effects

♦♦ Hematopoietic stem cell transplantation may slow the course of disease progression in asymptomatic patients and individuals with only minimal neurologic involvement ♦♦ Treatment remains primarily supportive/symptomatic

Metachromatic Leukodystrophy Chromosome and Gene Location ♦♦ 22q13.31–qter

Inheritance ♦♦ Autosomal recessive

♦♦ Late infantile (50–60% of cases) −− Onset typically between 1 and 2 years −− Hypotonia, weakness, clumsiness, frequent falls, toe walking, inability to stand −− Progressive neurologic deterioration −− Increased muscle tone

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Human Genetic Disorders

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Fabry Disease Chromosome and Gene Location ♦♦ Xq22.1

Inheritance ♦♦ X-linked

Incidence ♦♦ 1/40,000 males

Clinical Manifestations ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Onset typically in childhood or adolescence Also cardiac and renal variants with variable presentation Pain in distal extremities (acroparesthesias) Fever due to hypohidrosis (reduced sweating) Corneal opacities Angiokeratomas (Fig. 13.9) Proteinuria; this can lead to end stage renal disease typically occurs in the third to fifth decade ♦♦ Cardiovascular disease ♦♦ Carrier females are usually asymptomatic, but may be as severely affected as males or have an attenuated form of the disease due to random X-inactivation

Molecular Basis of Disease ♦♦ The GLA gene codes for alpha galactosidase A, an enzyme involved in the degradation of glycosphingolipids ♦♦ Mutations in the GLA gene result in the accumulation of globotriaoslyceramide (Gb3) and other glycosphingolipids in bodily fluids, lysosomes, and cell types of various other tissues in organs

Fig. 13.9. Fabry disease – angiokeratomas.

Laboratory ♦♦ Deficient alpha galactosidase A activity in leukocytes, tears, cultured fibroblasts, plasma, or serum (unreliable for carrier determination) ♦♦ Molecular sequence analysis is available ♦♦ Prenatal diagnosis available

Treatment ♦♦ Enzyme replacement therapy ♦♦ Symptoms of peripheral neuropathy may respond to carbamazepine or diphenylhydantoin; however, the neuropathy does not diminish ♦♦ Renal dialysis and transplantation

FAMILIAL CANCER SYNDROMES Familial Adenomatous Polyposis Chromosome and Gene Location ♦♦ 5q21–q22

Inheritance ♦♦ Autosomal dominant ♦♦ 20–25% are the result of new mutations

Incidence ♦♦ 3/100,000

Clinical Manifestations ♦♦ Multiple (>100) polyps early in life (by age 20 over 90% of gene carriers will develop polyps) ♦♦ Polyps progress to colonic carcinoma by age 40 ♦♦ Additional features include congenital hypertrophy of the retinal pigment epithelium (CHRPE) and supernumerary teeth

♦♦ Other tumors may occur [duodenal, thyroid, brain, liver, desmoid tumors (Fig. 13.10), childhood hepatoblastomas] ♦♦ “Gardner syndrome” refers to individuals with familial adenomatous polyposis (FAP) who have extracolonic manifestations such as tumors of the jaw, lipomas, and fibromas

Molecular Basis of Disease ♦♦ Numerous mutations have been identified in the adenomatous polyposis coli (APC) gene; most mutations lead to truncated protein product ♦♦ The protein is thought to be involved in maintaining ­normal apoptosis and decreasing cell proliferation. The APC ­protein may also be involved in maintaining chromosomal stability

Laboratory ♦♦ Direct mutation analysis is available. Linkage testing is also available for families without an identifiable mutation

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Molecular Basis of Disease ♦♦ Two mutations account for ~85% of mutations within the European Caucasian population (Y165C, G382D). Therefore, only ~2% of people with biallelic mutations will have a negative DNA test, when only these two mutations are studied ♦♦ Other founder mutations exist in certain ethnic groups (i.e., Indian, Pakistani) ♦♦ The MYH protein repairs DNA by removing adenine residues that are mispaired with 8-oxoguanine during replication of oxidized DNA. Deficiency in this base excision repair leads to somatic mutations in APC, hence the clinical similarity to FAP ♦♦ Biallelic MYH mutations are identified in up to 30% of individuals with 15–100 polyps and up to 7% with greater than 100 polyps

Laboratory Fig. 13.10. Familial adenomatous polyposis – desmoid tumor.

Treatment/Surveillance

♦♦ Direct mutation analysis for the two common mutations is clinical available; full gene sequencing can also be performed. Predictive genetic testing can be offered once mutations have been identified within a family

♦♦ Genetic consultation is necessary to determine the utility of genetic testing in these families ♦♦ For individuals with a diagnosis of FAP, colectomy is advised when polyps become too numerous to remove or watch, to prevent colorectal carcinoma ♦♦ For individuals who have a positive gene test or who have not had genetic testing and are at risk, flexible sigmoidoscopy every 1–2 years beginning at age 10–12 years through age 35, colonoscopy when polyps are detected. Esophagogastroduodenoscopy should be initiated when colonoscopies are started or by age 25 ♦♦ Annual thyroid palpation is advised ♦♦ Ophthalmologic examination for CHRPE is done if confirmation of diagnosis is sought. These lesions are harmless ♦♦ For children at risk, alpha fetoprotein testing and abdominal palpation is recommended for hepatoblastoma annually until age 6

Treatment/Surveillance

MYH Associated Polyposis Chromosome and Gene Location

Inheritance

♦♦ 1p34.3–p32.1

Incidence

Inheritance

♦♦ 1/55,000 (in United Kingdom)

♦♦ Autosomal recessive

Clinical Manifestations

Incidence

♦♦ The following criteria have been proposed for a making a diagnosis. (The sensitivity and specificity are not known). A diagnosis is made when two major or two minor and one major criterion are fulfilled −− Major criteria (a) Multiple basal cell carcinomas (b) Basal cell nevi (c) Odontogenic keratocyst (d) Polyostotic bone cyst (e) Palmar or plantar pits

♦♦ About 1–2% of the general population are carriers of one MYH mutation

Clinical Manifestations ♦♦ Multiple (>15–100) adenomatous polyps early in life, similar to the presentation of attenuated FAP ♦♦ Polyps are likely to progress to carcinoma if left untreated (80% cumulative risk to age 80 years) ♦♦ Additional features include similar extracolonic manifestations exhibited with FAP

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♦♦ Genetic consultation is necessary to determine the utility of genetic testing in these families ♦♦ For individuals with a diagnosis of attenuated FAP without clear evidence of dominant inheritance, testing for MYH should be offered ♦♦ Treatment/surveillance of families with biallelic MYH mutations should include colonoscopy initiation between ages 25 and 30 years and repeated every 3–5 years thereafter. Esophagogastroduodenoscopy is advised from age 30 to 35 years, every 3–5 years. If adenomas are found, management proceeds akin to that of classical FAP

Basal Cell Nevus Syndrome (Gorlin Syndrome) Chromosome and Gene Location ♦♦ 9q22.3 ♦♦ Autosomal dominant

Human Genetic Disorders

(f) Ectopic calcification (g) Family history of basal cell nevus syndrome −− Minor criteria (a) Congenital skeletal anomaly (b) Bifid, fused, splayed or missing rib (c) Bifid wedged or fused vertebra (d) Head circumference in the 97th percentile (e) Cardiac or ovarian fibroma (f) Medulloblastoma (g) Lymphomesenteric cysts (h) Congenital malformation (i) Cleft lip and/or palate (j) Polydactyly (k) Eye anomaly −− Other (a) Tall stature (b) Frontal bossing with large head (c) Ocular hypertelorism (d) Broad nasal root (e) Enlarged jaw

Molecular Basis of Disease ♦♦ Mutations in PTCH lead to premature stop or frameshift, 20–40% of which arose de novo at conception ♦♦ The protein is thought to be involved in controlling cell fates, patterning, and growth in numerous tissues

Laboratory ♦♦ Molecular genetic testing is available by direct DNA analysis

Treatment/Surveillance ♦♦ Advise regarding avoidance of sun exposure and radiation ♦♦ Screening by dermatologist in puberty and every 4–12 months thereafter with early excision of basal cell cancers ♦♦ Jaw radiograph after the age of 8 years and every 12–18 months thereafter for keratocysts ♦♦ Gynecologic exam done annually in adulthood

Birt–Hogg–Dube Syndrome Chromosome and Gene Location ♦♦ FLCN located at 17p11.2

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ Unknown; under recognized

Clinical Manifestations ♦♦ BHDS manifests cutaneous triad of multiple fibrofolliculomas, trichodiscomas, and acrochordons, which usually develop initially in the third to fourth decade of life. The skin lesions are easily overlooked. Pulmonary cysts (present in 90%) with spontaneous pneumothorax (20%) may be the presenting

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f­ eature. Bilateral and multiple renal tumors may be seen around mid life, and histology is variable; oncocytomas, chromophobe, clear cell, or papillary renal cell carcinomas, and hybrid oncocytic neoplasms have been reported. An average number of renal tumors per patient have been reported as 5.3 with a range of 1–28 tumors. Non-renal malignancies have not been confirmed in this disorder

Molecular Basis of Disease ♦♦ FLCN encodes a protein called folliculin, which appears to be involved in AMPK and TOR signaling

Laboratory ♦♦ Skin biopsy is required to confirm a diagnosis of fibrofolliculomas and trichodiscomas, both of which are fibroepithelial hamartomas of the hair follicles

Treatment/Surveillance ♦♦ Genetic consultation is necessary to determine if clinical genetic testing will be of utility in a given family ♦♦ Surveillance is not indicated for the cutaneous lesions as they are not premalignant ♦♦ Annual imaging of kidneys by MRI or ultrasound has been advised starting at age 35 or 10 years younger than the youngest known renal tumor in the family ♦♦ Renal sparing surgery should be offered due to the propensity for multifocal tumor development ♦♦ Affected individuals should be counseled on the signs, symptoms, and management of spontaneous pneumothorax

Breast/Ovarian Cancer Chromosome and Gene Location ♦♦ 17q12 (BRCA1) ♦♦ 13q12 (BRCA2)

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ Varies by population −− About 1/800 BRCA1 or BRCA2 mutation found in general non-Ashkenazi Caucasian population −− 1/50 Ashkenazi Jewish individuals carry one of three founder mutations in BRCA1 or BRCA2. −− Less is known about mutation frequency in other populations.

Clinical Manifestations ♦♦ Early onset (premenopausal) adenocarcinoma of the breast, often bilateral disease ♦♦ Additionally, ovarian cancer is a prominent feature of BRCA1 families, but not BRCA2 ♦♦ Breast cancer in males is more common in BRCA2 families but also present in BRCA1 families ♦♦ Males carrying a mutated BRCA1 gene are at an increased risk (3.3 relative risk) of developing prostate cancer

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♦♦ Males and females carrying BRCA1or BRCA2 gene are at an increased risk for pancreatic cancer ♦♦ BRCA1 is thought to account for 50% of all familial earlyonset cases (2.5–5% of all breast cancer) and about 80% of inherited breast and ovarian cancer ♦♦ BRCA2 is estimated to account for 17–35% of hereditary breast cancer ♦♦ It is estimated that individuals who carry a BRCA1 or BRCA2 gene mutation may have as high as 56–87% risk of developing breast cancer and 27–63% risk of developing ovarian cancer by age 70, compared with the lifetime general population risk of one-eighth for breast cancer and 1/70 for ovarian cancer

Molecular Basis of Disease ♦♦ Various mutations (deletions, insertion, point mutations) have been identified; most result in truncation or absence of BRCA1 and BRCA2 proteins ♦♦ Both are thought to be tumor suppressor genes

Laboratory ♦♦ Molecular testing available for BRCA1 and BRCA2

Treatment/Surveillance ♦♦ Chemoprophylaxis with tamoxifen or related compounds can be considered, but about two-thirds of breast cancers arising in the context of BRCA1 mutations are “triple negative” (estrogen receptor/progesterone receptor/HER2/neu negative) whereas breast cancers in BRCA2 gene mutations carriers are more like sporadic breast cancers ♦♦ Screening recommendations include monthly breast self examination ages 18–21, annual or semiannual clinical breast exam for ages 25–35, and imagine with mammography alternating with MRI starting at the same age ♦♦ Annual or semiannual screening using transvaginal ultrasound and serum CA-125 ages 25–35 (caution: less than half of early stage ovarian tumors produce elevated levels of CA-125; there is no evidence of efficacy of screening for ovarian cancer); oophorectomy is advised after childbearing is completed ♦♦ Primary peritoneal cancer and fallopian tube cancers also occur with increased frequency in BRCA1/2 gene mutations carriers ♦♦ For prostate cancer surveillance in BRCA1 and BRCA2 carriers, rectal examination and PSA level are offered annually ♦♦ Prophylactic mastectomy and/or oophorectomy are both effective in reducing cancer risks

Lynch Syndrome ♦♦ Sometimes called hereditary nonpolyposis colon cancer syndrome or HNPCC

Chromosome and Gene Location ♦♦ Caused by of mutations in one of four DNA mismatch repair genes −− 3p21.3 (hMLH1) −− 2p22–p21 (hMSH2)

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−− 2p16 (hMSH6) −− 7p22 (hPMS2)

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ Accounts for 1–3% of all colon cancer

Clinical Manifestations ♦♦ Colorectal cancer −− Two-third in right colon −− Average age at diagnosis is 45 −− 80% lifetime risk for colon cancer ♦♦ Endometrial adenocarcinoma lifetime risk varies by gene but may be up to 60% for MSH2 mutation carriers ♦♦ Increased risk for ovarian, transitional cell renal collecting system, ureter, stomach, small bowel, hepatobiliary tract, and pancreatic cancers. Also at an increased risk for sebaceous carcinomas, basal and squamous cell carcinomas of the skin ♦♦ Muir–Torre syndrome is a variant form of Lynch syndrome characterized by a combination of benign or malignant sebaceous skin tumors and internal malignancy due to mutations in MMR gene ♦♦ Turcot syndrome is characterized by brain tumor (glioblastoma multiforme) and colorectal tumors, and is also associated with Lynch syndrome ♦♦ The following Amsterdam criteria were developed to define HNPCC. All four conditions need to be fulfilled to meet the Amsterdam criterion. However, the criteria have been found to be over-restrictive for clinical use −− Three cases of colon cancer of which two people are first degree relatives of the third person −− Colon cancer occuring in two generations −− One colon cancer diagnosed before age 50 −− The family does not have FAP ♦♦ Note that only about half of families that fulfill these strict criteria actually have defective DNA mismatch repair (i.e., have Lynch syndrome). Hence, there has been a call for the retirement of the term, HNPCC, which includes Lynch syndrome and families that do not have DNA mismatch repair defects

Molecular Basis of Disease ♦♦ The products of the genes hMLH1, hMSH2, hMSH6, and hPMS2 participate in a DNA mismatch repair complex ♦♦ The hMLH1 and hMSH2 account for most of the mutations found in Lynch syndrome families to date ♦♦ Colon cancer is a multistep process, meaning that a number of mutations in different genes need to occur before the onset of colon cancer ♦♦ When a mutation occurs in a mismatch repair complex, the ability to repair other random mutations is compromised, thus leading to an accumulation of mutations (microsatellite instability [MSI])

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♦♦ The mutations may inactivate tumor suppresser genes and lead to the subsequent penetrance of colon cancer

−− Fibromas −− Hemangiomas and progressive macrocephaly −− Mild to moderate developmental delay may be present at an early age

Laboratory ♦♦ Nearly all colorectal tumors in Lynch syndrome show widespread MSI. MSI in combination with immunostaining is a useful tool to identify which gene may be involved ♦♦ Immunohistochemistry (IHC) can be utilized on the tumor ­tissue to identify the presence or absence of protein expression for hMLH1, hMSH2, hMSH6, and hPMS2 proteins. IHC helps to determine the gene or interest for a given family ♦♦ Mutational analysis for point mutations and large genomic rearrangements (duplications and deletions) is available ♦♦ Histological appearance of tumors is nondiagnostic, but increase in tumor infiltrating lymphocytes and mucinous histology is characteristic of tumors with MSI

Treatment/Surveillance ♦♦ For asymptomatic, suspected or known gene carriers, a full colonoscopy every 1–3 years beginning at ages 20–25 ♦♦ Annual screening for endometrial cancer beginning ages 30–35 ♦♦ Annual urinalysis and cytology beginning at age 25–35 years ♦♦ Annual skin surveillance ♦♦ Consideration of upper gastrointestinal endoscopy for families in which gastric cancer has occurred ♦♦ Prophylactic subtotal colectomy and hysterectomy and oophorectomy after childbearing reduces risk

Molecular Basis of Disease ♦♦ Mutations in PTEN gene thought to disrupt the tyrosine/ dual-specificity phosphatase domain of this gene

Laboratory ♦♦ Molecular mutation analysis is available

Treatment/Surveillance ♦♦ Surveillance for thyroid masses, breast cancer beginning age 20 ♦♦ May consider prophylactic mastectomy for women at risk ♦♦ Endometrial cancer screening beginning around age 35 years ♦♦ Annual urinalysis to help detect renal carcinoma ♦♦ Annual physical examination starts at age 18 years for skin changes and baseline thyroid ultrasound examination

Li–Fraumeni Syndrome Chromosome and Gene Location ♦♦ 17p13.1 (TP53) ♦♦ And rarely, 22q12.1 (CHEK2)

Inheritance ♦♦ Autosomal dominant

Cowden Syndrome (Multiple Hamartoma Syndrome) Chromosome and Gene Location

Incidence

♦♦ 10q23 (PTEN)

Clinical Manifestations

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ Unknown

Clinical Manifestations ♦♦ Multiple hamartomas including −− Cobblestone-like hyperkeratotic papules of gingiva and buccal mucosa −− Fibroadenomatous breast enlargement −− Hamartomatous polyps of the stomach, small bowel, and colon −− Cerebellar gangliocytomatosis −− Breast cancer in 25–50% of female gene carriers −− May also be increased risk for endometrial cancer and thyroid adenoma and carcinomas ♦♦ In children −− Mucocutaneous lesions −− Lipomas

♦♦ Rare ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Soft tissue sarcomas Early onset breast cancer Adrenocortical and brain tumors Osteosarcomas Leukemia Risk of developing invasive cancer is approximately 50% by age 30 and 90% by age 70 ♦♦ Classical definition requires one patient with sarcoma under age 45; a first degree relative under age 45 with any cancer, and a third affected first or second degree relative with either sarcoma at any age or any cancer under age 45. About 50% of families meeting these criteria have identifiable mutation in TP53

Molecular Basis of Disease ♦♦ Mutation types include nonsense mutations and splice site mutations, which generate truncated protein products

Laboratory ♦♦ Mutation analysis available for TP53 and CHEK2, otherwise no other specific laboratory findings

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Treatment/Surveillance

Inheritance

♦♦ Efficacy not well established, but usually includes monthly self breast exam beginning in adulthood, clinician exam of breasts every 6 months, and imaging of breasts as well. There is no guideline on screening for sarcomas, leukemias, brain tumors, adrenal tumors. Careful annual exam with aggressive evaluation of all symptoms is indicated

♦♦ Autosomal dominant

Multiple Endocrine Neoplasia Type 1 Chromosome and Gene Location ♦♦ 11q13

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ 1/5,000–1/50,000 live births

Clinical Manifestations (Also See Chapter 20) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hyperparathyroidism Peptic ulcer disease Parathyroid adenomas Pancreatic islet cell tumors (most commonly gastrinomas) Insulinoma Pituitary adenoma (prolactinoma) Features are relatively consistent within families

Molecular Basis of Disease ♦♦ MEN1 encodes a transcript called menin ♦♦ Numerous frameshift, nonsense, missense, and in-frame deletions have been reported ♦♦ Function of protein is not known

Laboratory ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Elevated ACTH Abnormal secretin test Hypoglycemia Hypergastrinemia Hyperparathyroidism Glucose intolerance Molecular analysis is available

Incidence ♦♦ 1/30,000 ♦♦ About 5–10% of thyroid cancers are of the medullary type, of these, 20% are due to germline RET mutations

Clinical Manifestations (Also See Chapter 20) ♦♦ MEN2A −− Medullary thyroid carcinoma (>95%) −− Pheochromocytoma (>50%) −− Hyperparathyroidism (parathyroid hyperplasia or adenoma) (15–30%) ♦♦ MEN2B −− Same features as MEN2A but earlier onset (10 years) −− Parathyroid disease is rare −− Additional findings include (a) Mucosal neuromas (Fig. 13.11) (b) Thickened corneal nerves (c) Marfanoid habitus (d) Gastrointestinal involvement ♦♦ Familial medullary thyroid carcinoma (FMTC) −− Medullary thyroid carcinoma only −− More indolent than MEN2A or 2B

Molecular Basis of Disease ♦♦ Mutations in cysteine residues of extracellular binding domain in exons 10, 11, 13, 14, and 15 of the RET protooncogene account for most of the cases of MEN2A and FMTC ♦♦ A single point mutation in RET exon 16 (M918T) is the most common cause for MEN2B ♦♦ Mutations within these exons of the RET protooncogene account for ~95% of MEN2A families, 85% of FMTC, and 95% of MEN2B families

Treatment/Surveillance ♦♦ Screening recommendations include an annual evaluation for prolactin, cortisol, glucose, calcium, phosphorus ♦♦ Physical exam with endocrinologic review of systems ♦♦ Imaging of pituitary and pancreas are now available

Multiple Endocrine Neoplasia Types 2A, 2B and Familial Medullary Thyroid Carcinoma Chromosome and Gene Location ♦♦ 10q11.2 (RET protooncogene)

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Fig.  13.11. Multiple endocrine neoplasia type 2b – mucosal ganglioneuroma.

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Laboratory

Molecular Basis of Disease

♦♦ Mutations in RET ♦♦ Elevated calcitonin after pentagastrin stimulation ♦♦ Metanephrines may be elevated if pheochromocytoma is present ♦♦ Parathyroid hormone and calcium elevation may also be present

♦♦ Disorder is due to mutations in the serine threonine kinase, STK11 ♦♦ About 50% are due to a new mutation

Treatment/Surveillance ♦♦ Screening recommendations include genetic testing for at risk individuals ♦♦ For positive individuals, prophylactic thyroidectomy and screening for pheochromocytoma and hyperparathyroidism is indicated

Peutz–Jeghers Syndrome Chromosome and Gene Location ♦♦ 19p13.3 (STK11)

Inheritance ♦♦ Autosomal dominant

Incidence ♦♦ 1/125,000–1/50,000 births

Clinical Manifestations ♦♦ Numerous pigmented spots found on lips and buccal mucosa (more rarely on face, forearms hands, feet, and perianal area) (Fig. 13.12) ♦♦ Multiple gastrointestinal hamartomatous polyps found in the jejunum (malignant transformation not common) ♦♦ Risk of any malignancy estimated as 67–85% by age 70 years ♦♦ Most reported cancers are breast or gastrointestinal tract in patients who are under 40 years ♦♦ Also reported are cancers of the cervix, ovaries, testis, ­pancreas, lung, uterus

Laboratory ♦♦ Polyps can have a unique cellular morphology imparting branching tree-like appearance of mucosa with interdigitating smooth muscle ♦♦ Molecular testing available

Treatment/Surveillance ♦♦ Removal of polyps if feasible to prevent small bowel intussusception ♦♦ Screening includes upper and lower GI endoscopy and small bowel X-rays at age 10. Regular breast examination and imaging starting age 25–35 years ♦♦ Gynecologic screening with ultrasound starting at age 20 ♦♦ Testicular examination annually starting at age 10

Retinoblastoma Chromosome and Gene Location ♦♦ 13q14 (RB1)

Inheritance ♦♦ Approximately 60% are unilateral and sporadic ♦♦ 15% are unilateral and hereditary ♦♦ 25% are bilateral and hereditary and autosomal dominant with 90% penetrance ♦♦ In inherited cases, an affected individual will have a 50% risk of passing the gene on the their offspring ♦♦ One altered gene is NOT sufficient to cause retinoblastoma (RB) ♦♦ Another sporadic event needs to occur in this gene to cause RB (thus incomplete penetrance) ♦♦ Individuals who carry the gene and do not have RB still have a 50% risk of passing the gene on their offspring

Incidence ♦♦ 1/15,000–1/20,000 live births

Clinical Manifestations ♦♦ Strabismus and/or leukocoria, multifocal, and bilateral tumors of the retina ♦♦ Other secondary cancers include −− Osteosarcomas −− Fibrosarcomas −− Melanomas ♦♦ May also be at an increased risk for lung, prostate, and breast cancer

Molecular Basis of Disease Fig. 13.12. Peutz–Jegher syndrome with freckles on lips.

♦♦ Numerous large and small deletions as well as point mutations have been found in the RB1 gene

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♦♦ The protein is involved in cell cycle and cell growth regulation

Laboratory ♦♦ Deletions and point mutations are found in RB1 (molecular mutation analysis and FISH analysis are available)

Treatment/Surveillance ♦♦ Surgical options include enucleation, cryosurgery, photo­ coagulation ♦♦ Chemotherapy and radiation are also utilized ♦♦ Screening includes ophthalmologic examination at birth and every 4–6 weeks for 3 months, then at increasing intervals until age 13, then annual or semiannual thereafter

von Hippel–Lindau Chromosome and Gene Location ♦♦ 3p25–26 (VHL)

Inheritance ♦♦ Autosomal dominant ♦♦ Approximately 100% penetrant by age 65

Incidence ♦♦ 1/36,000

Clinical Manifestations (Used Prior to Advent of Molecular Testing) ♦♦ Diagnosis of von Hippel–Lindau (VHL) if patient has one symptom from section A plus one symptom from section B or two symptoms from section A or a family history of VHL and one symptom from either section −− Section A (a) Retinal hemangioblastomas (45–59%) (b) Cerebellar hemangioma (44–72%) (c) Spinal hemangiomas (13–59%) −− Section B (a) Pheochromocytoma (15%) (b) Pancreatic cystic disease (c) Cystadenoma of the epididymis (10–26%) (d) Renal cysts (60%) (e) Renal carcinoma

Molecular Basis of Disease ♦♦ Numerous deletions, insertions, nonsense, and missense mutations in VHL ♦♦ VHL is a tumor suppressor gene ♦♦ The gene product functions to negatively regulate trans­ cription

Laboratory ♦♦ Mutation analysis of VHL

Treatment/Surveillance ♦♦ For hemangioblastomas of the eye, treatment with laser, photocoagulation may be used. Surgery is utilized for symptomatic hemangioblastomas of the central nervous system

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♦♦ Nephron-sparing surgery is used for renal tumors greater than 3 cm in size ♦♦ Screening recommendations include −− Annual physical exam with neurologic evaluation for signs of cerebellar or cord lesions −− Annual ophthalmologic examination, blood pressure check, red blood cell count for polycythemia, urinalysis, fractionated metanephrines −− Baseline MRI imaging of CNS and cord at age 11, with repeat studies guided by clinical symptoms −− Annual imaging no later than age 16 for kidneys and pancreas by CT and/or ultrasound

Wilms Tumor Chromosome and Gene Location ♦♦ 11p13 (WT1) ♦♦ 11p15.5 (associated with Beckwith–Weidemann syndrome, although a specific gene causing Wilms tumor has not been identified here) ♦♦ Plus several additional loci by linkage

Inheritance ♦♦ Uncommon: most Wilms tumors are sporadic. 1–2% of patients with Wilms tumor have a family history of Wilms tumor

Incidence ♦♦ 1/10,000 in the general population −− Fewer than 5% of apparently sporadic Wilms tumors have germline mutations in WT1. Presence of germline WT1 mutations associated with earlier age at diagnosis (age 1 vs. age 4) and increased chance of being bilateral (38 vs. 5%)

Clinical Manifestations ♦♦ Wilms tumor is a nephroblastoma. Tumor development requires two hits to the WT1 gene: one germline mutation and another somatic mutation ♦♦ 2–3% of Wilms tumor occurs as part of a multiple congenital anomaly syndrome. Deletions that lead to hemizygosity (one copy) of the gene WT1 are associated with WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation) ♦♦ Missense mutations in WT1 zinc finger region lead to Denys–Drash syndrome, which includes male pseudohermaphrodism and nephropathy progressing to renal failure ♦♦ The 11p15.5 locus is subject to genomic imprinting ♦♦ Paternal UPD of chromosome 11p15 (two copies of the gene from the father) leads to Beckwith–Weidemann syndrome (overgrowth condition with hemihypertrophy, macroglossia, omphalocele, abdominal organomegaly, ear pits and creases and predisposition to Wilms tumor)

Molecular Basis of Disease ♦♦ The WT1 gene product is a developmentally regulated transcription factor of the zinc finger family, which is expressed primarily in the gonads and kidneys, it is thought to be a

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tumor suppressor gene, which binds to p53 gene and suppresses expression

Laboratory ♦♦ Molecular testing available

Treatment/Surveillance ♦♦ Surgery, chemotherapy, and radiation therapy ♦♦ Screening includes abdominal exams every 1–2 months and ultrasound every 4–6 months through age 7 years

MITOCHONDRIAL DISORDERS ♦♦ Mitochondria are cellular organelles, which generate energy for cellular processes by producing ATP by means of the electron-transport chain and the oxidative-phosphorylation system (the “respiratory chain”). The respiratory chain is located in the inner mitochondrial membrane. It consists of five multimeric protein complexes −− Reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase–ubiquinone oxidoreductase (complex I, 45 subunits) −− Succinate dehydrogenase–ubiquinone oxidoreductase (complex II, four subunits) −− Ubiquinone–cytochrome c oxidoreductase (complex III, 11 subunits) −− Cytochrome c oxidase (complex IV, 13 subunits) −− ATP synthase (complex V, 16 subunits)

Chromosome and Gene Location ♦♦ Apart from the nucleus, mitochondria are the only cellular organelles that contain their own DNA (called mtDNA) for synthesizing RNA and proteins. Cells contain hundreds to thousands mitochondria, and each has approximately five mitochondrial genomes ♦♦ The mtDNA contains 37 genes, but most of the gene products (approximately 1,000) required for mitochondrial functioning are encoded by nuclear DNA (nDNA) and imported from the cytoplasm ♦♦ Mitochondrial DNA is a double-stranded circular molecule, which encodes 13 protein respiratory chain subunits and 24 RNAs (two ribosomal RNAs and 22 transfer RNAs) required within the mitochondria for translation of the protein-coding units

Inheritance ♦♦ Mitochondrial inheritance (mtDNA) (Maternal inheritance) −− Generally, all mitochondria in the zygote are derived from the ovum. Therefore, a mother carrying an mtDNA mutation passes it onto all her children, but only her daughters will transmit it to their offspring. Most mtDNA-related diseases are maternally inherited, but there are exceptions. The occurrence of large deletions is almost always sporadic, probably taking place in oogenesis or early embryogenesis −− Homoplasmy refers to the presence of all normal or all mutant mitochondrial DNA −− Heteroplasmy: mtDNA pathogenic mutations are present in some but not all mtDNA molecules in each cell.

As a result, cells and tissues harbor both normal (wildtype) and mutant mtDNA −− A minimal number of mutant mtDNAs must be present before oxidative dysfunction occurs and clinical signs become apparent: threshold effect −− During mitotic segregation, the random redistribution of organelles during cell division might alter the proportion of mutant mtDNAs received by daughter cells; if the pathogenic threshold in a previously unaffected tissue is surpassed, the phenotype might also change. This underlies the age-related and tissue-related variability of clinical features in mtDNA-related diseases ♦♦ Mendelian inheritance −− Most mitochondrial dysfunction is due to alterations in nuclear genes and is inherited according to Mendelian laws with autosomal recessive pattern thought to be the most common

Incidence ♦♦ Mitochondrial diseases are not rare; incidence 1:10,000 live births

Clinical Manifestations ♦♦ Nearly all tissues depend on oxidative metabolism. Therefore, mitochondrial diseases are complex multisystem disorders, which include a variety of neurologic, ophthalmologic, cardiac, endocrine, gastrointestinal, and pulmonary manifestations. Specific examples are provided below

Molecular Basis of Disease ♦♦ Mutations in mtDNA can affect specific structural respiratory chain proteins or the synthesis of all/many mitochondrial proteins (mutations in RNA genes, or mtDNA rearrangements) ♦♦ Examples of the clinical manifestation of various mutation types are provided below Respiratory-chain disorders due to defects in mtDNA ♦♦ Point mutations in protein-encoding genes −− Neurogenic weakness, ataxia, and retinitis pigmentosa (NARP) ♦♦ Mutation in transfer RNA −− Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (a) Seizures (b) Stroke-like episodes

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(c) Psychomotor regression (d) Weakness and exercise intolerance (e) Intestinal pseudoobstruction (f) Sensorineural hearing loss −− Myoclonic Epilepsy with Ragged-Red Fibers (MERRF) (a) Myoclonus (b) Seizures (c) Cerebellar ataxia (d) Mitochondrial myopathy ♦♦ Mutation in messenger RNA −− Leber Hereditary Optic Neuropathy (LHON) (a) Bilateral visual loss (b) Central scotomas (c) Abnormal color vision ♦♦ Mutation in ribosomal RNA −− Aminoglycoside-induced non-syndromic deafness ♦♦ Rearrangements/deletions in mtDNA −− Kearns–Sayre syndrome (KSS) (a) Chronic progressive external ophthalmoplegia (b) Ptosis (c) Retinal degeneration (d) Heart block Nuclear encoded mitochondrial diseases, which exhibit Mendelian inheritance (examples) ♦♦ Structural OXPHOS gene defects −− Complex I deficiency (a) Leigh (-like) syndrome – NDUFS4 (NADH dehydrogenase (ubiquinone) Fe–S protein), NDUFS7, NDUFS8 genes * Progressive central nervous system neurological deterioration * Characteristic radiographic features with symmetric involvement of brainstem and basal ganglia (b) Hypertrophic cardiomyopathy and encephalomyopathy – NDUFS2 gene (c) Macrocephaly, leukodystrophy, and myoclonic epilepsy – NDUFV1 gene

−− Complex II deficiency (all complex II enzymes are nuclear encoded [none are in the maternally inherited genome]) (a) Leigh (-like) syndrome – flavoprotein (Fp) gene ♦♦ Nonstructural OXPHOS gene defects −− Intergenomic (mitochondrial and nuclear DNA) communication defects (a) Mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) *  Mutations in thymidine phosphorylase gene *  Ophthalmoparesis *  Peripheral neuropathy *  Leukoencephalopathy *  Gastrointestinal symptoms −− Assembling defects (a) Complex IV deficiencies (Leigh syndrome, mutations in SURF1 gene) −− Homeostasis and import defects (a) Deafness-dystonia syndrome – DDP gene (involved in protein transport) *  X-linked recessive *  Sensorineural hearing loss *  Dystonia *  Dementia *  Psychotic features *  Optic atrophy

Laboratory ♦♦ Biochemical investigations – elevated serum and cerebrospinal fluid lactate ♦♦ Tissue evaluation – Ragged-red fibers in skeletal muscle, defective oxidative phosphorylation on biopsied (affected) tissue ♦♦ Electromyography, nerve conduction studies – myopathic potentials, axonal, and demyelinating peripheral neuropathy ♦♦ ECG, ECHO – cardiac conduction defects, cardiomyopathy ♦♦ Mitochondrial and nuclear gene mutations

Treatment ♦♦ Supportive/symptomatic

SUGGESTED READING Online Resources GeneReviews – http://www.geneclinics.org. Online Mendelian Inheritance in Man (OMIM) – http://www.ncbi.nlm. nih.gov.

General Genetic Resources Charles R. Scriver, et  al. (eds.). The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.

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David L. Rimoin, Michael Connor J, Reed E. Pyeritz, Emery AEH, (eds.). Emery and Rimoin’s Principles and Practice of Medical Genetics. 5th ed. New York: Churchill Livingstone, 2007. Jones KL. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Philadelphia: Elsevier, 2006.

Chromosomal Disorders ACOG Practice Bulletin – Clinical Management Guidelines for Obstetrician–Gynecologists. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109:217–227.

Human Genetic Disorders

De Decker HP, Lawrenson JB. The 22q11.2 deletion: from diversity to a single gene theory. Genet Med 2001;3:2–5. Duker NJ. Chromosome breakage syndromes and cancer. Am J Med Genet 2002;115:125–129. Gardner RJ, Sutherland G. Chromosome Abnormalities and Genetic Counseling. New York: Oxford University Press, 2004. Horsthemke B, Wagstaff J. Mechanisms of imprinting of the Prader–Willi/ Angelman region. Am J Med Genet A 2008;146A:2041–2052. Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2001;2:446–457. Mitchell EB, et al. Ready reference to common segmental aneusomies by syndromic names, major features and chromosomal locations. J Assoc Genet Technol 2008;34:5–7.

Trinucleotide Repeat Disorders Evidente VG, Gwinn-Hardy KA, Caviness JN, Gilman S. Hereditary ataxias. Mayo Clinic Proc 2000;75:475–490. Shao J, Diamond MI. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet 2007;16:R115–123. Wenstrom KD. Fragile X and other trinucleotide repeat diseases. Obstet Gynecol Clin North Am 2002;29:367–388.

Neuromuscular Disorders Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet 2002;111:477–500. Saifi GM, Szigeti K, Snipes GJ, et al. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot– Marie–Tooth disease and related peripheral neuropathies. J Invest Med 2003;51:261–268.

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Other Genetic Disorders Kulczycki LL, Kostuch M, Bellanti JA. A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype–phenotype manifestations. Am J Hum Genet 2003;116A: 262–267. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol 2004;19:643–649. Watson MS, Cutting GR, Desnick RJ, et  al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 2004;6:387–391.

Metabolic Disorders: Inborn Errors of Metabolism Blau N, Duran M, Blaskovics M, Gibson KM, (eds.). Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Verlag, Berlin, Heidelberg, New York: Springer, 2003. Fearing MK, Levy HL. Expanded newborn screening using tandem mass spectrometry. Adv Pediatr 2003;50:81–111. Fernandes J, Saudubray JM, van den Berghe G, (eds.). Inborn Metabolic Diseases Diagnosis and Treatment. 3rd ed. Verlag, Berlin, Heidelberg, New York: Springer, 2000. Rinaldo P, Lim JS, Tortorelli S, Gavrilov D, Matern D. Newborn screening of metabolic disorders: recent progress and future developments. Nestle Nutr Workshop Ser Paediatr Program. 2008;62:81–93; discussion 93–96. Seashore MR, Rinaldo P. Metabolic disease of the neonate and young infant. Semin Perinatol 1993;17:318–329.

Lysosomal Storage Diseases

Zatz M, de Paula F, Starling A, et al. The 10 autosomal recessive limbgirdle muscular dystrophies. Neuromuscul Disord 2003;13:532–544.

Beck M. New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 2007; 121:1–22.

Skeletal Disorders

Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disorders in the newborn (review). Pediatrics 2009;123:1191–1207.

Kimonis V, et  al. Genetics of craniosynostosis. Semin Pediatr Neurol 2007;14:150–161. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363: 1377–1385. Wilkie AO, Patey SJ, Kan SH, et  al. FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet 2002;112:266–278.

Connective Tissue Disorders Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-B receptor. N Engl J Med 2006;355:788–798. Milewicz DM, Guo DC, Tran-Fandulu V, et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 2008;9:283–302.

Hematologic Disorders Old JM. Screening and genetic diagnosis of haemoglobin disorders. Blood Rev 2003;17:43–45. Pruthi RK. Hemophilia: a practical approach to genetic testing. Mayo Clin Proc 2005;80:1485–1499. Schrier SL. Pathophysiology of thalassemia. Curr Opin Hematol 2002;9: 123–126. Thein SL. Genetic insights into the clinical diversity of beta thalassaemia. Br J Haematol 2004;124:264–274.

Familial Cancer Syndromes Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol 2001;13:44–51. Boardman LA. Heritable colorectal cancer syndromes: recognition and preventive management. Gastroenterol Clin North Am 2002;31: 1107–1131. Classon M, Harlow E. The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002;2:910–917. Dome JS, Coppes MJ. Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002;14:5–11. Eng C. PTEN: One gene, many syndromes. Hum Mutat 2003;22:183–198. Fleischmann C, Peto J, Cheadle J, et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int J Cancer 2004;109:554–558. Frank TS, Deffenbaugh AM, Reid JE, et  al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002;20:1480–1490. Leggett BA, Young JP, Barker M. Peutz–Jeghers syndrome: genetic screening. Expert Rev Anticancer Ther 2003;3:518–524. Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes – second edition. J Natl Cancer Inst Monogr 2008;38:1–93.

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Markey K, Axel L, Ahnen D. Basic concepts for genetic testing in common hereditary colorectal cancer syndromes. Curr Gastroenterol Rep 2002; 4:404–413. Robbins DH, Itzkowitz SH. The molecular and genetic basis of colon cancer. Med Clin North Am 2002;86:1467–1495. Sims KB. Von Hippel–Lindau disease: gene to bedside. Curr Opin Neurol 2001;14:695–703. Varley JM. Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 2003;21:313–320. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348:2339–2347.

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Mitochondrial Disorders DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656–2668. Haas Rh, Parikh S, Falk Mj, Saneto Rp, Wolf Ni, Darin N, Wong L-J, Cohen Bh, Naviaux Rk. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94:16–37. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2007;2:342–352. Van den Heuvel L, Smeitink J. The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases. Bioessays 2001;23: 518–525.

Part II Organ Systems

14 Neuropathology Eyas M. Hattab, md, Matthew C. Hagen, md, phd, Bernd W. Scheithauer, md, and Arie Perry, md

CONTENTS

I. Normal Histology/General Reactions to Injury............................14-5 Normal Cellular Constituents.........................14-5 Neurons (Ganglion Cells, Neurocytes).........................................14-5 Astrocytes................................................14-5 Oligodendrocytes....................................14-5 Microglia.................................................14-5 Ependymal cells......................................14-5 Choroid Plexus........................................14-5 Common and Unique Special Stains..............14-5 Macrophage/Microglial Reactions..................14-5 Gitter Cells..............................................14-5 Microglial Activation (Rod Cells, Microglial Nodules)...........................14-6 Gliosis (Reactive Astrocytosis)........................14-6 Acute/Subacute Gliosis...........................14-6 Chronic Gliosis........................................14-6 Pilocytic/Piloid Gliosis............................14-6 Cerebral Edema................................................14-6 Vasogenic Edema....................................14-6 Cytotoxic Edema.....................................14-6 Hydrocephalus..................................................14-7 Herniation Syndromes.....................................14-7 Cingulate (Subfalcine) Herniation........14-7 Uncal (Transtentorial) Herniation........14-7 Tonsillar Herniation...............................14-7 Duret (Secondary Brainstem) Hemorrhage.......................................14-7

II. Gliomas.............................................14-7 Key Features in Differential Diagnosis of CNS Tumors............................................14-7

Diffuse (Infiltrative) Astrocytomas.................14-9 Cytologic/Histologic Variants................14-9 Architectural Variants..........................14-10 Prognostic Variables.............................14-10 Grading Schemes..................................14-11 Grade II Astrocytoma (Fibrillary Astrocytoma)....................................14-11 Grade III Astrocytoma (Anaplastic Astrocytoma)...............14-12 Grade IV Astrocytoma (Glioblastoma)..................................14-12 Circumscribed Astrocytomas........................14-12 Pilocytic Astrocytoma (WHO Grade I)................................14-12 Pleomorphic Xanthoastrocytoma (WHO Grade II–III)........................14-14 Subependymal Giant Cell Astrocytoma (WHO Grade I).........14-16 Oligodendroglioma (WHO Grade II-III)..................................14-17 Mixed Oligoastrocytoma (WHO Grade II-III)..................................14-18 Ependymoma (WHO Grade I-III)................14-18 Subependymoma (WHO Grade I)................14-21 Astroblastoma (WHO Grade I)....................14-22 Chordoid Glioma of the Third Ventricle (WHO Grade II).......................14-23 Angiocentric Glioma (WHO Grade I)..........14-23

III. Neuronal/Glioneuronal Neoplasms.......................................14-25

Derivations/Definitions Used in Neuronal Tumors..................................14-25

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_14, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Ganglion Cell Tumors (Ganglioglioma/ Gangliocytoma) (WHO Grade I).............14-25 Papillary Glioneuronal Tumor (WHO Grade I).........................................14-27 Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle (WHO Grade I).........................................14-28 Central Neurocytoma and Extraventricular Neurocytoma (WHO Grade II)........................................14-28 Dysembryoplastic Neuroepithelial Tumor (DNT) (WHO Grade I).................14-29 Paraganglioma (WHO Grade I)...................14-30

IV. Pineal Parenchymal Tumors.............14-31 Pineocytoma (WHO Grade I).......................14-31 Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grades II–III)................................14-32 Pineoblastoma (WHO Grade IV).................14-32 Papillary Tumor of the Pineal Region (WHO Grades II–III)................................14-32

V. Embryonal Tumors............................14-34 Medulloblastoma/PNET (WHO Grade IV)...................................................14-34 Atypical Teratoid/Rhabdoid Tumor.............14-34 Olfactory Neuroblastoma (WHO Grade III)......................................14-35 Retinoblastoma...............................................14-35

VI. Choroid Plexus Neoplasms..............14-37 Choroid Plexus Papilloma (WHO Grade I).........................................14-37 Choroid Plexus Carcinoma (WHO Grade III)......................................14-38

Papillary Craniopharyngioma (WHO Grade I)................................14-43 Germ Cell Tumors..........................................14-44 Lymphoma/Leukemia....................................14-44 Primary CNS Lymphoma....................14-44 Secondary (Systemic) Lymphoma/ Leukemia..........................................14-44 Metastases.......................................................14-44

IX. Trauma.............................................14-45 Closed Head Injury........................................14-45 Open Head Injury..........................................14-45 Blunt Head Injury..........................................14-46 Skull Fractures......................................14-46 Epidural Hematoma.............................14-46 Subdural Hematoma............................14-46 Subarachnoid Hemorrhage.................14-46 Cortical Contusion................................14-46 Diffuse Axonal Injury .........................14-46 Pontomedullary Transection (Brainstem Avulsion).......................14-46 Gunshot Wounds............................................14-46 Penetrating Wound...............................14-46 Perforating Wound...............................14-46 Entrance Wound...................................14-46 Exit Wound............................................14-46 Bullet Track: Low Velocity Missiles..............................................14-46 Secondary Track...................................14-46 Spinal Cord Trauma......................................14-47 Upper Cervical Injuries.......................14-47 C4–C8 Injuries......................................14-47 Cervical Spondylosis............................14-47 Central Cord Necrosis..........................14-47 Posttraumatic Syringomyelia..............14-47

X. Ischemic/Anoxic/Vascular Disorders.........................................14-48 Meningioma (WHO Grade I)........................14-38

VII. Meningeal Neoplasms......................14-38

Atypical Meningioma (WHO Grade II).......14-39 Malignant (Anaplastic) Meningioma (WHO Grade III)......................................14-40 Hemangiopericytoma (WHO Grade II or III)..........................................14-40 Other Primary Mesenchymal Neoplasms....14-41 Benign....................................................14-41 Sarcomas...............................................14-42 Dural Metastases..................................14-42 Inflammatory Myofibroblastic Tumor (IMT)....................................14-42

VIII. Other Nonglial Neoplasms..............14-42 Hemangioblastoma (WHO Grade I)............14-42 Craniopharyngioma.......................................14-43 Adamantinomatous Craniopharyngioma (Grade I).......14-43

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Cerebral Infarct (Cerebrovascular Accident “Stroke”)....................................14-48 Lacunar Infarct..............................................14-48 Anoxic Encephalopathy (Global Ischemic Injury)..........................14-48 Hippocampal Necrosis..........................14-49 Purkinje Cell Necrosis (Cerebellar Cortex)..........................14-49 Watershed (Borderzone) Infarct.........14-49 Selective Neuronal Necrosis.................14-49 Laminar/Pseudolaminar Necrosis.......14-49 Brain Death Syndrome (“Respirator Brain”).......................14-49 Multi-infarct Dementia..................................14-50 Venous Infarcts...............................................14-50 Small Vessel Disease/Deep Infarcts...............14-50 Arteriolosclerosis..................................14-50

Neuropathology

Binswanger Disease..............................14-50 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy..............14-50 “Leukoaraiosis”....................................14-51 Related Disorders (Patterns of Selective Vulnerability).............................................14-51 Hypoglycemic Brain Injury.................14-51 Carbon Monoxide Poisoning...............14-51 Methanol Poisoning..............................14-51 Intracranial Hemorrhage (also see Trauma).......................................14-51 Berry (Saccular) Aneurysm/ Subarachnoid Hemorrhage............14-51 Hypertensive Intracerebral Hemorrhage.....................................14-51 Cerebral Amyloid Angiopathy and Superficial Lobar Hemorrhage.....................................14-51 Vascular Malformations................................14-51 Berry (Saccular) Aneurysm.................14-51 Arteriovenous Malformation...............14-51 Cavernous Angioma (“Cavernoma”) . ..............................14-52 Others....................................................14-52 Other Vascular Disorders..............................14-52 Vasculitis................................................14-52 Intravascular Lymphoma....................14-52

XI. Neurodegenerative Disorders..........14-53 Summary Table..............................................14-53 Alzheimer Disease..........................................14-53 Frontotemporal Lobar Degeneration...........14-53 Multi-infarct Dementia..................................14-53 Idiopathic Parkinson Disease........................14-53 Huntington Disease........................................14-53 Pick Disease (Lobar Atrophy).......................14-53 Creutzfeldt–Jakob Disease/Spongiform Encephalopathies......................................14-55 Other Spongiform Encephalopathies...........14-56 Variant CJD..........................................14-56 Gerstmann–Sträussler–Scheinker Disease (GSS)...................................14-56 Fatal Familial Insomnia.......................14-56 Kuru.......................................................14-56 Progressive Supranuclear Palsy (Steele–Richardson–Olszewski Disease).......................................................14-57 Corticobasal (Ganglionic) Degeneration..............................................14-57 Multisystem Atrophy.....................................14-57 Amyotrophic Lateral Sclerosis/Motor Neuron Disease..........................................14-57 Spinal Muscular Atrophy..............................14-57

14-3

Friedreich Ataxia............................................14-58 Spinocerebellar Ataxia...................................14-58 Neuroaxonal Dystrophy.................................14-59 Lafora Disease (Myoclonic Epilepsy)...........14-59

XII. Inflammatory/Infectious Diseases...........................................14-60 Acquired Demyelinating Disorders..............14-60 Multiple Sclerosis..................................14-60 Acute Disseminated Encephalomyelitis/Perivenous Encephalomyelitis............................14-61 Guillain–Barré Syndrome /Acute Inflammatory Demyelinating Polyneuropathy................................14-61 Demyelinating Viral Infections............14-61 Paraneoplastic Encephalomyelitis................14-61 Neurosarcoidosis.............................................14-61 Bacterial Infections........................................14-61 Meningitis..............................................14-61 Abscess...................................................14-61 Tuberculosis...........................................14-62 Neurosyphilis.........................................14-62 Whipple Disease....................................14-62 Fungal Infections............................................14-62 Meningitis..............................................14-62 Granuloma/Abscess..............................14-63 Angioinvasive Forms............................14-63 Viral Infections...............................................14-63 Viral (Aseptic) Meningitis....................14-63 Encephalitis...........................................14-63 Herpes Simplex.....................................14-63 HIV Encephalitis/AIDS Dementia Complex............................................14-63 Vacuolar Myelopathy of AIDS............14-64 Cytomegalovirus...................................14-64 JC Virus/Progressive Multifocal Leukoencephalopathy......................14-64 Subacute Sclerosing Panencephalitis................................14-65 Rabies.....................................................14-65 Poliomyelitis..........................................14-65 Parasites..........................................................14-65 Cysticercosis..........................................14-65 Toxoplasmosis.......................................14-65 Amebic Meningoencephalitis...............14-66 Cerebral Malaria..................................14-66

XIII. Pediatric and Seizure Neuropathology...............................14-66 Malformations................................................14-66 Neural Tube Defects.............................14-66 Holoprosencephaly...............................14-66 Congenital Hydrocephalus..................14-66 Migrational/Gyral Defects...................14-67

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Destructive Malformations..................14-68 Agenesis of Corpus Callosum..............14-69 Syringomyelia/Syringobulbia..............14-69 Fetal/Perinatal Insults....................................14-69 Intraventricular Hemorrhage.............14-69 Gray Matter Ischemia..........................14-69 White Matter Ischemia/ Periventricular Leukomalacia (PVL).................................................14-69 Kernicterus............................................14-70 Chromosomal Syndromes..............................14-70 Down Syndrome (Trisomy 21).............14-70 Edward Syndrome (Trisomy 18).........14-70 Patau Syndrome (Trisomy 13).............14-70 Fragile X................................................14-70 Seizure-Associated Pathology........................14-70 Mesial Temporal Sclerosis (Hippocampal Sclerosis)..................14-70 Malformations.......................................14-71 Tuberous Sclerosis................................14-71 Tumors...................................................14-71 Inflammatory/Infectious......................14-71 Vascular Malformations.......................14-71

XIV. Toxic/Metabolic Disorders...............14-71 Alcohol- (and/or Malnutrition-) Related Pathology......................................14-71 Trauma..................................................14-71 Wernicke–Korsakoff Syndrome..........14-71 Cerebellar Degeneration......................14-71 Peripheral Neuropathy.........................14-71 Central Pontine Myelinolysis...............14-71 Hepatic Encephalopathy......................14-72 Subacute Combined Degeneration of Spinal Cord..................................14-72 Fetal Alcohol Syndrome.......................14-72 Other Toxic Injuries.......................................14-72 Carbon Monoxide.................................14-72 Methanol................................................14-72 Arsenic Poisoning.................................14-72 Lead Poisoning......................................14-73

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Methotrexate Toxicity..........................14-73 Metabolic Disorders.......................................14-73 Lysosomal (Enzyme) Storage Disorders...........................................14-73 Mucopolysaccharidoses........................14-73 Peroxisomal Disorders.........................14-73 Leukodystrophies..................................14-73 Adrenoleukodystrophy.........................14-73

XV. Sellar/Suprasellar Pathology............14-73 Pituitary Adenomas.......................................14-73 Prolactinoma (Lactotrophic Adenoma).........................................14-75 Corticotrophic (ACTH) Adenomas.....14-75 Growth Hormone Adenoma................14-76 Growth Hormone and ProlactinProducing Adenomas.......................14-76 Gonadotrophic (FSH/LH) and Null Cell (IP-) Adenomas................14-76 Thyrotrophic Adenoma/ Hyperplasias.....................................14-76 Atypical Pituitary Adenoma................14-76 Pituitary Carcinoma.............................14-76 Pituitary Hyperplasia...........................14-76 Apoplexy................................................14-76 Craniopharyngioma.......................................14-76 Rathke Cleft Cyst...........................................14-76 Pituicytoma (WHO Grade I).........................14-76 Granular Cell Tumor.....................................14-77 Spindle Cell Oncocytoma of the Adenohypophysis (WHO Grade I)..........14-77 Histiocytosis X (Langerhans Cell Histiocytosis)......................................14-77 Hypothalamic Hamartoma............................14-77 Other Tumors.................................................14-77 Lymphocytic Hypophysitis............................14-77 Empty Sella Syndrome..................................14-77 Primary..................................................14-77 Secondary..............................................14-77

XVI. Suggested Reading...........................14-78

Neuropathology

14-5

NORMAL HISTOLOGY/GENERAL REACTIONS TO INJURY Normal Cellular Constituents Neurons (Ganglion Cells, Neurocytes) ♦♦ Signaling cells of the nervous system ♦♦ Basic cell architecture consisting of dendrites (branching, tree-like cytoplasmic extensions; receptive [postsynaptic]), cell body (AKA perikaryon, soma), and axons (single cytoplasmic process attached at the axon hillock; propagates action potentials to terminal buds [presynaptic]) ♦♦ Histologically, appear as cells with abundant eosinophilic cytoplasm; ovoid nuclei with generally prominent nucleoli (dendrites and axons are frequently not apparent on H&E) ♦♦ Great diversity in morphology and size, dependent on functional specialization (e.g. Betz cells: large pyramidal neurons of primary motor cortex; Purkinje cells: large, arborizing neurons in cerebellar cortex; granular cells: small neurons in cerebellar and cerebral cortices) ♦♦ Neurofilament (NF)+, synaptophysin (SYN)+, NeuN+, NSE+, MAP-2+, tau+, GFAP−, keratin−

Astrocytes ♦♦ Primary support cells of the CNS that regulate electrolyte (e.g., K+) balance, neurotransmitter metabolism, repair (gliosis and phagocytic properties), and formation of external and internal limiting membrane with pia, ependymal, and blood vessels (blood–brain barrier) ♦♦ Slightly angulated to oblong nuclei with lighter, looser chromatin than oligodendrocytes ♦♦ Cytoplasm and cell membrane/processes generally difficult to distinguish on H&E (blends with background neuropil) ♦♦ Mitoses exceedingly uncommon in normal tissue ♦♦ Morphologic subclassification: protoplasmic (mainly in grey matter) or fibrillary/fibrous (in subcortical white matter) ♦♦ Bergmann glia: specialized astrocytes in cerebellar cortex with cell bodies in Purkinje cell layer and processes in molecular layer ♦♦ Glial fibrillary acidic protein (GFAP) + , SYN−, NeuN−, vimentin+, typically keratin−

Oligodendrocytes ♦♦ Produce myelin for CNS, single cell produces more than one myelin segment (as opposed to Schwann cells in PNS, which envelopes axon, producing a single segment) ♦♦ Small, prominent, dark round nuclei, frequently with perinuclear halos (“fried egg” appearance; artifact of fixation) ♦♦ Cells often satellite around neurons and are arranged in linear patterns within white matter ♦♦ Luxol fast blue stains myelin ♦♦ No reliable routine immunostains; GFAP usually negative (except gliofibrillary and minigemstocytic variants); olig-1 and olig-2+ but not specific

Microglia ♦♦ Monocytic cells derived from hematopoietic progenitors; function as scavengers and immune accessory cells ♦♦ Those dispersed in parenchyma show little turnover; perivascular microglia are periodically replaced ♦♦ Usually inconspicuous with H&E, though comprise ~20% of glial population ♦♦ Small, elongate cells with long, thin, dark nuclei (“rod cells”) when activated (see below) ♦♦ CD45+, CD68+, HAM-56+, CD11b+, CD11c+

Ependymal cells ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Line ventricles and central canal of spinal cord Single layer of cuboidal to columnar cells with cilia Rest directly on neuropil (no basement membrane) Limited regenerative capacity Tanycytes: specialized ependymal cells with processes extending to subependymal vasculature, most numerous in third ventricular region ♦♦ GFAP+, EMA+, SYN−, NeuN−

Choroid Plexus ♦♦ Produces cerebral spinal fluid (CSF) as filtrate of blood plasma, active transport of Na+, Cl−, and bicarb ♦♦ Present in each of the four ventricles ♦♦ Papillary projections composed of stratified/pseudostratified cuboidal to low columnar cells overlying capillaries within a loose stroma ♦♦ CK+, VIM+, EMA±, GFAP mostly negative

Common and Unique Special Stains ♦♦ Luxol fast blue (LFB): stains myelin, frequently used with a PAS or H&E counterstain, used to demonstrate demyelination ♦♦ Modified Bielschowsky or Bodian silver stain: highlights axons, neurofibrils, and neurofibrillary tangles ♦♦ Reticulin: silver impregnation method highlighting reticulin fibers, useful in some CNS tumors and pituitary adenomas ♦♦ Congo red: amyloid ♦♦ Cajal gold stain: not commonly used, stains a subset of astrocytes ♦♦ Phosphotungstic acid hematoxylin (PTAH): highlights ­astrocytosis/gliosis, largely replaced by GFAP immuno­ histochemistry

Macrophage/Microglial Reactions Gitter Cells (Fig. 14.1) ♦♦ Central nervous system (CNS) macrophages recruited from native microglia or systemic circulation ♦♦ Large accumulations in infarcts and demyelinating disease

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Fig. 14.1. Active demyelination with foamy macrophages, reactive astrocytes with abundant eosinophilic cytoplasm, and perivascular lymphoplasmacytic inflammation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 14.2. Encephalitis with perivascular inflammation, microglial activation (rod cells), microglial nodules, and neuronophagia.

♦♦ Wide range of morphology with accompanying subacute gliosis and occasional mitoses; commonly leads to a misdiagnosis of glioma

Microglial Activation (Fig. 14.2) (Rod Cells, Microglial Nodules) ♦♦ Microglia are specialized antigen-presenting mononuclear cells of the CNS that are involved in the following −− Become elongated when activated (rod cells) −− Surround dying neurons, a process known as neuronophagia −− Cluster to form microglial nodules, a characteristic response in viral and paraneoplastic (autoimmune) encephalitis

Gliosis (Reactive Astrocytosis) (Fig. 14.1) ♦♦ Accompanies all forms of brain injury

Acute/Subacute Gliosis ♦♦ Astrocytic hypertrophy with prominent radially oriented, stellate processes and often plump eccentric cytoplasm (gemistocytes, gemistos = full in Greek); cells are evenly ­distributed (as opposed to astrocytoma) and have no mitoses −− GFAP immunostains highlight reactive astrocytes

Chronic Gliosis ♦♦ Difficult to discern individual processes; dense fibrillary background; other signs of chronic injury (neuronal loss, rarefaction, hemosiderin, etc.); grossly firm, rubbery, atrophic, and/or dark, associated T2 MRI changes

Pilocytic/Piloid Gliosis (Fig.14.3) ♦♦ Chronic gliosis with Rosenthal fibers (elongated, carrotshaped, densely eosinophilic cytoplasmic inclusions of astrocytes composed of GFAP) ♦♦ Common adjacent to cysts and slow-growing neoplasms, especially craniopharyngioma, pineal cyst, ependymoma, hemangioblastoma, and syrinx

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Fig. 14.3. Pilocytic gliosis found adjacent to a craniopharyngioma composed of elongated, bipolar cells with “hair-like” appearance. Numerous Rosenthal fibers are present within the gliotic tissue. ♦♦ Potential confusion with pilocytic astrocytoma on small suprasellar, posterior fossa, or spinal cord biopsies, but less cellular and lacks microcystic component and eosinophilic granular bodies

Cerebral Edema ♦♦ Component of most forms of brain injury; occurs in two types (often admixed)

Vasogenic Edema ♦♦ Most common type, predominantly extracellular, results from breakdown of blood–brain barrier (BBB)

Cytotoxic Edema ♦♦ Intracellular, generally ischemic or toxic etiology (osmotic imbalance, ionic pump failure, etc.)

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Hydrocephalus ♦♦ Acute −− Often due to intraventricular hemorrhage or meningitis; life-threatening ♦♦ Chronic −− Most are caused by obstruction to flow, e.g., tumor; increased CSF production also a factor in choroid plexus papilloma ♦♦ Obstructive hydrocephalus −− Obstruction within ventricular system ♦♦ Nonobstructive hydrocephalus −− Extraventricular obstruction (e.g., arachnoid granulations blocked by hemorrhage) ♦♦ Hydrocephalus without increased intracranial pressure −− Ex vacuo: secondary to parenchymal loss (e.g., Alzheimer disease (AD)) −− Normal pressure hydrocephalus: clinical triad of dementia, gait disturbance, and urinary incontinence; etiology unclear; some clinical evidence of intermittently raised CSF pressure

Herniation Syndromes ♦♦ Secondary to mass effect from edema, hemorrhage, tumor, abscess, etc.; high mortality ♦♦ Result of unyielding surrounding structures (skull, dural folds); therefore, more common after closure of cranial sutures

Cingulate (Subfalcine) Herniation ♦♦ Inferomedial herniation of cingulate gyrus (above corpus callosum) under falx cerebri; occasional superimposed anterior cerebral artery infarct from arterial compression

Fig. 14.4. Closed head injury from motor vehicle accident with marked edema, right uncal herniation, and Duret (secondary brainstem) hemorrhage involving central portion of midbrain. ♦♦ Compression of adjacent vessel leads to posterior cerebral artery infarct ♦♦ Displacement of opposite cerebral peduncle (corticospinal tract) into tentorium results in Kernohan notch (indentation of cerebral peduncle), with false lateralizing hemiplegia on same side as herniation

Tonsillar Herniation ♦♦ Downward herniation of cerebellar tonsils into foramen magnum ♦♦ Resulting compression of medulla can lead to respiratory arrest ♦♦ Tonsils may fragment and fall into spinal subarachnoid space

Uncal (Transtentorial) Herniation (Fig.14.4)

Duret (Secondary Brainstem) Hemorrhage (Fig. 14.4)

♦♦ Inferomedial herniation of uncus (posteromesial temporal structure) under tentorium cerebelli ♦♦ Compression of oculomotor nerve (CN III) may first result in “blown pupil” because parasympathetic fibers run along the periphery of the nerve; later produce fixed gaze (inferolaterally) because of paralysis of all extraocular muscles except the superior oblique (CN IV) and lateral rectus (CN VI)

♦♦ Downward herniation of brainstem results in kinking of penetrating arteries (perpendicular branches off basilar artery) with acute hemorrhagic infarctions in pons, (characteristically narrow and medial in anteroposterior plane) ♦♦ In contrast, primary hypertensive brainstem hemorrhages are often globular and internal contusions (diffuse axonal injury (DAI)) are typically posterolateral

GLIOMAS Key Features in Differential Diagnosis of CNS Tumors Precise Location ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Intra-axial (parenchymal) vs. extra-axial (dural) Superficial (cortical) vs. deep Intraventricular vs. paraventricular Supratentorial vs. infratentorial Sellar, suprasellar, hypothalamic

♦♦ Pineal region ♦♦ Cerebellar vs. cerebellopontine angle vs. brainstem (ventral or dorsal) ♦♦ Spinal cord: intradural vs. extradural; intramedullary vs. extramedullary

Age/Sex (Imaging Appearance = “Equivalent to Gross Examination” for Biopsy Specimens) ♦♦ Site of origin or epicenter

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♦♦ ♦♦ ♦♦ ♦♦

Mass effect Edema Infiltrative vs. discrete Enhancing: uniform vs. irregular; focal mural nodule vs. ring; nonenhancing ♦♦ Cystic vs. solid

♦♦ ♦♦ ♦♦ ♦♦

Single vs. multiple Calcified vs. noncalcified Tumoral seeding (leptomeningeal or nerve root enhancement) Others: melanin, lipid, hemorrhage (MRI), calcium (CT)

Histology/Immunohistochemistry ♦♦ See Table 14.1

Table 14.1. Typical Immunoprofiles of CNS Neoplasms Tumor

+

+/−

−

Astrocytoma

S-100 , GFAP

CKa, LCA, SYN, HMB 45

Oligodendroglioma

S-100

Ependymoma

S-100, GFAP

EMA (lumens), CK

LCA, SYN

Choroid plexus tumors

CD99 (membrane and lumens), S-100, CK, VIM, transthyretinc

GFAP

EMA, CEA

Metastatic carcinoma

EMA and CK, CK7 TTF1 (Lung), CK20 (colon)

CEA, S-100, SYN

GFAP, LCA, HMB 45

Melanoma

S-100, HMB 45, melan A

Lymphoma

LCA, CD20 (L26)

Meningioma

EMA, VIM, Claudin

Hemangiopericytoma

VIM, CD99, bcl-2, factor XIII

Medulloblastoma Atypical teratoid/rhabdoid tumor Ganglioglioma

SYN, NF, CG, GFAP, CD34

Central neurocytoma

SYN, NeuN

GFAP, S-100

Schwannoma

S-100 , CD34, Coll 4

GFAP, HMB 45

EMA, NF, CK

CKa, LCA, SYN

GFAP b

GFAP, CK, LCA EMA

CK, GFAP, HMB 45, SYN

S-100, CD34, CKe

GFAP, HMB 45

CD34

EMA, CK, GFAP, S-100

SYN, BAF 47 (lost in AT/RT)

S-100, GFAP

CK, LCA, EMA

EMA, CK, actin

SYN, GFAP, desmin, AFP

PLAP, b-hCG, LCA, BAF 47

d

g

f

NeuN, CK, EMA, PLAP NF, CG, CK, LCA h

Paraganglioma

SYN, CG, S-100

NF

GFAP, CK, HMB 45

Hemangioblastoma

S-100, NSE, inhibin

GFAP

CK, EMA

Germinoma

PLAP, OCT4, CD117 (c-Kit)

b-hCG, CK

AFP, EMA, HMB 45, LCA

Yolk sac tumor

AFP, CK, glypican-3

PLAP, EMA

b-hCG, GFAP, CD30

Choriocarcinoma

b-hCG, CK

PLAP

AFP, GFAP, HMB 45, LCA

Embryonal carcinoma

CK, PLAP, OCT4, CD30

Teratoma

CK, PLAP, EMA

i

b-hCG, AFP, EMA, LCA, CD117(c-Kit) AFP

b-hCG

GFAP glial fibrillary acidic protein; CK cytokeratin; LCA leukocyte common antigen; SYN synaptophysin; EMA epithelial membrane antigen; VIM vimentin; CEA carcinoembryonic antigen; PLAP placental alkaline phosphatase; AFP a-fetoprotein; b-hCG b-human chorionic gonadotrophin; CG chromogranin; Coll 4 collagen type IV; NSE neuron specific enolase; NF neurofilament a CAM 5.2 recommended because AE1/AE3 frequently stains gliomas b Strongly positive in microgemistocytes c Not specific for choroid plexus d Positive in myeloma e Positive in secretory variant f Characteristic pattern of scattered, individual immunoreactive cells g Diffuse, strong expression h Positive in melanocytic variant i Positive in sustentacular cells

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Diffuse (Infiltrative) Astrocytomas Cytologic/Histologic Variants Fibrillary (Fig. 14.5A, B)

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Giant Cell (Fig. 14.5D)

♦♦ Most common cell type ♦♦ Elongate or irregular, hyperchromatic nuclei ♦♦ Cytoplasm varies from indiscernible and GFAP− to be apparent as processes and GFAP+

♦♦ Multinucleate giant astrocytes with abundant cytoplasm and bizarre nuclei; GFAP+; often deceptively circumscribed grossly; usually grade IV ♦♦ ~5% of glioblastomas; arise de novo without lower grade precursor; younger patient age, may have slightly better prognosis; genetically; ~90% have TP53 mutations and one-third show PTEN mutations; EGFR amplification usually absent

Gemistocytic (Fig. 14.5C)

Small Cell (Fig. 14.6)

♦♦ Abundant, eccentric, eosinophilic, GFAP-rich cytoplasm; short, eccentric cytoplasmic processes; round, variably hyperchromatic nuclei; irregular distribution of tumor cells (unlike reactive gemistocytic astrocytes); often associated perivascular inflammation; infrequent mitoses, but high grade examples frequently associated with proliferating small cell astrocytes; high rate of anaplastic transformation

♦♦ Small cells with minimal cytoplasm and oval mildly hyperchromatic nuclei that may resemble oligodendroglioma; high mitotic index, usually grade IV with high proliferative activity; differential diagnosis = other small cell malignancies or anaplastic oligodendroglioma; GFAP often highlights thin processes though reactivity may be focal or minimal; genetically, 70% have EGFR amplification and >95% have chr. 10q deletion

Fig. 14.5. Diffuse astrocytomas of various grade and variant morphology. Low grade (WHO II) fibrillary astrocytoma displays nuclear clustering, irregular shape, and hyperchromasia with minimal cytoplasm imparting the appearance of “naked nuclei” (A). Immunoreactivity of p53 protein further supports the diagnosis (B). Gemistocytic astrocytoma with similar nuclear features, but eccentric bellies of eosinophilic cytoplasm (C). Bizarre mono- and multinucleate giant cells characterize the giant cell glioblastoma (D).

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Fig. 14.6. The small cell glioblastoma is defined by monomorphous oval nuclei (A), high proliferative index (B; MIB-1), minimal cytoplasm with thin GFAP + processes (C), and EGFR gene amplification in ~70% of cases (D; FISH analysis with EGFR in red and the chromosome 7 centromere in green).

Gliosarcoma (Fig. 14.7) ♦♦ A variant of glioblastoma (2–8%) with both astrocytic and sarcomatous/mesenchymal elements ♦♦ Sarcoma derived by metaplasia from glioma (analogous to carcinosarcoma) ♦♦ Sarcoma usually fibrosarcoma or malignant fibrous histiocytoma-like, but may include bone, cartilage, muscle, and even epithelium ♦♦ Often superficial and deceptively circumscribed; in cerebral hemispheres

Architectural Variants Gliomatosis Cerebri (Fig. 14.8) ♦♦ A clinicopathologic diagnosis indicating extensive tumoral involvement of the CNS, in some cases the entire neuraxis ♦♦ Most often it manifests as involvement of more than two cerebral lobes ♦♦ Cytologically, nuclei are typically elongate, twisted, and bland

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♦♦ May be associated with multiple foci of dedifferentiation to glioblastoma

Glioneuronal Tumor with Neuropil-Like Islands (WHO Grade II–III) (Fig. 14.9) ♦♦ An infiltrating astrocytoma (or rarely oligodendroglioma) with well-defined neuropil-like islands featuring a granular matrix intensely positive for synaptophysin and typically surrounded by fibrillary or gemistocytic astrocytes ♦♦ Clinical and radiographic features and clinical outcome similar to that of corresponding infiltrative gliomas

Prognostic Variables ♦♦ Patient age: strongest predictor in many series; survival time decreases with advancing age ♦♦ Histologic grade ♦♦ Histologic cell type: oligo better than oligoastro better than astrocytoma ♦♦ Preoperative performance status (better neurologic function relates to better prognosis)

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Fig. 14.7. Gliosarcoma with alternating zones of glial (upper right) and sarcomatous (lower left) differentiation (A). A focus of chondrosarcoma is seen (B). The sarcomatous and glial elements are individually highlighted by reticulin (C) and GFAP (D) stains, respectively.

♦♦ Extent of resection: variable conclusions among series, but gross total resection likely beneficial

Grading Schemes ♦♦ See Table 14.2 ♦♦ World Health Organization (WHO) most commonly used

Grade II Astrocytoma (Fibrillary Astrocytoma) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Age peak = 30–40 years old Insidious onset Seizures > functional deficits Survival 5–8 years High rate of anaplastic transformation in adults; death due to infiltration of vital structures or to herniation

Imaging/Gross (Fig. 14.10A–C) ♦♦ Ill-defined low-density lesion on CT or T1 MRI; nonenhancing

♦♦ Bright T2 on MRI ♦♦ Noncircumscribed; rubbery ♦♦ Epicenter in white matter; variable obliteration of gray-white matter junction

Smear ♦♦ Minimal to mild hypercellularity ♦♦ Nuclear atypia (hyperchromasia, cigar shape, or pleomor­ phism) ♦♦ Variable cytology: inconspicuous cytoplasm (“naked nuclei”) to variable size cell body or process formation

Microscopic (Fig. 14.5A) ♦♦ Same features as above plus the following −− Predominantly white matter involvement but cortical infiltration also common −− Uneven distribution of cells −− “Secondary structures” – perivascular, perineuronal, subpial, or subependymal cell accumulation (Fig. 14.11)

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Microscopic (Fig. 14.12A) ♦♦ Same features as above plus the following −− Mitotic activity −− No endothelial proliferation or necrosis −− May have a lower grade component

Grade IV Astrocytoma (Glioblastoma) Clinical ♦♦ Age peak = 50–60 years old ♦♦ Rapid onset with functional deficits, when primary glioblastoma (i.e., de  novo); slower evolution when secondary ­glioblastoma (i.e., arising from a lower grade precursor) ♦♦ Survival is age dependent, but often short (<1 year)

Imaging/Gross (Fig. 14.10D–F) ♦♦ ♦♦ ♦♦ ♦♦

Deceivingly circumscribed Ring enhancing Variegated gross appearance due to hemorrhage/necrosis May cross corpus callosum (butterfly lesion); occasionally multifocal

Smear ♦♦ Marked pleomorphism frequent but not invariable; may be monomorphous (e.g. small cell variant) ♦♦ Variable process formation and cytoplasm ♦♦ Endothelial proliferation and/or necrosis

Microscopic (Fig. 14.12B–D)

Fig. 14.8. Gliomatosis cerebri: The tumor extensively involves the CNS. Cytologically, the tumor cells are typically elongated, twisted, and bland. The dedifferentiated tumor cells in this case were negative for GFAP and synaptophysin. Tissue section (A) and smear preparation (B).

Grade III Astrocytoma (Anaplastic Astrocytoma) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Age peak = 40–50 years old Often more rapid onset than grade II Seizures less common; deficits more frequent High rate of transformation to glioblastoma Survival 2–3 years

Imaging/Gross ♦♦ Similar to grade II astros; often show focal enhancement on CT/MRI but no ring enhancement ♦♦ May cross corpus callosum

Smear ♦♦ Increased cellularity ♦♦ Like grade II but often with greater atypia

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♦♦ Same as above plus −− Endothelial proliferation = apparent multilayering of endothelium; not simply glomeruloid capillaries with numerous tiny lumens as seen commonly in pilocytic astrocytomas −− Necrosis often geographic; usually but not invariably associated with nuclear pseudopalisading −− Infiltrative margin (relative circumscription may be seen in primary glioblastoma) −− Frequent presence of lower grade component in secondary glioblastoma ♦♦ Several histologic variants are recognized, including giant cell glioblastoma, small cell glioblastoma, and gliosarcoma (see above)

Differential Diagnosis ♦♦ See Table 14.3

Circumscribed Astrocytomas Pilocytic Astrocytoma (WHO Grade I) Clinical ♦♦ Children/young adults ♦♦ Predilection: cerebellum, hypothalamus third ventricle, optic nerve, cerebral hemisphere, and spinal cord ♦♦ Slowly progressive symptoms

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Fig. 14.9. Glioneuronal tumor with neuropil-like islands: (A) A neuropil-like island rimmed by neurocytes is present in the middle of this otherwise infiltrative oligodendroglioma. Note the typical oligodendroglial morphology. While this pattern has been mostly noted in association with infiltrative astrocytomas, examples like this do exist. (B) The neuropil-like island stains intensely with synaptophysin. (C) The neurocytes are characteristically immunoreactove for the nuclear neuronal marker NeuN. (D) Note the low grade nature of the neurocytes (center) as they essentially lack proliferative activity to MIB-1 compared to the oligondendroglioma cells toward the periphery. ♦♦ Excellent prognosis (80% 20-year survival) ♦♦ Malignant transformation exceedingly rare

Imaging/Gross (Fig. 14.13) ♦♦ Demarcated ♦♦ Enhancing ♦♦ Bright T1 MRI signal due to mucinous/proteinaceous fluid in cystic element ♦♦ Often partially cystic with mural nodule

Smear ♦♦ Bipolar cells with bland, oval to elongated nuclei and long piloid (hair-like) processes ♦♦ Note: cytology similar to fibrillary astrocytoma in many cases ♦♦ Rosenthal fibers (RFs) ♦♦ Eosinophilic granular bodies (EGBs) ♦♦ Bizarre or multinucleated cells (“pennies on a plate” arrangement of nuclei) ♦♦ Glomeruloid vessels, no prognostic significance

Microscopic (Fig. 14.14) ♦♦ Variable: same as above plus the following −− Often biphasic compact (piloid) and loose (microcystic) pattern; either pattern may predominate −− “Diffuse” variant may simulate grade II fibrillary astrocytoma −− Oligodendroglioma-like regions may be seen

Variant ♦♦ Pilomyxoid astrocytoma (WHO grade II) −− A monomorphous, more aggressive variant occurring predominantly in infants −− Midline suprasellar masses, frequently arising in hypothalamic region with symptoms including failure to thrive, developmental delay, vomiting, and feeding difficulties (headaches, nausea, and visual symptoms more common in older children) −− MRI: well-circumscribed, solid, and homogenously enhancing

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Table 14.2. Grading Schemes for Astrocytoma Three-tiered

Four-tiered

Ringertz Modified Ringertz (Burger) WHO (see below)

Kernohan St. Anne-Mayo (see below)

St. Anne-Mayo (functionally three-tiered) (AMEN) Criteria

Scoring

Equivalents in terms of WHO grade

Atypia (nuclear) Mitoses (1 is enough) Endothelial proliferation Necrosis

Grade 1 = 0 criteria (very rare) Grade 2 = 1 criterion (nearly always atypia) Grade 3 = 2 criteria (usually addition of mitoses) Grade 4 = 3 or 4 criteria

Grade 1 has no WHO equivalent Grade 2 = (differentiated) astrocytoma Grade 3 = anaplastic astrocytoma Grade 4 = glioblastoma multiforme (GBM)

WHO Adopted the morphologic parameters of the St. Anne-Mayo scheme but does not score and uses Roman numerals (II, III, IV) instead Gr. II defined by atypia only Gr. III defined by mitotic activity (number not specified) Gr. IV defined by necrosis or endothelial proliferation, typically in association with atypia and mitoses (Note: Kernohan, Ringertz, and modified Ringertz schemes require necrosis for glioblastoma) Note: WHO Grade I corresponds to pilocytic astrocytoma

−− Hypercellular, monomorphous population of piloid cells typically within a rich myxoid matrix, often vague perivascular pseudorosettes (Fig. 14.14D) −− Lacks RFs; very rare to no EGBs −− Mitoses present, but not abundant; MIB-1 labeling index: ~5% −− Slight tendency for peripheral infiltration of adjacent parenchyma −− Increased tendency to leptomeningeal seeding

Differential Diagnosis ♦♦ Pilocytic/piloid gliosis (other underlying lesion; no microcysts or EGBs) ♦♦ Ganglioglioma (dysmorphic neurons) ♦♦ Pleomorphic xanthoastrocytoma (PXA) (more pleomorphic, occasional lipidized giant cells, partly reticulin-rich, EGBs) ♦♦ Fibrillary astrocytoma (nonenhancing, generally noncystic, no RFs or EGBs) ♦♦ Oligodendroglioma (lacks piloid component, RFs and EGBs; rarely in cerebellum or spinal cord)

Pleomorphic Xanthoastrocytoma (WHO Grade II–III) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Children/young adults Chronic seizures Relatively good prognosis in most cases Worse prognosis with anaplastic transformation (15%); still far more favorable prognosis than glioblastoma

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Imaging/Gross ♦♦ Cyst with enhancing mural nodule ♦♦ Superficial; often with leptomeningeal component ♦♦ Temporal lobe (less often parietal)

Smear ♦♦ Marked cellular pleomorphism; bizarre nuclei, nuclear-­ cytoplasmic pseudoinclusions ♦♦ Glial appearance ♦♦ Eosinophilic granular bodies

Microscopic (Fig. 14.15) ♦♦ Same as above plus the following −− Xanthomatous cells variable, often few −− Perivascular lymphocytic cuffing −− Spindled, mesenchymal-like cells −− Scant mitoses −− No endothelial proliferation or necrosis −− Often reticulin-rich (Fig. 14.11B) and GFAP+ −− Anaplastic transformation (15%) = monomorphic smaller, often epithelioid cells, frequent mitoses (³5/10 HPF), necrosis, and occasional endothelial proliferation

Differential Diagnosis ♦♦ Ganglioglioma (dysmorphic neurons) ♦♦ Pilocytic astrocytoma (less pleomorphic, reticulin poor) ♦♦ Glioblastoma (Situated deeper in brain; brisk mitotic activity, endothelial proliferation, necrosis, no EGBs) ♦♦ Dural-based sarcoma, e.g., MFH (GFAP−, mitoses)

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Fig.  14.10. T2 (A, D), FLAIR (B, E), and TI-gadolinium (C, F) MRI sequences from cases of diffuse astrocytoma, grade II (A–C) and glioblastoma, grade IV (D–F). The former is nonenhancing, whereas the latter shows ring enhancement.

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Fig.  14.11. Secondary structures of Scherer found in an ­infiltrating glioma: subpial condensation (A), perineuronal ­satellitosis (B), and perivascular accumulation (C).

Subependymal Giant Cell Astrocytoma (WHO Grade I) Clinical ♦♦ Children/young adults

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Fig. 14.12. Grading of diffuse astrocytomas relies on the ­presence or absence of mitoses (A), endothelial hyperplasia (B), and necrosis (C), the latter often associated with nuclear pseudopalisading.

♦♦ Obstructive hydrocephalus ♦♦ Tuberous sclerosis associated (may be first manifestation); rarely syndrome-unassociated ♦♦ Excellent prognosis (possibly hamartomatous in nature)

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Table 14.3. Common Differential Diagnoses of Astrocytomas Common diagnosis

Useful stains

Astrocytoma vs. reactive gliosis

GFAP shows equally spaced astrocytes with radiating processes, MIB-1 = low

Astrocytoma vs. demyelinating disease

LFB-PAS shows myelin loss; Bielschowsky or neurofilament IPs show axonal sparing; KP-1 shows numerous macrophages

Diffuse vs. circumscribed astrocytoma

PAS with diastase highlights EGBs; neurofilament IPs = relatively solid growth (i.e., rare axons within the tumor)

Recurrent tumor vs. radiation necrosis

H&E shows coagulative necrosis without pseudopalisading; dystrophic Ca2+; vascular hyalinization/telangiectasias; MIB-1 = low

Glioblastoma vs. metastasis vs. lymphoma vs. small cell carcinoma

CAM 5.2 (epithelial), EMA (epithelial, meningothelial), S-100 (melanocytic, glial), HMB 45 (melanocytic), GFAP (glial), LCA (lymphoid), CD20 (B-Cell), cytokeratin (CK) 7 (lung  or breast primary), CK20 (GI, especially colon primary), synaptophysin (SYN) (primitive neuroectodermal tumor (PNET), neuroendocrine -ex. small cell carcinoma)

Note: Some keratins (e.g., AE1/AE3) stain neoplastic and nonneoplastic glial cells

Imaging/Gross (Fig. 14.16A) ♦♦ Intraventricular (anterior within lateral ventricles, typically near foramen of Monro) ♦♦ Large, sharply demarcated, solid, often calcified ♦♦ “Candle guttering”-associated

−− Grade III: 3–5 years ♦♦ Treated with radiation ± chemotherapy (e.g. PCV, temozolomide) ♦♦ Anaplastic transformation less frequent and slower than in diffuse astrocytoma

Smear

Imaging/Gross

♦♦ Large spindled to epithelioid cells with primarily glial and less often neuron-like features

♦♦ ♦♦ ♦♦ ♦♦

Microscopic (Fig. 14.16B) ♦♦ Same as above plus the following −− Truly giant cells uncommon −− Perivascular pseudorosettes −− Noninfiltrative of surrounding tissue (NF stain) −− Scattered mast cells −− Variable GFAP staining; ± minor NF, SYN, or neurotransmitter substance staining

Differential Diagnosis ♦♦ Gemistocytic astrocytoma (infiltrative, more uniformly GFAP+, white matter epicenter; no syndrome association) ♦♦ Giant cell astrocytoma (often at least partly infiltrative, somewhat more GFAP+, white matter epicenter; no syndrome association) ♦♦ Ependymoma (no syndrome association; more GFAP+, periventricular rather than intraventricular)

Oligodendroglioma (WHO Grade II-III) Clinical ♦♦ 30–40 years old ♦♦ History of seizures > focal neurologic deficits ♦♦ Survival −− Grade II: 10–15 years

Cerebral hemisphere, especially frontal lobes Extensive cortical involvement Demarcated relative to deeper white matter Calcification common

Smear ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Uniform round nuclei in a loose background of axons Bland chromatin, small nucleoli Small skirt of cytoplasm; occasional “minigemistocytes” Few cytoplasmic processes Microcalcifications common

Microscopic (Fig. 14.17) ♦♦ Same as above plus the following −− Perinuclear clear halo artifact fried-egg appearance (lacking in frozen sections and promptly fixed specimens) −− “Chicken-wire” capillary pattern −− Microgemistocytes (GFAP+; smaller and rounder than gemistocytes; nuclei round and regular) −− Gliofibrillary oligodendrocytes (small GFAP + cytoplasmic rim, torch-shaped process) (Fig. 14.18A) −− Extensive cortical infiltration with secondary structures (Fig. 14.11) (a) Perineuronal satellitosis (b) Subpial condensation (c) Perivascular aggregation (d) Hypercellular, patternless nodules (occasional)

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♦♦ WHO: high mitotic index (e.g. >5/10 HPF) and/or conspicuous endothelial hyperplasia = anaplastic oligo (III) ♦♦ Gr III: anaplastic oligo: hypercellular, mitotically active, endothelial proliferation or necrosis; high MIB-l (Ki-67) proliferative index also helpful (Fig. 14.18B) ♦♦ Glioblastoma with oligodendroglioma component is currently recognized by the 2007 WHO though a WHO grade IV oligodendroglioma is yet to be fully endorsed

Genetics ♦♦ Chromosome 1p and 19q codeletions in 70–85% (Fig. 14.18C, D): constitutes a “genetically favorable” pattern −− Pattern associated with longer survival and enhanced therapeutic sensitivity

Differential Diagnosis ♦♦ Demyelinating disease/infarct (Many KP1+ macrophages; axonal sparing in demyelination, axonal loss in infarct) ♦♦ Pilocytic astrocytoma (classic locations and imaging, macrocysts, RFs, EGBs) ♦♦ Central neurocytoma (intraventricular, neuropil containing rosettes) ♦♦ Clear cell ependymoma (perivascular pseudorosettes, sharp demarcation, solid, no axons on NF stain) ♦♦ Dysembryoplastic neuroepithelial tumor (intracortical, patterned nodules, floating neurons) ♦♦ Mixed glioma (oligo and astro elements)

Mixed Oligoastrocytoma (WHO Grade II-III)

Fig. 14.13. Typical MRI appearance of cerebellar pilocytic astrocytoma with sharp demarcation and a cystic mass with a mural contrast enhancing nodule. T1-weighted images without (A) and with (B) gadolinium (images courtesy of Dr. Robert McKinstry, Mallinckrodt Institute of Radiology, St. Louis, MO).

Grading ♦♦ WHO = oligo (II) vs. anaplastic oligo (III) ♦♦ Gr II: conventional oligodendroglioma

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♦♦ Controversial entity with varying definitions among experts ♦♦ For example −− Diffuse glioma with separate discrete oligodendroglial and astrocytic zones −− Both clearly recognizable cell types intermixed −− Single cell type with features intermediate between oligodendroglioma and astrocytoma ♦♦ Similar presentation, imaging, and therapy as pure oligodendroglioma; graded the same way as pure oligodendrogliomas though the presence of necrosis is viewed less favorably with soligoastrocytoma ♦♦ Generally behave better than pure astrocytoma and worse than pure oligo; however, difficult to predict on histology alone ♦♦ There is no convincing evidence for the existence of other types of mixed gliomas, such as “oligoependymoma” or “astroependymoma”

Ependymoma (WHO Grade I-III) Clinical ♦♦ Children/young adults ♦♦ Anywhere along the ventricular system or spinal canal; ♦♦ Fourth ventricle favored in children, spinal cord favored in adults; less common in lateral and third ventricles

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Fig. 14.14. Pilocytic astrocytoma is most commonly characterized by limited cellularity, thin hair-like processes, and Rosenthal fibers (A). An oligodendroglioma-like component is not uncommon, though other features of pilocytic astrocytoma, such as EGBs help to establish the diagnosis (B). Endothelial hyperplasia is common in pilocytic astrocytoma (C), but has no prognostic significance. Pilomyxoid astrocytoma appears similar, but forms ependymoma-like perivascular pseudorosettes and lacks Rosenthal fibers and EGBs (D).

♦♦ Paraventricular, or even cortical in supratentorial brain ♦♦ May cause obstructive hydrocephalus ♦♦ Prognosis difficult to predict; age >2  years and gross total removal are favorable factors ♦♦ Spinal ependymomas have a better prognosis, particularly myxopapillary tumors ♦♦ CSF dissemination in <5% of ependymomas, usually those of high grade ♦♦ Extraneural examples on record

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Sharp demarcation Calcification (intracranial) Cyst formation (supratentorial) Enhancement on CT/MRI

Smear ♦♦ ♦♦ ♦♦ ♦♦

Often cohesive cells Uniform round nuclei in fibrillary background Distinct nucleolus Perivascular pseudorosettes

Microscopic (Fig. 14.19) ♦♦ Same as above plus the following −− Ependymal true rosettes or canals (infrequent) (5–10%) −− Sharp demarcation −− May have membrane and/or cytoplasmic dot-like EMA and CD99 immunopositivity −− Diagnostic ultrastructural features include zipper-like intercellular junctions and intra/intercellular lumina containing cilia and microvilli

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Fig. 14.15. PXA with multinucleate giant cells, EGBs (A), and increased reticulin deposition (B).

Grading ♦♦ No consensus; less correlation with clinical behavior than in astrocytoma and oligodendroglioma ♦♦ WHO grading = ependymoma (II) vs. anaplastic epen­dy­ moma (III) −− Gr I: only applied to myxopapillary variant −− Gr II: ependymoma: few mitoses −− Gr III: anaplastic ependymoma: numerous mitoses, ± endothelial proliferation (a) Necrosis not important unless associated with ­palisading

Variants ♦♦ Clear cell ependymoma −− Mimics oligodendroglioma; look for demarcation and perivascular pseudorosettes; supratentorial, young adults, less favorable prognosis ♦♦ Papillary ependymoma −− Papillary cores are glial rather than fibrovascular as seen in choroid plexus tumors

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Fig.  14.16. SEGA presenting as an enhancing intraventricular mass (A). Histologically, it is characterized by cells with ­neuron-like nuclei (vesicular with nucleoli) and astrocyte-like cytoplasm (eosinophilic), sometimes arranged in perivascular pseudorosettes (B).

♦♦ Myxopapillary ependymoma −− WHO grade I variant, filum terminale, myxoid perivascular stroma, thin capsule; excellent prognosis if resected intact; may seed spontaneously or if ruptured intraoperatively (a) Rare primary pre- or postsacral soft tissue examples show a tendency to undergo lung metastases

Tanycytic Ependymoma ♦♦ Extremely long, thin processes forming vague pseudorosettes

Neuropathology

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Fig. 14.17. Oligodendrogliomas with uniform rounded nuclei, clear perinuclear haloes, perineuronal satellitosis (A), and minigemistocytes with small rounded bellies of eosinophilic cytoplasm (B). Endothelial hyperplasia (C) and necrosis (D) may be seen in high grade examples.

Differential Diagnosis ♦♦ Medulloblastoma/primitive neuroectodermal tumor (PNET) (SYN+) ♦♦ Oligodendroglioma (lacks sharp circumscription and pseudorosettes) ♦♦ Central neurocytoma (origin in septum pellucidum, SYN+) ♦♦ Choroid plexus papilloma (origin in choroid plexus, connective tissue stroma; strong uniform cytokeratin staining) ♦♦ Papillary meningioma (falls apart to form pseudopapillae, EMA+, GFAP−) ♦♦ Pilocytic astrocytoma (some infiltration on NF stain; frequent biphasic pattern, RFs, and EGBs) ♦♦ Schwannoma of cauda equina region (nerve origin; reticulinrich, collagen IV+, may be GFAP+) ♦♦ Paraganglioma of cauda equina region (origin in filum or nerve root; Zellballen or carcinoid-like pattern; chromogranin (CG)+)

Subependymoma (WHO Grade I) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Usually older patient Often incidental; otherwise hydrocephalus-associated Benign despite occasional mitoses Intratumoral hemorrhage in large examples is rare; may be life-threatening

Imaging/Gross (Fig. 14.20A, B) ♦♦ Intraventricular: 4th > lateral > 3rd; rare in spinal cord ♦♦ Sessile and demarcated ♦♦ Often calcified

Smear/Histology (Fig. 14.20C, D) ♦♦ ♦♦ ♦♦ ♦♦

Ependymoma-like nuclear features, lobulated Immediately subependymal Microcysts with a nodular/lobular architecture Paucicellular with prominent clustering of cells

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Fig. 14.18. Special studies in oligodendrogliomas. GFAP is typically negative or highlights minigemistocytes and gliofibrillary oligodendrocytes with a thin rim of cytoplasmic reactivity (A). Anaplasia may be focal and is often accompanied by an elevated MIB-1 labeling index (B). FISH analysis reveals codeletion of 1p (C; 1p32 in green and 1q42 in red) and 19q (D; 19p13 in green; 19q13 in red) in roughly 80% of cases. ♦♦ Clusters surrounded by skeins of glial cell processes ♦♦ Degenerative features: nuclear atypia, hyalinized vessels, calcium, hemosiderin deposits ♦♦ May have minor component of ependymoma with pseudorosettes; if more than minor, they are termed “mixed subependymoma-ependymoma” WHO grade II

Differential Diagnosis ♦♦ Ependymoma: more cellular, occasional true rosettes ♦♦ Fibrillary astrocytoma: intraparenchymal, infiltrative, lacks distinctive clustering

Astroblastoma (WHO Grade I) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Rare, controversial entity Children, adolescents, and young adults Female predominance Favorable outcome with gross total resection

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Imaging/Gross ♦♦ Cerebral hemispheres ♦♦ Well-circumscribed, nodular/lobulated, usually with cystic component ♦♦ Noncalcified ♦♦ Contrast-enhancing

Smear/Histology (Fig. 14.21) ♦♦ Well-demarcated, noninfiltrative borders ♦♦ Prominent perivascular arrangements of GFAP + polygonal or spindled cells with broad processes ♦♦ Sclerotic hyalinized vessels ♦♦ Round or oval nuclei with coarse chromatin ♦♦ Well-differentiated or anaplastic (mitoses, atypia, vascular proliferation, palisading necrosis); currently not assigned a WHO grade ♦♦ Nonpalisading necrosis not indicative of high grade/ anaplastic

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Fig. 14.19. Ependymomas are characterized most commonly by perivascular nuclear-free zones or pseudorosettes (A). True rosettes with lumens are rarer but more specific (A). Intracellular lumina occasionally yield intracytoplasmic EMA (B) and CD99 (C) positive dot-like structures. Ultrastructural features include long zipper-like intercellular junctions (D).

Differential Diagnosis ♦♦ Ependymoma: longer, more tapered perivascular processes

Chordoid Glioma of the Third Ventricle (WHO Grade II) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Rare, slowly growing Adults Female predominance Obstructive hydrocephalus

Imaging/Gross ♦♦ Third ventricle; usually anterior; midline ♦♦ Well-circumscribed, solid ♦♦ Contrast-enhancing

Smear/Histology ♦♦ Noninfiltrative ♦♦ Clusters/cords of epithelioid cells with eosinophilic cytoplasm

♦♦ Mucinous, vacuolated background with lymphoplasmacytic infiltrate ♦♦ Uniform nuclei ♦♦ Rare or no mitoses ♦♦ GFAP+, low proliferative index

Differential Diagnosis ♦♦ Chordoid meningioma: usually dural-based, GFAP−, EMA+ ♦♦ Ependymoma ♦♦ Pilocytic astrocytoma

Angiocentric Glioma (WHO Grade I) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

New entity in 2007 WHO Children and young adults Seizures Slow growing with stable clinical course Cured by surgical resection alone

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Fig. 14.20. Intraventricular subependymoma detected on T1 (A) and T2 (B) weighted MR images. Histologically, there are clusters of ependymoma-like nuclei embedded in a densely fibrillary background (C, D).

Imaging/Gross ♦♦ Frontal, temporal, or parietal lobes; usually centered in the cortex ♦♦ MRI: hyperintense on T2 or FLAIR sequences, but generally nonenhancing

Smear/Histology (Fig. 14.22) ♦♦ Uniform, spindle-shaped cells with oval to elongated nuclei and speckled chromatin; pink, tapering cytoplasm ♦♦ Monomorphous, bipolar cells intimately associated with vessels; often oriented parallel to the vessels; may form streaming arrays in perivascular space with either single or multilayered cells ♦♦ May be radially oriented to vessels forming pseudorosettelike structures

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♦♦ May accumulate perpendicularly beneath the pia mater with palisading appearance ♦♦ Mitoses generally absent with a low MIB-1 proliferation index: 1–5% ♦♦ Immunostains: GFAP + (strong), S-100+, vimentin+, EMA (dot-like pattern, like ependymoma) ♦♦ Electron microscopy (EM): ependymal differentiation (microlumen formation, microvilli, cilia, complex zipperlike intermediate junctions)

Differential Diagnosis ♦♦ Ependymoma ♦♦ Pilomyxoid/pilocytic astrocytoma

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Fig. 14.21. Astroblastoma often display marked vascular hyalinization (A, C). Tumor cells rosette around blood vessels with short, broad processes (B, D).

NEURONAL/GLIONEURONAL NEOPLASMS Derivations/Definitions Used in Neuronal Tumors ♦♦ Ganglio = ganglion cell ♦♦ Neurocyte = small mature neuron (e.g., cerebellar internal granular layer, dentate fascia) ♦♦ Neuroblast = primitive small cells with “neuropil” or Homer Wright rosette formation ♦♦ Medulloblast = theoretical cerebellar precursor cell (external granular layer?) ♦♦ Paraganglio = specialized autonomic neuroendocrine cell ♦♦ Medullo (neuro) epithelium = primitive epithelial tubules/ canals resembling the embryonic neural tube

♦♦ Pineo, esthesio, retino = derived from or differentiating toward specialized neuronal receptor cells ♦♦ Cytoma = mature; blastoma = primitive

Ganglion Cell Tumors (Ganglioglioma/ Gangliocytoma) (WHO Grade I) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Children/young adults Chronic seizures Benign/surgically curable Hamartomatous versus tumoral nature of the lesion is unsettled

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Fig. 14.22. Angiocentric glioma: (A) Proliferation of spindled, bipolar glial cells in an intimate perivascular pattern. (B) Note the perpendicular arrangement of intensely GFAP positive cells around blood vessels. The cells comprising angiocentric glioma show ependymal features as manifested by the dot like staining for EMA (C) and the presence of ultrastructural microlumens filled with microvilli and cilia (D).

♦♦ Rare malignant transformation (usually astrocytic component): WHO grade III

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Superficial Temporal lobe favored Demarcated Cystic with enhancing mural nodule or solid and variably enhancing

Smear/Histology (Fig. 14.23) ♦♦ Lobular/nodular ♦♦ Spongy/microcystic ♦♦ Dysmorphic/binucleate ganglion cells (SYN/NF/CG+, NeuN usually-) ♦♦ Perivascular chronic inflammation ♦♦ Eosinophilic granular bodies/Rosenthal fibers

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♦♦ Collagen containing stroma in some (reticulin, trichrome+) ♦♦ Glial component: pilocytic or fibrillary in nature; ­oligodendroglial elements rare ♦♦ CD34+ cells often present (progenitor cells?)

Special Variants ♦♦ Desmoplastic infantile ganglioglioma (DIG) −− Age <2, supratentorial, hemispheric, cyst-mural nodule architecture −− Nodule firm, often dura attached −− Spindle cells far exceed prevalence of ganglion-like cells ♦♦ Dysplastic cerebellar gangliocytoma (Lhermitte–Duclos disease) −− Unilateral expanded folia with replacement of internal granular layer by dysmorphic ganglion cells; associated with Cowden syndrome (PTEN gene)

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Fig. 14.23. Gangliogliomas are characterized by dysmorphic ganglion cells, perivascular lymphocytes, and EGBs (A, B). The glial component is highlighted with GFAP (C), whereas the neuronal element is positive for synaptophysin, chromogranin, and ­neurofilament (D).

Differential Diagnosis ♦♦ Infantile desmoplastic astrocytoma of infancy – identical but without ganglion-like cells ♦♦ Pilocytic astrocytoma (no ganglionic-like cells, contains RFs and EGBs) ♦♦ PXA (bizarre, multinucleate astrocytic cells, rare ganglion cells)

Papillary Glioneuronal Tumor (WHO Grade I) Clinical ♦♦ Newly described entity; rare ♦♦ Predominantly young adults ♦♦ Signs/symptoms of seizures, headaches, and focal ­neurologic manifestations due to tumor location ♦♦ Favorable outcome

Imaging/Gross ♦♦ Predominantly in cerebral hemispheres (temporal)

♦♦ Well-circumscribed; solid to cystic; contrast enhancing ♦♦ Little mass effect or surrounding edema

Smear/Histology (Fig. 14.24) ♦♦ Obvious papillary/pseudopapillary architecture at low power ♦♦ Noninvasive ♦♦ Two distinct cell types surrounding central fibrovascular cores −− Innermost layer: small, cuboidal cells with eosinophilic cytoplasm and round nuclei −− Outer layer: larger clear cells with neurocytic or ganglioid appearance ♦♦ Immunostains −− Inner layer – strong GFAP+ −− Outer layer – strong reactivity for neuronal markers (NeuN, SYN) −− Both layers – cytologically low grade with rare to absent mitoses ♦♦ MIB-1 labelling index: 1–2%

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Differential Diagnosis ♦♦ Ganglioglioma: papillary glioneuronal tumor was previously regarded as a variant of ganglioglioma ♦♦ Neurocytoma (when showing pseudopapillary growth pattern) ♦♦ Other gliomas/neurocytic tumors with pseudopapillary features

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle (WHO Grade I) Clinical ♦♦ Newly described entity; rare ♦♦ Adults; slight female predominance ♦♦ Symptoms of headache, ataxia, or hydrocephalus due to obstructed CSF flow ♦♦ Benign but high risk for serious surgical complications

Imaging/Gross ♦♦ Found exclusively in the posterior fossa; arising in the midline ♦♦ Often occupying a large portion of the 4th ventricle ♦♦ MRI: Circumscribed, solid mass with heterogeneous enhancement

Smear/Histology (Fig. 14.25) ♦♦ Biphasic with clearly defined and spatially separate neurocytic and glial components ♦♦ Neurocytic component with homogeneous population of small, clear cells in rosettes with large central spaces or papillae around central vessels; delicate processes form a neuropil matrix adjacent to tumor cells and extending to central vessels ♦♦ Glial component with solid pattern of highly fibrillary cells resembling pilocytic astrocytoma; may have an oligodendroglioma-like appearance, microcysts, Rosenthal fibers, and eosinophilic granular bodies (like a pilocytic astrocytoma) ♦♦ Both neurocytic and glial components histologically low grade; no overt invasion ♦♦ Rare mitoses; MIB-1 labeling index: 1–3%

Differential Diagnosis ♦♦ Pilocytic astrocytoma ♦♦ Glioneuronal tumor with neuropil-like islands: usually part of an otherwise infiltrating glioma and in locations typical of those tumors (cerebral hemispheres)

Fig. 14.24. Papillary glioneuronal tumor: (A) Single as well as multiple layers of uniform, small, round glial cells characterized by round nuclei and scant cytoplasm surround hyalinized blood vessels in a pseudopapillary pattern. Note the interpapillary areas occupied by aggregates and sheets of larger size neurocytes amid a neuropil-like matrix. The intimately perivascular glial cells are immunoreactive for GFAP (B) while the majority of the interpapillary cells (neurocytes) react with ­synaptophysin (C).

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Central Neurocytoma and Extraventricular Neurocytoma (WHO Grade II) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Young/middle-age adults Signs/symptoms of obstructive hydrocephalus Vast majority surgically curable Rare atypia, mitoses, and/or MIB-1 >2% (atypical central neurocytoma) ♦♦ Increased risk of recurrence with necrosis, vascular proliferation, increased mitoses (>3/10 HPFs), or subtotal resection

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Fig.  14.25. Rosette-forming gloneuronal tumor: (A) Small, back-to-back, ring-like rosettes of monotonous neurocytic cells ­surrounding small islands/cores of eosinophilic neuropil characterizes this biphasic glioneuronal tumor. Elsewhere, the tumor showed a scant pilocytic component. (B) Note the synpatophysin reactive neuropil cores. Photo courtesy of Dr. Jon D. Wilson, MD; Beaumont Hospital, Royal Oak, Michigan.

Imaging/Gross (Fig. 14.26A, B)

Differential Diagnosis

♦♦ Lateral ventricle near foramen of Monro; origin in septum pellucidum ♦♦ Rarely extraventricular; most often cerebral hemispheres, rare at other sites ♦♦ Often large and globular ♦♦ Calcified

♦♦ Oligodendroglioma (superficial, SYN-) ♦♦ Cellular or clear cell ependymoma (paraventricular, GFAP +)

Smear/Histology (Fig. 14.26C, D) ♦♦ Uniform, round nuclei; speckled chromatin (oligo-like) ♦♦ Streaming sheets, clusters, ribbons, or vague perivascular pseudorosettes ♦♦ Fine neuropil-like background ♦♦ Extraventricular neurocytomas −− May have identical histology as central neurocytomas −− Often more complex and less cellular −− More likely to contain true ganglion cells or ganglioid cells ♦♦ Calcification ♦♦ SYN+, NeuN+, NF ±, GFAP ± (focal)

Dysembryoplastic Neuroepithelial Tumor (DNT) (WHO Grade I) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Age of onset <20 years Longstanding chronic seizures (partial complex type) Slow or no growth Benign/surgically curable Hamartoma vs. neoplasm; nature of tumor unsettled

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Supratentorial; temporal lobe, infrequent at other sites Intracortical Multinodular May be “cystic appearing” on imaging due to high mucin content, infrequent calcification

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Fig. 14.26. Enhancing intraventricular mass in a case of central neurocytoma detected by T1-weighted MRI without (A) and with (B) gadolinium. Cytologically, it resembles oligodendroglioma but is associated with neurocytic rosettes with central neuropil (C). The neuronal character is confirmed with a synaptophysin stain (D).

Microscopic (Fig. 14.27) ♦♦ Patterned, mucin-rich intracortical nodules ♦♦ “Specific glioneuronal element” between nodules features both −− “floating neurons” and oligo-like cells ♦♦ Minimal perineuronal satellitosis ♦♦ Cortical dysplasia may be seen at periphery of the lesion

Differential Diagnosis ♦♦ Oligodendroglioma (white matter involvement, occasional nonpatterned nodules, perineuronal satellitosis, subpial tumor cell accumulation, no floating neurons)

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♦♦ Oligoastrocytoma (same as above) ♦♦ Ganglioglioma (cyst-mural nodule, lymphocytic infiltrate, no floating neurons)

Paraganglioma (WHO Grade I) Clinical ♦♦ Adults ♦♦ Back pain, radiculopathy, or incontinence ♦♦ Almost always benign/surgically curable

Imaging/Gross ♦♦ Filum terminale or nerve root (rarely skull base or sella)

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Fig. 14.27. DNT is an intracortical mass (A) with patterned mucin-rich nodules (B), oligodendroglioma-like cells, and floating neurons (C, D). ♦♦ Ganglion cells in 50% (“gangliocytic paraganglioma”) ♦♦ SYN/CG+; NF± ♦♦ S-100 + sustentacular cells

♦♦ Enhancing/discrete ♦♦ Large feeder vessels

Smear/Histology ♦♦ Zellballen and/or carcinoid-like pattern ♦♦ Neuroendocrine cells with salt and pepper chromatin

Differential Diagnosis ♦♦ Myxopapillary ependymoma (GFAP+, SYN-, CG-)

PINEAL PARENCHYMAL TUMORS Pineocytoma (WHO Grade I) Clinical ♦♦ Middle to late adulthood ♦♦ Pineal region symptoms (Parinaud syndrome, i.e., paralysis of upward gaze, etc.) ♦♦ Favorable outcome; gross total resection curative

Imaging/Gross ♦♦ Globular, discrete ♦♦ Contrast enhancing, variable calcification

Smear/Histology ♦♦ Round salt and pepper nuclei ♦♦ Loss of normal lobularity

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♦♦ Solid sheets of cells ♦♦ Pineocytic rosettes (large, exaggerated Homer Wright rosettes) ♦♦ Argyrophilic, club-shaped neuritic processes (Bodian, Bielschowsky) ♦♦ SYN+, NeuN + in most

Differential Diagnosis ♦♦ Normal pineal (no rosettes, may be difficult diagnosis on small biopsy) ♦♦ Pineoblastoma (scant cytoplasm, PNET-like, no pineocytic rosettes, increased proliferation, necrosis, CSF seeding common) ♦♦ Pineal parenchymal tumor, of intermediate differentiation (lacks pineocytomatous rosettes, scant mitoses, only occasional seeding) ♦♦ Ependymoma (GFAP+, SYN-)

Pineal Parenchymal Tumor of Intermediate Differentiation (WHO Grades II–III) Clinical ♦♦ Wide age range ♦♦ Presentation similar to pineocytoma ♦♦ Survival intermediate between that of pineocytoma and pineoblastoma

Smear/Histology ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Small “blue cell tumor” No pineocytomatous rosettes Occasional Homer Wright rosettes Occasional photoreceptor differentiation (“fleurettes”) Rare glial or mesenchymal differentiation

Differential Diagnosis ♦♦ Pineocytoma (low proliferation, pineocytomatous rosettes) ♦♦ Cellular ependymoma (low proliferation, GFAP+) ♦♦ Seeding from medulloblastoma (clinicopathologic correlation required) ♦♦ Malignant germ cell tumor (OCT4, PLAP, AFP, b-hCG, CK, etc.)

Papillary Tumor of the Pineal Region (WHO Grades II – III) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Imaging/Gross

Newly described entity; rare Children and adults; no sex predilection Signs/symptoms of obstructive hydrocephalus Majority of cases show tumor progression Recurrence associated with marked mitotic activity (³5/10 HPFs) and incomplete resection

♦♦ Indistinguishable from pineocytoma

Imaging/Gross

Smear/Histology

♦♦ ♦♦ ♦♦ ♦♦

♦♦ ♦♦ ♦♦ ♦♦

Sheet-like growth pattern Moderate to high cellularity Rosettes usually absent or infrequent and small Immunohistochemistry similar to pineocytoma

Smear/Histology (Fig. 14.28)

Differential Diagnosis ♦♦ Pineocytoma ♦♦ Pineoblastoma

Pineoblastoma (WHO Grade IV) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Childhood CSF seeding Rapid recurrence Association with retinoblastoma”)

bilateral

retinoblastoma

Exclusively arise in pineal region Large, well circumscribed (similar to pineocytoma) Occasional cystic component Variably contrast enhancing

(“trilateral

♦♦ Epithelial-appearing with round to oval nuclei, stippled chromatin ♦♦ Papillary architecture with more densely cellular regions ♦♦ Often ependymal-like differentiation (true rosettes) ♦♦ Papillary areas with radially arranged large, pale ­eosinophilic columnar cells ♦♦ Cellular areas with clear, vacuolated cytoplasm ♦♦ Necrotic foci occasionally seen ♦♦ Hyalinized vessels ♦♦ Keratin (AE1/AE3,CAM5.2,CK18)+, vim+, S-100+, NSE+, transthyretin+, NFP-

Imaging/Gross

Differential Diagnosis

♦♦ Enhancing ♦♦ Infiltrative, CSF seeding

♦♦ Pineocytoma (lack papillary architecture) ♦♦ Choroid plexus tumors (Kir 7.1+, stanniocalcin-1+)

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Fig. 14.28. Papillary tumor of the pineal region. (A) Pale columnar epithelial cells line the blood vessels in a papillary fashion. Note the presence of solid areas of the tumor with pseudopapillary rosettes similar to those of ependymoma (B). (C) The epithelial nature of the tumor cells is evident in their reactivity to CAM 5.2 immunostains. Tumor cells are also immunoreactive for vimentin (D) and NSE (E). (F) PAS positive cytoplasmic masses are noted in the cytoplasm of the tumor cells.

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EMBRYONAL TUMORS Types ♦♦ Medulloepithelioma (age <5, epithelial canals) ♦♦ Medulloblastoma and variants −− Classic (vermis, infiltrative, PNET cytology) −− Nodular/Desmoplastic (reticulin-rich between nodules, most advanced neuroglial differentiation within nodules) −− Large cell (vesicular nuclei with large nucleoli, ­“cannibalization,” aggressive variant prone to seed) −− Medullomyoblastoma (rhabdomyoblastic differentiation; may also be anaplastic) −− Melanotic (pigmented, aggressive) −− Extensively nodular (bunch of grapes appearance on MRI, extensive neurocytic neuronal differentiation, less aggressive) ♦♦ PNET = medulloblastoma-like tumor outside the cerebellum ♦♦ Ependymoblastoma (PNET with well differentiated ependymal true rosettes) ♦♦ Pineoblastoma (pineal region, neuroblastic/retinal differen­ tiation) ♦♦ Neuroblastoma/ganglioneuroblastoma ♦♦ Olfactory neuroblastoma (esthesioneuroblastoma, paraganglioma-like) ♦♦ Retinoblastoma (eye, Flexner–Wintersteiner rosettes, fleurettes) ♦♦ Atypical teratoid/rhabdoid tumor (carcinoma-like, PNETlike element, spindle cells, clear cells, rhabdoid cells may be rare)

Medulloblastoma/PNET (WHO Grade IV) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Children/young adults Rapid, aggressive clinical course Rapidly fatal without therapy (Rx) 5-year survival with Rx = 60–70% in medulloblastoma; less with PNET ♦♦ Rx = surgery, craniospinal radiation, multidrug chemotherapy

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Solid Noncalcified Homogeneously enhancing CSF spread/drop metastases

Smear/Histology (Fig. 14.29) ♦♦ Small “carrot-shaped” to round nuclei, inapparent nucleoli (except in large cell anaplastic variant), scant cytoplasm ♦♦ Classic pattern: reticulin-free sheets ♦♦ Nodular/desmoplastic variant: reticulin-rich internodular regions, “germinal center-like” nodules with evidence of neuronal differentiation, “Indian filing”

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♦♦ Undifferentiated or with lines of differentiation ♦♦ Neuroblastic differentiation (fibrillarity, Homer Wright rosettes) ♦♦ Glial, mesenchymal, or melanocytic differentiation less common ♦♦ Subarachnoid invasion ♦♦ SYN+, GFAP±

Differential Diagnosis ♦♦ Small blue cell tumors (primary or metastatic) ♦♦ Cellular ependymoma (lower proliferation, GFAP+, SYN−) ♦♦ Atypical teratoid/rhabdoid tumor (variable cytology including rhabdoid, epithelioid, and spindle cells; EMA+, CK+, actin+, desmin±)

Atypical Teratoid/Rhabdoid Tumor Clinical ♦♦ ♦♦ ♦♦ ♦♦

Infants <2 years old Rapid, highly aggressive clinical course CSF seeding seen at presentation in 35% Almost uniformly fatal within 1  year, minimal therapeutic response

Imaging/Gross ♦♦ Similar to medulloblastoma/PNET ♦♦ All sites; cerebellum most common

Smear/Histology (Fig. 14.30) ♦♦ Epithelioid component resembles carcinoma or malignant rhabdoid tumor of kidney ♦♦ PNET component in 65% ♦♦ Spindled cells or even chondroid foci may be seen ♦♦ Vimentin, EMA+, CK+, actin + in majority of cases ♦♦ SYN+, GFAP + in some cases ♦♦ b-HCG−, PLAP− (i.e., not a germ cell tumor despite occasional alpha fetoprotein+) ♦♦ Immunohistochemically detectable loss of INI1/hSNF5 protein (Fig. 14.30C) ♦♦ Chromosome 22q loss or monosomy 22 in 70–80% (Fig. 14.30D)

Differential Diagnosis ♦♦ Small blue cell tumors (primary or metastatic) ♦♦ Cellular ependymoma (low proliferation, EMA−, CK−, actin−, synaptophysin− SYN) ♦♦ Medulloblastoma/PNET (more uniformly small cells, EMA−, CK−, actin−, INI1 retained expression)

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Fig. 14.29. Pale nodule in a nodular/desmoplastic medulloblastoma (A). There is increased internodular reticulin deposition (B), intranodular synaptophysin positivity (C), and internodular MIB-1 labeling (D).

Olfactory Neuroblastoma (WHO Grade III) Clinical ♦♦ Bimodal peaks; adolescent and elderly patients ♦♦ Epistaxis, nasal obstruction ♦♦ Favorable prognosis in most, especially with gross total resection ♦♦ Subset is aggressive, difficult to predict ♦♦ Metastases, neuroblastic predominance, and high MIB-1 equate with lower survival

Imaging/Gross ♦♦ Cribriform plate ♦♦ Polypoid intranasal extension ♦♦ Intracranial extension

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Nests/lobules/sheets “Neuroendocrine nuclei” Delicate fibrillary background may be seen Rare rosettes (Homer Wright or Flexner types) SYN, NF, and CG+ Usually CKS-100 + sustentacular cells in paraganglioma like pattern

Differential Diagnosis ♦♦ Sinonasal undifferentiated carcinoma (large anaplastic cells; CK+, SYN−, S-100−) ♦♦ Neuroendocrine carcinoma (CK+, SYN+, S-100−) ♦♦ Small cell melanoma (HMB 45+)

Smear/Histology

Retinoblastoma Clinical

♦♦ Mixed patterns of paraganglioma and neuroblastoma

♦♦ Age < 3

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Fig. 14.30. AT/RTs often have a small round cell component (A), though the diagnostic cell type is the rhabdoid cell with an eccentrically placed vesicular nucleus and a globular paranuclear inclusion (B). The diagnosis is supported by loss of INI1 protein expression (C) and a chromosome 22q deletion by FISH (D; BCR in green, NF2 in red).

♦♦ Leukocoria, strabismus ♦♦ Sporadic or familial; linked to Rb gene on 13q14 ♦♦ Favorable prognosis in developed countries due to early stage at detection and effective adjuvant therapy ♦♦ Familial cases at risk for other neoplasms, especially osteosarcoma

Macroscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Arise in retina Often bilateral and multifocal in familial form Gray-white Fleshy Necrotic with dystrophic calcification Optic nerve margin important

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Smear/Histology ♦♦ ♦♦ ♦♦ ♦♦

Small blue cell tumor Flexner–Wintersteiner rosettes Homer Wright rosettes (rare) Fleurettes (extremely rare)

Spread ♦♦ ♦♦ ♦♦ ♦♦

Along optic nerve Leptomeningeal spread or cerebrospinal deposits Extraocular extension Lymphatic and/or hematogenous metastases

Differential Diagnosis ♦♦ Lymphoma (LCA+, SYN−)

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CHOROID PLEXUS NEOPLASMS Choroid Plexus Papilloma (WHO Grade I) Clinical ♦♦ Hydrocephalus (mechanisms: both obstruction and increased CSF production) ♦♦ Lateral ventricle in congenital/childhood cases ♦♦ Fourth ventricle in adults ♦♦ Benign/surgically curable

Radiology/Gross ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Intraventricular Enhancing Polypoid/papillary (“cauliflower” appearance) Discrete Often calcified

Smear/Histology (Fig. 14.31A, B) ♦♦ True papillae (fibrovascular cores) ♦♦ Simple cuboidal to columnar epithelium lacking “cobblestone” cell surfaces characteristic of normal choroid plexus ♦♦ Limited architectural complexity ♦♦ Low mitotic rate ♦♦ Occasionally necrosis or calcification (no prognostic significance) ♦♦ Focal ependymal differentiation common (GFAP + tapered processes) ♦♦ IHC = S-100+, CAM 5.2+, transthyretin (prealbumin)+, GFAP ±, EMA−, CEA−

Variant ♦♦ Atypical choroid plexus papilloma (WHO grade II): ³2 mitoses/10 HPF ± increased cellularity, nuclear pleomorphism and/or solid growth pattern

Fig. 14.31. Choroid plexus papillomas show well formed fibrovascular cores and typically a single layer of cuboidal to columnar epithelium (A, B). Choroid plexus carcinomas have solid foci, typically a high grade cytology, and numerous mitoses (C, D).

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Differential Diagnosis ♦♦ Normal choroid plexus (smaller cells, “cobblestone” epithelial lining) ♦♦ Papillary ependymoma (falls apart to form pseudopapillae, lack of collagenous papillary stroma, fibrillary processes, GFAP+, CAM 5.2−) ♦♦ Choroid plexus carcinoma (more solid, complex, infiltrative, mitotically active)

Choroid Plexus Carcinoma (WHO Grade III) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Rare Vast majority age <3 years; some congenital Highly aggressive/nearly uniformly fatal High rate of metastasis, mainly cerebrospinal Rare long-term survivors with complete excision

Imaging/Gross ♦♦ Intraventricular

♦♦ Enhancing ♦♦ Infiltrative ♦♦ CSF seeding in some

Smear/Histology (Fig. 14.31C, D) ♦♦ ♦♦ ♦♦ ♦♦

More solid and complex than papillomas High mitotic rate High grade cytology Infantile examples may be markedly pleomorphic with eosinophilic globules ♦♦ IHC = S-100+, CAM 5.2+, transthyretin (prealbumin) + GFAP±, EMA−, CEA−

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Anaplastic ependymoma (GFAP+, nonuniform CK+) Glioblastoma (GFAP+, CAM 5.2−) Medulloblastoma/PNET (SYN+, CK−) Atypical teratoid/rhabdoid tumor (paranuclear inclusion, EMA+, actin+) ♦♦ Metastatic carcinoma (adult patient, EMA+, CEA−, S-100±)

MENINGEAL NEOPLASMS Meningioma (WHO Grade I) Clinical ♦♦ Adults ♦♦ F:M ratio = 1.5:1 intracranial, 10:1 spinal (possible hormonal basis) ♦♦ NF2 gene (chromosome 22) implicated in most familial and half of sporadic cases ♦♦ Insidious/asymptomatic onset ♦♦ Occasionally radiation-induced ♦♦ Slow growth (unless atypical or malignant) ♦♦ Recurrence −− 5–10% in gross totally resected, benign (WHO I) meningiomas −− 40–60% in subtotal resection or atypical/malignant grade (WHO II/III) meningiomas ♦♦ Decreased survival in atypical and malignant meningioma

Imaging/Gross ♦♦ Extra-axial location ♦♦ “Dural tail” sign (wisp of enhancement around base of tumor; represents either tumor or hypervascular dural tissue) ♦♦ Hyperostosis of adjacent skull related to bone invasion in most cases

Smear ♦♦ Cellular smears with 3D clusters; fibrous tumors smear poorly ♦♦ Epithelioid to spindle cells

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♦♦ Nuclear pseudoinclusions

Microscopic (Fig. 14.32) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Highly variable Polygonal epithelioid to elongated cells Nuclear pseudoinclusions Stroma scant, collagenous, or mucinous Whorls Psammoma bodies Hyalinized vessels Bone invasion is not an indicator of malignant behavior

Immunohistochemistry ♦♦ See Table 14.4

Variants (Fig. 14.33) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Meningothelial (WHO I) Fibrous (fibroblastic) (WHO I) Transitional (mixed) (WHO I) Psammomatous (WHO I) Microcystic (WHO I) Secretory (WHO I) Lymphoplasmacyte-rich (WHO I) Angiomatous (WHO I) Metaplastic (WHO I) Chordoid (WHO II) Clear cell (WHO II)

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Fig. 14.32. Meningioma, grade I, with whorl formation and psammoma bodies (A). An atypical meningioma, grade II, with sheeting architecture and numerous mitotic figures (B). Brain invasion (C) is another criterion for a grade II designation. Anaplastic meningioma, grade III, with melanoma-like cytology (D).

Table 14.4. Immunohistochemistry of Meningiomas Positive EMA (weak; membrane pattern) CK (secretory variant; otherwise rare) Progesterone receptor Vimentin S-100 (20%: 80% fibrous variant) CEA (secretory variant) Claudin Prostaglandin D synthase

Negative Estrogen receptor GFAP CD34(+)

♦♦ Rhabdoid (WHO III) ♦♦ Papillary (WHO III)

Differential Diagnosis ♦♦ Metastatic carcinoma (strong, uniform CK+)

♦♦ ♦♦ ♦♦ ♦♦

Melanoma (HMB 45+) Hemangiopericytoma/other sarcoma (reticulin rich, EMA−) Solitary fibrous tumor (strong and diffuse CD34+, EMA−) Schwannoma (strong and diffuse S-100 and collagen IV+, EMA−) ♦♦ Inflammatory pseudotumor (entrapped microscopic meningothelial nests only) ♦♦ Glioma with dural invasion (GFAP+, EMA−)

Atypical Meningioma (WHO Grade II) (Fig. 14.32B, C) ♦♦ Eightfold increased risk of recurrence (up to 52%) even after gross total resection ♦♦ Note: nuclear hyperchromasia/pleomorphism is unimportant, as it is often a degenerative phenomenon similar to that seen in ancient schwannoma! ♦♦ WHO definition −− High mitotic index, e.g. ³4/10 HPF (may be focal) or

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Fig.  14.33. Aggressive variants include chordoid, grade II (A), clear cell, grade II (B), papillary, grade III (C), and rhabdoid, grade III (D) meningiomas.

−− Brain invasion or −− Three of these five features (a) Sheeting (patternless growth with loss of whorls and fascicles) (b) Small cells (lymphocyte-like nests with high N/C ratio) (c) Hypercellularity (d) Macronucleoli (e) Spontaneous necrosis not induced by embolization or radiation

Malignant (Anaplastic) Meningioma (WHO Grade III) ♦♦ Definitions vary ♦♦ Extracranial metastasis −− Note: so-called “benign metastasizing meningioma” may be indolent ♦♦ Anaplasia

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−− Carcinoma, sarcoma, or melanoma-like appearance, focally or diffusely (requires IHC or EM demonstration of meningothelial features) (Fig. 14.32D) ♦♦ High mitotic index (e.g., >20/10 HPF) ♦♦ Median survival <2 years

Hemangiopericytoma (WHO Grade II or III) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Adults F:M = 1:1.4 No chromosome 22 abnormality Considered a meningeal sarcoma Recurrence rate = 60–90% Majority eventually metastasize Mean survival 7 years Tumor related death ~ 60%

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Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Extra-axial, dural-based Densely contrast-enhancing on CT/MRI Highly vascular on angiogram Frequently invades adjacent bone No associated hyperostosis

Smear ♦♦ Cellular without the molding/whorling of meningiomas

Microscopic (Fig. 14.34) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Monotonous, patternless cellularity Staghorn vessels Pale zones Only minor collagen deposition, if any Intercellular reticulin staining, variable but usually dense Anaplastic hemangiopericytoma (WHO III) −− High mitotic activity (³5/10 HPFs) or

♦♦ ♦♦ ♦♦ ♦♦

−− Necrosis and two of following: hemorrhage, moderate to high nuclear atypia, or high cellularity EMA− (except in rare examples with focal staining), S-100− CD34− or patchy+ Vim+, Factor XIIIa+, and Leu-7+ Strongly bcl-2 and CD99+ in most cases

Differential Diagnosis ♦♦ Meningioma (tight whorls, psammoma bodies, reticulin poor, EMA+) ♦♦ Solitary fibrous tumor (strong, diffuse CD34+; malignant examples may be difficult to differentiate from hemangiopericytoma) ♦♦ Other sarcomas (e.g., mesenchymal chondrosarcoma)

Other Primary Mesenchymal Neoplasms Benign ♦♦ Generally rare; includes most soft tissue neoplasms (e.g., chondroma, fibrous histiocytoma, hemangioma, solitary fibrous tumor, etc.)

Fig. 14.34. Hemangiopericytoma with increased cellularity, oval to spindled cells, arborizing thin-walled vessels (A), increased reticulin deposition (B), and immunoreactivity for CD99 (C), and bcl-2 (D).

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♦♦ Lipoma variants represent ~0.4% of intracranial tumors

Inflammatory Myofibroblastic Tumor (IMT)

Sarcomas

♦♦ Neoplasm formerly considered an inflammatory pseudo­ tumor ♦♦ Demonstrates ALK fusion genes ♦♦ Not associated with immunodeficiency (unlike inflammatory pseudotumors) ♦♦ Clinically and radiologically mimic meningioma ♦♦ Dura-based nonspecific plasma cell-rich fibroinflammatory masses; differential diagnosis includes rheumatoid arthritis, Rosai–Dorfman disease, Erdheim–Chester disease, and a variety of granulomatous disorders

♦♦ Typically high grade malignant; includes fibrosarcoma, MFH, osteosarcoma, chondrosarcoma (especially mesenchymal chondrosarcoma), etc ♦♦ Some are radiation-induced ♦♦ Poor prognosis

Dural Metastases ♦♦ Lung or breast carcinoma, melanoma, leukemia/lymphoma most common

OTHER NONGLIAL NEOPLASMS Hemangioblastoma (WHO Grade I) Clinical ♦♦ Adults (30–65) ♦♦ Polycythemia (10%) ♦♦ Sporadic or von Hippel–Lindau (VHL) disease ­associated (~20% of cases, gene on chromosome 3p) ♦♦ Single or multiple ♦♦ Multiple, supratentorial, younger age, or occurrences ­outside the CNS favor VHL association ♦♦ Benign

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Intra-axial Cerebellum, less often brainstem or cord Rare supratentorial or peripheral nerve involvement Cyst with enhancing mural nodule

Smear ♦♦ Misleading pseudofibrillarity may mimic astrocytoma ♦♦ Variable nuclear pleomorphism ♦♦ Lipidized stromal cells

Microscopic (Fig. 14.35) ♦♦ Highly vascular with thin-walled vessels ♦♦ Lipidized stromal cells ♦♦ Reticulin rich (reticular variant) or poor (cellular variant featuring lobules) ♦♦ Foci of extramedullary erythropoiesis (~10–15%) ♦♦ May incite marked intra- and peritumoral pilocytic gliosis ♦♦ Inhibin+, NSE+, S-100+, GFAP±, EMA−

Differential Diagnosis ♦♦ Pilocytic astrocytoma (reticulin-; lacks lipidized cells)

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Fig.  14.35. Hemangioblastoma with foamy stromal cells (A) and inhibin positivity (B).

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♦♦ Metastatic renal cell carcinoma (EMA and/or CK+, CD10+, Inhibin−)

Craniopharyngioma Adamantinomatous Craniopharyngioma (Grade I) ♦♦ ♦♦ ♦♦ ♦♦

Bimodal, children (5–15) and adults (45–60) Diabetes insipidus Frequently recurs Significant morbidity and long-term mortality due to ­hypothalamic injury, despite benign histology

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Suprasellar/third ventricle Spongy/cystic lobulated mass “Motor oil” contents Calcifications

Smear ♦♦ 3D clusters ♦♦ Squamous cells with intercellular bridges ♦♦ Wet keratin (diagnostic; resembles ghost cells pilomatrixoma) ♦♦ Cholesterol crystals (well seen in polarized light)

of

Microscopic (Fig. 14.36) ♦♦ Resembles adamantinoma of bone and ameloblastoma of jaw ♦♦ Complex layered squamous epithelium consisting of basal palisading columnar cells, loosely disposed cells with processes (stellate reticulum), a malpighian-like layer, and a keratin producing layer ♦♦ Wet keratin that may undergo calcification ♦♦ Xanthogranulomatous, cholesterol-rich debris ♦♦ Infiltrative growth ♦♦ Accompanying pilocytic gliosis

Differential Diagnosis ♦♦ Papillary craniopharyngioma (nonkeratinizing squamous epithelium) ♦♦ Rathke cleft cyst −− Ciliated and mucin-producing respiratory type epithelium −− Mucin content common −− Squamous metaplasia ♦♦ Dermoid/epidermal inclusion cyst (keratohyalin granules, lamellated keratin, skin adnexa in dermoid)

Papillary Craniopharyngioma (WHO Grade I) Clinical ♦♦ Adults (40–55) ♦♦ Less frequently invasive and presumably more resectable than adamantinomatous variant

Fig.  14.36. Craniopharyngioma with cystic degeneration, ­stellate reticulum, and basal palisading of epithelium (A, B).

♦♦ Possibly lower recurrence rate than adamantinomatous variant

Imaging/Gross ♦♦ ♦♦ ♦♦ ♦♦

Third ventricle, suprasellar Solid/cystic Noncalcified Cyst fluid clear

Histology ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Demarcated Solid sheets undergoing papillary dehiscence Nonkeratinizing squamous epithelium No granular layer Mucin containing goblet cells are a common focal feature

Differential Diagnosis ♦♦ Adamantinomatous craniopharyngioma (infiltrative growth, complex, epithelium, wet keratin undergoing calcification, “machine oil-like” cyst content) ♦♦ Rathke cleft cyst (squamous metaplasia beneath ­respiratory epithelium)

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Germ Cell Tumors Clinical ♦♦ Peripubertal children/young adults ♦♦ Parinaud syndrome (paralysis of upward gaze) in pineal examples ♦♦ Visual field defects and pituitary failure in suprasellar cases ♦♦ Precocious puberty (even in nonsuprasellar/third ventricular examples) ♦♦ Male predilection of pineal region lesions ♦♦ Treatment varies ♦♦ Pure germinoma, most common; radioresponsive ♦♦ Mature teratoma resectable ♦♦ Nongerminomatous germ cell tumors variably chemo­ sensitive

Imaging/Gross ♦♦ Generally midline, pineal and/or suprasellar location ♦♦ Solid or cystic ♦♦ Calcification common in teratomas

Smear/Histology ♦♦ Both identical to lesions in testis ♦♦ Immature teratoma = primitive (fetal-like) tissue; often feature CNS elements ♦♦ Malignant teratoma = carcinoma/sarcoma elements supervening upon a teratoma

Prognosis ♦♦ Histological subtype is single most predictive factor ♦♦ Good: pure germinoma, mature teratoma ♦♦ Intermediate: immature teratoma and mixed germ cell tumor (predominantly germinoma or teratoma) ♦♦ Poor: choriocarcinoma, yolk sac tumor, embryonal carcinoma, malignant teratoma, and mixed germ cell tumor ­(predominantly malignant, nongerminomatous mixtures)

Essentials of Anatomic Pathology, 3rd Ed.

Smear/Histology (Fig. 14.37) ♦♦ Angiocentric infiltration ♦♦ Tumor cells cuff vessels with concentric reticulin deposits, but also permeate parenchyma ♦♦ >95% are diffuse large B-cell type ♦♦ Component of small, reactive CD3+ T-cells ♦♦ Focal prominent astrocytic and microglial response ♦♦ Geographic necrosis is common ♦♦ EBV-immunopositivity often seen in AIDS/immuno­ suppression

Differential Diagnosis ♦♦ Oligodendroglioma (superficial, S-100+, LCA−, CD20−) ♦♦ Inflammatory/demyelinating process demarcated plaques, uniform myelin loss, numerous KP1+ macrophages) ♦♦ Small cell carcinoma (CAM 5.2+, SYN+, CD20−) ♦♦ Small cell glioblastoma (GFAP±, S-100+, CD20−) ♦♦ Medulloblastoma/PNET (SYN+, CD20−) ♦♦ Melanoma (HMB 45+, S-100+, CD20−

Secondary (Systemic) Lymphoma/Leukemia ♦♦ Epidural, dural or leptomeningeal are principle sites ♦♦ Cranial or spinal nerve roots involvement common ♦♦ Parenchymal involvement is secondary by inward extension along perivascular spaces ♦♦ Intravascular lymphoma: rare form of lymphoma featuring infarcts due to plugging of vessels (see Vascular Disorders)

Metastases Clinical

♦♦ Elderly or immunosuppressed patients ♦♦ Steroid responsive initially ♦♦ Improving prognosis with methotrexate-based therapy (75% 5-year survival in patients < 61) ♦♦ HAART and radiotherapy for HIV-associated disease improved median survival to 36 months

♦♦ Most common CNS neoplasm ♦♦ Most common sources in descending order −− Adults: lung (small cell; adeno), breast, melanoma, renal, and colon −− Children: leukaemia, lymphoma, osteogenic sarcoma, rhabdomyosarcoma, and Ewing sarcoma ♦♦ Hematogenous (parenchymal: lung primary; meningeal: breast/GI/prostate primary) ♦♦ Perineural (direct extension from head and neck primary) ♦♦ Direct extension from bone ♦♦ Poor prognosis ♦♦ Overall improved survival may be seen with resection of solitary metastases (e.g., renal cell carcinoma, melanoma)

Imaging/Gross

Imaging/Gross

Lymphoma/Leukemia Primary CNS Lymphoma Clinical

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Single or multiple, homogenously enhancing lesions Periventricular Supra- and/or infratentorial Brainstem and spinal cord uncommon Disappearance of lesions after steroid therapy

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♦♦ Single or multiple, circumscribed ♦♦ Gray-white junction ♦♦ Leptomeningeal metastases may diffusely involve the subarachnoid space ♦♦ Contrast enhancing

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Fig. 14.37. Primary CNS lymphoma is typically a diffuse large cell lymphoma with discohesive (A) and perivascular or angiocentric (B) growth patterns. Nearly all are positive with the B-cell marker, CD20 (C), though small mature CD3 positive T-cells are also invariably present (D).

Smear/Histology ♦♦ Discrete margin ♦♦ Often expand through growth within Virchow–Robin spaces, causing destruction of neuroglial tissue ♦♦ Limited parenchymal spread in small cell carcinoma and melanoma

Patterns ♦♦ Hemorrhagic −− Melanoma

−− Renal cell carcinoma −− Choriocarcinoma ♦♦ Tumors in young patients with frequent CNS metastases −− Germ cell tumors −− Alveolar soft parts sarcoma ♦♦ Unknown primary −− Adenocarcinoma (lung or breast are CK7+, lung is often TTF1+, GI are CK20+ (see Table 14.1) −− Melanoma (skin; primary may have regressed)

TRAUMA (SEE CHAPter 7 FORENSIC PATHOLOGY) Closed Head Injury

Open Head Injury

♦♦ Most common form ♦♦ Dura intact; may be associated with serious brain injury despite minor or no external injuries

♦♦ Dura breached and brain exposed to environment; increased risk of infection in survivors

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Blunt Head Injury ♦♦ Common cause of traumatic death ♦♦ Generally multilevel, involving external to internal ­structures (e.g., scalp laceration, skull fracture, subdural hematoma, cortical contusion, internal contusion)

Skull Fractures ♦♦ Need to strip dura for adequate examination ♦♦ Linear: follow direction of force and spread along paths of least resistance ♦♦ Depressed: impact over small surface (e.g., hammer) ♦♦ Comminuted: impact over larger surface (e.g., brick) ♦♦ Compound: associated with scalp laceration ♦♦ Basilar: often complex, patterns include hinge and ring fractures (e.g., MVA, landing on feet from high fall, or forceful hyperextension) ♦♦ “Raccoon eyes”: hemorrhage into eyelids due to orbital roof fracture ♦♦ “Battle sign”: hemorrhage overlying mastoid region because of petrous temporal fracture

Epidural Hematoma ♦♦ Relatively uncommon: usually result of skull fracture with laceration of middle meningeal artery ♦♦ Lens-shaped with concave indentation of brain parenchyma

Subdural Hematoma (Fig. 14.38A) ♦♦ Common, often fatal, usually traumatic; skull fracture in 50% ♦♦ Caused by tearing of bridging veins ♦♦ Direct impact not necessary (e.g., shaken infant); common in child abuse ♦♦ Organized examples have thin inner membrane and a thick outer membrane attached to dura ♦♦ May coexist with DAI

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Generally secondary to inertial forces (rotational or acceleration/deceleration injury) ♦♦ Silver impregnation stains used to demonstrate and grade axonal damage (axonal swellings and retraction balls) ♦♦ Damaged axons rapidly accumulate amyloid precursor protein (APP) proximal to the injury ♦♦ Frequently coexists with diffuse vascular injury (DVI) evidenced by multiple small hemorrhages ♦♦ Evolves over time: acute (hours-days): axonal swellings and retraction balls; intermediate (days-weeks): microglial starlike clusters; long-term (weeks-months): degeneration of fiber tracts ♦♦ Severity of DAI graded by macroscopic and microscopic findings: −− Grade I: widespread axonal damage in corpus callosum, cerebral white matter, and brainstem −− Grade II: grade I plus focal macroscopic abnormalities (e.g. hemorrhage) in corpus callosum −− Grade III: grade II plus focal macroscopic lesions in rostral brainstem

Pontomedullary Transection (Brainstem Avulsion) ♦♦ Results from extremely forceful hyperextension ♦♦ Partial or complete; instantly fatal in most cases

Gunshot Wounds (See Chapter 7) ♦♦ An unfortunately common cause of death in urban American life, damage generally described in terms of direction of missile trajectory (e.g., entrance wound, bullet tract, exit wound)

Penetrating Wound ♦♦ Bullet enters, but does not exit

Subarachnoid Hemorrhage (Fig. 14.38B)

Perforating Wound

♦♦ Trauma is the most common cause; may accompany contusion, laceration, or subdural hematoma ♦♦ Nontraumatic form is associated with ruptured aneurysms and other vascular malformations ♦♦ Hemorrhage extends into sulci and Virchow–Robin spaces

♦♦ Bullet enters and exits

Cortical Contusion ♦♦ Maximum damage over gyral crests with sparing of sulci (opposite of pattern in infarct) −− Coup: adjacent to point of impact; most prominent with mobile object striking stationary head (e.g., hammer) −− Contacoup: opposite point of impact; prominent when mobile head hits stationary object (e.g., frontal lobe injury when hitting back of head during fall) −− Common sites include fronto-orbital and temporal poles where they contact irregular bony surfaces of the skull base

Entrance Wound ♦♦ Abrasion ring −− Close or contact: soot deposits and burns −− Intermediate: “powder tattoo” −− Distant: no deposits −− Skull surface bevels in at entrance (wider inner table defect)

Exit Wound ♦♦ Skull defect bevels out (wider outer table defect)

Bullet Track: Low Velocity Missiles ♦♦ Associated with contusion-lined cavity; high velocity missiles: extensive damage (avulsion, “burst lobe”)

Diffuse Axonal Injury

Secondary Track

♦♦ Widespread, multifocal form of traumatic axonal injury

♦♦ Caused by ricochet of bullet off inner table of skull

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Fig. 14.38. Chronic subdural hematoma with typical attachment to overlying dura (A). Subarachnoid hemorrhage at the base of the brain (B) is often due to a ruptured Berry aneurysm, in this case located around the anterior communicating artery (C). A stain with smooth muscle actin shows the thinning and disruption of the vascular wall within the aneurysmal dilatation (D).

Spinal Cord Trauma

Cervical Spondylosis

♦♦ Motor vehicle accident and falls most common cause

♦♦ May predispose to hyperextension injuries

Upper Cervical Injuries

Central Cord Necrosis

♦♦ Usually instantly fatal and associated with brain injury

C4–C8 Injuries ♦♦ Most common site of nonfatal trauma; region susceptible to hyperextension, hyperflexion, etc

♦♦ Common in nonpenetrating injury; generally fusiform and extending over multiple segments

Posttraumatic Syringomyelia ♦♦ Late complication of central cord necrosis; may extend rostrally over time, causing neurologic deterioration in paraplegics

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ISCHEMIC/ANOXIC/VASCULAR DISORDERS Cerebral Infarct (Cerebrovascular Accident “Stroke”) (Fig. 14.39) ♦♦ Obstruction of major arterial (ACA, MCA, PCA, basilar, vertebral) or smaller branch (e.g., PICA, cortical/leptomeningeal) vascular distributions ♦♦ Cerebral atherosclerosis, thromboembolic disease, or combination; individual susceptibility due to variations in anatomy of circle of Willis and its collaterals ♦♦ Embolic disease from heart or neck vessels (e.g., carotid bifurcation); MCA territory most common (straight shot); often multiple and hemorrhagic ♦♦ Time course of infarct (see Table 14.5)

Lacunar Infarct ♦♦ Small, £1.0 cm in diameter ♦♦ Same histologic evolution as other infarcts ♦♦ Occurs in regions where small, penetrating vessels branch directly off large arteries ♦♦ Subcortical grey matter (basal ganglia), thalamus, cerebral white matter, and pons ♦♦ Frequently associated with hypertension ♦♦ Often multiple and bilateral ♦♦ May be asymptomatic dependent on location and volume affected

Anoxic Encephalopathy (Global Ischemic Injury) ♦♦ Systemic circulatory failure/hypotension (e.g., resuscitation after cardiac arrest) ♦♦ “Selective vulnerability” = regional (e.g., hippocampus CA1 and CA4 > CA2 and CA3) and cellular (e.g., neuronal > glial) variations in susceptibility to ischemia ♦♦ Includes hippocampal necrosis, Purkinje cell necrosis, watershed infarcts, selective neuronal necrosis, laminar/pseudolaminar necrosis, and “brain death syndrome” (see below)

Fig.  14.39. Typical wedge shaped distribution of this acute ­hemorrhagic infarct involving the MCA territory (A). Remote infarcts undergo cystic degeneration (B).

Table 14.5. Gross and Micro Features of Cerebral Infarct Gross features

Micro features

Acute (hours–days)

Soft, edematous; anemic = nonreperfused Coagulative necrosis, “red dead” neurons, spongy neuropil, mild Hemorrhagic = reperfused neutrophil response

Subacute (days–weeks)

Partially liquefied

Chronic (months–years) Cystic cavity with collapse of surrounding tissue

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Liquefactive necrosis, neuronal and glial dropout, marked macrophage (Gitter cell) response, reactive capillaries and gliosis at periphery Cyst lined by “gliotic scar” (no collagen), parenchymal loss in vascular distribution, subpial sparing (as opposed to old contusion); ± hemosiderin, ± scattered macrophages

Neuropathology

Hippocampal Necrosis (Fig. 14.40A, B) ♦♦ Affects pyramidal neurons of Sommer sector (CA1) and sometimes endplate (CA4) with relative sparing of CA2 and CA3

Purkinje Cell Necrosis (Cerebellar Cortex) ♦♦ Red Purkinje cells with intact internal granular cell neurons

Watershed (Borderzone) Infarct ♦♦ Typically linear and hemorrhagic, between two or all three of the major arterial zones of vascular supply (e.g., ACA and MCA territories) ♦♦ Susceptibility of endarterial vascular supply (i.e., tissue farthest from arterial source is ischemic first)

Selective Neuronal Necrosis ♦♦ Scattered necrotic neurons in cortex (especially depths of sulci) and/or deep gray matter with preservation of intervening cells

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Laminar/Pseudolaminar Necrosis (Fig. 14.40C, D) ♦♦ Extensive, typically bilateral linear intracortical infarcts involving entire cortex (laminar) or the middle to deeper layers (pseudolaminar)

Brain Death Syndrome (“Respirator Brain”) ♦♦ Extensive global ischemic insult ♦♦ Marked edema results in increased intracranial pressure (ICP) rising above systemic blood pressure, thus preventing brain perfusion ♦♦ If “life” maintained by respirator (too philosophical to discuss here, but legally, brain death = patient death), brain autolysis occurs in vivo −− Note: respirator does not cause the injury, thus the objection to the term “respirator brain” ♦♦ Gross and microscopic appearance is identical to postmortem autolysis (i.e., without reactive changes)

Fig. 14.40. Patterns of selective vulnerability associated with global hypoxia include eosinophilic neuronal necrosis of hippocampal sector CA1 (A, B) and laminar cortical necrosis with middle to deeper cortical layers most affected (C, D).

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Multi-infarct Dementia

Small Vessel Disease/Deep Infarcts

♦♦ Overdiagnosed clinically; many have AD with one or more incidental infarcts at autopsy; diagnosis requires extensive cortical damage, typically with a stepwise clinical course ♦♦ Rare cases are due to extensive cortical microinfarcts secondary to small vessel leptomeningeal disease with gross appearance of “granular atrophy”

♦♦ Arteriolar disease with deep grey and white matter infarcts, myelin rarefaction, and/or frank demyelination

Arteriolosclerosis

Venous Infarcts

♦♦ Rare complication of hypertension with diffuse cerebral white matter disease and clinical dementia

♦♦ Because of cerebral venus thrombosis (CVT) of dural sinuses or cerebral veins; may complicate infection or hypercoagulable state ♦♦ Typically hemorrhagic, bilateral, and affects white > grey matter ♦♦ Superior sagittal sinus most common site of involvement ♦♦ Produces bilateral parasagittal hemorrhagic infarction, edema, and marked leukocytic invasion

♦♦ Associated with hypertension, diabetes, and advanced age

Binswanger Disease

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (Fig. 14.41) ♦♦ Familial neurodegenerative disorder associated with missense mutations in the Notch 3 gene on chromosome 19q ♦♦ Mid-late adult onset dementia and/or pseudobulbar palsy; infrequent hemorrhage

Fig.  14.41. CADASIL is characterized by vascular thickening with granular eosinophilic deposits in the media or arteries and ­arterioles (A, B). They are PAS positive (C) and correspond to pockets of granular osmiophilic deposits at the edges of smooth muscle cells ultrastructurally (D).

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♦♦ Identical distribution to Binswanger disease, except no hypertension ♦♦ Pathognomonic PAS+; granular, electron dense deposits in media of small and perforating arterioles

“Leukoaraiosis” ♦♦ Radiologic term for white matter changes often incidentally found in elderly patients; thought to represent small vessel ischemic changes

Related Disorders (Patterns of Selective Vulnerability) Hypoglycemic Brain Injury ♦♦ Rare in pure form ♦♦ Resembles global ischemia except no gross infarcts; relative sparing of Purkinje cells ♦♦ Pseudolaminar necrosis affects superficial laminae (rather than the middle/deep layers as in hypoxia)

Carbon Monoxide Poisoning ♦♦ Carbon monoxide outcompetes oxygen for hemoglobin binding ♦♦ Resembles hypoxia except that there is selective ­vulnerability for globus pallidus and white matter ♦♦ Acute death: cherry red discoloration, body and brain ♦♦ Delayed death: pallidal necrosis, white matter necrosis/ demyelination, and/or cortical, hippocampal, and cerebellar ischemic damage

Methanol Poisoning ♦♦ Metabolized by liver to formaldehyde and formic acid, which causes most of the damage ♦♦ Selective vulnerability (necrosis): retinal ganglion and photoreceptor cells (blindness); basal ganglia (putamen and claustrum)

Intracranial Hemorrhage (also see Trauma) Berry (Saccular) Aneurysm/Subarachnoid Hemorrhage (Fig. 14.38B–D) ♦♦ Saccular outpouchings (as opposed to fusiform atherosclerotic aneurysms of posterior circulation) at bifurcations in circle of Willis, especially the anterior circulation ♦♦ Most common source of spontaneous subarachnoid hemorrhage (SAH) ♦♦ Risk of rupture is proportional to size and is associated with high mortality/morbidity ♦♦ Higher incidence in polycystic kidney disease, Ehlers– Danlos syndrome, Marfan syndrome, and neurofibromatosis type 1 (NF1)

Hypertensive Intracerebral Hemorrhage (Fig. 14.42) ♦♦ Deep, especially basal ganglia, thalamus, cerebellum, and pons

Fig.  14.42. Large hypertensive intracerebral hemorrhage with displacement, rather than destruction of adjacent parenchyma.

♦♦ Displaces, rather than destroys tissue (unlike hemorrhagic infarct); thus, once resolved/resorbed, leaves a slit-like (rather than rounded) space

Cerebral Amyloid Angiopathy and Superficial Lobar Hemorrhage (Fig. 14.43) ♦♦ Affect the elderly ♦♦ bA4 amyloid (CNS form, identical to that in neuritic plaques) deposited in leptomeningeal and superficial cortical vessels ♦♦ Not associated with systemic amyloid ♦♦ Most Alzheimer patients have CAA, but those presenting with lobar hemorrhage are not always demented ♦♦ Clinical differential includes intratumoral hemorrhage, so it may be seen as a surgical specimen

Vascular Malformations Berry (Saccular) Aneurysm ♦♦ See Fig. 14.38C, D

Arteriovenous Malformation ♦♦ Mostly intracerebral (particularly middle cerebral artery territory), occasionally spinal ♦♦ Presents with hemorrhage in more than half; seizures and headaches are also common

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Fig.  14.44. Large cavernous angioma yielding sponge-like gross appearance (A) with dilated, partially hyalinized ­vascular spaces and surrounding hemosiderin deposition ­histologically (B). Fig. 14.43. Amyloid angiopathy involving a superficial cortical vessel (A; photo courtesy of Dr. Ben Tu, Washington U., St. Louis, MO), with confirmation on thioflavin S stain (B). ♦♦ Consists of tortuous arterial, venous, and arteriovenous vessels, often with chronic degenerative changes (hyalinization, Ca2+, thrombosis, hemosiderin, gliosis) ♦♦ Extensive intervening brain parenchyma; arterial ­component is elastin+

Cavernous Angioma (“Cavernoma”) (Fig. 14.44) ♦♦ Large, thin-walled, elastic stain and actin immunonegative vessels, and often minimal intervening brain parenchyma ♦♦ Grossly spongy, chronic degenerative changes (hyalinization, Ca2+, thrombosis, hemosiderin, gliosis) ♦♦ Incidental finding or associated with hemorrhage and/or seizures; 1% chance of bleed/year

Others ♦♦ Venous angiomas and capillary telangiectasias consist of thin-walled vessels with intervening brain parenchyma devoid of reactive or degenerative changes ♦♦ Typically cerebral white matter or pons; often incidental

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Other Vascular Disorders Vasculitis ♦♦ Often secondary to meningitis or other inflammatory/infectious process ♦♦ Primary CNS vasculitis is commonly granulomatous; probably autoimmune; inflammation confined to vessel wall and causes secondary infarcts in young to middle-aged adults −− Poor prognosis unless treated aggressively with immuno­ suppressives −− May be missed on biopsy because of patchy distribution; angiography helpful

Intravascular Lymphoma ♦♦ Previously termed “angioendotheliomatosis,” but it is not an endothelial tumor ♦♦ Rather, it is a highly aggressive, systemic lymphoma largely confined to intravascular spaces of various organs including the CNS ♦♦ Most present with confusing neurologic manifestations due to vascular occlusion with multiple infarcts ♦♦ Diagnosis is often missed antemortem ♦♦ Usually large cell morphology, B-cell phenotype

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NEURODEGENERATIVE DISORDERS Summary Table (Table 14.6) ♦♦ Neurodegenerative disorders are progressive, fatal, and ­usually idiopathic with regional atrophy, neuronal loss, and gliosis

Alzheimer Disease (Fig. 14.45) ♦♦ Most common neurodegenerative disorder ♦♦ Incidence increases with age ♦♦ Varying criteria, but diagnosis based on neocortical (not hippocampal) burden of neuritic plaques (NP) and/or neurofibrillary tangles (NFT), highlighted by silver stains (Bielschowsky, Bodian, Gallyas, etc.), or immunostains for Tau (microtubule associated protein) ♦♦ Coexistent cerebral amyloid angiopathy (CAA) in most (Fig. 14.43) ♦♦ bA4 amyloid (CNS form of amyloid) in both NPs and CAA ♦♦ NFTs in neuronal perikarya and neuritic processes are composed of paired helical filaments on EM ♦♦ Majority are sporadic ♦♦ Higher risk associated with apoE4 and lower risk with apoE2 alleles ♦♦ ~10% familial forms (autosomal dominant in most) with younger age of onset; AD1 (APP or amyloid precursor protein) gene on chr. 21, AD2 (ApoE) on chr. 19, AD3 (presenilin-1 or PSEN1) on chr.14, and AD4 (presenilin-2 or PSEN2) on chr. 1 ♦♦ Down syndrome patients get early onset AD, probably because of overexpression of AD1 gene

Frontotemporal Lobar Degeneration ♦♦ Third most common cause of dementia after AD and DLBD in some series ♦♦ Frontal lobe symptoms include personality changes, dysinhibition, etc ♦♦ Nonspecific pathology (neuronal loss and gliosis) without NFTs, NPs, Lewy bodies, Pick bodies, swollen neurons, etc. (i.e., diagnosis of exclusion) ♦♦ Generally sporadic and idiopathic ♦♦ Ubiquitin+, TDP-43+ inclusions in neuronal cell nuclei, cytoplasm, and/or dystrophic neurites in a large portion of cases ♦♦ Occasionally associated with motor neuron disease (MND) (amyotrophic lateral sclerosis (ALS)/frontal lobe dementia)

Multi-infarct Dementia ♦♦ See Mutli-infarct Dementia in Ischemic/Anoxic/Vascular Disorders section

Idiopathic Parkinson Disease (Fig. 14.46) ♦♦ Most common cause of parkinsonism (masked facies, shuffling gate, resting tremor, etc.)

♦♦ Other forms of parkinsonism are usually associated with additional symptoms and are typically not l-Dopa responsive (“Parkinson Plus”), including PSP, CBD, multisystem atrophy (MSA), postencephalitic parkinsonism, ALS/ dementia/Parkinsonism of Guam, dementia pugilistica, drug-induced (MPTP) parkinsonism, etc ♦♦ Often affects lateral substantia nigra most severely (Lateral = Least pigment, Medial = Most pigment) ♦♦ Lewy body (LB) = diagnostic hallmark; immunoreactive for ubiquitin and alpha synuclein ♦♦ Dementia not uncommon; most due to coexistent AD (AD/IPD) and/or cortical Lewy bodies, others likely subcortical in nature ♦♦ If cortical LBs also found, diagnosis = diffuse Lewy body disease (DLBD) and is often associated with psychiatric symptoms; if AD changes as well, diagnosis = Lewy body variant of AD ♦♦ Some of the symptoms are also partially treated surgically with either ablative techniques (e.g., pallidotomy; Fig. 14.46d) or via deep brain stimulators (e.g. placed into subthalamic nuclei)

Huntington Disease (see Chapter 13, Human Genetic Disorder) ♦♦ Autosomal dominant; average onset in fourth to sixth decade (i.e., after procreation, thus allowing for gene survival) ♦♦ Slowly progressive; uniformly fatal ♦♦ Chorea usually precedes dementia ♦♦ Atrophy, neuronal loss, and gliosis of neostriatum (caudate and putamen); some cortical atrophy in late stage disease ♦♦ Huntington gene on chr. 4q with CAG triple repeat expansion (<37 copies = normal; >37 copies = disease) ♦♦ Genetic anticipation = younger onset and increased severity with each generation due to continued expansion of triple repeat ♦♦ Repeat expansion most likely to occur in paternal ­transmissions (i.e., during spermatogenesis) ♦♦ Lateral ventricles have “bat wing” configuration because of atrophy of caudate head

Pick Disease (Lobar Atrophy) ♦♦ Rare form of dementia; usually sporadic, <20% familial ♦♦ Earlier onset than AD (45–65 years) ♦♦ Frontotemporal disease with symptoms similar to ­frontotemporal lobar degeneration (FTLD) (see above) ♦♦ Sparing of precentral gyrus and posterior two-third of superior temporal gyrus ♦♦ Striking cortical atrophy described as “knife edge” or “walnut brain”; typically asymmetric ♦♦ Pick bodies=round, slightly basophilic, silver stain and Tau immunopositive neuronal inclusions in cortex and mesial

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Type I infantile (Werdnig–Hoffman)floppy infant, LMN only

Ataxia, cardiac disease, neuropathy

Ataxia, variable sx’s depending on variant, some overlap with MSA

Infantile and adult forms, Hallervorden–Spatz disease (HSD)

Seizures, myoclonus, dementia, visual sx’s

Spinal muscular atrophies (SMA)

Friedrich ataxia

Spinocerebellar ataxias (SCA)

Neuroaxonal dystrophies

Lafora disease (Myoclonic epilepsy)

Cortex, globus pallidus, nigra, thalamus, PNS, cerebellum

Widespread in infantile, globus pallidus in HSD

5–10% familial; minority with super­ oxide dismutase (SOD) gene mutations

PrP gene/protein (all forms), Bovine SE and nvCJD, GH extracts, grafts, etc. Also iatrogenic CJD, cannibalism and Kuru

Huntington gene (chr 4p), aut.dom., triple repeat expansion

Combined AD/IPD, DLBD, LB variant of AD

Rare familial associations

ALS/dementia complex (Rare)

ApoE4 allele, AD1 (APP) gene-chr.21 (Down syn.), AD2-AD4 genes

Genetic/other associations

Myelin pallor, neuronal loss

Lafora body

Axonal spheroids (swellings) + iron deposition in HSD

Aut. Rec., gene on chr. 6q

Aut. Rec. in most, genes not yet identified

Aut. Dom. In most, caused by triple repeat expansion

Aut. Rec., frataxin gene (chr. 9q), triple repeat expansion

Myelin pallor, neuronal loss, characte­ristic Aut. Rec., gene(s) on chr. 5q muscle histology in infantile form

Variable, Purkinje cells, OPCA, Myelin pallor, neuronal loss spinocerebellar tracts, MND (type 3)

Post. columns + roots, periph. N., lat. columns, dentate, sup. cerebellar ped.

Ant. horns + roots, skeletal muscle atrophy

Ant. horns and roots, lat. columns, XII cr. N.

Upper and lower motor neuron disease (weakness, hyperreflexia, fasciculations)

Amyotrophic lateral sclerosis (ALS)/MND

Myelin pallor, neuronal loss, Bunina bodies, LB-like inclusions

Glial inclusions, neuropil threads

Putamen, subst. nigra, locus ceruleus, basis pontis, Purkinje cells

Striatonigral degeneration (parkinsonism) ± olivopontocerebellar atrophy (ataxia), ± Shy–Drager syn (autonomic dysfunction)

Neurofibrillary tangles, (globose type), glial inclusions, neuropil threads

Spongiform change, amyloid (Kuru) plaques

Multisystem atrophy (MSA)

Gray matter (cerebral/ cerebellar cortex, deep gray)

Neuronal loss and gliosis only

Swollen neurons, neurofibrillary tangles, glial inclusions, neuropil threads

Dementia, myoclonus, EEG findings

Creutzfeldt–Jakob disease (CJD)

Caudate, putamen

Lewy bodies (LB)

Frontotemporal cortex, subst. nigra, other subcortical nuclei

Chorea, dementia

Huntington disease (HD)

Subst. nigra, locus ceruleus

Pick bodies, swollen neurons (Pick cells)

Dementia, “alien limb” syndrome, parkinsonism

Parkinsonism, ± dementia

Parkinson disease (IPD)

Frontotemporal cortex

Neuronal loss and gliosis only (Dx of exclusion)

Corticobasal degene­ ration (CBD)

Dementia, frontal lobe sx’s

Pick disease

Frontotemporal cortex

Neurofibrillary tangles, plaques, amyloid angiopathy

Histology

Subcortical, esp. brainstem nuclei, globus pallidus, and dentate

Dementia, frontal lobe sx’s

Frontotemporal lobar degeneration

Cortex, mesial temporal lobe, nucleus basalis

Regions of pathology

Progressive supra­nuclear Parkinsonism, upward gaze palsy, ± palsy (PSP) dementia

Dementia

Clinical

Alzheimer disease (AD)

Disorder

Table 14.6. Neurodegenerative Disorders, The Minimalist Approach

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Fig. 14.45. Alzheimer disease characterized by generalized cortical atrophy (A), a neuritic plaque with an amyloid core on H&E (B), and cortical plaques and tangles on Bielschowski silver stain (C). The latter also highlights more lightly stained ghost tangles in the hippocampus, where neurons have died off (D).

temporal structures (hippocampus, amygdala, entorrhinal cortex) ♦♦ Pick cells = swollen (achromatic or chromatolytic) cortical neurons which appear large and pink; NF positive and devoid of Nissl substance (thus resembles central chromatolysis)

Creutzfeldt–Jakob Disease/Spongiform Encephalopathies (Fig. 14.47) ♦♦ Rapidly fatal form of dementia ♦♦ Uniform worldwide incidence of 1/1,000,000 per year ♦♦ Majority are sporadic (i.e., no evidence of infectious or genetic cause) ♦♦ 10% familial (PrP gene mutations) ♦♦ Rare cases are iatrogenic (infectious) due to inadvertent inoculation of contaminated tissue such as dural graft, corneal transplant, EEG electrodes, or human growth hormone extracts

♦♦ Transmissible agent is protease-resistant prion protein (PrP) ♦♦ Disease occurs with conformational change of PrP structure into b-pleated sheet (amyloidogenic) −− Some gene mutations increase likelihood of this conversion (familial) −− Single pathogenic PrP can induce further protein conversions of wild type protein, thus creating a chain reaction ♦♦ Etiology of sporadic CJD is poorly understood, but most likely represents somatic age-related gene mutation or spontaneous protein conversion; homozygosity for Met or Val at codon 129 increases risk of sporadic CJD ♦♦ Classic cases have triad of rapid dementia, myoclonus, and periodic short wave activity on EEG ♦♦ Classic histology shows triad of neuronal loss, gliosis, and spongiform change (often patchy) defined by small, “sharply defined, punched out” vacuoles in gray matter (cortex and/or deep nuclei) ♦♦ Cerebellar amyloid plaques in ~5%

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Fig.  14.46. Idiopathic Parkinson disease and diffuse Lewy body disease are characterized by pallor of the substantia nigra, ­particularly the lateral portions (A), Lewy bodies in residual nigral neurons (B), and more subtle Lewy bodies in small cortical neurons, particularly in the cingulate gyrus (C). Pallidotomy is a common surgical approach for alleviating some of the ­involuntary movements (D).

Differential Diagnosis ♦♦ Microvacuolar change; superficial cortical vacuolation commonly seen in end-stage AD; in comparison, CJD typically affects deep cortex or entire cortex ♦♦ Edema or ischemia: vacuoles larger and more ill-defined ♦♦ Artifacts: vacuoles larger and ill-defined; also affects white matter

Other Spongiform Encephalopathies Variant CJD ♦♦ Cluster of cases reported from England linked to human infection by bovine spongiform encephalopathy (BSE) agent ♦♦ Unusually young age of onset (<40 years) ♦♦ Prolonged clinical course ♦♦ Dementia less prominent; behavioral changes ♦♦ Numerous cerebral cortical and cerebellar amyloid plaques (unique histology among the SEs)

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♦♦ Patients homozygous for Met at codon 129 ♦♦ Link to BSE puzzling because bovine skeletal muscle contains little to no pathogenic PrP (as compared to brain), speculation that exposure associated with products containing mechanically recovered meat products (containing tissue other than muscle)

Gerstmann–Sträussler–Scheinker Disease (GSS) ♦♦ Rare familial SE with cerebellar ataxia, progressive dementia, and amyloid plaques in cerebellar molecular layer (“GSS plaques”); various PrP gene mutations

Fatal Familial Insomnia ♦♦ Autosomal dominant SE with rapid course, sleep ­disturbances, hallucinations, motor and autonomic ­symptoms, prominent thalamic, and inferior olive disease; PrP gene mutations

Kuru ♦♦ Literally “trembling disease” in the Fore language of New Guinea

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Corticobasal (Ganglionic) Degeneration ♦♦ Relative newcomer to neurodegenerative world; mostly sporadic ♦♦ Cortical and subcortical (basal ganglia, substantia nigra) pathology ♦♦ Overlap with Pick disease; = asymmetrical frontal lobe dementia with swollen neurons ♦♦ Overlap with PSP; subcortical NFTs, neuropil threads, and GCIs with parkinsonism ♦♦ “Alien limb” syndrome typical, but not always present

Multisystem Atrophy (Fig. 14.48) ♦♦ Three formerly separate clinical syndromes, with same underlying pathologic process; mostly sporadic −− Striatonigral degeneration (SND): putamen and nigra = parkinsonism −− Olivopontocerebellar atrophy (OPCA): inf. olives, basis pontis, Purkinje cells = ataxia −− Shy–Drager: intermediolateral spinal columns (thoracic cord) = autonomic dysfunction ♦♦ Now clinically classified by dominant motor symptoms: MSA-P (predominantly parkinsonism), MSA-C (cerebellar symptoms) ♦♦ Gross atrophy with subcortical Gallyas and alpha synuclein positive GCIs and neuropil threads ♦♦ Some clinical overlap with inherited spinocerebellar ataxia (SCA), PSP, and CBD

Fig. 14.47. Creutzfeld–Jacob disease (CJD) is recognized as the prototype spongiform encephalopathy with numerous small punched out vacuoles in regions of both cortical and subcortical gray matter (A, B). ♦♦ Largely of historic interest; it established the “transmissible agent” from diseased brains ♦♦ Linked to cannibalistic ritual involving brains of deceased; now discontinued, the disease is disappearing ♦♦ Predominantly a cerebellar disease with “spiked-ball” amyloid (“Kuru”) plaques

Progressive Supranuclear Palsy (Steele–Richardson–Olszewski Disease) ♦♦ Supranuclear (upward) gaze palsy due to involvement of oculomotor (CN III) nucleus (similar to Parinaud syndrome, see pineal tumors) ♦♦ Parkinsonism and/or dementia (subcortical), clinical syndrome nonspecific: overlaps with IPD, CBD, MSA, etc ♦♦ Subcortical NFTs with globose configuration ♦♦ Tau immunopositive glial cytoplasmic inclusions (GCI) within oligodendrocytes and neuropil threads (overlap with CBD and FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17)

Amyotrophic Lateral Sclerosis/Motor Neuron Disease (Fig. 14.49) ♦♦ Combined upper (UMN) and lower motor neuron (LMN) disorder, but occasionally only one level is involved ♦♦ Weakness, wasting, fasciculations, hyperreflexia, Babinski sign, EMG signs of denervation, etc ♦♦ 5–10% familial, of which a minority have mutation in superoxide dismutase (SOD) gene (i.e., most cases are sporadic/ idiopathic) ♦♦ Clinical mimics may include polio, HIV, HTLV−1, lead poisoning, autoimmune disease, etc. (“secondary MND”) ♦♦ Grossly, atrophy of anterior spinal roots is the most prominent pathologic feature ♦♦ Histology shows myelin pallor (LFB-PAS or other myelin stain) of lateral columns and anterior roots, loss of anterior horn neurons, Bunina bodies (small eosinophilic cytoplasmic inclusions; ubiquitin and TDP-43+), Lewy body-like inclusions, and neurogenic pattern of muscle fiber atrophy ♦♦ Rare cases are associated with frontal lobe dementia (FTLD)

Spinal Muscular Atrophy ♦♦ Group of autosomal recessive MNDs (LMN only), one or more genes on chr. 5q (also see Chapter 13) ♦♦ Histology shows loss of anterior horn neurons, atrophy of anterior nerve roots, and neurogenic muscle fiber atrophy

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Fig. 14.48. Multiple systems atrophy (MSA) is another parkinsonian disorder with striatonigral degeneration (A, B) and olivopontocerebellar atrophy (C; pontine component) representing the two most common gross patterns of involvement. A Gallyas silver stain highlights the typical glial cytoplasmic inclusions (D).

Variants ♦♦ Type 1 = infantile (Werdnig–Hoffman disease): most common spinal muscular atrophy (SMA), “floppy baby,” dies within a couple of months from respiratory failure; characteristic skeletal muscle histology with large group neurogenic atrophy (small and round, not angulated) and scattered round hypertrophic fibers ♦♦ Type 2 = chronic infantile: intermediate severity with ­survival into teens ♦♦ Type 3 = chronic, proximal (Kugelberg–Welander syndrome); clinical presentation similar to muscular dystrophy; generally normal life expectancy

Friedreich Ataxia (see Chapter 13) ♦♦ Most common form of inherited ataxia; autosomal recessive inheritance ♦♦ GAA triple repeat expansion (see HD) in frataxin gene, chr 9q ♦♦ Onset in childhood or teens with variable survival (rarely past 30s)

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♦♦ Cardiomyopathy typical (unlike SCA, see below) ♦♦ Ataxia due to combined peripheral neuropathy, atrophy of spinocerebellar tracts (cerebellar afferents), and degeneration of superior cerebellar peduncle (efferents) ♦♦ Myelin pallor in posterior columns, dorsal nerve roots, lateral columns, spinocerebellar tracts, superior cerebellar peduncles, and peripheral nerve ♦♦ Neuronal loss in dentate nucleus and others

Spinocerebellar Ataxia ♦♦ Group of inherited, mostly autosomal dominant forms of ataxia ♦♦ Number of variants growing (25+, see Chapter 3) ♦♦ Wide range of severity, age of onset, and clinical ­manifestations, dependent on specific variant ♦♦ Many are CAG triple repeat expansions ♦♦ Genetic a­ nticipation (see HD) ♦♦ Some overlap with MSA, but no GCIs or neuropil threads

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Fig. 14.49. ALS characterized by atrophy of anterior nerve roots (A), a Bunina body within a motor neuron of the anterior horn (B), and marked pallor of the corticospinal tracts on LFB-PAS stain (C). ♦♦ Machado–Joseph disease = form of SCA3 with parkinsonism, bulging eyes, and anterior horn cell loss (MND) that may mimic ALS

Neuroaxonal Dystrophy (Fig. 14.50) ♦♦ Group of neurodegenerative disorders characterized by axonal spheroids (swellings) ♦♦ May be physiologic, primary (several types), or secondary ♦♦ Infantile form = autosomal recessive; widespread CNS and PNS disease; death in early childhood; diagnosis can be made on skin, nerve, conjunctival, or rectal biopsy ♦♦ Hallervorden–Spatz disease is autosomal recessive in most; early and late onset variants; movement disorder and dementia; characteristic “eye of tiger” sign on MRI; spheroids and iron accumulation in globus pallidus and substantia nigra

Lafora Disease (Myoclonic Epilepsy) ♦♦ Rare neurodegenerative disorder of carbohydrate metabolism ♦♦ Autosomal recessive, gene on chromosome 6q

Fig. 14.50. Infantile neuroaxonal dystrophy (NAD) with numerous axonal swellings or spheroids.

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Onset in childhood or teens; death in early adulthood Myoclonic seizures, cerebellar symptoms, dementia Widespread CNS and PNS disease PAS + Lafora body (similar to corpora amylacea, polyglucosan bodies, brain sand, “blue balls”) that normally accumu-

lates in brain with age, except that they are intracytoplasmic (neuronal processes, glia, Schwann cells, endothelium, skeletal and cardiac muscle, hepatocytes, sweat ducts) and surrounded by haloes ♦♦ Diagnosis can be made on skin, liver, or nerve bx

INFLAMMATORY/INFECTIOUS DISEASES Acquired Demyelinating Disorders Multiple Sclerosis (Fig. 14.51) ♦♦ Prototypic CNS demyelinating disorder ♦♦ Idiopathic, probably multifactorial with genetic and environmental components

♦♦ Young adults, multifocal, remitting-relapsing disease, many exceptions ♦♦ Periventricular, subcortical, optic pathway, brainstem, spinal cord lesions ♦♦ Gross = sharply demarcated gray, translucent plaques (i.e., white matter without myelin resembles gray matter)

Fig. 14.51. Biopsy from a patient with active demyelinating disease (A), showing marked loss of myelin on an LFB-PAS stain (B) with relative preservation of Bielschowski positive axons (C). At higher magnification, PAS positive myelin debris is seen within macrophages (D; LFB-PAS stain). See also Fig. 14.1.

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♦♦ Histology = triad of numerous macrophages, perivascular lymphocytes, and gliosis ♦♦ LFB-PAS and Bielschowsky or NF immunostain useful to show loss of myelin with relative sparing of axons (in contrast to infarcts); PAS + myelin debris in macrophages ♦♦ Activity of plaques relates to degree of inflammation; “Shadow plaques” represent partial remyelination

Variants ♦♦ Marburg variant = acute fulminant multiple sclerosis (MS); severe, rapid course, often fatal: some overlap with acute disseminated encephalomyelitis (ADEM) (see below); occasional solitary lesion mimics tumor ♦♦ Schilder variant = giant, bilateral plaques, usually in children; some cases have turned out to represent adrenoleukodystrophy (see metabolic disorders) ♦♦ Balo concentric sclerosis = rare pattern with alternating rings of myelin loss and preservation/remyelination

Acute Disseminated Encephalomyelitis/ Perivenous Encephalomyelitis ♦♦ Spectrum of disorders including postinfectious/postvaccinial encephalomyelitis and acute hemorrhagic encephalomyelitis (AHEM) −− Research model = experimental allergic encephalomyelitis (EAE) ♦♦ Often, but not invariably associated with inciting viral infection or vaccination ♦♦ Acute, fulminant course, though most patients recover ♦♦ Probably autoimmune attack against CNS myelin or related antigen (analogous to Guillain–Barré syndrome (GBS) and PNS myelin) due to cross reactivity with viral antigen ♦♦ Widespread, perivenous demyelination, inflammation, and/ or hemorrhage ♦♦ Brainstem and spinal cord involvement is common and may predominate

Guillain–Barré Syndrome /Acute Inflammatory Demyelinating Polyneuropathy ♦♦ Rapid, progressive radiculopathy/polyneuropathy with paralysis ♦♦ Analogous to ADEM, except PNS ♦♦ Inciting events include viral infection, vaccination, surgery, trauma, and neoplastic disease ♦♦ Research model = experimental allergic neuritis (EAN) ♦♦ CIDP = chronic form with onion bulbs in nerve biopsy representing multiple bouts of demyelination and remyelination

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Paraneoplastic Encephalomyelitis ♦♦ Rare complication of neoplasia, especially lung (small cell), ovarian, and breast carcinomas ♦♦ Associated with serologically detectable antibodies in most; e.g., antineuronal nuclear antibody type 1 (ANNA-1 or anti-Hu) ♦♦ Probably cross reactivity of neuronal and tumor antigens; therefore, primary tumor is often small, low stage, and associated with inflammation ♦♦ Affects any level of CNS, PNS, and/or muscle; combinations common ♦♦ Histology is identical to viral encephalitis ♦♦ Clinical disease patterns include limbic, cerebellar, or brainstem encephalitis; opsoclonus/myoclonus; myasthenic syndromes; gastric paresis; etc ♦♦ Lambert–Eaton myasthenic syndrome due to effects of presynaptic calcium channel antibodies ♦♦ Patients often die of paraneoplastic disease rather than of tumor

Neurosarcoidosis ♦♦ CNS disease in ~5% of sarcoidosis, though systemic disease may not be obvious ♦♦ Predilection for basal meninges, thus affecting cranial nerves (esp. CN VII), optic pathway, pituitary, and hypothalamus ♦♦ Parenchymal (brainstem, spinal cord, or cerebral) disease may also occur ♦♦ Granulomas tend to spread into deeper brain along Virchow– Robin spaces ♦♦ Variable clinical course; generally slow, but some fatal despite therapy

Bacterial Infections Meningitis (Fig. 14.52) ♦♦ Purulent leptomeningeal inflammation, often with secondary vasculitis and infarcts ♦♦ Typically because of hematogenous source with initial access to the CSF via the choroid plexus where there is no BBB; therefore, there is frequently a coexisting ependymitis/ plexitis ♦♦ Neonates = group B Streptococcus; E. coli, other Gram negative rods ♦♦ Children = H. influenzae (less common now due to vaccination), N. meningitidis, S. pneumoniae ♦♦ Adults = S. pneumoniae, N. meningitidis ♦♦ Complications = venous infarcts, hydrocephalus, deafness, cranial palsies, postmeningitic epilepsy, developmental delays, and cognitive deficits

Demyelinating Viral Infections

Abscess

♦♦ HIV, HTLV−1, JC virus (progressive multifocal leukoencephalopathy (PML)), measles virus (SSPE)

♦♦ Usually hematogenous (e.g., septic emboli); occasionally because of contiguous spread

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♦♦ Tend to lodge at microvascular branch points near cortical gray-white junction, especially in MCA territory ♦♦ Early cerebritis (presuppurative) progresses to microabscess, which progresses to walled-off abscess ♦♦ Neuroimaging may mimic primary or metastatic neoplasm

Tuberculosis ♦♦ Commonly nonspecific prodromal symptoms for 2–8 weeks ♦♦ Basal meninges and cranial nerves (causing palsies) ♦♦ Parenchymal disease = tuberculoma; cerebellum, and pons commonly affected ♦♦ May develop secondary vasculitis with multiple infarcts ♦♦ High mortality without early treatment

Neurosyphilis ♦♦ Typically presents in late tertiary stage ♦♦ Meningeal and/or parenchymal involvement; spinal cord and/or brain ♦♦ Hallmark = microglial activation and endarteritis obliterans (crescentic collagenous intimal thickening; “Heubner arteritis”) with secondary infarcts ♦♦ Paretic dementia (general paresis of insane) = meningeal fibrosis, hydrocephalus, and cortical atrophy with ­perivascular lymphoplasmacytic cellular inflammation, and microglial activation (i.e., encephalitis); organisms (Treponema pallidum) demonstrable on silver stains ♦♦ Tabes dorsalis = atrophy of posterior nerve roots, DRGs, and posterior spinal columns, especially lumbosacral and/or cervical; no organisms, no inflammation, so etiology is uncertain

Whipple Disease ♦♦ CNS disease rare, but may occur without obvious systemic findings ♦♦ Dementia, ophthalmoplegia, myoclonus, hypothalamic/pituitary dysfunction ♦♦ Cortical subpial, basal ganglia, hypothalamus, brainstem, and cerebellum ♦♦ Inflammatory nodules ♦♦ Hallmark = perivascular macrophages stuffed with Gram+, PAS + bacilli (Tropheryma whippelii) −− Free organisms may also be found ♦♦ EM or PCR may be helpful

Fig.  14.52. Acute bacterial meningitis with leptomeningeal opacification (A), a neutrophil-rich subarachnoid infiltrate, and gram-positive organisms (B). ♦♦ Predisposing factors = endocarditis, heart valve disease, congestive heart disease with L to R shunt, IV drug abuse, immunosuppression, periodontal disease, dental work, sinus infection, and mastoiditis

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Fungal Infections Meningitis (Fig. 14.53A, B) ♦♦ Cryptococcus most common; especially frequent in AIDS patients: −− Yeast with thick polysaccharide-rich capsule results in grossly mucoid exudate −− Process extends deep within Virchow–Robin spaces to form microabscesses −− Minimal inflammatory response

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−− High mortality −− Diagnosis made by antigen testing of CSF or serum

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♦♦ Most CNS viral infections include meningeal inflammation (e.g. meningoencephalitis)

Granuloma/Abscess (Fig. 14.53C)

Encephalitis (Fig. 14.2)

♦♦ Candida, coccidioidomycosis, and histoplasmosis are most common ♦♦ Organism load and inflammatory response vary with immunocompetence

♦♦ Herpes is the most common cause of sporadic cases (see below) ♦♦ Arboviruses (arthropod borne; e.g. West Nile, JE, TBE) the most common cause of epidemic cases −− Transmitted to humans from animal reservoirs (e.g., horse) via arthropods (e.g., mosquito) −− No inclusions, specific diagnosis depends on serology −− Variable mortality rates

Angioinvasive Forms (Fig. 14.53D) ♦♦ Aspergillus and Mucor (Zygomycetes) ♦♦ Hemorrhagic and necrotizing because of vascular involvement ♦♦ Mucor likes low pH and high glucose; therefore, increased incidence in diabetics with ketoacidosis −− Frontal lobe disease results from spread of primary sinus infection

Viral Infections ♦♦ Characterized by microglial nodules, microglial activation, perivascular lymphocytes, and/or viral inclusions

Viral (Aseptic) Meningitis ♦♦ Transient, less severe than bacterial ♦♦ Perivascular lymphocytic infiltrate, superficial cortical infiltrate, and CSF lymphocytosis ♦♦ Most common agents: echovirus, coxsackievirus, and other enteroviruses

Herpes Simplex ♦♦ Mostly type I; type II occurs in infants exposed during vaginal delivery ♦♦ Temporal lobes almost always involved; bilateral, asymmetric ♦♦ Hemorrhagic and necrotizing ♦♦ Cowdry A and B nuclear inclusions, may be difficult to find in biopsy; immunostains helpful, though most cases are now diagnosed clinically with CSF PCR studies ♦♦ Most cases fatal unless treated early (acyclovir)

HIV Encephalitis/AIDS Dementia Complex ♦♦ Common complication of AIDS with cognitive, behavioral, and motor deficits ♦♦ Mild cerebral atrophy grossly

Fig. 14.53. Patterns of fungal CNS infections, including cryptococcal meningitis (A, B: PAS stain), granulomatous blastomycosis (C), and angioinvasive Aspergillosis (D).

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♦♦ Abnormalities in white matter, thalamus, and basal ganglia (subcortical dementia) ♦♦ Hallmark macrophage-derived multinucleated giant cells (HIV+) ♦♦ Perivascular lymphocytes and macrophages, microglial nodules (i.e., encephalitis), myelin rarefaction, or frank white matter necrosis

Vacuolar Myelopathy of AIDS ♦♦ Less common, but also felt to represent direct consequence of HIV infection ♦♦ Vacuolation of myelin in posterior and lateral columns, mainly thoracic cord, with minimal to no inflammation; resembles vitamin B12 deficiency ♦♦ Paraparesis, ataxia, and incontinence ♦♦ Most patients have coexisting HIV encephalitis

Cytomegalovirus ♦♦ Common opportunistic infection, especially in AIDS patients and in neonates

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Represents “reactivation disease” in most adult cases ♦♦ Ventriculitis, choroid plexitis, and encephalitis (especially periventricular regions) ♦♦ Nuclear and cytoplasmic inclusions in glial, neuronal, choroid plexus, endothelial, and histiocytic cells ♦♦ Congenital: represents the “C” in TORCH; results in microcephaly, chorioretinitis, hydrocephalus, periventricular calcifications, and CNS malformations

JC Virus/Progressive Multifocal Leukoencephalopathy (Fig. 14.54) ♦♦ Papovavirus named after the first described patient’s initials (JC) (nothing to do with CJD) ♦♦ Virtually uniformly fatal infection of immunocompromised, especially AIDS ♦♦ Is a “reactivation disease”; most of population is seropositive ♦♦ Hallmark = demyelinating (or frankly necrotizing) plaques featuring enlarged, nuclear inclusion bearing oligoden­ drocytes

Fig. 14.54. PML with multiple, bilateral foci of demyelination (A), a macrophage-rich infiltrate within demyelinating foci (B), plumbcolored viral inclusions within oligodendrocytes (C), and bizarre, virally infected astrocytes (D).

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♦♦ Also typical are large, bizarre astrocytes that may mimic astrocytoma on biopsy ♦♦ Minimal inflammation ♦♦ EM and/or in situ hybridization is diagnostically useful ♦♦ Immunostains for other polyoma viruses (BK, SV40) will label infected cells

Subacute Sclerosing Panencephalitis ♦♦ Rare reactivation disease of children who had measles years earlier ♦♦ Generally fatal with gray and white matter involvement ♦♦ Encephalitis histology with intranuclear oligodendroglial and neuronal inclusions; neuronophagia common ♦♦ Patients typically have high measles antibody titers ♦♦ EM and PCR also diagnostically useful

Rabies ♦♦ Single stranded RNA virus ♦♦ Enters CNS via axonal transport from peripheral nerves; therefore incubation period relates to site of inoculation ♦♦ Typically, but not invariably, transmitted through bite of rabid animal ♦♦ Histology = encephalomyelitis pattern and/or neuronophagia ♦♦ Hallmark = Negri body (one or more eosinophilic, ­bullet-shaped cytoplasmic inclusions) in hippocampal, neocortical, or Purkinje cell neurons

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Toxoplasmosis (Fig. 14.55) ♦♦ Acquired by ingestion of Toxoplasma gondii oocysts in cat feces or tissue cysts in raw or undercooked meat ♦♦ Common opportunistic infection of AIDS patient and of neonates (“T” in TORCH) ♦♦ Represents a “reactivation disease” in immunosuppressed adults ♦♦ One of only a few treatable CNS disorders in AIDS; therefore, often treated empirically prior to resorting to biopsy ♦♦ Multiple, enhancing deep and cortical lesions; main differential diagnosis = lymphoma ♦♦ Necrotizing encephalitis with microglial nodules, macrophages, secondary vasculitis, and/or abscess formation ♦♦ Chorioretinitis also common ♦♦ Encysted and free organisms seen at periphery necrosis on H&E stain ♦♦ Immunostains useful for confirmation ♦♦ Healed lesions show abundant lipid-laden macrophages and dystrophic calcification

Poliomyelitis ♦♦ CNS disease develops in <10% of patients with enteric infection ♦♦ Rare in USA because of widespread vaccination ♦♦ Same syndrome may occur with a variety of enteroviruses ♦♦ Hemorrhagic, necrotizing myelitis involving predominantly lower motor neurons of anterior horns; microglial nodules, neuronophagia ♦♦ Brain involvement in some fatal cases

Parasites Cysticercosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Most common CNS parasitic infection Most common cause of epilepsy in Mexico Encysted larval form of the pig tapeworm, Taenia solium Becomes symptomatic when organism dies and elicits a host inflammatory response Multiloculate cysts often at base of brain or in subarachnoid space/fourth ventricle = racemose form Single or multiple; parenchymal or intraventricular, and/or hydrocephalus Gross = cyst with larval nodule Micro = larva with diagnostic scolex (with suckers and hooklets)

Fig. 14.55. Encysted forms of toxoplasma on a brain biopsy (A), with additional tachyzoites identified on an i­mmunostain (B).

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Amebic Meningoencephalitis

Cerebral Malaria

♦♦ Rare disorder usually due to Naegleria fowleri ♦♦ Lethal, hemorrhagic meningoencephalitis at base of brain (frontotemporal) ♦♦ Children/young adults diving/swimming in warm fresh water ♦♦ Gains access through nose to region of cribriform plate ♦♦ Acanthamoeba species is a rare cause of granulomatous encephalitis in the immunocompromised or of keratitis in contact lens users

♦♦ Most serious complication of malaria; associated with high mortality ♦♦ P. falciparum most common; lesions due to high parasite load creating sticky red cells that occlude micro­ circulation ♦♦ Petechial hemorrhages, mild edema, parasitized RBCs may be visible in vessels, hemozoin pigment ♦♦ Ring hemorrhages are typical

PEDIATRIC AND SEIZURE NEUROPATHOLOGY Malformations Neural Tube Defects Anencephaly (Fig. 14.56A)

Spina Bifida Occulta

♦♦ Most common brain malformation ♦♦ Frog-like facies (shallow orbits); sphenoid wing deformity resembles “bat with folded wings” ♦♦ Area cerebrovasculosa = ectatic vessels and brain remnants ♦♦ Underdeveloped hypothalamus/pituitary leads to adrenocortical hypoplasia ♦♦ Interaction of environmental/genetic factors poorly understood ♦♦ Associated with high amniotic fluid alpha fetoprotein

♦♦ Failure of cerebral hemispheres to separate: “face predicts brain”; cyclopia, proboscis, agnathia, cleft lip/palate, etc, often present ♦♦ Most cases are sporadic ♦♦ Common associations = maternal diabetes, TORCH infections, fetal alcohol syndrome, trisomy 13, and (less commonly) trisomy 18 and triploidy ♦♦ Variations −− Alobar = small, monoventricular brain, no ­interhemispheric fissure, olfactory aplasia, fused basal ganglia and thalami, thin membrane over posterior ventricle (posterior cyst) −− Semilobar = shallow interhemispheric fissure, minimal gyration −− Lobar = normal interhemispheric fissure, well-developed gyration, fusion of midline structures, absent or ­hypoplastic corpus callosum −− Arrhinencephaly = olfactory aplasia with lack of bulbs, tracts, and gyrus rectus (i.e., no olfactory sulcus)

Craniorachischesis (Fig. 14.56B) ♦♦ Most severe neural tube defect ♦♦ Anencephaly and lack of spinal closure, flattened, malformed spinal cord or area medullovasculosa (tissue similar to area cerebrovasculosa)

Encephalocele ♦♦ Herniation of brain through skull defect ♦♦ Usually occipital; occasionally anterior (frontal) at bridge of nose ♦♦ Typically asymmetric and/or overlying skin ulceration ♦♦ Neurologic deficit depends on extent of herniation and other malformations

Myelomeningocele ♦♦ Herniation of malformed spinal cord and meninges through a vertebral defect and/or overlying skin ulceration ♦♦ Usually associated with Arnold–Chiari malformation and hydrocephalus ♦♦ Neurologic deficit depends on level of defect and associated rostral spinal malformations; lumbosacral level is most common

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♦♦ Minor lumbosacral defect with intact overlying skin

Holoprosencephaly

Congenital Hydrocephalus Arnold–Chiari (Chiari II) Malformation ♦♦ Elongated, S-shaped brainstem with herniation of medulla and cerebellar vermis below foramen magnum ♦♦ “Beaking” of quadrigeminal plate with fusion of inferior colliculi ♦♦ Compressed fourth ventricle with obstructive hydrocephalus ♦♦ Associated myelomeningocele in most ♦♦ Associated migrational/gyral defects in some ♦♦ Other Chiari malformations:

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Fig. 14.56. Frog facies (A) and lack of spinal fusion (B) encountered in anencephaly with craniorachischesis.

−− Chiari type I – conical elongation of tonsils and medial hemispheres extending into vertebral canal; often asymptomatic, but may cause late-onset hydrocephalus; close association with syringomyelia; not associated with myelomeningocele −− Chiari type III – rare; herniation of cerebellum into encephalocele through occipitocervical bony defect

Dandy Walker Malformation (Fig. 14.57) ♦♦ Agenesis of cerebellar vermis with dilated fourth ventricle cyst covered by thin membrane (easily torn) ♦♦ Large posterior fossa ♦♦ Etiology of hydrocephalus uncertain; aqueductal stenosis in some ♦♦ Associated malformations common (e.g., polymicrogyria, agenesis of corpus callosum, etc.)

Aqueductal Stenosis ♦♦ Rare cause of hydrocephalus ♦♦ Histologically associated with atresia, forking, etc ♦♦ Ependymal granulations and gliosis suggest prior infection (e.g., TORCH)

Migrational/Gyral Defects ♦♦ Often associated with seizures, mental/psychomotor retardation, learning disorders, etc ♦♦ Timing of insult (ischemic, infectious, genetic, etc.) determines abnormality ♦♦ Normally, neuroblasts migrate from periventricular germinal matrix to cortex (inside out manner: deepest layer first, superficial layers last) and other sites; excess neurons are removed by apoptosis and the remaining neurons mature

Polymicrogyria (Fig. 14.58) ♦♦ Most common gyral abnormality ♦♦ Small gyri with shallow sulci and “fused” molecular layers ♦♦ Cortical dysplasia (architectural distortion) with simplified 2- to 4-layer neocortex ♦♦ Underlying neuronal heterotopias common (“migrational arrest”) ♦♦ Commonly seen at the edge of a porencephalic cyst

Lissencephaly/Pachygyria ♦♦ Small brain (microcephaly) with broad or no gyri

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♦♦ Thick cortex extending almost all the way down to ­ventricles (minimal white matter) ♦♦ Other coexisting malformations common ♦♦ Sporadic or familial ♦♦ Type I – lissencephaly −− Large scale disruption of neuronal migration −− Isolated lissencephaly sequence (ILS) – deletion LIS-1 on 17p −− Miller–Dieker syndrome caused by deletion of LIS-1 and contiguous genes including 14-3-3 −− Additional X-linked and recessive forms ♦♦ Type II – cobblestone lissencephaly −− Cortical surface with cobblestone appearance due to heterotopic neurons in subpial zone −− Because of different genetic mutations, each with different associated malformations or clinical manifestations

Gray Matter Heterotopia (Fig. 14.58A) ♦♦ Defect of neuroblast migration (get stuck before reaching cortex) ♦♦ Diffuse neuronal heterotopia = numerous neurons scattered throughout white matter ♦♦ Nodular heterotopia = subcortical or subependymal nodules, most common form ♦♦ Laminar heterotopia = band of gray matter between cortex and ventricle (“double cortex”)

Cortical Dysplasia (Fig. 14.59)

Fig.  14.57. Dandy-Walker malformation in a fetus, showing nearly complete agenesis of the cerebellar vermis (A, B). The delicate, thin-walled meningeal lining covering the posterior fossa cyst ruptured during extraction of the brain.

♦♦ Umbrella term for all forms of disordered neuronal architecture; microdysgenesis and hamartia represent subtle microscopic forms

Destructive Malformations ♦♦ Intrauterine ischemia, infections (TORCH), etc

Fig. 14.58. Polymicrogyria and nodular gray matter heterotopia adjacent to the ventricle (A). Note the shallow-appearing sulci and reduction of white matter development. Microscopically, polymicrogyria is characterized by hypergyration and the appearance of fused molecular layers resulting from the lack of adequate sulcal formation (B, C: H&E and LFB-Cresyl violet stains) (D, E: H&E and NeuN stains, courtesy of Dr. Robert Schmidt, Washington U., St. Louis, MO).

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Agenesis of Corpus Callosum ♦♦ Complete vs. partial (posterior portion only) ♦♦ No overlying cingulate gyrus (helpful in distinguishing postmortem artifacts) ♦♦ “Bat wing”-shaped lateral ventricles ♦♦ Probst bundles = callosal remnants in lateral roof of ventricle ♦♦ May be associated with callosal lipoma or other malformations ♦♦ In isolation, may be asymptomatic

Syringomyelia/Syringobulbia ♦♦ Cystic cavity in spinal cord or brainstem without ependymal lining ♦♦ Hydromyelia = distension of central canal (ependymal lining may slough, so often lumped with syringomyelia or syrinx)

Variants −− Idiopathic or primary type usually associated with Chiari  type I malformation (chronic cerebellar tonsillar herniation and/or hydrocephalus) with cerebellar ataxia and dissociated sensory loss from cervical syrinx; young adult, often progressive −− Secondary types associated with tumor, trauma, infarcts, etc.

Fetal/Perinatal Insults Intraventricular Hemorrhage (Fig. 14.60)

Fig. 14.59. Focal cortical dysplasia or tuber (in a patient with tuberous sclerosis) is characterized by both neuronomegaly (A) and balloon cells containing neuron-like nuclei and eccentric collections of astrocyte-like cytoplasm (B).

Sclerotic Ulegyria ♦♦ Mushroom-shaped gyri (“ulegyria”) ♦♦ Cortical microinfarcts of sulcal depths (narrow) with sparing of gyral crests (wide) ♦♦ Associated neuronal loss and gliosis (“sclerotic”)

Porencephaly ♦♦ Large area of cystic degeneration (intrauterine infarct), often MCA territory ♦♦ Result of liquefactive necrosis ♦♦ Large cyst, often extending from meninges to ventricle ♦♦ Polymicrogyria common at edge of cyst

Hydranencephaly ♦♦ “Basket brain” ♦♦ Severe, bilateral cerebral damage ♦♦ Most of cortex and white matter lost resulting in large, bilateral thin cysts ♦♦ Thalamus usually preserved

♦♦ Premature infants <32 weeks estimated gestational age most commonly affected ♦♦ Usually arise from dissection of germinal matrix ­hemorrhage (poorly developed capillaries presumably undergoing involution) ♦♦ Associated with perinatal ischemia/respiratory distress syndrome ♦♦ Choroid plexus hemorrhage is more common source in term infants ♦♦ High mortality unless it is a small, contained hemorrhage

Gray Matter Ischemia ♦♦ Produces ulegyria, porencephaly, and migrational defects (see above) ♦♦ Status marmoratus (marbled state) −− Ischemic damage to basal ganglia and/or thalamus prior to myelination −− Abnormal myelination occurs over gliotic fibers resulting in marbled appearance −− Common in cerebral palsy ♦♦ Pontosubicular necrosis: reflects perinatal selective vulnerability with pontine nuclei and subiculum being more sensitive than CA1 of hippocampus

White Matter Ischemia/Periventricular Leukomalacia (PVL) ♦♦ White matter is a site of selective vulnerability in premature infants

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Fig.  14.60. Fetus with bilateral intraventricular hemorrhages. These hemorrhages start in the subependymal germinal matrix, typically near the head of the caudate (see right side). ♦♦ Sharply demarcated infarcts ♦♦ Become cystic upon resolution ♦♦ Often coexists with other ischemic lesions

Kernicterus ♦♦ Necrosis of globus pallidus and hippocampus in premature infants ♦♦ Unconjugated bilirubin (immature liver) crosses BBB to produce bright yellow gross appearance ♦♦ Rare today as a result of “bilirubin lights” and other preventive therapies

Fig. 14.61. Mesial temporal sclerosis with marked hippocampal atrophy (A; right side) and loss of neurons in the CA4 and CA1 sectors (B) NeuN stain; photo courtesy of Dr. Robert Schmidt, Washington U., St. Louis, MO).

Chromosomal Syndromes (see Chapter 13) Down Syndrome (Trisomy 21) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Gross changes not always obvious Brain short and blunted in AP direction Narrow superior temporal gyrus Small cerebellum and brainstem Premature Alzheimer (see Neurodegenerative section)

Edward Syndrome (Trisomy 18) ♦♦ Microcephaly, gyral defects

Patau Syndrome (Trisomy 13) ♦♦ Holoprosencephaly in most

Fragile X ♦♦ ♦♦ ♦♦ ♦♦

Most common form of familial mental retardation M > F (i.e., X-linked) Associated with triple repeat expansion of FMR-1 gene on Xq Microcephaly, neuronal heterotopias

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Seizure-Associated Pathology ♦♦ Increasingly seen in surgical specimens (refer to individual lesions in previous sections for details)

Mesial Temporal Sclerosis (Hippocampal Sclerosis) (Fig. 14.61) ♦♦ Most common form of pathology in surgical specimens from patients with temporal lobe seizures ♦♦ Hippocampus atrophic with variable degrees of neuronal loss and gliosis, most commonly involving CA1 and CA4 sectors (same regions of selective vulnerability to ischemia) ♦♦ Long standing debate about whether MTS is the cause or the result of the seizure disorder, as patients often suffer hypoxic injury during prolonged seizures ♦♦ High likelihood of seizures being cured or reduced in frequency after temporal lobectomy

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Malformations

Tumors

♦♦ Any of the ones previously discussed; most common are polymicrogyria and neuronal heterotopias

♦♦ Dysembryoplastic neuroepithelial tumor (DNET): quasihamartomatous intracortical lesion featuring ­patterned mucin-rich nodules and “floating neurons” (see Fig. 14.27) −− Often misdiagnosed as oligodendroglioma or oligoastro; common in epilepsy specimens (7%) −− Excellent prognosis ♦♦ Low grade diffuse gliomas: oligodendroglioma, oligoastrocytoma, astrocytoma ♦♦ Pilocytic astrocytoma ♦♦ Ganglioglioma ♦♦ PXA

Tuberous Sclerosis ♦♦ Triad of seizures, resultant mental retardation, facial angiofibromas ♦♦ Tubers = cortical dysplasia with balloon cells (Fig.  14.59), mono- and multinucleated dysmorphic glioneuronal cells; associated gliosis and/or calcification firm, “potato-like” cortical lesion with subcortical degenerative changes ♦♦ Gray matter heterotopias = similar histology (balloon cells) to tubers, but deeper and often perivascular ♦♦ Subependymal giant cell astrocytoma (SEGA) = malformative intraventricular tumor near foramen of Monro composed of spindle, epithelioid, and occasional giant cells forming sweeping fascicles and perivascular pseudorosettes; neuronlike cells less common; calcification; noninfiltrative growth pattern ♦♦ Candle gutterings = identical to SEGA, but smaller, waxy subependymal nodules throughout lateral ventricles (precursors to SEGA) ♦♦ Continuous, radial abnormalities from cortex to ventricle suggest migrational disturbance ♦♦ Non-CNS lesions = cutaneous angiofibroma, renal angiomyolipoma, pulmonary lymphangioleiomyomatosis (LAM), and cardiac rhabdomyoma ♦♦ Two genes identified: TSC1 (hamartin) on 9q, TSC2 (tuberin) on l6p

Inflammatory/Infectious Cysticercosis ♦♦ Most common cause of epilepsy in Mexico

Rasmussen Encephalitis ♦♦ Progressive, unilateral process often associated with intractable seizures in young patients ♦♦ Hemispherectomy may be necessary for seizure control ♦♦ Histology identical to viral encephalitis ♦♦ Autoimmune vs. infectious; associated with autoantibodies to glutamate receptor in some patients

Vascular Malformations ♦♦ Most commonly cavernous angioma or arteriovenous malformation (AVM)

TOXIC/METABOLIC DISORDERS Alcohol- (and/or Malnutrition-) Related Pathology

♦♦ Chronic = atrophy, hemosiderin, axonal/myelin loss, and vascular prominence

♦♦ Not restricted to alcoholics

Cerebellar Degeneration

Trauma

♦♦ Because of thiamine (vitamin B1) deficiency ♦♦ Atrophy of anterior superior cerebellar vermis with Purkinje cell loss and Bergmann layer gliosis ♦♦ Truncal ataxia

♦♦ Alcoholics fall a lot; subdural hematomas and cortical contusions are common

Wernicke–Korsakoff Syndrome ♦♦ Because of thiamine (vitamin B1) deficiency ♦♦ Wernicke encephalopathy = nystagmus, ataxia, confusion, and stupor ♦♦ Korsakoff psychosis = anterograde and retrograde amnesia, confabulation (e.g., “Yes, I see the invisible pink thread you’re holding”) ♦♦ Mamillary bodies/periventricular thalamus and brainstem affected ♦♦ Acute-subacute = petechial hemorrhages, capillary ­proliferation, gliosis, and/or necrosis with neuronal sparing

Peripheral Neuropathy ♦♦ “Glove and stocking” distal (dying back) neuropathy with axonal degeneration ♦♦ Etiology poorly understood; may be multifactorial ♦♦ Yet another source of ataxia ♦♦ Associated tract degeneration of posterior spinal columns

Central Pontine Myelinolysis (Fig. 14.62) ♦♦ Most often associated with too rapid correction of ­hyponatremia (an iatrogenic process)

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Fig. 14.62. Characteristic central triangular shaped region of myelin pallor in a case of central pontine myelinolysis. (A) H&E stain; (B) LFB-PAS stain. ♦♦ Symmetric, triangle-shaped zone of demyelination in central basis pontis ♦♦ Relatively high mortality ♦♦ Extrapontine lesions noted in 10%

Hepatic Encephalopathy ♦♦ Liver failure with hyperammonemia ♦♦ Dementia/delirium/stupor/coma ♦♦ Grossly, the brain is normal to edematous; bilirubin staining (jaundice) of dura, meninges, and choroid plexus (i.e., sites lacking BBB) ♦♦ Micro = Alzheimer type II astrocytes (enlarged nuclei with pale, open chromatin and little cytoplasm) in gray matter, especially deep cortex, globus pallidus, and dentate nucleus

Subacute Combined Degeneration of Spinal Cord ♦♦ Because of vitamin B12 deficiency ♦♦ Vacuolation/myelin pallor of posterior and lateral columns; thoracic levels emphasized in books, but cervical levels are also involved frequently (identical to vacuolar myelopathy in AIDS) ♦♦ Combined sensory and upper motor neuron deficits

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♦♦ Similar, but reversible symptoms can be seen with folate deficiency

Fetal Alcohol Syndrome ♦♦ Complex etiology related to timing and volume consumed during pregnancy, genetic influences, etc ♦♦ Common cause of mental retardation ♦♦ Facial abnormalities ♦♦ Growth retardation

Other Toxic Injuries Carbon Monoxide ♦♦ See “Patterns of selective vulnerability”

Methanol ♦♦ See “Patterns of selective vulnerability”

Arsenic Poisoning ♦♦ GI symptoms, sensory neuropathy, weakness ♦♦ No morphologic CNS changes ♦♦ Peripheral neuropathy with segmental demyelination, axonal degeneration, and occasionally onion bulb formation (repeated exposures)

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Lead Poisoning ♦♦ Usually children ingesting lead-based paint from old houses ♦♦ Cerebral edema and petechial hemorrhages associated with lead encephalopathy ♦♦ Peripheral neuropathy with segmental demyelination and/or axonal degeneration ♦♦ Anemia, renal and GI symptoms, lead lines in bone on x-ray

Methotrexate Toxicity ♦♦ Follows intrathecal or IV therapy for leukemias, ­lymphomas, etc ♦♦ May cause a necrotizing leukoencephalopathy, especially when combined with radiation therapy

Lysosomal (Enzyme) Storage Disorders (see Table 14.7) ♦♦ Involve CNS and/or other organs ♦♦ Enlarged lysosomes often result in the formation of PAS + granules ♦♦ EM shows membranous cytoplasmic bodies (MCBs) often morphologically nonspecific, but supportive of a storage disorder

Mucopolysaccharidoses ♦♦ Include many subtypes: gargoyle-like dysmorphism, Hurler (type I) = most severe, Hunter (type II) = X-linked: “Hunters are men”

Peroxisomal Disorders (see Table 14.7)

Metabolic Disorders ♦♦ Generally due to enzyme defects with accumulation of toxic byproducts ♦♦ Almost always autosomal recessive ♦♦ Diagnosed by biochemical analyses, biopsy of skin, conjunctiva, rectum, etc ♦♦ Almost all exist as variants wherein youngest age = most severe, oldest age = least severe ♦♦ Table  14.7 summarizes the most common and most severe CNS forms ♦♦ Lipid accumulations may be seen in frozen sections, but are often lost in processing of paraffin sections ♦♦ Variable gross appearance: encephalomegaly from storage vs. microcephaly from atrophy

♦♦ Because of absence or decreased numbers of peroxisomes vs. abnormality of peroxisomal protein

Leukodystrophies (see Table 14.7) ♦♦ Metabolic disorder of myelin synthesis/breakdown ♦♦ Dysmyelination (abnormal formation) instead of demyelination (loss of normally formed myelin as in MS) ♦♦ Diffuse, symmetric, and bilateral, with sparing of ­subcortical U-fibers

Adrenoleukodystrophy ♦♦ X-linked, peroxisomal disorder/leukodystrophy with inflammation that can mimic MS (e.g., many cases of “Schilder variant of MS” have turned out to be ­adrenoleukodystrophy [ALD])

SELLAR/SUPRASELLAR PATHOLOGY Pituitary Adenomas (Fig. 14.63) General Features ♦♦ Most common sellar neoplasm; 20% incidental autopsy finding ♦♦ Hormonally functional tumors often present at microadenoma (<1 cm) stage, especially patients with Cushing disease ♦♦ Nonfunctional tumors present as macroadenoma (>1  cm) because of mass effects, including visual deficits and/or hypopituitarism ♦♦ “Stalk effect” = mild prolactin (PRL) elevation due to compression of stalk (blocks transport of dopamine, the normal PRL-inhibiting factor from the hypothalamus to the pituitary) ♦♦ “Invasive adenoma” = gross intraoperative or radiologic descriptor; affects management and likelihood of recurrence −− Simple microscopic invasion of dura alone is unimportant ♦♦ Differential diagnosis only theoretically includes ependymoma (perivascular rosettes), and olfactory neuroblastoma (involves cribriform plate)

−− Small cell carcinoma is simulated by crush artifact of normal or adenomatous tissues ♦♦ Loss of acinar architecture and the presence of prominent nucleoli are helpful in distinguishing adenoma from normal pituitary ♦♦ Reticulin stain helpful to highlight architecture, especially in crushed specimens or with freezing artifacts; adenomas are reticulin-poor compared to normal adenohypophysis which features reticulin encircled acini

Histology Clues (Often True) ♦♦ Psammomatous calcification = prolactinoma ♦♦ Spherical lamellated amyloid bodies (rare) = prolactinoma ♦♦ High N/C ratio and fibrosis = result of medical treatment of prolactinomas with dopamine agonists ♦♦ Perivascular rosettes or papillae = gonadotrophic adenoma ♦♦ Crooke hyaline change in normal pituitary = results from hypercortisolism of any cause ♦♦ Strong PAS+ = corticotroph adenoma ♦♦ Weak PAS+ = glycoprotein adenoma (FSH, LH, TSH)

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Usually infants/ kids, early bone marrow Tx helpful

Death < age 2, cherry-red macula

Metachromatic leukodystrophy

Krabbes leukodystrophy

Galactocerebrosidase

Galactocerebroside +  psychosine

Sulfatides

Very long chain fatty acids

Numerous biochemical abnormalities

Diffuse myelin loss, “Globoid cells” = clusters of macrophages with eccentric nuclei

Diffuse myelin loss; metachromasia on frozen sections. EM-prismatic inclusions

Diffuse myelin loss and inflame.; mimics MS. Adrenal atrophy with “balloon cells”

Migrational defects (patcy polymicrogyria, herotopia), myelin loss, cirrhosis

Vacuolar myopathy. In infantile form: heart, liver, neurons, and astrocytes affected

Vascular dz. With cerebral infarcts, PAS + deposits in meninges, vessel walls, and other cells

Thick skull and dura, perivasc. “pits” = GAG deposits. EM = “zebra bodies”

Perivasc. PAS + Gaucher cells (macrophages) with “crumpled tissue paper”; neuronal loss

Foamy neurons, endothelial cells and macrophages

Cerebral atrophy, thick dura, N. loss, PAS +, EM fingerprint + curvilinear bodies

Like Tay-Sachs + foamy hepatocytes, macrophages and endothelial cells

Foamy CNS, PNS, + retinal neurons; LFB+, PAS + granules. EM-MCBs

Cystic deg. of putamen, Alz. type II astros, perivascular copper + iron deposits

Pathology

AR autosomal recessive; XL X-linked; TX transplant; FTT failure to thrive; Alz Alzheimer; N neuron; MCB membranous cytoplasmic bodies; MS multiple sclerosis; MR mental retardation

AR, Chr. 14

Arylsulfatase A

Peroxisomal membrane protein

XL, Chr. Xq

Boys (“Lorenzo oil”), rapid course, CNS + adrenal disease

Adrenoleukodystrophy AR, Chr. 22

Peroxisomes absent (along with enzymes)

AR

Dysmorphic, floppy, FTT, liver dz, death < age 1

Zellwegers syndrome

Glycogen

Acid maltase

AR, Chr. 17

Limb-girdle + resp. weakness, death < age 2

Glucocerebroside

Glycogen storage dx (II-Pompes)

Fabry disease

Glucocerebrosidase

Sphingomyelin

Ceramides

Hurlers (I) + Hunters (II-males), MR, dysmorphic

Mucopolysaccharidoses

AR, Chr. 1

Sphingomyelinase

“Lipofuscin”

a-galactosidase A

Neuronopathic, CNS + visceral, death < age 2

Gaucher disease (type II)

AR, Chr. 11

Various enzyme defects

XL, Chr. Xq

Visceromegaly, cherry-red macula, death < age 5

Niemann–Pick disease (type A)

AR, Multiple

GMI-ganglioside

b-galactosidase

Males, renal/heart failure, p. neuropathy, death ~ age 40

Various subtypes, ages, and severity

Ceroid lipofuscinosis

AR, Chr. 3

GM2-ganglioside

Hexosaminidase A

Copper ↓ serum ceruloplasmin

Accumulations

Glycosaminoglycan (GAG) high in urine

Like Tay-Sachs plus dysmorphism and visceromegaly

GMI-gangliosidosis

AR, Chr.15

Cu transporting ATPase (not ceruloplasmin)

Enzyme

Various enzyme defects

Ashkenazi Jews; death < age 5, cherry-red macula

Tay–Sachs disease

AR, Chr. 13

Genetics

AR, except II = XL

Liver failure, movement disorder

Clinical

Wilson disease

Disease

Table 14.7. Metabolic Disorders

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Fig. 14.63. Nesting (A) and pseudorosette-like (B) patterns in cases of pituitary adenoma. Crooke hyalin is characterized by rings of eosinophilic material in the nonneoplastic corticotroph cells of the adenohypophysis (C), which are reacting to the negative feedback stimuli from the patient’s hypercortisolism. Cytokeratin-positive fibrous bodies forming paranuclear balls of staining in a growth hormone producing adenoma (D).

♦♦ CK + paranuclear “fibrous bodies” = GH-producing adenoma ♦♦ Immunostaining for hormones most useful in confirming prolactinoma (a medically treatable tumor) or in establishing the pituitary origin of tumor outside the sella ♦♦ EM is most useful in cases where immunostains are nonconfirmatory or equivocal, as well as in establishing the diagnosis of rare aggressive forms such as acidophil stem cell or silent subtype III adenomas

Prolactinoma (Lactotrophic Adenoma) ♦♦ F > M; women present with amenorrhea and/or galactorrhea while tumor is still small ♦♦ In men, the tumor is often asymptomatic until large; decreased libido is only symptom ♦♦ Medically treatable with dopamine agonists which cause cellular atrophy and decreased cell proliferation

Corticotrophic (ACTH) Adenomas Cushing Syndrome ♦♦ Clinical manifestations of hypercortisolism of any cause

Nelson Syndrome ♦♦ Bilateral adrenalectomy in setting of Cushing disease wherein microadenoma is undetected −− Results in uncontrolled tumoral growth because of the loss of end-organ feedback ♦♦ Most are aggressive and difficult to manage ♦♦ May undergo progression to pituitary carcinoma

Crooke Hyaline Change ♦♦ Ring-like, keratin accumulations in normal ACTH cells ♦♦ Result of hypercortisolism of any cause

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Silent Corticotroph Adenoma

♦♦ Usually PRL+, GH+, or ACTH + (functioning adenomas)

♦♦ ACTH + adenoma unassociated with clinical and/or biochemical evidence of Cushing disease; often invasive macroadenomas

Pituitary Carcinoma

Growth Hormone Adenoma ♦♦ Three forms −− Densely granulated GH adenoma −− Sparsely granulated GH adenoma which features cytoplasmic “fibrous bodies” −− Plurihormonal (a) Adenomas which produce multiple hormones (GH, PRL, TSH-producing) (b) May consist of 1–3 separate cell types *  All cause acromegaly *  About 50% invasive

Growth Hormone and Prolactin-Producing Adenomas ♦♦ Three types −− Mixed GH cell-PRL cell adenoma (a) Two distinct cell types present (b) Relatively indolent −− Mammosomatotroph adenoma = GH and PRL produced by same cells (a) Signs of GH excess (b) Relatively indolent −− Acidophil stem cell adenoma = rare variant (a) Serum PRL > GH level (b) Clinically mimics prolactinoma (c) Infrequent acromegaly (d) Features giant mitochondria and misplaced exocytosis at EM level (e) Aggressive and relatively nonresponsive to dopamine agonists

Gonadotrophic (FSH/LH) and Null Cell (IP-) Adenomas ♦♦ Elderly, M > F ♦♦ Clinically nonfunctioning; macroadenomas ♦♦ Most indolent and least invasive adenomas

Thyrotrophic Adenoma/Hyperplasias ♦♦ Rarest of the adenomas in pure form ♦♦ Many arise because of the loss of T3/T4 feedback in primary hypothyroidism

Atypical Pituitary Adenoma ♦♦ New diagnostic category ♦♦ Increased proliferative activity (mitoses, MIB-1 >3%); often p53 immunoreactive ♦♦ Thought to have increased risk of recurrence and, rarely, transformation to pituitary carcinoma

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♦♦ Rare ♦♦ Brain invasion (exceptional finding during life) or ­intracranial (CSF) and/or extracranial metastases ♦♦ Most PRL + or ACTH + (latter often occur in setting of Nelson syndrome) ♦♦ Usually p53+ and high MIB-1 index ♦♦ High morbidity/mortality

Pituitary Hyperplasia ♦♦ Diffuse form is difficult to document ♦♦ Nodular form features expanded acini filled by a ­disproportionate number of one cell type; reticulin stain useful to show acinar enlargement −− PRL: pregnancy, estrogen therapy −− GH: hypothalamic or ectopic (neuroendocrine tumor) source of growth hormone-releasing hormone −− ACTH: hypothalamic or ectopic (neuroendocrine tumor) source of corticotropin-releasing hormone −− FSH/LH: Klinefelter and Turner syndrome due to gonadal nonfunction −− TSH: hypothyroidism: also associated with PRL hyperplasia as thyrotropin-releasing hormone stimulates not only TSH cells but PRL cells as well

Apoplexy ♦♦ Spontaneous hemorrhagic infarction of pituitary adenoma; usually large, nonfunctioning ♦♦ Surgical emergency ♦♦ Reticulin stains still show vessels and effaced acinar architecture ♦♦ Immunostains may be helpful in partly preserved tissue

Craniopharyngioma ♦♦ See “Other Nonglial Neoplasms” section

Rathke Cleft Cyst ♦♦ Developmental lesion; small examples often an incidental autopsy finding between anterior and posterior pituitary lobes ♦♦ Symptomatic lesions generally >1  cm; cause hyperprolactinemia and/or visual disturbance ♦♦ Slow growing, surgically curable ♦♦ Clear, mucoid cyst contents ♦♦ Cuboidal to columnar, ciliated, and nonciliated cells, goblet cells −− Same histology as colloid cyst of third ventricle and enterogenous cyst of spinal cord ♦♦ Squamous metaplasia in some; differential diagnosis includes craniopharyngioma

Pituicytoma (WHO Grade I) ♦♦ New entity in 2007 WHO

Neuropathology

♦♦ Term previously applied to many nonrelated low grade tumors in sellar/suprasellar region

Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Rare; arises in posterior pituitary or stalk Adult Symptoms: visual disturbance, hypopituitarism, and headache Surgical resection usually possible because of circumscription If attached to critical structures causes subtotal resection, typically shows slow regrowth

Imaging/Gross ♦♦ Sellar/suprasellar mass ♦♦ CT/MRI: Solid and circumscribed; homogenous enhancement

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Histiocytosis X (Langerhans Cell Histiocytosis) ♦♦ ♦♦ ♦♦ ♦♦

Smear/Histology ♦♦ Bipolar, spindle cells in interlacing fascicles or storiform pattern ♦♦ Moderate to abundant eosinophilic cytoplasm; plump, fusiform ♦♦ Moderate-sized, oval to elongate nuclei without significant atypia ♦♦ Rare to absent mitoses ♦♦ No Rosenthal fibers or eosinophilic granular bodies ♦♦ Tumor cells are believed to arise from pituicytes, ­specialized astrocytes that are the supporting glial cell of the posterior pituitary and stalk ♦♦ Immunostains: vimentin+, S-100+, GFAP+ ♦♦ MIB-1 labeling index: 0.5–2%

Differential Diagnosis ♦♦ Pilocytic astrocytoma (Rosenthal fibers; eosinophilic granular bodies) ♦♦ Granular cell tumor (cytoplasmic granularity) ♦♦ Oncocytoma (abundant mitochondria)

Pink, granular cytoplasm on H&E; cytologically low grade Abundant mitochondria by EM Immunostains: S-100+, EMA+, vimentin+ MIB-1 labeling index: ~3% Rare recurrent cases with elevated MIB-1 indices

Most represent secondary CNS involvement from skull base Predilection for hypothalamus/infundibulum ± Diabetes insipidus May appear xanthomatous; differential diagnosis includes Rosai–Dorfman disease; Erdheim–Chester disease

Hypothalamic Hamartoma ♦♦ Uncommon, incidental autopsy finding −− Rarely symptomatic −− Malformative in nature ♦♦ Some present with precocious puberty or gelastic seizures (uncontrollable laughter) −− Rare pituitary hyperfunction due to releasing hormone production ♦♦ Sessile or pedunculated attachment to floor of third ventricle; some lie separate from brain ♦♦ Resembles normal hypothalamus, but less organized ♦♦ Surgically curable

Other Tumors ♦♦ Covered elsewhere; include pilocytic astrocytoma, meningioma, hemangioma, sarcoma (often postirradiation), and metastases

Granular Cell Tumor

Lymphocytic Hypophysitis

♦♦ Benign tumor of pituicytes (specialized astrocytes in the posterior pituitary and stalk) ♦♦ Small, incidental examples common at autopsy; ­symptomatic lesions rare ♦♦ Identical morphology to granular cell tumors elsewhere ♦♦ Packed with PAS + lysosomes, S-100 protein+ ♦♦ Differential diagnosis includes pituitary adenoma with oncocytic change (mitochondria instead of lysosomes; secretory granules and hormones are demonstrable)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Spindle Cell Oncocytoma of the Adenohypophysis (WHO Grade I) ♦♦ Rare tumor of adults ♦♦ Circumscribed, solid, contrast-enhancing sellar/suprasellar mass ♦♦ Symptoms secondary to mass effect (pituitary insufficiency, visual field defects, headaches) ♦♦ Plump, eosinophilic spindled or epithelioid cells in fascicles with classic oncocytic features

Autoimmune disorder associated with hypopituitarism Almost exclusively in postpartum women Other minor coexistent autoimmune disorders in some Lymphoplasmacytic infiltrate without granulomas Treated with surgery and hormone replacement; fatal if untreated

Empty Sella Syndrome Primary ♦♦ Congenital defect in diaphragma sella permits downward herniation of leptomeninges (“arachnoidocele”) with resulting compression of pituitary

Secondary ♦♦ “Ex vacuo,” (i.e., parenchymal loss) −− Sheehan syndrome = infarction due to postpartum shock −− Apoplexy of an intrasellar adenoma −− Postsurgical or postirradiation loss of sellar volume

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Suggested Reading Gliomas Brat DJ, Scheithauer BW, Staugaitis SM, Cortez SC, Brecher K, Burger PC. Third ventricular chordoid glioma: a distinct clinicopathologic entity. J Neuropathol Exp Neurol 1998;57:283–290. Burger PC. Pathology of brain stem astrocytomas. Pediatr Neurosurg 1996;24:35–40. Burger PC, Pearl DK, Aldape K, et  al. Small cell architecture – a ­histological equivalent of EGFR amplification in glioblastoma ­multiforme? J Neuropathol Exp Neurol 2001;60:1099–1104. Choi YE, Chi JG, Suh YL. CD99 immunoreactivity in ependymoma. Appl Immunohistochem Mol Morphol 2001;9:125–129. Emestus RI, Schroder R, Stutzer H, et  al. The clinical and prognostic relevance of grading in intracranial ependymomas. Br J Neurosurg 1997;11:421–428. Fernandez C, Figarella-Branger D, Girard N, et  al. Pilocytic astrocytomas in children: prognostic factors – a retrospective study of 80 cases. Neurosurgery 2003;53:544–555. Giannini C, Scheithauer BW, Burger PC, et al. Pleomorphic xanthoastrocytoma. What do we really know about it? Cancer 1999;85:2033–2045. Hirose T, Scheithauer BW, Lopes MBS, et al. Tuber and sub-ependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron microscopic study. Acta Neuropathol 1995;90:387–399. Kepes JJ. Pleomorphic xanthoastrocytoma: the birth of a diagnosis and a concept. Brain Pathol 1993;3:269–274. Komotar RJ, Burger PC, Carson BS, et  al. Pilocytic and pilomyxoid hypothalamic/chiasmatic astrocytomas. Neurosurgery 2004;54:72–80. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, (eds.). WHO Classification of Tumours of the Central Nervous System. WHO Classification of Tumours (4th Edition). Lyon: IARC Press; 2007. Min KW, Scheithauer BW. Clear cell ependymoma: a mimic of oligodendroglioma: clinicopathologic and ultrastructural considerations. Am J Surg Pathol 1997;21:820–826. Morales H, Gaskill-Shipley M. Imaging of common adult and pediatric primary brain tumors. Semin Roentgenol 2010;45:92–106. Perry A. Oligodendroglial neoplasms: current concepts, misconceptions, and folklore. Adv Anatomic Pathol 2001;8:183–199. Perry A. Pathology of low-grade gliomas. An update of emerging concepts. Neuro-Oncology 2003;5: 168–178. Pfister S, Hartmann C, Korshunov A. Histology and molecular pathology of pediatric brain tumors. J Child Neurol 2009;24:1375–1386. Reifenberger G, Kaulich K, Wiestler OD, Blumcke I. Expression of the CD34 antigen in pleomorphic xanthoastrocytomas. Acta Neuropathol 2003;105:358–364. Rosenblum MK. Ependymal tumors: a review of their diagnostic surgical pathology. Pediatr Neurosurg 1998;28:160–165. Sato K, Kubota T, Ishida M, Yoshida K, Takeuchi H, Handa Y. Immunohistochemical and ultrastructural study of chordoid glioma of the third ventricle: its tanycytic differentiation. Acta Neuropathol 2003;106:176–180. Scheithauer BW, Fuller GN, VandenBerg SR. The 2007 WHO ­classification of tumors of the nervous system: controversies in surgical neuropathology. Brain Pathol 2008;18:307–316. Sonneland PR, Scheithauer BW, Onofrio BM. Myxopapillary ependymoma. A clinicopathologic and immunocytochemical study of 77 cases. Cancer 1985;56:883–893.

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Neuronal/Glioneuronal Neoplasms Behdad A, Perry A. Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol 2010;20:441–450. Daumas-Duport C, Scheithauer BW, Chodkiewicz JP, et  al. Dysembryoplastic neuroepithelial tumor: a surgically curable tumor of young patients with intractable partial seizures. Report of thirty-nine cases. Neurosurgery 1988;23:545–556. Eberhart CG, Burger PC. Anaplasia and grading in medulloblastomas. Brain Pathol 2003;13:376–385. Edgar MA, Rosenblum MK. Mixed glioneuronal tumors: recently described entities. Arch Pathol Lab Med 2007;131:228–233. Fuller CE, Pfeifer J, Humphrey P, Bruch LA, Dehner LP, Perry A. Chromosome 22q dosage in composite extrarenal rhabdoid tumors: clonal evolution or a phenotypic mimic? Hum Pathol 2001;32: 1102–1108. Giangaspero F, Perilongo G, Fondelli MP, et al. Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 1999;91:971–977. Hassoun J, Söylemezoglu F, Gambarelli D, et al. Central neurocytoma: a synopsis of clinical and histological features. Brain Pathol 1993; 3:297–306. Hirose T, Scheithauer BW, Lopes MBS, et al. Olfactory neuroblastoma. As immunohistochemical, ultrastructural, and flow cytometric study. Cancer 1995;76:4–19. Ho DMT, Hsu CY, Wong TT, Ting LT, Chiang H. Atypical teratoid/­ rhabdoid tumor of the central nervous system: a comparative study with primitive neuroectodermal tumor/medulloblastoma. Acta Neuropathol 2000;99:482–488. Honavar M, Janota I, Polkey CE. Histological heterogeneity of ­dysembryoplastic neuroepithelial tumour: identification and differential diagnosis in a series of 74 cases. Histopathology 1999;34:342–356. Luyken C, Blumcke I, Fimmers R, Urbach H, Wiestler OD, Schramm J. Supratentorial gangliogliomas: histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years. Cancer 2004;101:146–155. McManamy CS, Lamont JM, Taylor RE, et  al. Morphophenotypic ­variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 2003;62:627–632. Perry A. Medulloblastomas with favorable vs. unfavorable histology. How many small blue cell tumor types are there in the brain? Adv Anat Pathol 2002;9:345–350. Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/ rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 1996;85:56–65. Schmidt MH, Gottfried ON, von Koch CS, Chang SM, McDermott MW. Central neurocytoma: a review. J Neurooncol 2004;66:377–383. Tamburrini G, Colosimo C, Giangaspero F, Riccardi R, Di Rocco C. Desmoplastic infantile ganglioglioma. Childs Nerv Syst 2003;19: 292–297. VandenBerg SR. Desmoplastic infantile ganglioglioma and desmoplastic cerebral astrocytoma of infancy. Brain Pathol 1993;3:275–281.

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Pearl GS. Traumatic neuropathology. Clin Lab Med 1998;18:39–64.

Perry A, Scheithauer BW, Stafford SE, et al. “Rhabdoid” meningioma: an aggressive variant. Am J Surg Pathol 1998;22:1482–1490. Perry A, Stafford SE, Scheithauer BW, et  al. “Malignancy” in meningiomas: a clinicopathologic study of 116 patients. Cancer 1999;85: 2046–2056. Rajaram V, Brat DJ, Perry A. Anaplastic meningioma vs. meningeal hemangiopericytoma: immunohistochemical and genetic markers. Hum Pathol 2004;135:1413–1418. Riemenschneider MJ, Perry A, Reifenberger G. Histological classification and molecular genetics of meningiomas. Lancet Neurol 2006;5: 1045–1054. Tihan T, Viglione M, Rosenblum MC, Olivi A, Burger PC. Solitary fibrous tumors in the central nervous system. A clinicopathologic review of 18 cases and comparison to meningeal hemangiopericytomas. Arch Pathol Lab Med 2003;127:432–439. Zorludemir S, Scheithauer BW, Hirose T, et al. Clear cell meningioma. A  clinicopathologic study of a potentially aggressive variant of ­meningioma. Am J Surg Pathol 1995;19:493–505.

Other Nonglial Neoplasms Bataille B, Delwail V, Menet E, et  al. Primary intracerebral malignant ­lymphoma: report of 248 cases. J Neurosurg 2000;92:261–266. Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D. Hemangioblastomas of the central nervous system in von ­Hippel–Lindau syndrome and sporadic disease. Neurosurgery 2001;48:55–63. Crotty TB, Scheithauer BW, Youn WF Jr., et al. Papillary craniopharyngioma: a clinicopathological study of 48 canes. J Neurosurg 1995;83: 206–214. Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol 2003;27: 1152–1156. Matsutani M, Sano K, Takakura K, et  al. Primary intracranial germ cell  tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg 1997;86:446–455. Paulus W. Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol 1999;43:203–208. Perry A, Parisi JE, Kurtin PJ. Metastatic adenocarcinoma to the brain. An immunohistochemical approach. Hum Pathol 1997;28:938–943. Schild SE, Scheithauer BW, Haddock MG, et al. Histologically ­confirmed pineal tumors and other germ cell tumors of the brain. Cancer 1996;78:2564–2571. Srodon M, Westra WH. Immunohistochemical staining for thyroid ­transcription factor-1: a helpful aid in discerning primary site of tumor origin in patients with brain metastases. Hum Pathol 2002;33:642–645. Wolff JEA, Sajedi M, Brant R, Coppes MJ, Egeler RM. Choroid plexus tumours. Br J Cancer 2002;87:1086–1091.

Ischemic/Anoxic/Vascular Disorders Black M, Graham DI. Sudden unexplained death in adults caused by intracranial pathology. J Clin Pathol 2002;55:44–50. Kalimo H, Ruchoux MM, Vitanen M, Kalaria RN. CADASIL: a ­common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 2002;12:371–384. Lammie GA. Hypertensive cerebral small vessel disease and stroke. Brain Pathol 2002;12:358–370. Pantoni L, Garcia JH. Cognitive impairment and cellular/vascular changes in the cerebral white matter. Ann N Y Acad Sci 1997;826:92–102. Parisi JE, Moore PM. The role of biopsy in vasculitis of the central ­nervous system. Semin Neurol 1994;14:341–348. Reevesz T, Holton JL, Lashley T, et  al. Sporadic and familial cerebral amyloid angiopathies. Brain Pathol 2002;12:343–357. Ruchoux MM, Maurage CA. CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol 1997;56:947–964.

Neurodegenerative Disorders Budka H, Aguzzi A, Brown P, et al. Neuropathological diagnostic criteria for Creutzfeldt–Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 1995;5:459–466. Chen-Plotkin AS, Lee VM, Trojanowski JQ. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol 2010;6:211–220. Dickson DW. Neuropathology of Alzheimer’s disease and other dementias. Clin Geriatric Med 2001;17:209–228. Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 1996;55:259–272. Hansen LA, Cram BJ. Making the diagnosis of mixed and non-Alzheimer’s dementias. Arch Pathol Lab Med 1995;119:1023–1031. Ironside JW. Prion diseases in man. J Pathol 1998;186:227–234. Jellinger KA. Neuropathology of movement disorders. Neurosurg Clin N Am 1998;9:237–262. Li SH, Li XJ. Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 2004;20:146–154. Liscic RM, Grinberg LT, Zidar J, Gitcho MA, Cairns NJ. ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol 2008;15:772–780. Mirra SS, Hart MN, Terry RD. Making the diagnosis of Alzheimer’s disease. A primer for practicing pathologists. Arch Pathol Lab Med 1993;117:132–144. Nance MA. Clinical aspects of CAG repeat diseases. Brain Pathol 1997;7:881–900. Trojanowski JQ, Dickson D. Update on the neuropathological diagnosis of frontotemporal dementias. J Neuropathol Exp Neurol 2001;60:l 123–1 126.

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Vinters HV, Ellis WG, Zarow C, et al. Neuropathologic substrates of ­ischemic vascular dementia. J Neuropathol Exp Neurol 2000;59:931–945. Yoshida M. Multiple system atrophy a-synuclein and neuronal degeneration. Neuropathol 2007;27:484–493.

Inflammatory/Infectious/Demyelinating Diseases Botero D, Tanowitz HB, Weiss LM, Wittner M. Taeniasis and ­cysticercosis. Infect Dis Clin North Am 1993;7:683–697. Burns DK, Risser RC, White CL. The neuropathology of human ­immunodeficiency virus infection. The Dallas, Texas experience. Arch Pathol Lab Med 1991;115:1112–1124. Chimelli L, Mahler-Araujo MB. Fungal infections. Brain Pathol 1997;7:613–627. Gray F. Bacterial Infections. Brain Pathol 1997:7:629–647. Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: ­intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33:18–27. Kleinschmidt-DeMasters BK. Central nervous system aspergillosis: a 20- year retrospective series. Hum Pathol 2002;33:116–124. Kleinschmidt-DeMasters BK, Gilden DH. The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 2001;11: 440–451. Kuhlmann T, Lassmann H, Brück W. Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol 2008;115:275–287. Nowak DA, Widenka DC. Neurosarcoidosis: a review of its intracranial manifestation. J Neurol 2001;248:363–372. Omalu BI, Shakir AA, Wang G, Lipkin WI, Wiley CA. Fatal fulminant pan-meningopolioencephalitis due to West Nile virus. Brain Pathol 2003;13:465–472. Thomas G, Murphy S, Staunton H, O’Neill S, Farrell MA, Brett FM. Pathogen-free granulomatous diseases of the central nervous system. Hum Pathol 1998;29:1110–1115. Zagzag D, Miller DC, Kleinman GM, et al. Demyelinating disease versus tumor in surgical neuropathology. Am J Surg Pathol 1993;17:537–545.

Pediatric and Seizure Neuropathology Arid Y, Edwards V, Becker LE. A comparison of cell phenotypes in hemimegalencephaly and tuberous sclerosis. Acta Neuropathol 1999;98:407–413. Black M, Graham DI. Sudden unexplained death in adults caused by intracranial pathology. J Clin Pathol 2002;55:44–50. Frater JL, Prayson RA, Morris HH, III, Bingaman WE. Surgical pathologic findings of extratemporal-based intractable epilepsy. A study of 133 consecutive resections. Arch Pathol Lab Med 2000;124:545–549. Golden JA. Holoprosencephaly: a defect in brain patterning. J Neuropathol Exp Neurol 1998;57:991–999.

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Luyken C, Blumcke I, Fimmers R, et  al. The spectrum of long-term ­epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003;44:822–830. Marcorelles P, Laquerriere A. Neuropathology of Holoprosencephaly. Am J Med Genet C Semin Med Genet 2010;154C:109–119. Mizuguchi M, Takashima S. Neuropathology of tuberous sclerosis. Brain Dev 2001;23:508–515. Norman MG. Malformations of the brain. J Neuropathol Exp Neurol 1996;55:133–143. Pilz D, Stoodley N, Golden JA. Neuronal migration, cerebral cortical development, and cerebral cortical anomalies. J Neuropathol Exp Neurol 2002;61:1–11. Prayson RA. Diagnostic challenges in the evaluation of chronic epilepsyrelated surgical neuropathology. Am J Surg Pathol 2010;34:e1–e13. Volpe JJ. Neurologic outcome of prematurity. Arch Neurol 1998;55: 297–300.

Toxic/Metabolic Disorders Harper C. The neuropathology of alcohol-related brain damage. Alcohol Alcohol 2009;44:136–140. Kolodny EH, Cable WJ. Inborn errors of metabolism. Ann Neurol 1982;11:221–232. Krill JJ. Neuropathology of thiamine deficiency disorders. Metab Brain Dis 1996;11:9–17. Moser HW, Powers JM, Smith KD. Adrenoleukodystrophy: molecular genetics, pathology, and Lorenzo’s oil. Brain Pathol 1995;5:259–266.

Sellar/Suprasellar/Pituitary Pathology Gaffey TA, Scheithauer BW, Lloyd RV, et al. Corticotroph carcinoma of the pituitary: a clinicopathological study. Report of four cases. J Neurosurg 2002;96:352–360. Kovacs K, Scheithauer BW, Horvath E, et  al. The World Health Organization classification of adenohypophyseal neoplasms. A proposed five-tier scheme. Cancer 1996;78:502–510. Lloyd RV, Scheithauer BW, Kovacs K, Roche PC. The immunophenotype of pituitary adenomas. Endocr Pathol 1996;7:145–150. Pernicone PJ, Scheithauer BW, Horvath E, Kovacs K. Pituitary and sellar region. In: Sternberg SS (ed) Diagnostic Surgical Pathology, 2nd Ed, Philadelphia, PA, Lippincott Williams & Wilkins; 1997:1053–1107. Perry A, Scheithauer BW. Commentary: classification and grading of pituitary tumors. Observations of two working neuropathologists. Acta Neuropathol 2006;111:68–70. Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 2007;156:203–216.

15 Lymph Node Ellen D. McPhail, md and Paul J. Kurtin, md

Contents

I. How to Work up a Lymph Node..................................................15-3

II. Classification of Diseases...................15-3

Lymphoid Hyperplasias...................................15-3 Follicular Hyperplasias..........................15-3 Sinus Hyperplasias.................................15-3 Paracortical Hyperplasias......................15-3 Necrotizing Granulomatous Lymphadenitis....................................15-3 Necrotizing Nongranulomatous Lymphadenitis....................................15-3 Malignant Lymphoma/Leukemia (WHO Classification)..................................15-3 Precursor B- and T-Cell Neoplasms......15-3 Mature B-Cell Neoplasms......................15-3 Mature T-Cell and NK-Cell Neoplasms...........................................15-3 Hodgkin Lymphoma...............................15-4 Histiocytic Lymph Node Tumors....................15-4 Spindle Cell Lesions of Lymph Node..............15-4

III. Lymphoid Hyperplasias......................15-4 Follicular Hyperplasias....................................15-4 Reactive Follicular Hyperplasia............15-4 Toxoplasmosis.........................................15-4 Cytomegalovirus.....................................15-5 Human Immunodeficiency Virus..........15-5 Rheumatoid Arthritis.............................15-5 Syphilis (Luetic Lymphadenitis)...........15-5 Progressive Transformation of Germinal Centers..........................15-5 Castleman Disease: Hyaline Vascular Type.....................................15-5

Castleman Disease: Plasma Cell Variant........................................15-6 Sinus Hyperplasias...........................................15-6 Whipple Disease......................................15-6 Hemophagocytic Syndrome...................15-6 Vascular Transformation of Lymph Node Sinuses.......................................15-6 Paracortical Hyperplasias...............................15-7 Infectious Mononucleosis.......................15-7 Atypical Immunoblastic Reaction..............................................15-7 Dermatopathic Lymphadenopathy.......15-7 Necrotizing Granulomatous Lymphadenitis.............................................15-7 Cat Scratch Disease................................15-7 Lymphogranuloma Venereum...............15-8 Tularemia.................................................15-8 Yersinia....................................................15-8 Tuberculosis.............................................15-8 Fungal Infection......................................15-8 Necrotizing Nongranulomatous Lymphadenitis.............................................15-8 Kikuchi–Fujimoto Disease.....................15-8 Systemic Lupus Erythematosis.............15-8

IV. Malignant Lymphoma/Leukemia (WHO Classification)........................15-9 Precursor B- and T-Cell Neoplasms...............15-9 B-Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified....................15-9 B-Lymphoblastic Leukemia/ Lymphoma with Recurrent Genetic Abnormalities.....................15-10 T-Lymphoblastic Leukemia/ Lymphoma........................................15-10

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_15, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Mature B-Cell Neoplasms..............................15-11 Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma......15-11 B-Cell Prolymphocytic Leukemia..........................................15-12 Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia..........................15-12 Splenic Marginal Zone Lymphoma....15-14 Hairy Cell Leukemia............................15-15 Plasma Cell Neoplasms........................15-16 Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma).............15-16 Nodal Marginal Zone B-Cell Lymphoma............................15-17 Follicular Lymphoma...........................15-18 Mantle Cell Lymphoma.......................15-20 Diffuse Large B-Cell Lymphoma, Not Otherwise Specified..................15-22 T-Cell/Histiocyte-Rich Large B-Cell Lymphoma........................................15-23 Primary Mediastinal (Thymic) Large B-Cell Lymphoma.................15-23 Burkitt Lymphoma...............................15-24 Mature T-Cell and NK-Cell Neoplasms.......15-25 T-Cell Prolymphocytic Leukemia.......15-25 T-Cell Large Granular Lymphocytic Leukemia..........................................15-26 Aggressive NK-Cell Leukemia............15-26 Adult T-Cell Leukemia/Lymphoma (ATL/L).............................................15-26 Extranodal NK/T-Cell Lymphoma, Nasal Type........................................15-27 Enteropathy-Associated T-Cell Lymphoma............................15-27 Hepatosplenic T-Cell Lymphoma........15-28 Subcutaneous Panniculitis-Like T-Cell Lymphoma............................15-28 Mycosis Fungoides/Sézary Syndrome..........................................15-29

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Angioimmunoblastic T-Cell Lymphoma........................................15-30 Peripheral T-Cell Lymphoma, Not Otherwise Specified..................15-30 Anaplastic Large Cell Lymphoma......15-31 Hodgkin Lymphoma......................................15-32 Nodular Lymphocyte Predominant Hodgkin Lymphoma........................15-32 Classic Hodgkin Lymphoma.........................15-34 Nodular Sclerosis Hodgkin Lymphoma........................................15-34 Mixed Cellularity Hodgkin Lymphoma........................................15-34 Lymphocyte-Rich Classic Hodgkin Lymphoma........................................15-35 Lymphocyte Depleted Hodgkin Lymphoma........................................15-35

V. Histiocytic and Dendritic Cell Lymph Node Tumors.................15-36 Langerhans Cell Histiocytosis.......................15-36 Langerhans Cell Sarcoma.............................15-36 Sinus Histiocytosis with Massive Lymphadenopathy.....................................15-36 Histiocytic Sarcoma........................................15-37 Blastic Plasmacytoid Dendritic Cell Neoplasm............................................15-37 Interdigitating Dendritic Cell Sarcoma......................................................15-37 Follicular Dendritic Cell Sarcoma......................................................15-37

VI. Spindle Cell Lesions of Lymph Nodes...............................15-38 Bacillary Angiomatosis..................................15-38 Kaposi Sarcoma..............................................15-38 Palisaded Myofibroblastoma.........................15-38 Inflammatory Pseudotumor of Lymph Node..........................................15-39

VII. Suggested Reading...........................15-39

Lymph Node

15-3

HOW TO WORK UP A LYMPH NODE ♦♦ Receive lymph node fresh ♦♦ Ensure excellent fixation (B5 or zinc sulfate formalin preferred) ♦♦ Snap freeze a portion (for molecular genetics) ♦♦ Flow cytometry (selected cases) ♦♦ Virtually all diagnostic problems involving hematolymphoid neoplasms can be resolved by a combination of flow cytom-

etry, paraffin section immunoperoxidase stains, fluorescence in situ hybridization/chromogenic in situ hybridization (for specific genetic abnormalities), and/or molecular genetics studies ♦♦ Phenotypic approach: Most cost effective approach should be driven by the morphologic differential diagnosis. Remember: reimbursement is not guaranteed if ancillary studies cannot be shown to be diagnostically justified

CLASSIFICATION OF DISEASES Lymphoid Hyperplasias Follicular Hyperplasias ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Reactive follicular hyperplasia Toxoplasmosis Cytomegalovirus (CMV) Human immunodeficiency virus (HIV) Rheumatoid arthritis Syphilis Progressive transformation of germinal centers Castleman disease, hyaline vascular type Castleman disease, plasma cell type

Sinus Hyperplasias ♦♦ Whipple disease ♦♦ Hemophagocytic syndrome ♦♦ Vascular transformation of lymph node sinuses

Paracortical Hyperplasias ♦♦ Infectious mononucleosis ♦♦ Atypical immunoblastic reaction ♦♦ Dermatopathic lymphadenopathy

Necrotizing Granulomatous Lymphadenitis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Cat scratch disease Lymphogranuloma venereum Tularemia Yersinia Tuberculosis (TB) Fungal infection

Necrotizing Nongranulomatous Lymphadenitis ♦♦ Kikuchi–Fujimoto disease ♦♦ Systemic lupus erythematosis

Malignant Lymphoma/Leukemia (WHO Classification) Precursor B- and T-Cell Neoplasms ♦♦ B-lymphoblastic leukemia/lymphoma ♦♦ T-lymphoblastic leukemia/lymphoma

Mature B-Cell Neoplasms ♦♦ Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) ♦♦ B-cell prolymphocytic leukemia (B-PLL) ♦♦ Lymphoplasmacytic lymphoma/Waldenström macroglo­ bulinemia ♦♦ Splenic marginal zone lymphoma ♦♦ Hairy cell leukemia ♦♦ Plasma cell neoplasms ♦♦ Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) ♦♦ Nodal marginal zone B-cell lymphoma ♦♦ Follicular lymphoma (FL) ♦♦ Mantle cell lymphoma ♦♦ Diffuse large B-cell lymphoma ♦♦ Mediastinal (thymic) large B-cell lymphoma ♦♦ Burkitt lymphoma

Mature T-Cell and NK-Cell Neoplasms ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

T-cell prolymphocytic leukemia (T-PLL) Aggressive NK-cell leukemia Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma (EATL) Hepatosplenic T-cell lymphoma

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Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome (MF/SS) Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, not otherwise specified Anaplastic large cell lymphoma

Hodgkin Lymphoma ♦♦ Nodular lymphocyte predominant Hodgkin lymphoma ♦♦ Classic Hodgkin lymphoma −− Nodular sclerosis Hodgkin lymphoma (NSHL) −− Mixed cellularity Hodgkin lymphoma (MCHL) −− Lymphocyte-rich classic Hodgkin lymphoma (LRCHL) −− Lymphocyte depleted Hodgkin lymphoma (LDHL)

Histiocytic Lymph Node Tumors ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Sinus hyperplasia with massive lymphadenopathy Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma

Spindle Cell Lesions of Lymph Node ♦♦ ♦♦ ♦♦ ♦♦

Bacillary angiomatosis Kaposi sarcoma Palisaded myofibroblastoma Inflammatory pseudotumor of lymph node

LYMPHOID HYPERPLASIAS Follicular Hyperplasias Reactive Follicular Hyperplasia Differential Diagnosis ♦♦ Follicular lymphoma (see Table 15.1)

Toxoplasmosis Clinical

Microscopic (Fig. 15.1)

♦♦ Mostly young females (if pregnant, may result in birth defects in developing fetus)

Table 15.1. Comparison of Follicular Hyperplasia and Follicular Lymphoma Follicular hyperplasia Younger patients Normal follicle density Follicles vary in size and shape Well-defined mantle zone Cellular polarization present Heterogeneous follicle cells Tingible body macrophages present Mitoses common Follicles confined to node No atypical cells between follicles Follicle center cells (FCC) bcl-2 negative FCC not light chain restricted Ig/bcl-2 genes not rearranged

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♦♦ Transmitted by exposure to oocysts in cat feces or by ingestion of poorly cooked meat ♦♦ Symptoms: flu-like or asymptomatic ♦♦ Site of involvement: posterior cervical nodes most common

Follicular lymphoma Older patients Increased follicle density (back to back) Follicles homogeneous Thin or absent mantle zone Cellular polarization absent Homogeneous follicle cells Tingible body macrophages absent (usually) Mitoses uncommon Follicles may be seen in perinodal tissue Interfollicular regions may contain neoplastic cells Follicle center cells bcl-2 positive (usually) FCC light chain restricted Ig/bcl-2 genes rearranged (usually)

♦♦ Toxo triad −− Florid follicular hyperplasia −− Monocytoid B-cell hyperplasia expanding and surrounding sinuses −− Paracortical epithelioid histiocyte clusters that encroach on germinal centers (a) No necrosis ♦♦ Confirm diagnosis with serologic studies

Fig. 15.1. Toxoplasmosis lymphadenitis.

Lymph Node

Cytomegalovirus Microscopic ♦♦ Florid follicular hyperplasia ♦♦ Monocytoid B-cell hyperplasia expanding sinuses (CMV inclusions may sometimes be identified here) ♦♦ +/− Immunoblastic proliferation (may be atypical) ♦♦ Confirm diagnosis serologically, immunohistochemically, or by in situ hybridization techniques

Human Immunodeficiency Virus Microscopic (Fig. 15.2) ♦♦ Early stage −− Florid reactive lymphoid hyperplasia with absent mantle zones and follicle lysis of germinal centers (germinal centers disrupted by hemorrhage, disrupted FDC [follicular dendritic cell] meshwork, and increased T-cells) −− Monocytoid B-cell hyperplasia expanding sinuses −− Epithelioid histiocyte clusters −− Increased plasma cells and polykaryocytes (large multinucleated giant cells) in interfollicular zones ♦♦ Late stage −− Regressively transformed germinal centers −− Depletion of lymphocytes from paracortex

Differential Diagnosis ♦♦ Castleman disease, hyaline vascular type: Expanded mantle zones, hyalinized vessels

Rheumatoid Arthritis Microscopic ♦♦ Florid follicular hyperplasia ♦♦ Marked interfollicular plasmacytosis (plasma cells also present within follicles) ♦♦ Clusters of neutrophils in sinuses

15-5

Differential Diagnosis ♦♦ Other inflammatory disorders (e.g., Sjögren syndrome, Felty syndrome, Still disease) ♦♦ HIV infection ♦♦ Syphilis ♦♦ Castleman disease, plasma cell type

Syphilis (Luetic lymphadenitis) Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Florid follicular hyperplasia Interfollicular plasmacytosis Epithelioid granulomas Thick, fibrotic capsule – perivascular plasma cells +/− Arteritis/phlebitis Confirm diagnosis serologically

Progressive Transformation of Germinal Centers ♦♦ Rarely precedes, accompanies, or succeeds nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)

Microscopic ♦♦ Associated with reactive follicular hyperplasia in the same node ♦♦ Large follicles with indistinct germinal center/mantle zone borders due to infiltration of germinal centers by mantle zone lymphocytes ♦♦ Residual centroblasts may mimic L&H cells of NLPHL

Differential Diagnosis ♦♦ NLPHL −− Neoplastic Hodgkin cells have nuclear lobulation, centroblasts usually do not ♦♦ Follicular lymphoma, floral variant −− Neoplastic follicle center cells usually bcl-2+ and exhibit kappa or lambda light chain restriction ♦♦ Mantle cell lymphoma −− Neoplastic cells surround atrophic follicles −− Monoclonal B-cells CD5+

Castleman Disease: Hyaline Vascular Type Clinical ♦♦ Usually solitary mediastinal mass, may involve other sites

Microscopic (Fig. 15.3)

Fig. 15.2. Human immunodeficiency virus lymphadenitis.

♦♦ Atrophic germinal centers (regressively transformed) with expanded mantle zones composed of concentric layers of lymphocytes ♦♦ Multiple regressively transformed germinal centers in one “cloud” of mantle zone lymphocytes

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Whipple Disease Clinical ♦♦ Age: middle-aged adults ♦♦ Sex: M > F ♦♦ Etiology: infectious disease of small bowel (etiologic agent: Tropheryma whipplei, formerly called Tropheryma whippelii) ♦♦ Site of involvement: small bowel, abdominal lymph nodes, +/− peripheral lymph nodes

Microscopic

Fig. 15.3. Castleman disease, hyaline vascular type.

♦♦ Hyalinized blood vessels penetrate into follicles; interfollicular vascularity increased ♦♦ Few interfollicular plasma cells or transformed lymphocytes

Differential Diagnosis ♦♦ HIV infection −− Absent mantle zones −− Increased interfollicular plasma cells and polykaryocytes

Castleman Disease: Plasma Cell Variant Clinical ♦♦ Patients may have POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin lesions) or a variety of other signs and symptoms ♦♦ Sites of involvement: abdominal cavity and mediastinum, peripheral lymph nodes, extranodal sites ♦♦ Clinicopathologic diagnosis

Microscopic

♦♦ Sinuses distended by large lipid vacuoles surrounded by vacuolated histiocytes ♦♦ PAS+ bacilli present within histiocyte cytoplasm in sinuses and in germinal centers ♦♦ Confirm diagnosis by PCR or electron microscopy

Differential Diagnosis ♦♦ Mycobacterium avium intracellulare (MAI): organisms are acid-fast + as well as PAS+ ♦♦ Lymphangiogram effect: histiocytes are PAS−, acid-fast − ♦♦ Lipogranuloma: diagnosis of exclusion ♦♦ Silicon

Hemophagocytic Syndrome Synonym ♦♦ Virus-associated hemophagocytic syndrome

Clinical ♦♦ Immunocompromised host ♦♦ Usually due to viral infection, may result from bacterial, fungal, or parasitic infection ♦♦ May complicate certain lymphomas −− Subcutaneous panniculitis-like T-cell lymphoma −− ALCL −− Extranodal NK/T-cell lymphoma, nasal type ♦♦ Sites of involvement: lymph nodes, spleen, bone marrow

♦♦ Florid follicular hyperplasia with regressive transformation of germinal centers ♦♦ Marked interfollicular plasmacytosis that extends to the lymph node capsule

Microscopic

Differential Diagnosis

Vascular Transformation of Lymph Node Sinuses Clinical

♦♦ Rheumatoid arthritis ♦♦ HIV infection ♦♦ Syphilis

Sinus Hyperplasias ♦♦ Differential diagnosis of all sinus hyperplasias −− Metastatic carcinoma −− Metastatic malignant melanoma −− Anaplastic large cell lymphoma (ALCL)

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♦♦ Sinuses distended by benign-appearing histiocytes containing phagocytized erythrocytes or other hematopoietic elements

♦♦ Lymph node enlargement ♦♦ Sometimes associated with deep venous thrombosis in adjacent vein

Microscopic ♦♦ Sinuses distended by proliferating anastamosing vascular channels, often with fibrosis ♦♦ Capsule spared

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Differential Diagnosis

Atypical Immunoblastic Reaction

♦♦ Kaposi sarcoma −− Capsular/subcapsular involvement −− Spindle cell proliferation without distinct vascular channels −− PAS + hyaline globules

Microscopic

Paracortical Hyperplasias ♦♦ Differential diagnosis of all paracortical hyperplasias −− Peripheral T-cell lymphoma −− Interfollicular Hodgkin lymphoma

Infectious Mononucleosis Microscopic (Fig. 15.4) ♦♦ Paracortical expansion (EBV+ cells located in paracortex) ♦♦ Focal necrosis ♦♦ Sinuses distended by atypical lymphocytes, monocytoid B-cells, and/or immunoblasts ♦♦ +/− Follicular hyperplasia ♦♦ Cytology: polymorphous population of transformed lymphocytes, immunoblasts, RS-like cells, plasma cells, and histiocytes ♦♦ Confirm diagnosis by serologic studies or blood findings (lymphocytosis with >50% lymphocytes, >10% atypical lymphocytes)

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Diffuse large B-cell lymphoma Classic Hodgkin lymphoma Viral infection (e.g., CMV) Drug reaction (especially hydantoin)

♦♦ Similar to infectious mononucleosis

Causes ♦♦ Drug reaction (especially hydantoin): eosinophils often numerous ♦♦ Herpes simplex: viral inclusions may be seen in and around necrotic areas ♦♦ CMV: accompanied by monocytoid B-cell hyperplasia, CMV inclusions

Dermatopathic Lymphadenopathy Clinical ♦♦ Usually associated with skin lesions

Microscopic ♦♦ Subcapsular paracortical regions expanded (often focally) by small lymphocytes, some with convoluted nuclei resembling small Sézary cells, interdigitating reticulum cells, Langerhans cells, and histiocytes containing melanin, lipid, and hemosiderin ♦♦ Residual node displaced centrally

Differential Diagnosis ♦♦ Mycosis fungoides −− More architectural effacement, large and medium-sized pleomorphic lymphocytes present −− Aberrant T-cell phenotype −− May require molecular genetics

Necrotizing Granulomatous Lymphadenitis Cat Scratch Disease Clinical ♦♦ Sites of involvement: axillary and cervical lymph nodes ♦♦ Etiologic agent: Bartonella henselae

Microscopic ♦♦ Central stellate abscesses containing neutrophils, surrounded by palisaded histiocytes and fibroblasts; sparse to no multinucleated giant histiocytes ♦♦ +/− Follicular hyperplasia ♦♦ +/− Monocytoid B-cells distending sinuses ♦♦ Bacilli (found in necrotic areas) stain positively with Warthin–Starry stain ♦♦ Diagnosis can be confirmed by PCR

Differential Diagnosis

Fig. 15.4. Infectious mononucleosis.

♦♦ Lymphogranuloma venereum (LGV), tularemia, Yersinia −− All – on Warthin–Starry stain ♦♦ Toxoplasmosis: no necrosis, Warthin–Starry − ♦♦ Hodgkin lymphoma

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Lymphogranuloma Venereum Clinical ♦♦ Sexually transmitted disease caused by Chlamydia trachomatis ♦♦ Involves inguinal lymph nodes in males, pelvic lymph nodes in females

Microscopic ♦♦ Morphologically indistinguishable from cat scratch disease, tularemia, yersinia ♦♦ Confirm diagnosis serologically

Tularemia ♦♦ Often history of tick bite ♦♦ Involves axillary lymph nodes ♦♦ Morphologically indistinguishable from cat scratch disease, LGV, Yersinia ♦♦ Confirm diagnosis by serology or cultures

Yersinia ♦♦ Clinical history of abdominal pain and diarrhea, signs suggesting appendicitis ♦♦ Involves mesenteric lymph nodes ♦♦ Morphologically indistinguishable from cat scratch disease, LGV, tularemia

Tuberculosis Microscopic ♦♦ Necrotizing granulomas with central caseous necrosis without neutrophils ♦♦ AFB + bacilli present in necrotic areas (may be difficult to find); PCR may help

Fungal Infection ♦♦ Morphologically similar to TB, but granulomas more commonly contain neutrophils and karyorrhectic nuclear debris ♦♦ Organisms GMS+, PAS+

Necrotizing Nongranulomatous Lymphadenitis

Fig. 15.5. Kikuchi–Fujimoto disease (A, B).

♦♦ Immunoblasts, histiocytes, and plasmacytoid monocytes peripherally ♦♦ No granulocytes, few plasma cells

Systemic Lupus Erythematosis Clinical

Kikuchi–Fujimoto Disease

♦♦ Young adult females ♦♦ Cervical or generalized lymphadenopathy

Synonym

Microscopic

♦♦ Histocytic necrotizing lymphadenitis

♦♦ Follicular hyperplasia ♦♦ Interfollicular zones contain increased plasma cells and immunoblasts ♦♦ Areas of necrosis may contain neutrophils or plasma cells ♦♦ Hematoxylin bodies (composed of DNA aggregates, polysaccharides, and immunoglobulin) found within areas of necrosis as well as in walls of blood vessels

Clinical ♦♦ Young adult females ♦♦ Involves cervical lymph nodes

Microscopic (Fig. 15.5) ♦♦ Patchy cortical and paracortical necrosis with extensive karyorrhectic debris and histiocytes centrally

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MALIGNANT LYMPHOMA/LEUKEMIA (WHO CLASSIFICATION) Precursor B- and T-Cell Neoplasms B-Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified Synonyms ♦♦ Rappaport: lymphoblastic (formerly diffuse poorly differentiated lymphocytic [PDL]) ♦♦ Kiel: lymphoblastic, B-cell type ♦♦ Lukes–Collins: undefined cell ♦♦ Working formulation: lymphoblastic ♦♦ FAB: L1 and L2 ♦♦ REAL: precursor B-lymphoblastic leukemia/lymphoma

Clinical ♦♦ Age: children > adults ♦♦ Presentation −− Acute lymphoblastic leukemia (bone marrow and peripheral blood involvement) – more common. Pancytopenia, adenopathy, hepatosplenomegaly, bone pain −− Lymphoblastic lymphoma (solid tumor [lymph node, skin, bone], +/− minimal bone marrow or peripheral blood involvement (£25% lymphoblasts in bone marrow – arbitrary cut-off); mediastinum rarely involved in B-LBL) – less common ♦♦ Clinical course −− Highly aggressive −− Often curable with chemotherapy −− Better prognosis (a) >50 chromosomes (b) t(12;21)(p13;q22) −− Poorer prognosis (a) t(1;19), t(9;22), t(4;11)(q21;q23), hypodiploidy (b) Lack of CD10, CD34, or CD24 expression (c) CD13 or CD33 expression ♦♦ Postulated cell of origin −− Precursor B-lymphoblasts

Microscopic ♦♦ Low power −− Architecture effaced −− Invasion of perinodal fat common −− Tumor involves paracortex, may spare reactive follicles ♦♦ High power (Fig. 15.6) −− Monotonous population of lymphoblasts: medium-sized cells with round or convoluted nuclei, fine chromatin, inconspicuous nucleoli, scant cytoplasm −− Frequent mitoses

Fig. 15.6. B-lymphoblastic leukemia/lymphoma.

−− +/− Starry-sky pattern (tingible body macrophages) −− T and B phenotypes morphologically indistinguishable

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD19+, CD79a+ CD43+ TdT (terminal deoxynucleatidyl transferase) + CD34 usually + CD20, CD22 usually + CD10 usually + Surface immunoglobulin (sIg) − CD13 and/or CD33 may be present

Genetics ♦♦ Ig heavy chain genes rearranged ♦♦ Light chain genes may be rearranged (~50%) ♦♦ T-cell receptor gene may be rearranged in B-LBL

Differential Diagnosis (Table 15.2) ♦♦ More mature B-cell neoplasms (e.g., blastoid variant of mantle cell lymphoma) −− TdT and CD34− −− sIg+ ♦♦ T-lymphoblastic leukemia/lymphoma −− B-cell associated antigens− −− CD3, CD7+ −− CD34− ♦♦ Myeloid sarcoma (extramedullary myeloid tumor, granu‑ locytic sarcoma) −− CD13, CD33, myeloperoxidase (MPO), CD68, lysozyme + −− CD19, CD22, CD10, CD79a−

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Table 15.2. Paraffin Section Immunophenotype of Blastic Hematolymphoid Malignancies Disorder T-lymphoblastic leukemia/lymphoma B-lymphoblastic leukemia/lymphoma Myeloid sarcoma Burkitt lymphoma Blastoid mantle cell lymphoma

TdT

CD34

CD43

MPO/Lys

CD3

CD79a

+ + + − −

− + + − −

+ + + + +

− − + − −

+ − − − −

− + − + +

♦♦ Burkitt lymphoma −− More prominent starry-sky pattern, coarser chromatin, multiple nucleoli, amphophilic, granular cytoplasm −− sIg+ −− CD34, TdT−

B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities ♦♦ B-lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL1 −− More common in adults than children −− Worst prognosis among ALL patients ♦♦ B-lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged −− Usually occurs in infants −− Poor prognosis ♦♦ B-lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) −− Common in children, rare in adults −− Very favorable prognosis ♦♦ B-lymphoblastic leukemia/lymphoma with hyperdiploidy −− Common in children, rare in adults −− Very favorable prognosis ♦♦ B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1) −− Relatively common in children −− CD19+, CD10+, cytoplasmic m heavy chain-positive preB-cell phenotype

CD20 Cyclin D1 − + − + +

♦♦ Sex: M > F ♦♦ Presentation: rapidly enlarging mediastinal (thymic) mass, +/− lymphadenopathy, SVC syndrome, pericardial and pleural effusions ♦♦ Bone marrow involvement >25% = precursor T-lymphoblastic leukemia ♦♦ Clinical course: highly aggressive but potentially curable

Microscopic (Fig. 15.7) ♦♦ Monotonous population of lymphoblasts (medium-sized cells with round nuclei, fine chromatin, inconspicuous nucleoli, and scant cytoplasm) ♦♦ Numerous mitoses, tingible body macrophages (starry sky) ♦♦ Morphologically indistinguishable from B-LBL

Immunophenotype ♦♦ Mirrors stages of intrathymic T-cell ontogeny ♦♦ CD7+, CD3+ (cytoplasmic + even if surface −), CD2+, CD5+ ♦♦ Subset of cases expresses CD1, CD4, and CD8 ♦♦ TdT+ ♦♦ Immunoglobulin − ♦♦ B-cell associated antigens−

T-Lymphoblastic Leukemia/Lymphoma Synonyms ♦♦ Rappaport: poorly differentiated lymphocytic, diffuse (modified to lymphoblastic) ♦♦ Kiel: T-lymphoblastic ♦♦ Lukes–Collins: convoluted T-lymphocytic ♦♦ Working formulation: lymphoblastic, convoluted or nonconvoluted

Clinical ♦♦ Age: adolescents and young adults

690

NA NA NA − +

Fig. 15.7. T-lymphoblastic leukemia/lymphoma.

Lymph Node

Genetics ♦♦ T-cell receptor gene rearrangement variable ♦♦ Immunoglobulin heavy chain gene rearrangement may be present

Differential Diagnosis ♦♦ B-Lymphoblastic leukemia/lymphoma −− B-cell associated antigens+ −− T-cell associated antigens− −− CD10+ ♦♦ Mature B-cell lymphoma −− Lacks blastic cytology −− B-cell-associated antigens+ −− T-cell-associated antigens− −− TdT− ♦♦ Mature T-cell lymphoma −− Heterogeneous cell population that lacks blastic cytology −− TdT− ♦♦ Myeloid sarcoma (extramedullary myeloid tumor, granulocytic sarcoma) −− Eosinophilic cytoplasm −− Myeloperoxidase (MPO)+, lysozyme+, CD68+ −− T-cell associated antigens−

Mature B-Cell Neoplasms Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Synonyms ♦♦ ♦♦ ♦♦ ♦♦

Rappaport: well-differentiated lymphocytic, diffuse Kiel: CLL Lukes–Collins: small lymphocytic B, CLL Working formulation: small lymphocytic, consistent with CLL ♦♦ REAL: B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

Clinical ♦♦ ♦♦ ♦♦ ♦♦

♦♦ ♦♦ ♦♦ ♦♦

Age: older adults (median age 60–65 years) Sex: M > F (slight) History of waxing and waning adenopathy common SLL: Usually disseminated at presentation (involvement of bone marrow, multiple lymph nodes, spleen, and liver common) ~30% of patients with SLL progress to CLL CLL criteria: >5,000/mm3 circulating clonal B-cells CLL: lymph nodes (in addition to bone marrow and peripheral blood) usually involved SLL and CLL morphologically indistinguishable on lymph node biopsy

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♦♦ Clinical course −− Indolent but not curable with available therapy −− Median survival: 60–70 months −− May transform to large cell lymphoma; risk increases over time −− Postulated cell of origin (a) 40–50% – naïve B-cell (germline variable region IG genes) (b) 50–60% – post-germinal center B-cell (variable region IG genes contain somatic mutations) −− Poorer prognosis (a) Extensive clinical disease (b) Increased number of large cells (prolymphocytes and paraimmunoblasts) (c) 17p deletion, 11q deletion (d) Germline variable region genes (consistent with naive B-cell derivation) – may correlate with CD38 expression −− Better prognosis (a) Low stage * Low lymphocyte doubling rate (peripheral blood) * Isolated 13q deletion * Mutated IG genes * Lack of expression of CD38 * Lack of expression of ZAP-70

Microscopic ♦♦ Low power −− Effaced architecture (75% of cases) −− Extensive involvement of perinodal fat in one-third of cases −− May be interfollicular −− Pale zones (proliferation centers) alternating with darker zones (Fig. 15.8A) ♦♦ High power −− Monotonous population of small lymphocytes (rounded nuclei, clumped chromatin, scant cytoplasm, inconspicuous to small nucleoli, and infrequent mitotic figures) −− Most cases also contain larger lymphoid cells (prolymphocytes and paraimmunoblasts), frequently forming indistinct nodules known as pseudofollicles, proliferation centers or growth centers (Fig. 15.8B)

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦

CD19, CD20, CD79a+ (weak CD20 expression) CD23+ CD5+, CD43+ sIg weakly + (M+/−D), immunoglobulin light chain restricted ♦♦ CD10− ♦♦ Cyclin D1−

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♦♦ Mantle cell lymphoma (MCL) −− Slightly larger lymphocytes with cleaved nuclei; no proliferation centers −− CD23− −− Cyclin D1+ −− t(11;14) usually present ♦♦ Follicular lymphoma −− Follicular pattern (at least partially), centrocytes usually predominate, no proliferation centers −− CD5−, CD43−, CD23 usually − −− CD10+ −− Cyclin D1− −− t(14;18) common ♦♦ Marginal zone B-cell lymphoma −− Cellular heterogeneity, reactive follicles usually present, no proliferation centers −− CD5 usually −, CD23− ♦♦ T-cell prolymphocytic leukemia −− T-cell associated antigens+ −− B-cell associated antigens− ♦♦ B-cell prolymphocytic leukemia (see below)

B-Cell Prolymphocytic Leukemia Clinical ♦♦ Often present with higher WBC count and splenomegaly

Microscopic Fig.  15.8. Chronic lymphocytic leukemia/small lymphocytic lymphoma. (A) Low power; (B) high power–proliferation centers.

♦♦ 65% of blood lymphocytes are prolymphocytes (clumped chromatin with prominent single nucleolus) (defined on the basis of peripheral blood involvement; not tissue sections)

Immunophenotype Genetics ♦♦ Ig heavy and light chain genes are rearranged ♦♦ Trisomy 12 – common – intermediate prognosis ♦♦ 13q abnormalities (13q14) – most common – slightly better prognosis ♦♦ 11q deletion – poorer prognosis ♦♦ 17p deletion – poorer prognosis

Variant ♦♦ Interfollicular small lymphocytic lymphoma −− Microscopic: numerous residual follicles (tumor will subsequently spread through lymph node to obliterate architecture)

Differential Diagnosis (See Tables 15.3 and 15.4) ♦♦ Lymphoplasmacytic lymphoma −− Monoclonal plasmacytoid lymphocytes and plasma cells present; Dutcher bodies

692

♦♦ Strong sIg+, CD5 may be −, CD23 usually absent

Prognosis ♦♦ More aggressive clinical course

Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia Synonyms ♦♦ Rappaport: well-differentiated lymphocytic, plasmacytoid, diffused mixed lymphocytic and histiocytic ♦♦ Kiel: immunocytoma, lymphoplasmacytic type ♦♦ Lukes–Collins: plasmacytic–lymphocytic ♦♦ Working formulation: small lymphocytic, plasmacytoid, diffuse mixed small and large cell ♦♦ REAL: lymphoplasmacytoid lymphoma/immunocytoma

Clinical ♦♦ Age: older adults (median 63 years) ♦♦ Sex: M > F (slight)

Lymph Node

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Table 15.3. Morphologic Differential Diagnosis of B-Cell Lymphoproliferative Disorders in Lymph Node, Spleen and Bone Marrow Histologic Sections Lymph node

Spleen

Bone marrow

Cytology

Chronic lymphocytic leukemia/small lymphocytic lymphoma

Diffuse pattern, proliferation centers

Red pulp cords and sinusoids

Intertrabecular nodules and interstitial

Small lymphocytes, prolymphocytes, and paraimmunoblasts

Lymphoplasmacytic lymphoma

Diffuse pattern

Red pulp cords and sinusoids, encroaches on borders of white pulp

Intertrabecular nodules and interstitial, may be paratrabecular

Small lymphocytes, plasmacytoid lymphocytes, plasma cells, Dutcher bodies

Mantle cell lymphoma

Diffuse or nodular pattern with atrophic germinal centers

White pulp with atrophic germinal centers and obliterated marginal zones

Intertrabecular nodules and paratrabecular aggregates

Small lymphocytes with nuclear irregularity. No large cells

Nodal marginal zone lymphoma

Perisinusal or surrounding benign germinal centers and mantle zones

White pulp with small germinal centers and residual nonneoplastic mantle cells

Intertrabecular nodules and paratrabecular aggregates

Medium size cells with irregular nuclei, abundant pale cytoplasm. Occasional large transformed cells

Hairy cell leukemia

Rarely involved

Red pulp cords and sinusoids Blood lakes

Interstitial

Small to medium size lymphocytes with abundant pale cytoplasm

White pulp germinal centers expanded with benign mantle and marginal zone cells

Intertrabecular nodules and paratrabecular aggregates

Small cleaved cells and large noncleaved cells in varying proportions

Hilum, perinodal soft tissue involvement Follicular lymphoma

True follicular nodularity

Table 15.4. Immunophenotypic Features of Small B-Cell Lymphoproliferative Disorders sIg Chronic lymphocytic leukemia/ small lymphocytic lymphoma Lymphoplasmacytic lymphoma Mantle cell lymphoma Marginal zone lymphoma Hairy cell leukemia Follicular lymphoma a

CD19

CD20

CD23

CD10

CD5

CD3

Monoclonal (dim)

+

+ (dim)

+

−

+

−

Monoclonal cIg in plasma cell Monoclonal (bright) Monoclonal (bright) Monoclonal (bright) Monoclonal (bright)

+ + + + +

+ + (bright) + (bright) + + (bright)

−/+ − − − −/+

− − − − +

−/+ + −/+ − −

− − − − −

In addition, mantle cell lymphoma is the only lymphoma positive for cyclin D1 The cells of hairy cell leukemia characteristically and brightly coexpress CD22 and CD11c and are positive for CD103

b

♦♦ Monoclonal immunoglobulin serum or urine (usually IgM, occasionally IgG or IgA) usually present ♦♦ Waldenström macroglobulinemia: monoclonal IgM serum paraprotein ♦♦ Autoimmune hemolytic anemia, autoimmune thrombocytopenia, coagulation factor inhibitors, and cryoglobulinemia may be seen

♦♦ Sites of involvement −− Lymph nodes, bone marrow, spleen (usually stage III or IV at presentation) −− Peripheral blood lymphocytosis may be present ♦♦ Clinical course −− Similar to CLL/SLL

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−− Indolent but not curable with available therapy −− May transform to diffuse large B-cell lymphoma (~10%) – poor prognosis

Microscopic (Fig. 15.9) ♦♦ Diffuse or parafollicular proliferation of small lymphocytes, plasmacytoid lymphocytes (lymphocytic-like nuclei, plasma cell-like cytoplasm), and plasma cells ♦♦ Abnormal immunoglobulin production manifest by −− Dutcher bodies (intranuclear immunoglobulin inclusions) −− Russell bodies (extracellular hyaline immunoglobulin bodies) −− Crystalline immunoglobulin deposits (intracytoplasmic or extracellular) −− Amyloid deposits −− Intercellular light chain deposits, mimicking amyloid ♦♦ Sinuses spared (may contain immunoglobulin) ♦♦ Mast cells frequently seen ♦♦ Iron-containing epithelioid histiocytes may be present

Essentials of Anatomic Pathology, 3rd Ed.

Differential Diagnosis ♦♦ CLL/SLL −− Monoclonal plasmacytoid lymphocytes and plasma cells absent −− CD5+, CD23+, sIg weakly + ♦♦ Other small B-cell lymphomas

Splenic Marginal Zone Lymphoma Synonyms ♦♦ Rappaport: (not specifically listed) WDL or WDLplasmacytoid ♦♦ Kiel: not specifically listed ♦♦ Lukes–Collins: small lymphocyte B, lymphocytic–plasmacytic, small ♦♦ Lymphocyte B, monocytoid ♦♦ Working formulation: (not specifically listed) SLL ♦♦ REAL: splenic marginal zone lymphoma, with or without villous lymphocytes

Immunophenotype

Clinical

♦♦ Small lymphocytes, plasmacytoid lymphocytes and plasma cells are all light chain restricted ♦♦ sIg present (usually IgM; IgD absent), monoclonal cIg in plasma cells ♦♦ CD19, CD20, CD22, CD79a+ ♦♦ CD23 usually − ♦♦ CD43 − or + ♦♦ CD5 usually −, occasionally + ♦♦ CD10 usually −

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Genetics ♦♦ Ig heavy and light chain genes are rearranged

Age: older adults (median seventh decade) Sex: M > F Marked splenomegaly, often without adenopathy Bone marrow and peripheral blood usually involved May present as leukemia (+/− villous lymphocytes: lymphoid cells with abundant cytoplasm and small thin villi, often concentrated at one pole, as seen on peripheral blood smear) ♦♦ Clinical course: indolent ♦♦ Splenectomy may be treatment of choice (+/− chemotherapy)

Microscopic (Spleen) ♦♦ Low power −− Both mantle and marginal zones involved −− Residual germinal centers atrophic or hyperplastic −− Red pulp may be involved – sinusoidal involvement correlates with leukemic phase ♦♦ High power −− Biphasic pattern involving the mantle zone and marginal zone −− Mantle zone: Small neoplastic lymphoid cells with little cytoplasm −− Marginal zone: medium-sized neoplastic cells with moderate-abundant pale cytoplasm and scant large transformed lymphocytes with round nuclei, prominent nucleoli, dispersed chromatin and abundant cytoplasm −− Plasmacytic differentiation may be present

Immunophenotype Fig. 15.9. Lymphoplasmacytic lymphoma.

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♦♦ sIg+ (M > G or A), cIg may be +; light chain restricted ♦♦ CD19, CD20, CD22, CD79a+

Lymph Node

♦♦ CD5 and CD43 usually −, CD10− (may be + on flow cytometry) ♦♦ May be weakly TRAP + ♦♦ CD23−, cyclin D1− ♦♦ CD11c usually + ♦♦ CD103−

Genetic Features ♦♦ Loss of 7q31-32 common

Differential Diagnosis

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(b) Blood lakes (variable size) lined by neoplastic cells common −− High power (a) Monotonous population of small-medium lymphoid cells with oval-reniform nuclei and abundant pale cytoplasm (b) Cells appear widely spaced ♦♦ Lymph node (uncommonly involved) −− Diffuse involvement, prominent hilar and perinodal fat involvement, may spare follicles

♦♦ Splenic marginal zone hyperplasia −− sIg− polyclonal ♦♦ Hairy cell leukemia (HCL) −− Red pulp process, blood lakes common, monotonous tumor cells −− CD103+, TRAP+, DBA.44 +, Annexin A1+, T-bet+ ♦♦ CLL/SLL −− Red pulp process, architecture effaced, proliferation centers present, cells have scant cytoplasm −− CD5+, CD43+, CD23+ ♦♦ MCL −− Architecture effaced, monotonous cells with scant cytoplasm −− CD5+, CD43+, cyclin D1+ ♦♦ FL −− Follicular pattern, at least partially; germinal centers expanded −− CD10 and bcl-6 usually +

Immunophenotype

Hairy Cell Leukemia

♦♦ Splenic marginal zone lymphoma −− Involves white pulp mantle and marginal zones, blood lakes absent −− CD103−, TRAP weakly + in cell subset ♦♦ Mastocytosis −− Tryptase+, CD103−, TRAP− ♦♦ CLL/SLL −− Architecture effaced, proliferation centers present, cells have scant cytoplasm −− CD5+, CD43+, CD23+ −− CD103−, TRAP− ♦♦ MCL −− White pulp process, architecture effaced, monotonous cells with scant cytoplasm −− CD5+, CD43+, cyclin D1+ ♦♦ FL −− Follicular pattern, at least partially; germinal centers expanded −− Involves splenic white pulp −− CD10, bcl-6 usually + −− CD103−, TRAP−

Clinical ♦♦ Age: middle-aged to older adults ♦♦ Sex: M > F ♦♦ Presentation −− Splenomegaly, pancytopenia, monocytopenia −− Hepatomegaly variable, although liver is usually involved −− Lymphadenopathy is uncommon ♦♦ Peripheral blood: always involved, but characteristic hairy cells (lymphoid cells with abundant pale cytoplasm with circumferential hairy projections) may be hard to find ♦♦ Bone marrow: always involved, may be inaspirable due to increased reticulin fibrosis ♦♦ Clinical course −− Complete and durable remissions common with purine analog therapy

Microscopic ♦♦ Spleen −− Low power (a) Involves red pulp cords and sinusoids, white pulp atrophic

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

sIg+, light chain restricted CD19, CD20, CD22, CD79a+ CD11c+ (strong), CD25+ (strong) CD103+ (most specific marker) DBA.44+ (tissue sections) TRAP+ Annexin A1+, T-bet+ CD5−, CD10−, CD23−, cyclin D1−

Genetics ♦♦ Ig heavy and light chains rearranged (proves B-cell lineage)

Electron Microscopy ♦♦ Long microvilli with broad base and ribosome–lamella complexes ♦♦ Characteristic but not pathognomonic

Differential Diagnosis

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Plasma Cell Neoplasms Clinical ♦♦ Plasma cell myeloma (multiple myeloma) – disseminated bone marrow tumor – common ♦♦ Plasmacytoma – uncommon −− Solitary plasmacytoma of bone (a) Age: median sixth decade (b) Sex: M > F (c) Solitary bone lesion (d) 40–50% progress to multiple myeloma −− Extraosseous plasmacytoma (a) Age: median seventh decade (b) Sex: M>F (c) Usually involves upper aerodigestive tract, can arise in any organ (d) Regional lymph nodes may be involved (e) Primary plasmacytoma of lymph node extremely rare (f) 10–20% progress to multiple myeloma

Microscopic ♦♦ Monotonous infiltrate of mature to immature plasma cells ♦♦ No admixed lymphoid cells ♦♦ Lymph node: partially or completely effaced

Immunophenotype ♦♦ sIg−, cIg+ (G, A or light chain only; M, D or E rare), light chain restricted ♦♦ CD19, CD22− (CD79a often +); CD20 may be + ♦♦ CD45 usually – ♦♦ CD38+, CD138+

Genetics ♦♦ Ig heavy and light chain genes rearranged or deleted

Differential Diagnosis ♦♦ Reactive plasmacytosis −− Background of hyperplastic lymphoid follicles −− Heterogeneous population of plasma cells −− cIg not light chain restricted ♦♦ Lymphoplasmacytic lymphoma (and other low grade B-cell lymphomas) −− Plasma cells admixed with small lymphocytes (not pure plasma cell population) ♦♦ Diffuse large B-cell lymphoma (immunoblastic/plasmacytoid type) −− CD19, CD20+ −− CD45+ −− CD38−, CD138− ♦♦ Osteosclerotic myeloma (POEMS syndrome)

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Heavy chain disease (HCD) −− Gamma HCD −− Mu HCD −− Alpha HCD

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) Synonyms ♦♦ Rappaport: (not specifically listed) well-differentiated lymphocytic (WDL) or WDL-plasmacytoid, IDL, ILL, PDL, mixed lymphocytic–histiocytic (nodular or diffuse) ♦♦ Kiel: monocytoid B-cell, immunocytoma (some cases previously classified as centroblastic/centrocytic or centrocytic) ♦♦ Lukes–Collins: small lymphocyte B, lymphocytic– plasmacytic, small lymphocyte B, monocytoid ♦♦ Working formulation: (not specifically listed) SLL (some consistent with CLL, some plasmacytoid), small cleaved or mixed small and large cell (follicular or diffuse) ♦♦ REAL: extranodal marginal zone B-cell lymphoma

Clinical ♦♦ Age: adults (median age approximately 60 years) ♦♦ Sex: F > M (slight) ♦♦ May occur in patients with autoimmune disorder (e.g., Sjorgren syndrome) or chronic antigenic stimulation (e.g., Helicobacter gastritis) ♦♦ Sites of involvement −− Stomach, salivary gland, lung, thyroid, skin, etc −− May secondarily involve regional lymph nodes −− Bone marrow involvement uncommon (15–20%); peripheral blood involvement rare ♦♦ Clinical course −− Indolent; when disseminated, usually incurable with available therapy −− 5 year survival 75–80% −− May recur in other extranodal sites −− May transform to large B-cell lymphoma

Microscopic (Fig. 15.10) ♦♦ Low power: perisinusoidal, parafollicular, or marginal zone distribution; mantle zone preserved. Tumor gradually effaces architecture, circumscribing and infiltrating germinal centers (follicular colonization) ♦♦ High power: heterogeneous population of marginal zone cells (small-medium lymphoid cells with round-slightly indented nuclei, clumped chromatin, abundant pale cytoplasm, and well-defined cytoplasmic membranes), monocytoid B-cells, small lymphocytes, and plasma cells (plasma cells usually located in interfollicular zones). Occasional large transformed cells may be seen

Lymph Node

15-17

Differential Diagnosis ♦♦ Hairy cell leukemia (HCL) −− Peripheral blood, bone marrow, spleen involved. Lymph node involvement uncommon −− When lymph node is involved, HCL markedly infiltrates perinodal fat and nodal hilum. This feature is rare in MALT lymphoma −− CD11c+ (strong), CD25+ (strong), CD103+ (most specific) ♦♦ Mastocytosis −− Tryptase+ ♦♦ CLL/SLL −− Architecture effaced, proliferation centers present, cells have scant cytoplasm −− CD5+, CD43+, CD23+ ♦♦ MCL −− Architecture effaced; monotonous cells with scant cytoplasm −− CD5+, cyclin D1+ ♦♦ FL −− Follicular pattern, at least partially; centrocytes and centroblasts −− CD10 and bcl-6 usually + ♦♦ Monocytoid B-cell hyperplasia −− Germinal centers intact – not invaded by neoplastic monocytoid cells −− sIg− polyclonal

Fig.  15.10. Extranodal marginal zone lymphoma of mucosaassociated lymphoid tissue (MALT lymphoma) (A, B).

♦♦ Lymphoepithelial lesions (marginal zone cells infiltrating epithelium) typically seen ♦♦ Plasma cells often located in subepithelium

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

sIg+ (M>G or A), cIg may be + (40%) CD19, CD20, CD22, CD79a+ CD5, CD43 usually – CD10, CD23, cyclin D1− CD11c may be weakly +, CD25−

Genetics ♦♦ Multiple chromosomal abnormalities (t(11;18)(q21;q21)/ API2-MALT1, t(14;18)(q32;q21)/IGH-MALT1, t(1;14)(p22; q32)/IGH-BCL10, t(3;14)(p14.1;q32)/IGH-FOXP3) whose frequencies vary with site of primary disease – ♦♦ Trisomy 3 and trisomy 18 also not infrequent

Nodal Marginal Zone B-Cell Lymphoma Synonyms ♦♦ Rappaport: (not specifically listed) well-differentiated lymphocytic (WDL) ♦♦ WDL-plasmacytoid, IDL, ILL, PDL, mixed lymphocytic– histiocytic (nodular or diffuse) ♦♦ Kiel: monocytoid B-cell, immunocytoma (some cases previously classified as centroblastic/centrocytic or centrocytic) ♦♦ Lukes–Collins: small lymphocyte B, lymphocytic–plasmacytic, small lymphocyte B, monocytoid ♦♦ Working formulation: (not specifically listed) SLL (some consistent with CLL, some plasmacytoid), small cleaved or mixed small and large cell (follicular or diffuse)

Clinical ♦♦ Localized or generalized lymphadenopathy

Microscopic (Fig. 15.11) ♦♦ Low power −− Parafollicular or marginal zone distribution ♦♦ High power −− Marginal zone B-cells and/or monocytoid B-cells, +/− occasional large transformed cells

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Essentials of Anatomic Pathology, 3rd Ed.

Clinical ♦♦ Age: adults (median age 55–59 years) ♦♦ Sex: M = F ♦♦ Comprises 35–40% of non-Hodgkin lymphomas in USA (less common in other countries) ♦♦ Usually disseminated at presentation (>70% stage III/IV) ♦♦ Sites of involvement −− Lymph nodes, spleen (25–55%), liver, bone marrow (40%), peripheral blood (uncommon) −− Extranodal presentation without lymph node involvement uncommon (exception: primary cutaneous follicular center lymphoma) ♦♦ Clinical course −− Indolent but usually not curable with available therapy (grade 3: more aggressive but potentially curable with aggressive therapy) −− Repeated relapses despite achievement of complete remission with or without therapy (23% remit spontaneously) −− Transformation to large B-cell lymphoma common, regardless of treatment status −− 5 year overall survival 72%; 5 year failure-free survival 40% ♦♦ Adverse prognostic indicators −− High stage −− High International Prognostic Index for FL (FLIPI) −− Concurrent t(14;18)/IGH-BCL2 and t(8;14)/IGH-MYC

Terminology Fig. 15.11. Nodal marginal zone B-cell lymphoma (A, B).

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

sIg+ (M>G or A), cIg may be + (40%) CD19, CD20, CD22, CD79a+ CD5, CD43 usually − CD10, CD23, cyclin D1− CD11c may be weakly +, CD25−

Follicular Lymphoma Synonyms ♦♦ Rappaport: nodular poorly differentiated lymphocytic (PDL), mixed lymphocytic–histiocytic, or histiocytic ♦♦ Kiel: centroblastic/centrocytic follicular, follicular centroblastic ♦♦ Lukes–Collins: small cleaved, large cleaved, or large noncleaved follicular center cell (FCC), follicular ♦♦ Working formulation: follicular, small cleaved mixed, or large cell ♦♦ REAL: follicular center lymphoma, follicular

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♦♦ Subtype according to architectural pattern and follicular center cell composition −− Architecture: state approximate percent follicular pattern in report (a) Follicular (>75% follicular pattern) (b) Follicular and diffuse (25–75% follicular pattern) (c) Focally follicular (<25% follicular pattern) −− Follicular center cell composition (a) Grade 1 (Fig. 15.12) * 0–5 large noncleaved cells (centroblasts)/40× high power field (hpf) – must count cells in ten follicles (b) Grade 2 * 6–15 large noncleaved cells/hpf (c) Grade 3 * >15 large noncleaved cells/hpf * Counting method cut-offs are based on hpf of 0.159  mm2. Compensatory factor must be used for different oculars * Grade 3A: >15 large noncleaved cells/hpf but small cleaved cells still present (Fig. 15.13A) * Grade 3B: solid sheets of centroblasts (Fig. 15.13B)

Lymph Node

Fig. 15.12. Follicular lymphoma, grade 1.

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Fig.  15.14. Follicular lymphoma with follicular and diffuse architecture.

♦♦ Back to back arrangement of relatively uniform follicles (increased follicle density); intervening lymphoid stroma compressed ♦♦ Tumor may infiltrate nodal capsule, perinodal blood vessels, and perinodal fat ♦♦ Limited or absent mantle zone ♦♦ Follicles lack cellular polarization ♦♦ Follicles composed of centrocytes (small cleaved follicular center cells – usually predominate) and centroblasts (large noncleaved follicular center cells – usually in the minority) ♦♦ Follicles lack tingible body macrophages (may be present in grade 3 subtype)

Immunohistochemistry

Fig. 15.13. Follicular lymphoma, grade 3A (A) and grade 3B (B).

Microscopic ♦♦ Follicular pattern (at least partially); diffuse areas may be present (Fig. 15.14)

♦♦ sIg + (usually IgM) ♦♦ Ig light chain restricted ♦♦ bcl-6+, CD10 usually + (75%), interfollicular neoplastic cells also usually CD10+ (albeit more weakly) ♦♦ CD19, CD20, CD22, CD79a+ ♦♦ CD5−, CD43− ♦♦ CD23 usually− ♦♦ Cyclin D1− ♦♦ Intrafollicular lymphocytes usually bcl-2+ (83–100% of grade 1, 52–85% of grade 3) ♦♦ N.B.: bcl-2 is positive in many other small B-cell lymphomas (as well as normal B- and T-cells, normal hematopoietic precursors, and many other nonhematopoietic cells and tumors), therefore bcl-2 is −− Useful in distinguishing FL from follicular hyperplasia −− Not useful in distinguishing FL from other small B-cell lymphomas

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Genetics ♦♦ t(14;18)(q32;q21): bcl-2 gene (chromosome 18) juxtaposed to J-region of immunoglobulin heavy chain gene (chromosome 14) leading to increased bcl-2 protein expression ♦♦ bcl-2 protein: prevents B-cell apoptosis (programmed cell death) leading to extended B-cell survival ♦♦ t(14;18) also present in 20% of diffuse large B-cell lymphomas ♦♦ Additional genomic defects (e.g., involving 3q27 or 17p, del 6q, trisomy 2,3,7,12,18, or 21, dup 2p) may be associated with grade 2 or 3 subtypes and more aggressive clinical course

Variants ♦♦ Pediatric FL −− Localized disease −− Head and neck or inguinal region −− Grade 2 or 3 subtypes common −− Favorable outcome ♦♦ Primary intestinal FL −− Localized disease −− Favorable outcome ♦♦ Primary cutaneous follicle center lymphoma −− Localized disease ♦♦ Favorable outcome In situ FL −− Architecturally normal lymph node with one or more follicles with bcl-2-positive centrocytes and centroblasts −− Clinical significance unclear if de novo finding ♦♦ Diffuse follicular lymphoma −− Diffuse architecture −− Majority of centrocytes with occasional centroblasts −− Immunophenotype of follicle center cells (pan B-antigen+, sIg+, CD10+, bcl-2+, bcl-6+)

Differential Diagnosis ♦♦ Follicular hyperplasia (FH) −− See Table 15.1 ♦♦ Castleman disease, hyaline vascular type −− Reactive condition −− Broad mantle zones with onionskin pattern −− Small (regressively transformed) germinal centers containing hyalinized vessels −− Intrafollicular lymphocytes bcl-2−, polyclonal −− Interfollicular lymphocytes CD10− ♦♦ PTGC −− Reactive condition, rarely associated with NLPHL −− Expansile follicles in background of reactive follicles −− No atypical cells in interfollicular zones or perinodal tissue −− Intrafollicular lymphocytes bcl-2−, polyclonal −− Interfollicular lymphocytes CD10−

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♦♦ NLPHL −− Nodules larger than follicles of FL −− Centrocytes scant −− L&H cells may resemble centroblasts, but have more pronounced nuclear lobulation, delicate chromatin, small nucleoli, wispy pale cytoplasm −− L&H cells are often surrounded by CD57+ T-cells −− Nodular lymphocytes CD10− ♦♦ MCL −− Diffuse or vaguely nodular pattern, cells homogeneous −− CD5+, CD43+ −− CD10−, bcl-6− −− Cyclin D1+ ♦♦ MALT lymphoma −− Lymphoepithelial lesions in extranodal sites −− Perifollicular growth pattern −− More abundant pale cytoplasm in centrocyte-like cells −− Monoclonal plasma cells common −− Neoplastic cells CD10− (although residual normal follicle center cells may be CD10+) −− CD43 may be + ♦♦ CLL/SLL with prominent proliferation centers −− Proliferation centers composed of prolymphocytes and paraimmunoblasts −− CD5+, CD43+, CD23+ −− CD10− ♦♦ Lymphoblastic lymphoma with lobular pattern −− Blast-like cytology −− TdT+, sIg− −− Both may be CD10+

Mantle Cell Lymphoma Synonyms ♦♦ Rappaport: intermediately or poorly differentiated lymphocytic, diffuse or nodular (ILL/IDL/PDL) ♦♦ Kiel: centrocytic (mantle cell) lymphoma ♦♦ Lukes–Collins: small cleaved follicular center cell (FCC) ♦♦ Working formulation: small cleaved cell, diffuse or nodular; rarely diffuse mixed or large cleaved cell ♦♦ Other: mantle zone lymphoma

Clinical ♦♦ Age: older adults (median age 63 years) ♦♦ Sex: M > F ♦♦ Sites of involvement −− High stage at presentation: lymph nodes, spleen (~60%), peripheral blood (at least 25%) −− Extranodal sites, especially GI tract (lymphomatous polyposis) and Waldeyer ring

Lymph Node

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♦♦ Clinical course −− Moderately aggressive, incurable with available therapy −− Median survival: 3–5 years −− May progress to blastoid variant ♦♦ Adverse prognostic indicators −− Blastoid subtype −− High mitotic rate −− Peripheral blood involvement

Microscopic (Lymph Node) ♦♦ Low power −− Architecture effaced −− Diffuse or vaguely nodular pattern (Fig. 15.15) −− Tumor may involve or expand mantle zones of some reactive follicles (pure mantle zone pattern less common) −− Hyalinized small capillaries in ~75% −− Scattered epithelioid histiocytes without tingible bodies common (starry-sky pattern on low power) −− Monotonous population of small to medium-sized lymphoid cells without proliferation centers, paraimmunoblasts, or transformed cells (Fig. 15.16) ♦♦ High power −− Neoplastic cells: round to irregular nuclei (+/− clefts), clumped chromatin, scant cytoplasm −− Few mitoses

Fig. 15.16. Mantle cell lymphoma.

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

sIg+ (M+/−D) Immunoglobulin light chain restricted (lambda > kappa) CD19, CD20, CD22, CD79a+ Cyclin D1+ (specific for MCL) CD5+, CD43+ CD23−, CD10−

Fig. 15.17. Mantle cell lymphoma, blastoid variant.

Genetics ♦♦ t(11;14)(q13;32) demonstrable in nearly 100% of cases by fluorescence in situ hybridization −− Translocation of CCND1 (bcl-1) oncogene (chromosome 11) into Ig heavy chain locus (chromosome 14) results in overexpression of cyclin D1 (bcl-1 [PRAD-1]) gene product-required for progression from G1 to S phase in cell cycle; not normally over-expressed in lymphoid cells ♦♦ Variable region genes unmutated in most cases, consistent with pre-germinal center B-cell derivation

Variants

Fig. 15.15. Mantle cell lymphoma.

♦♦ Blastoid type (Fig. 15.17) −− Composed of lymphoblast-like cells with dispersed chromatin, small nucleoli, and high mitotic rate (+/− starrysky pattern) −− May indicate progression/transformation

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♦♦ Pleomorphic variant −− May indicate progression/transformation

Differential Diagnosis ♦♦ CLL/SLL −− Proliferation centers −− Dim sIg expression, CD23+ −− Cyclin D1− ♦♦ Marginal zone B-cell lymphoma −− Parafollicular proliferation of monocytoid-like cells −− CD5 usually −, may be cIg+ (40%), CD43 usually −, CD23 may be + (<50%) −− Cyclin D1− ♦♦ Follicular lymphoma −− Follicular architecture, at least partially −− CD5−, CD10 and bcl-6 usually +, CD23 may be + (<50%) −− Cyclin D1− −− t(14;18) usually present ♦♦ Large B-cell lymphoma −− Larger cells, prominent nucleoli, mitoses common −− CD5−, CD43− −− Cyclin D1− ♦♦ Lymphoblastic lymphoma −− Lymphoblastic cytology, numerous mitoses −− TdT +, sIg− −− CD34 usually + −− Cyclin D1− −− T-cell antigen expression in most cases −− B-cell precursor phenotype in rare cases

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified Synonyms ♦♦ Rappaport: diffuse histiocytic, occasionally diffuse mixed lymphocytic–histiocytic ♦♦ Kiel: centroblastic, B-immunoblastic, large cell anaplastic (B-cell) ♦♦ Lukes–Collins: large cleaved or large noncleaved FCC, B-immunoblastic ♦♦ Working formulation: diffuse large cell cleaved, noncleaved, or immunoblastic, occasionally diffuse mixed small and large cell

Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

30–40% of all adult non-Hodgkin lymphomas Age: median seventh decade (wide age range) Sex: M > F (slight) Most arise de novo Some result from transformation of lower grade lymphoma (e.g., FL, CLL/SLL, or Hodgkin lymphoma [classic or lymphocyte predominant])

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♦♦ May occur in patients with AIDS ♦♦ Presentation −− Rapidly enlarging mass (up to 40% extranodal) −− 30% have B symptoms (fever, night sweats, or weight loss) −− Bone marrow involvement less frequent (10%) than in low grade lymphomas ♦♦ Clinical course −− Aggressive but potentially curable

Microscopic (Lymph Node) ♦♦ Low power −− Complete, partial, sinus, or interfollicular involvement −− Infiltration of perinodal tissue, sclerosis, necrosis (apoptosis or coagulative necrosis) common ♦♦ High power −− Variable cytology −− Large cells with vesicular nuclei, prominent nucleoli, cytoplasm variable −− Bizarre cells may be present −− Mitoses common

Immunophenotype −− −− −− −−

CD19, CD20, CD22, CD79a+ CD45 usually + May express CD10 (25–50%) or CD5 (10%) Bcl-2 expressed in 30–50% – associated with adverse disease-free survival

Genetics ♦♦ Bcl-2 gene (18q21) rearranged in 20% (e.g., t(14;18)) ♦♦ Bcl-6 gene (3q27) rearranged in 15–30%; point mutation in 70% ♦♦ Three different subtypes (germinal center B-cell-like, activated B-cell-like, and type 3) suggested by gene expression profiling

Differential Diagnosis ♦♦ Carcinoma −− CD45−, B-cell associated antigens –, keratin+ ♦♦ Malignant melanoma −− CD45−, B-cell associated antigens –, S100+, HMB45 usually + ♦♦ Hodgkin lymphoma (classic) −− Neoplastic (Hodgkin) cells larger with more prominent nucleoli −− CD45−, B-cell associated antigens− or weakly + in Hodgkin cell subset −− CD15 usually +, CD30 usually + −− Inflammatory background present ♦♦ Kikuchi–Fujimoto disease −− Zonation phenomenon, with karyorrhectic debris and phagocytic histiocytes in center, and immunoblasts, lymphocytes and plasmacytoid monocytes at periphery

Lymph Node

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♦♦ Atypical immunoblastic reaction (infections, mononucleosis, other viral infection, drug reaction, etc.) −− Partial preservation of lymph node architecture −− Large cells admixed with small lymphocytes and plasma cells −− Immunohistochemically, large cells are predominantly T-cells or mixture of T- and B-cells −− B-cell polyclonal

Variants ♦♦ WHO classification suggests that subclassifying large B-cell lymphoma is impractical (due to poor interobserver reproducibility) and irrelevant (as treatment is currently similar for all types) ♦♦ Centroblastic (Fig. 15.18) − − Composed of centroblasts (medium to large lymphoid cells with vesicular chromatin and multiple nucleoli) −− Monomorphous or polymorphous (may be multilobate) ♦♦ Immunoblastic (Fig. 15.19) −− >90% of cells are immunoblasts (single central nucleolus, ample basophilic cytoplasm) ♦♦ Anaplastic −− Large bizarre cells −− May grow in sheets and/or have sinusoidal growth pattern −− Unrelated to T-cell anaplastic large cell lymphoma

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Clinical ♦♦ Age: older adults (mean age 56 years) ♦♦ Sex: M > F (slight) ♦♦ Presentation −− Lymphadenopathy more common than extranodal involvement

Fig.  15.19. Diffuse large B-cell lymphoma, immunoblastic variant. −− Usually high stage at presentation (spleen, bone marrow involvement common)

Microscopic ♦♦ Low power −− diffuse architecture ♦♦ High power −− Neoplastic large B-cells associated with prominent reactive T-cell component (>75% of cell population) +/− histiocytes

Immunophenotype ♦♦ Small lymphocytes −− Mostly T-cells (immunologically normal) ♦♦ Large lymphoid cells −− React with B-cell markers; usually CD30−; light chain restricted (golgi or perinuclear staining)

Differential Diagnosis ♦♦ NLPHL −− Macronodular architecture −− L&H cells may be surrounded by CD57 + T-cells −− Follicular dendritic cells (CD21 +) may be prominent ♦♦ Other mature B-cell neoplasms ♦♦ ALCL ♦♦ Classic Hodgkin lymphoma ♦♦ Carcinoma ♦♦ Melanoma

Primary Mediastinal (Thymic) Large B-Cell Lymphoma Synonyms Fig. 15.18. Diffuse large B-cell lymphoma, centroblastic variant.

♦♦ Mediastinal large cell lymphoma with sclerosis ♦♦ Mediastinal clear cell lymphoma

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Clinical ♦♦ Age: young adults (median age fourth decade, mean 32 years) ♦♦ Sex: F > M (2:1) ♦♦ Presentation −− Locally invasive anterior mediastinal mass (derives from thymus) −− Superior vena cava (SVC) syndrome, cough, dyspnea, chest pain ♦♦ Relapses: extranodal (kidney, adrenal, liver, skin, brain, etc.)

Microscopic ♦♦ Thymus usually (if not always) involved ♦♦ Diffuse infiltrative growth into anterior mediastinal soft tissue ♦♦ Fine, compartmentalizing sclerosis common

Cytology ♦♦ Large cells with variable appearance ♦♦ Cells uniform to pleomorphic ♦♦ Nuclei round, elongate, folded, multilobated, or multi‑ nucleated ♦♦ Chromatin vesicular or granular, often with distinct nucleoli ♦♦ Moderate-abundant cytoplasm (formalin artifact) ♦♦ Associated small lymphocytes and histiocytes may be present

Immunophenotype ♦♦ sIg usually − ♦♦ CD19, CD20, CD22, CD79a+ −− CD45 usually + −− IRF4/MUM1 and CD23 often + ♦♦ CD30 usually − (may be weakly +) ♦♦ CD15 usually −; CD5−, CD10−

Genetics ♦♦ Ig heavy and light chains rearranged ♦♦ Molecular signature by gene expression profiling shares features with classic HL but differs from other DLBCL

Differential Diagnosis ♦♦ Thymic carcinoma −− More cohesive growth pattern, nuclei less irregular −− Keratin+, CD45− ♦♦ Classic Hodgkin lymphoma (e.g., syncytial variant of nodular sclerosis classic Hodgkin lymphoma) −− Larger neoplastic cells with prominent nucleoli −− Inflammatory background (eosinophils, neutrophils, plasma cells) −− CD15+, CD30+, CD45− ♦♦ Anaplastic large cell lymphoma −− Larger neoplastic cells with bizarre nuclei −− CD30+, ALK may be +, T-cell or null cell phenotype

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Seminoma −− Male predominance −− CD45−, PLAP (placental alkaline phosphatase) +

Burkitt Lymphoma Synonyms ♦♦ ♦♦ ♦♦ ♦♦

Rappaport: undifferentiated lymphoma, Burkitt type Kiel: Burkitt lymphoma Lukes–Collins: small noncleaved FCC Working formulation: small noncleaved cell, Burkitt type

Clinical ♦♦ Endemic (African) −− Age: young children (mean age 4–7 years) −− Sex: M > F (2–3:1) −− Geography: equatorial Africa (may be associated with both malaria and EBV) −− Majority (95%) are EBV-associated (clonally homogeneous EBV genomes present in tumor cells) −− Sites of involvement: extranodal (a) (b) (c) (d)

Jaws and other facial bones Ovary, testis, thyroid, salivary gland, kidney, CNS Bone marrow involvement rare (<10%) Lymph nodes and mediastinum spared

♦♦ Sporadic (nonendemic) −− Age: older children −− Sex: M > F −− Minority (<20%) associated with EBV −− Sites of involvement: extranodal (a) Abdominal cavity: intestine (especially terminal ileum, cecum, and mesentery), also stomach, peritoneum, and retroperitoneal tissue (b) Facial bones, ovary, testis, CNS, lymph nodes less common (c) Bone marrow involvement in 10–30% (d) Rarely presents as Burkitt leukemia (e) Mediastinal involvement infrequent ♦♦ Immunodeficiency associated (primarily associated with AIDS) −− Age: middle age −− Sex: M > F −− EBV+ in up to 50% −− Sites of involvement: extranodal (CNS, GI tract) −− Occurs early in course of AIDS ♦♦ Clinical course −− Aggressive but potentially curable ♦♦ Adverse prognostic indicators −− Large tumor bulk −− CNS or bone marrow involvement −− High pretreatment serum LDH

Lymph Node

Microscopic (Fig. 15.20) ♦♦ Low power −− Diffuse, infiltrative growth pattern −− Cells appear cohesive (jigsaw-puzzle-like appearance) −− Starry-sky pattern due to macrophages ingesting apoptotic tumor cells ♦♦ High power −− Monotonous population of medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm −− Numerous mitoses

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD19, CD20, CD22+ SIg+ (usually IgM) CD10 and bcl-6 usually + TdT−, CD34−, MPO−, cyclin D1− CD5−

Genetics ♦♦ 75–80%: t(8;14)(q24;q32) = translocation of c-myc (chr 8) to Ig heavy chain region (chr 14) ♦♦ 16%: t(8;22) = translocation of c-myc (chr 8) to Ig lambda light chain region (chr 22) ♦♦ 8%: t(2;8) = translocation of c-myc (chr 8) to Ig kappa light chain region (chr 2) ♦♦ Results in deregulation of myc gene leading to altered B-cell growth and differentiation

Differential Diagnosis ♦♦ Lymphoblastic lymphoma −− Mediastinum – most common site −− Blastic cytology (dispersed chromatin, inconspicuous nucleoli, scant cytoplasm) −− TdT+, sIg−, usually T-cell lineage ♦♦ Large B-cell lymphoma −− Uncommon in children −− Larger, more heterogeneous cells −− Fewer, more prominent nucleoli

Fig. 15.20. Burkitt lymphoma.

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♦♦ Myeloid sarcoma −− Eosinophilic cytoplasm −− Myeloperoxidase (MPO)+, lysozyme+, CD68+ −− CD34+, TdT may be + ♦♦ B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma −− Aggressive lymphoma with morphologic and genetic features of both DLBCL and BL (Fig. 15.21) ♦♦ B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma −− B-lineage lymphoma with overlapping features between DLBCL (especially primary mediastinal large B-cell lymphoma) and CHL

Mature T-Cell and NK-Cell Neoplasms T-Cell Prolymphocytic Leukemia Synonyms ♦♦ Rappaport: WDL, PDL ♦♦ Kiel: T-cell prolymphocytic leukemia/T-cell lymphocytic leukemia ♦♦ Lukes–Collins: small lymphocyte T, prolymphocytic ♦♦ Working formulation: small lymphocytic, consistent with CLL, diffuse small cleaved cell ♦♦ French-American-British (FAB): T-PLL ♦♦ REAL: T-cell chronic lymphocytic leukemia/prolymphocytic leukemia

Clinical ♦♦ 1–2% of all small lymphocytic leukemias −− Age: older adults −− Presentation: marked lymphocytosis (>100,000/mm3)

Fig. 15.21. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.

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−− Sites of involvement (a) Skin and mucosa (b) Bone marrow, spleen, liver, lymph nodes −− Clinical course (a) Aggressive (b) Median survival <1 year

Microscopic (Lymph Nodes)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Sites of Involvement −− Peripheral blood −− +/− Mild-moderate splenomegaly −− Bone marrow relatively spared −− No lymphadenopathy or hepatomegaly ♦♦ Clinical course −− Indolent

♦♦ Architecture −− Diffuse or paracortical involvement −− Pseudofollicles absent −− +/− Numerous prominent small vessels ♦♦ Cytology −− Morphologically similar to B-CLL, although nuclear contours usually more irregular and nucleoli often present −− “Small cell” variant – small cell size, nucleoli often not visible −− “Cerebriform” (Sézary cell-like) variant – very irregular nuclear contours

Microscopic

Immunophenotype

Genetics

♦♦ CD2, CD3, CD5, CD7+ ♦♦ CD4+ (65%) or CD4 and CD8+ (20%) or CD8+ (15%) ♦♦ TCL-1+

♦♦ T-cell lineage: T-cell receptor genes rearranged ♦♦ NK-cell lineage: Germline T-cell receptor genes ♦♦ Uniform expression of a single KIR isoform by flow cyto‑ metry can serve as a surrogate for clonality

Genetics ♦♦ T-cell receptor gene rearranged ♦♦ Inv 14(q11;q32) common

Differential Diagnosis ♦♦ All are positive for B-cell-associated antigens −− CLL/B-PLL −− MCL −− FL −− Marginal zone B-cell lymphoma

T-Cell Large Granular Lymphocytic Leukemia Synonyms ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Rappaport: SLL, CLL Kiel: T-CLL Lukes–Collins: small lymphocyte, T Working formulation: small lymphocytic, consistent with CLL FAB: T-CLL, T-LGL

Clinical ♦♦ Presentation −− Large granular lymphocytic (LGL) lymphocytosis (>1,000/mm3) −− Neutropenia +/− anemia −− May be associated with rheumatoid arthritis or + rheumatoid factor

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♦♦ Peripheral blood smear: lymphoid cells with round nuclei, rare nucleoli, and eccentric abundant pale blue cytoplasm with azurophilic granules ♦♦ Spleen: red pulp involvement, small lymphocytes, can be subtle

Immunophenotype ♦♦ CD2+, CD3+, CD8+; CD5 and CD7 often dim by flow cytometry ♦♦ CD16+, CD56−, CD57 sometimes + ♦♦ TIA-1+, granzyme B+

Aggressive NK-Cell Leukemia Clinical ♦♦ Rare overall (more common in Asia) ♦♦ Age: young adults ♦♦ Presentation: fever, hepatosplenomegaly +/− lymphadeno‑ pathy, leukemia blood picture +/− cytopenias ♦♦ Strongly associated with EBV ♦♦ Clinical course: aggressive/fulminant

Microscopic ♦♦ Peripheral blood −− Large granular lymphocytes with atypical features

Immunophenotype ♦♦ CD2+, CD56+ ♦♦ CD3− ♦♦ Cytotoxic granule-associated protein + (e.g., TIA-1, granzyme B) ♦♦ EBV usually +

Genetics ♦♦ T-cell receptor genes germline ♦♦ EBV commonly in clonal episomal form

Adult T-Cell Leukemia/Lymphoma (ATL/L) Synonyms ♦♦ Rappaport: diffuse PDL, mixed lymphocytic–histiocytic, or histiocytic

Lymph Node

♦♦ Kiel: pleomorphic small, medium, and large cell types (HTLV1+) ♦♦ Lukes–Collins: T-immunoblastic sarcoma ♦♦ Working formulation: diffuse small cleaved cell, mixed small and large cell, diffuse large cell, large cell immunoblastic ♦♦ REAL: adult T-cell lymphoma/leukemia

Clinical ♦♦ ♦♦ ♦♦ ♦♦

Age: adults All are HTLV-1+ Geography: Japan, Caribbean, Brazil; sporadic in USA Acute variant (most common) −− Presentation: marked lymphocytosis, hypercalcemia −− Sites of involvement: liver, spleen, lymph nodes, skin, bone marrow, bone (lytic bone lesions), lung, peripheral blood −− Clinical course: highly aggressive, rapidly fatal ♦♦ Lymphomatous variant −− Prominent lymphadenopathy, no leukemia phase −− Aggressive course ♦♦ Chronic variant −− Presentation: mild lymphocytosis, skin rashes −− Sites of involvement: lymph nodes, lung, skin, bone marrow, peripheral blood −− Clinical course: less aggressive, but may transform to acute phase ♦♦ Smoldering variant −− Skin or lung involvement, normal white blood cell count −− Less aggressive, but may transform to acute phase

Microscopic ♦♦ Peripheral blood: lymphoid cells with hyperlobated nuclei (“flower” cells) ♦♦ Lymph nodes −− Low power: diffuse involvement −− High power: markedly pleomorphic small and large lymphoid cells

Immunophenotype ♦♦ ♦♦ ♦♦ ♦♦

CD2, CD3, CD5+, CD7 usually − Most are CD4+ CD25+ FOXP3+

Genetics ♦♦ T-cell receptor genes rearranged ♦♦ HTLV-1 genomes present

Extranodal NK/T-Cell Lymphoma, Nasal Type Clinical ♦♦ Age: adults > children ♦♦ Geography: Asia and Latin America >> USA/Europe

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♦♦ Virtually all cases associated with EBV ♦♦ Sites of involvement: destructive nasal or midline facial tumor most common (“nasal NK/T-cell lymphoma”); may involve other extranodal sites (e.g., skin, soft tissue, testis, upper respiratory tract, gastrointestinal tract) ♦♦ May be complicated by hemophagocytic syndrome – adversely affects survival ♦♦ Treatment: radiotherapy and chemotherapy

Microscopic ♦♦ Low power: angiocentric/angioinvasive lymphoid infiltrate ♦♦ High power: broad cell spectrum: small, medium, and/or large atypical cells, any of which may predominate. A prominent inflammatory infiltrate may be present early in course of disease

Immunophenotype ♦♦ CD2 and CD56 usually + ♦♦ Surface CD3 (detected by monoclonal anti-CD3 antibodies) usually − (cytoplasmic CD3e, detected by polyclonal antiCD3 antibodies, often +) ♦♦ Other T-cell associated antigens including CD5 and CD7 occasionally + ♦♦ CD16, CD57 usually − ♦♦ Cytotoxic granule-associated proteins (TIA-1, granzyme B, perforin) usually +

Genetics ♦♦ EBV genome virtually always present, therefore in situ hybridization with probes to EBV-encoded small nuclear RNA may be helpful ♦♦ T-cell receptor and Ig genes usually germline

Enteropathy-Associated T-Cell Lymphoma Clinical ♦♦ Age: adults ♦♦ Most patients have history of gluten-sensitive enteropathy (celiac disease) ♦♦ Presentation: abdominal pain, jejunal perforation, peritonitis ♦♦ Clinical course: aggressive

Macroscopic ♦♦ Jejunal ulceration, often with perforation, +/− mass ♦♦ May be multifocal

Microscopic ♦♦ Ulcerated small bowel mucosa with underlying tumors +/− prominent inflammatory cells (histiocytes and eosinophils) ♦♦ +/− villous atrophy of adjacent small bowel mucosa ♦♦ EATL: varying proportions of small, medium, and/or large/ anaplastic atypical lymphoid cells ♦♦ Type II EATL: monotonous medium-sized cells

Immunophenotype ♦♦ EATL: CD3+, CD7+, CD103+, cytolytic granule-associated proteins +; CD5−, CD4−, CD8−/+

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♦♦ Type II EATL: CD3+, CD7+, CD8+, CD56+, cytolytic granule-associated proteins +; CD4−, CD5− ♦♦ Similar immunophenotype often seen in intraepithelial lymphocytes in adjacent mucosa

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Clinical course: aggressive ♦♦ Treatment: systemic chemotherapy

Microscopic (Fig. 15.22)

Age: young adults Sex: M > F Presentation: fever, cytopenias Sites of involvement: spleen, liver, bone marrow, +/− peripheral blood; lymph nodes spared ♦♦ Clinical course: highly aggressive, usually incurable with available therapy

♦♦ Low power −− Lymphoid infiltrate involving subcutaneous fat septae and lobules (+/− fat necrosis), +/− extension into deep dermis. Neoplastic cells frequently rim individual fat cells −− Epidermis and dermal appendages spared ♦♦ High power −− Neoplastic cells: variable mixture of small, medium, and large lymphoid cells, often very atypical, especially with progression of disease. Transmural vascular infiltrates may be present. Karyorrhexis common −− Background: Reactive histiocytes, +/− erythrophagocytosis (not necessarily indicative of clinical hemophagocytic syndrome)

Microscopic

Immunophenotype

Genetics ♦♦ T-cell receptor genes are clonally rearranged

Hepatosplenic T-Cell Lymphoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Architecture: splenic, hepatic, and bone marrow sinusoids involved ♦♦ Cytology: monotonous population of medium-sized round or folded lymphoid cells with abundant pale cytoplasm ♦♦ Cell may appear cohesive

♦♦ CD45+ ♦♦ CD2, CD3, CD43+, +/− aberrant absence of CD5 or CD7 ♦♦ Most are CD8+

Immunophenotype ♦♦ CD2, CD3, and CD7+, CD5 usually − ♦♦ CD4, CD8 usually − ♦♦ Most cases are gd T-cell receptor +; minority of cases are ab T-cell receptor +

Genetics ♦♦ Clonal rearrangement of T-cell receptor genes ♦♦ Iso (7q) common

Differential Diagnosis ♦♦ Hairy cell leukemia −− Older adults −− B-cell associated antigens+, T-cell associated antigens− −− CD103+, TRAP+

Subcutaneous Panniculitis-Like T-Cell Lymphoma Clinical ♦♦ Age: adults (median fifth decade, wide age range) ♦♦ Sex: F > M (slight) ♦♦ Presentation: Multiple red, painless, deep subcutaneous nodules, +/− ulceration ♦♦ Sites of involvement: Subcutaneous tissue (lower extremities > upper extremities > trunk) ♦♦ May be associated with systemic B symptoms ♦♦ May be complicated by hemophagocytic syndrome – frequently fatal

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Fig. 15.22. Subcutaneous panniculitis-like T-cell lymphoma (A, B).

Lymph Node

♦♦ Cytotoxic granule associated proteins (Tia-1, granzyme B, perforin)+ ♦♦ Most are αβ T-cell receptor+

Genetics ♦♦ T-cell antigen receptor genes usually rearranged

Differential Diagnosis ♦♦ Mycosis fungoides/Sezary syndrome −− Involves dermal-epidermal junction – rarely extends to subcutaneous tissue −− Histiocytic infiltrate absent ♦♦ Granulomatous slack skin syndrome (variant of cutaneous T-cell lymphoma) −− Extensive dermal granulomas, few atypical lymphoid cells −− Subcutaneous tissue spared ♦♦ FL −− B-cell process ♦♦ Infectious panniculitis −− Neutrophilic (bacterial/fungal) or granulomatous (mycobacterial) inflammation of fat septae and lobules; atypical lymphoid cells are rare/absent ♦♦ Erythema nodosum −− Involves fat septae, not lobules. Ulceration absent −− Mixed inflammatory infiltrate (lymphocytes, histiocytes, giant cells, neutrophils) −− Heals spontaneously in 3–6 weeks ♦♦ Erythema induratum −− Involves fat septae and lobules, and may cause medium and small-vessel vasculitis, but transmural vascular inflammation is mixed (neutrophils, histiocytes, giant cells); atypical lymphoid cells rare/absent ♦♦ Cutaneous γδ T-cell lymphoma −− Can involve dermis and epidermis as well as subcutaneous tissue −− CD56+, γδ-T-cell receptor + −− Usually negative for CD4 and CD8

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−− SS: diffuse skin involvement (erythroderma) with prominent peripheral blood involvement −− Lymph node and visceral organ (lung, liver, spleen) involvement occurs late in course of disease ♦♦ Clinical course −− MF: prognosis correlates with clinical stage −− SS: aggressive −− May eventually transform to LCL (ALCL-like)

Microscopic (Fig. 15.23) ♦♦ Skin: band-like infiltrate at dermal-epidermal junction, epidermal infiltration (Pautrier microabscesses) ♦♦ Lymph nodes: paracortical involvement initially, later becomes diffuse ♦♦ Cytology: predominantly small (and a minority of large) atypical lymphoid cells with convoluted, “cerebriform” nuclei associated with intermixed, nonneoplastic Langerhans cells

Immunophenotype ♦♦ CD2, CD3, CD5+, often CD7− (other combinations of “aberrant” phenotypes may be seen) ♦♦ Usually CD4+

Mycosis Fungoides/Sézary Syndrome Synonyms ♦♦ ♦♦ ♦♦ ♦♦

Rappaport: mycosis fungoides/Sezary syndrome Kiel: small cell, cerebriform Lukes–Collins: cerebriform T Working formulation: mycosis fungoides

Clinical ♦♦ Age: adults (median age 55 years) ♦♦ Sex: M > F (2:1) ♦♦ Sites of involvement −− MF: multifocal skin lesions (patch, plaque, and tumor stages), +/− subtle peripheral blood involvement

Fig. 15.23. Mycosis fungoides (A, B).

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Genetics ♦♦ T-cell receptor genes clonally rearranged

Differential Diagnosis ♦♦ Skin −− Inflammatory dermatoses with lichenoid pattern of skin involvement (e.g., drug eruption, autoimmune diseases, actinic reticuloid, etc.) −− Lymphomatoid papulosis −− Other malignant lymphomas ♦♦ Lymph nodes −− Dermatopathic lymphadenopathy – normal T-cell phenotype, polyclonal T-cell receptor genes −− Other malignant lymphomas

Angioimmunoblastic T-Cell Lymphoma Synonyms ♦♦ Rappaport: not listed (diffuse mixed lymphocytic–histiocytic, histiocytic) ♦♦ Kiel: T-cell, angioimmunoblastic (AILD) ♦♦ Lukes–Collins: immunoblastic lymphadenopathy-like T-cell lymphoma ♦♦ Working formulation: not listed (diffuse mixed small and large cell, diffuse large cell, large cell immunoblastic)

Clinical ♦♦ Age: adults (middle-age to elderly) ♦♦ Sex: M = F ♦♦ Presentation: fever, weight loss, skin rash, polyclonal hypergammaglobulinemia ♦♦ Sites of involvement: lymph nodes (generalized lympha­ denopathy) ♦♦ Clinical course −− Moderately aggressive, may respond to treatment −− Prone to infectious complications

Microscopic (Fig. 15.24) ♦♦ Architecture: paracortical to diffuse involvement; loss of germinal centers; sinuses open; tumor may invade perinodal fat ♦♦ Cytology: tumor composed of lymphoid cells including medium-sized cells with round nuclei and abundant clear cytoplasm, in background of small lymphocytes and immunoblasts, +/− epithelioid histiocytes, eosinophils, and/or plasma cells ♦♦ Follicular dendritic cell clusters surrounding arborizing high endothelial venules often prominent

Immunophenotype ♦♦ T-cell associated antigens+ ♦♦ CD4 usually + ♦♦ Follicular dendritic cells CD21 +

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Fig. 15.24. Angioimmunoblastic T-cell lymphoma (A, B). ♦♦ Neoplastic T-cells often have the phenotype of normal follicular helper T-cells (CD10+, CXCL13+, PD-1+) ♦♦ EBV+ B-cells usually present

Genetics ♦♦ T-cell receptor genes usually rearranged ♦♦ Ig heavy chain genes occasionally rearranged (10–30%) ♦♦ Trisomy 3, trisomy 5 may be present

Peripheral T-Cell Lymphoma, Not Otherwise Specified Synonyms ♦♦ Rappaport: diffuse PDL, diffuse mixed lymphocytic– histiocytic, histiocytic ♦♦ Kiel: T-zone lymphoma, lymphoepithelioid cell lymphoma, pleomorphic, small, medium, and large cell, T-immuno‑ blastic ♦♦ Lukes–Collins: T-immunoblastic lymphoma ♦♦ Working formulation: diffuse mixed small and large cell, large cell immunoblastic (polymorphous or clear cell)

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Clinical ♦♦ Age: adults ♦♦ Presentation: +/− eosinophilia, pruritus, or hemophagocytic syndrome ♦♦ Sites of involvement: lymph nodes, skin, subcutis, liver, spleen ♦♦ Clinical course: aggressive, usually incurable

Microscopic (Lymph Nodes) ♦♦ Architecture: paracortical or diffuse involvement ♦♦ Cytology (Fig. 15.25) −− Cell spectrum characterizes PTCL: small, medium, and large lymphocytes −− Nuclear irregularity and hyperchromasia in small and medium-sized cells −− Prominent nucleoli, dispersed chromatin, abundant clear cytoplasm in large cells −− Variable number of eosinophils and/or epithelioid histiocytes may be present −− Vascular proliferation may be seen

Variants ♦♦ T-zone variant −− Interfollicular growth pattern −− Small to medium-sized tumor cells with little pleomorphism, +/− clusters of clear cells −− Prominent high endothelial venules −− Abundant reactive cells (eosinophils, plasma cells, histiocytes) ♦♦ Lymphoepithelial cell variant (Lennert lymphoma) (Fig. 15.26) −− Diffuse growth pattern −− Small tumor cells with little pleomorphism −− Prominent clusters of epithelioid histiocytes

Fig. 15.26. Peripheral T-cell lymphoma, lymphoepithelial cell variant (Lennert lymphoma).

Immunophenotype ♦♦ Aberrant T-cell phenotypes, defined by loss of a pan-T-cell antigen from a cell population, are frequent. Antigens absent: CD7 (75%), CD5 (50%), CD3 (10%), CD2 (10%) ♦♦ CD4 + more commonly than CD8 ♦♦ Usually lacks follicular T helper phenotype (i.e., tumor cells usually CD10−, BCL6−, CXCL13−, PD1−) ♦♦ B-cell associated antigens−

Genetic Features ♦♦ T-cell receptor genes usually clonally rearranged

Anaplastic Large Cell Lymphoma Synonyms ♦♦ ♦♦ ♦♦ ♦♦

Rappaport: not listed (histiocytic, diffuse) Kiel: large cell anaplastic Lukes–Collins: T-immunoblastic sarcoma Working formulation: not listed (diffuse large cell, immunoblastic) ♦♦ Other: malignant histiocytosis, sinusoidal large cell lymphoma, regressing atypical histiocytosis, Ki-1 lymphoma

Clinical

Fig. 15.25. Peripheral T-cell lymphoma, not otherwise specified.

♦♦ Presentation: advanced stage disease, +/− B symptoms ♦♦ Sites of involvement: lymph nodes and extranodal sites (soft tissue, skin, bone, etc.) ♦♦ Age: bimodal −− Children/young adults: usually ALK+ (see genetic features below) −− Older adults: usually ALK− (see genetic features below) ♦♦ Better prognosis: ALK+ (median survival 14 years) ♦♦ Poorer prognosis: ALK − (median survival 3 years)

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Microscopic (common variant) ♦♦ Architecture −− Diffuse involvement, often with infiltration of sinuses −− Cohesive growth pattern common ♦♦ Cytology (Fig. 15.27) −− Very large pleomorphic cells with embryoid nuclei, multiple prominent nucleoli, and abundant cytoplasm −− +/− background of granulocytes and macrophages

Immunophenotype (Table 15.5) ♦♦ CD30+ (cell membrane and Golgi staining) ♦♦ Tumor usually + for at least one T-cell antigen (CD2 and CD4 more often + than CD3, CD5, or CD7) ♦♦ CD45 usually + ♦♦ CD43, CD45RO often +

♦♦ EMA usually + in ALK+ cases, EMA usually − in ALK– cases ♦♦ Fascin usually negative

Genetics ♦♦ ALK+ cases: genetic alterations of ALK locus −− t(2;5)(p23;q35)− most frequent translocation ⇒ juxtaposition of nucleophosmin (NPM) gene on chromosome 5 and anaplastic lymphoma kinase (ALK) gene on chromosome 2 ⇒ hybrid NPM-ALK gene expressed −− ALK antibody: detects ALK gene product (a) Cytoplasmic and nuclear staining associated with t(2;5) (b) Cytoplasmic or membranous staining with variant translocations – e.g., t(1;2), t(2;3), t(2;17), inv(2) −− ALK positivity associated with younger patients, EMA positivity, and better prognosis −− EBV genome absent ♦♦ ALK− cases −− Genetic alterations of ALK locus absent −− ALK negativity associated with older patients, EMA nega‑ tivity, and poorer prognosis, or with primary cutaneous ALCL −− T-cell receptor gene rearranged in ~90% of cases, regardless of expression of T-cell antigens

Morphologic Variants ♦♦ Lymphohistiocytic variant −− Infrequent smaller neoplastic cells and rare cells with bilobed nuclei in histiocytic background. Histiocytes have peculiar plasmacytoid cytology with eccentric round nuclei and abundant pink cytoplasm with perinuclear clearing ♦♦ Small cell variant −− Small to medium-sized neoplastic cells, often surrounding blood vessels

Fig. 15.27. Anaplastic large cell lymphoma.

Differential Diagnosis Table 15.5. Immunophenotypic Distinction Between Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma Marker CD30 CD45 CD15 PAX-5 Fascin CD43 CD45RO CD3 (paraffin) EMA ALK-1 CD20

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Anaplastic large cell lymphoma

Hodgkin lymphoma

+ (Strong, all cells) +/− − − − + (70%) + (50%) + (50%) +/− + (50%) −

+ − + (80%) + (weak) + − − − − − −/+

♦♦ ♦♦ ♦♦ ♦♦

Carcinoma: keratin+, CD45− Malignant melanoma: S-100+, HMB45 usually +, CD45− Sarcoma: Vimentin+, CD45− Classic Hodgkin lymphoma: CD15+, CD45−, EMA−, ALK−

Hodgkin Lymphoma Nodular Lymphocyte Predominant Hodgkin Lymphoma Synonyms ♦♦ Lukes et  al: lymphocytic and/or histiocytic, nodular, lymphocytic and/or histiocytic, diffuse (some cases) ♦♦ Lennert and Mohri: paragranuloma, nodular or diffuse

Clinical ♦♦ Age: median mid 30s (wide age range) ♦♦ Sex: male > female (2.5:1)

Lymph Node

♦♦ Presentation −− Localized involvement of peripheral lymph nodes (usually cervical, supraclavicular, axillary); mediastinum spared −− 70–80% present at stage I or II ♦♦ Better prognosis: younger patients, presentation at low stage ♦♦ Poorer prognosis: older patients, presentation at high stage ♦♦ Occasionally preceded, accompanied, or succeeded by progressive transformation of germinal centers (PTGC) ♦♦ Clinical course −− Vast majority have complete response to therapy −− May relapse or develop other lymphoma, especially large B-cell lymphoma

Microscopic (Fig. 15.28) ♦♦ Low power −− Macronodules (may be highlighted by immunostains, particularly CD21, which stains follicular dendritic cells), +/− diffuse areas, often with rim of uninvolved lymph node

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♦♦ High power −− Neoplastic cells (a) L&H cells (lymphocytic and/or histiocytic Reed– Sternberg [RS] cell variants; also called popcorn cells) may be numerous: large cells with multilobated vesicular nuclei, delicate chromatin, small nucleoli, and scant wispy cytoplasm (b) Classic RS cells rare or absent −− Background cells (a) Lymphocytes (polyclonal, mostly B-cells) and groups of epithelioid histiocytes (b) L&H cells may be surrounded by CD57+ T-cells (c) Follicular dendritic cells (CD21+) often prominent (d) Rare plasma cells, eosinophils, or neutrophils

Immunohistochemistry ♦♦ L&H cells −− CD45+ −− CD19, CD20, CD22, CD79a+, PAS-5+ −− CD15−, CD30 usually − −− EMA usually + −− May be kappa light chain restricted

Genetics ♦♦ Whole tissue DNA: polyclonal ♦♦ DNA isolated from individually selected L&H cells: usually monoclonal Ig gene rearrangements

Differential Diagnosis

Fig.  15.28. Nodular lymphocyte predominant Hodgkin lymphoma (A, B).

♦♦ Progressive transformation of germinal enters (PTGC) −− L&H cells have nuclear lobulation, centroblasts usually do not −− Centroblasts are EMA− ♦♦ Classic Hodgkin lymphoma, especially lymphocyte-rich type −− Neoplastic cells are classic RS cells morphologically and immunohistochemically (CD15+, CD30+, CD45−, B-cell-associated antigens−) ♦♦ FL, especially floral variant −− Lymph node architecture usually completely obliterated −− Follicles/nodules composed predominantly of neoplastic B-cells (e.g., few normal lymphocytes or epithelioid histiocytes) −− Intrafollicular lymphocytes are bcl-2+, monoclonal sIg ♦♦ Large B-cell lymphoma, T-cell/histiocyte-rich variant −− Diffuse architecture −− Tumor cells may be arranged in clusters, without being surrounded by rosettes of CD57+ T-cells −− No intermixed CD21 + FDCs −− Tumor cells often show monoclonal sIg

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Classic Hodgkin Lymphoma Nodular Sclerosis Hodgkin Lymphoma Clinical ♦♦ Age: young adults ♦♦ Sex: F > M (slight) ♦♦ Sites of involvement: lower cervical, supraclavicular, and anterior mediastinal lymph nodes are most common ♦♦ Poorer prognosis: higher stage, greater bulk of disease ♦♦ Clinical course: often curable (95% of patients presenting at stage I and II, 50–70% of patients present at stage III and IV)

Microscopic (Fig. 15.29) ♦♦ Low power −− Nodular pattern with fibrous band separating nodules, +/− diffuse areas, +/− necrosis −− May be interfollicular ♦♦ High power −− Hodgkin and Reed–Sternberg (HRS)

Essentials of Anatomic Pathology, 3rd Ed.

(a) Lacunar cells (RS cell variants) common: multilobated nuclei, small nucleoli, abundant pale cytoplasm that retracts with formalin fixation (b) Classic RS cells may be rare −− Background cells (a) Lymphocytes (mostly T-cells), eosinophils, histiocytes, plasma cells, neutrophils (associated with B symptoms), and fibroblasts (b) Broad range of appearances depending on relative contribution from different cell populations and degree of sclerosis. Hodgkin lymphoma (HL) is classified as NS type whenever there are collagen bands and lacunar cells, regardless of all else

Immunophenotype ♦♦ HRS cells −− CD30+ −− Usually CD15+ (paranuclear, cytoplasmic, and/or membranous staining pattern), at least in a subset of HRS cells −− CD45− −− Pax-5+ −− CD20−/+ −− T-cell associated antigens usually– −− ALK– −− Fascin usually+

Genetics ♦♦ Whole tissue DNA: polyclonal ♦♦ DNA isolated from isolated single HRS cells: usually monoclonal Ig gene rearrangements

NSHL Grading, BNLI (British National Lymphoma Investigation) Criteria ♦♦ Grade 1 −− Scattered RS cells in mixed inflammatory background in >75% of nodules ♦♦ Grade II −− Sheets of RS cells on ≥25% of nodules (syncytial variant of NSHL) ♦♦ Prognostic significance of grading NSHL is controversial

Mixed Cellularity Hodgkin Lymphoma Clinical ♦♦ Age: adults (wide age range) ♦♦ Sex: M > F ♦♦ Presentation: higher stage (lymph nodes, spleen, liver, bone marrow often involved)

Microscopic

Fig. 15.29. Nodular sclerosis Hodgkin lymphoma (A, B).

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♦♦ Architecture −− Diffuse or vaguely nodular −− Lymph node capsule intact −− No broad bands of fibrosis −− May be interfollicular

Lymph Node

♦♦ Cytology −− HRS cells (a) Classic RS cells common: large cells with large single or multiple nuclei that often have more than one lobe, a single prominent eosinophilic nucleolus per lobe, and abundant cytoplasm −− L&H cells, lacunar cells absent −− Background cells (a) Lymphocytes, epithelioid histiocytes, eosinophils, neutrophils, and plasma cells

Immunophenotype ♦♦ HRS cells −− CD30+ −− Usually CD15+ (paranuclear, cytoplasmic, and/or membranous staining pattern) −− CD45− −− Pax-5+ −− CD20−/+ −− T-cell associated antigens usually− −− EMA− −− ALK-1−

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−− T-cell-associated antigens usually − −− EMA−, ALK-1−

Differential Diagnosis ♦♦ NLPHL −− Immunophenotyping essential to make distinction

Lymphocyte Depleted Hodgkin Lymphoma Clinical ♦♦ RARE ♦♦ Age: older adults ♦♦ Also seen in HIV+ patients and patients from developing countries ♦♦ Sites of involvement: abdominal lymph nodes, spleen, liver, bone marrow ♦♦ Extranodal sites involved in HIV+ individuals (usually EBV+) ♦♦ Presentation: high stage

Microscopic (Fig. 15.30) ♦♦ Architecture −− Depleted appearance with disorganized collagen

Differential Diagnosis ♦♦ Large B-cell lymphoma, T-cell/histiocyte-rich type −− Immunophenotyping essential to make distinction

Lymphocyte-Rich Classic Hodgkin Lymphoma Clinical ♦♦ Age: adults ♦♦ Sex: M > F ♦♦ Presentation: lymphadenopathy; usually lower stage (I or II)

Microscopic ♦♦ Architecture −− Nodular or diffuse involvement ♦♦ Cytology −− Neoplastic cells: infrequent classic RS cells, +/− lacunar variants −− Background cells: numerous lymphocytes with occasional histiocytes, eosinophils, or plasma cells

Immunophenotype ♦♦ HRS cells −− CD30+ −− CD15+ (paranuclear, cytoplasmic, and/or membranous staining pattern) −− CD45− −− Pax-5+ −− CD20−/+

Fig. 15.30. Lymphocyte depleted Hodgkin lymphoma (A, B).

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♦♦ Cytology −− Innumerable RS cells, bizarre multinucleated cells and RS cell variants of no special type −− Minimal reactive elements

Immunophenotype ♦♦ HRS cells −− CD30+ −− Usually CD15+ (paranuclear, cytoplasmic, and/or membranous staining pattern) −− Fascin usually positive −− CD45− −− Pax-5+

−− CD20+/− −− T-cell associated antigens usually − −− EMA−, ALK-1−

Differential Diagnosis ♦♦ Diffuse large B-cell lymphoma −− CD45+ −− B-cell associated antigens+ −− CD15, CD30− ♦♦ Anaplastic large cell lymphoma −− CD45+, EMA+, ALK-1+ −− CD15− −− T-cell-associated antigens often +

HISTIOCYTIC AND DENDRITIC CELL LYMPH NODE TUMORS Langerhans Cell Histiocytosis Synonyms ♦♦ Langerhans cell granulomatosis ♦♦ Histiocytosis X

Electron Microscopy ♦♦ Langerhan cells contain Birbeck granules (racket- or rodshaped structures with osmiophilic core and double outer sheath)

Clinical

Langerhans Cell Sarcoma

♦♦ Age: children ♦♦ Sex: M > F ♦♦ Presentation: unifocal disease (solitary eosinophilic granuloma), multifocal unisystem disease (previously called Hand– Schuller–Christian syndrome), or multifocal multisystem disease (previously known as Letterer–Sewe syndrome) ♦♦ Sites of involvement −− Lymph nodes or other organs (skin, bone, lungs, etc.) ♦♦ Prognosis: related to number of affected organs at presentation

♦♦ High grade neoplasm with malignant cytologic features and a Langerhans cell immunophenotype

Microscopic ♦♦ Sinuses distended by Langerhans cells (mononuclear cells with fine chromatin, nuclear grooves, moderate eosinophilic cytoplasm) ♦♦ Background cells −− +/− Eosinophils, which may form microabscesses −− +/− Mononuclear and multinuclear histiocytes −− +/− Neutrophils and lymphocytes

Immunophenotype ♦♦ Langerhan cells −− S-100 protein + −− CD1a+ −− Langerin+ −− PLAP (placental alkaline phosphatase) usually +

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Sinus Histiocytosis with Massive Lymphadenopathy Synonym ♦♦ Rosai–Dorfman disease

Clinical ♦♦ Age: mean age 20 years (wide age range) ♦♦ Sex: M > F (slight) ♦♦ Sites of involvement −− Bilateral cervical lymphadenopathy most common; may involve other lymph nodes or other sites (e.g., skin, upper respiratory tract, bone) ♦♦ Clinical course: most cases spontaneously regress

Microscopic (Fig. 15.31) ♦♦ Capsular fibrosis ♦♦ Sinuses distended by large histiocytes containing intact intracytoplasmic lymphocytes as well as intracytoplasmic plasma cells and erythrocytes (“emperipolesis”) ♦♦ Medullary cords contain numerous plasma cells

Immunohistochemistry ♦♦ Histiocytes: S-100+, CD68+, CD1a−

Lymph Node

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♦♦ Negative for myeloid markers (myeloperoxidase, CD33, etc.), B-cell markers, and T-cell markers ♦♦ Negative for Langerhans cell markers (CD1a, Langerin) ♦♦ Negative for follicular dendritic cell markers (CD21, CD35) ♦♦ CD45 may be +

Differential Diagnosis ♦♦ Diffuse large B-cell lymphoma: CD20+ ♦♦ Carcinoma: keratin+ ♦♦ Melanoma: S-100, HMB-45+; may be CD68+; CD45 and lysozyme−

Blastic Plasmacytoid Dendritic Cell Neoplasm Synonyms ♦♦ Blastic NK-cell lymphoma ♦♦ Agranular CD4+ natural killer cell leukemia ♦♦ Agranular CD4+CD56+ hematodermic neoplasm

Clinical ♦♦ Rare overall ♦♦ Age: middle-aged to elderly ♦♦ Sites: skin, lymph node, soft tissue, peripheral blood/bone marrow ♦♦ Clinical course: aggressive

Microscopic ♦♦ Monotonous infiltrate of blast-like cells

Immunophenotype Fig. 15.31. Sinus histiocytosis with massive lymphadenopathy (A, B).

Histiocytic Sarcoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

RARE Age: adults; wide age range Sites of involvement: lymph nodes, skin, extranodal sites Clinical course: aggressive

Microscopic ♦♦ Low power −− Diffuse proliferation of large atypical cells ♦♦ High power −− Large pleomorphic cells with ample eosinophilic cytoplasm, +/− reactive cells (small lymphocytes, eosinophils, benign histiocytes)

Immunophenotype ♦♦ Positive for histiocytic markers (CD68, CD163, lysozyme, CD11c, CD14)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

CD56+, CD4+, CD123+, TCL1+, CD43 + CD3−, myeloperoxidase−, CD33− EBV− TdT may be + Extensive phenotyping required to exclude AML and T-Lymphoblastic Leukemia/Lymphoma (T-ALL/T-LBL)

Genetics ♦♦ Germline T-cell receptor genes

Interdigitating Dendritic Cell Sarcoma Microscopic ♦♦ Histologic spectrum from spindle cells to rounder, lymphoidlike cells

Immunophenotype ♦♦ S-100+, CD68, fascin usually + ♦♦ Clusterin, langerin, CD1a negative ♦♦ CD21−, CD35−

Follicular Dendritic Cell Sarcoma Microscopic ♦♦ Partial to complete replacement of lymph node

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♦♦ Fascicles and nests of oval to spindle shaped cells with bland vesicular nuclei, inconspicuous nucleoli, and pale cytoplasm ♦♦ Few mitoses ♦♦ Scattered small lymphocytes present

Immunophenotype ♦♦ CD21, CD35, clusterin usually + ♦♦ CD68 usually + ♦♦ S-100 usually −

SPINDLE CELL LESIONS OF LYMPH NODES Bacillary Angiomatosis Clinical

Etiologic Agent

♦♦ ♦♦ ♦♦ ♦♦

Microscopic

Etiologic agent: Bartonella henselae Patients are immunosuppressed (especially AIDS) Sites of involvement: skin, lymph nodes, spleen Treatment: antibiotics

Microscopic ♦♦ Multiple nodules composed of proliferating vessels lined by plump, +/− pleomorphic endothelial cells with pale, vacuolated cytoplasm ♦♦ Interstitium contains distinctive eosinophilic granular material (=aggregates of bacilli), +/− neutrophils ♦♦ +/− Foamy macrophages, granulomas, or peliotic spaces ♦♦ Bacilli+ on Warthin–Starry stain and Giemsa stain (less sensitive) ♦♦ Bartonella DNA can be detected in tissue sections by PCR

Differential Diagnosis ♦♦ Epithelioid hemangioma/hemangioendothelioma −− Cells have eosinophilic cytoplasm without vacuoles −− No extracellular granular material made up of aggregates of bacilli, Warthin–Starry stain − ♦♦ Kaposi sarcoma −− Based in lymph node capsule −− Fascicles of spindle cells present −− Warthin–Starry stain − for bacilli

Kaposi Sarcoma Clinical ♦♦ Classic: most common presentation is lower extremity skin lesions in elderly Jewish or Mediterranean men. Indolent clinical course ♦♦ African (endemic): Equatorial Africa −− Cutaneous: most common in young men; uncommon regional lymph node involvement −− Lymphadenopathic: most common in children, M > F; localized or generalized lymphadenopathy. Aggressive clinical course ♦♦ Epidemic: common in HIV+ patients, especially gay men. Involves lymph nodes, mucocutaneous sites, gastrointestinal tract, lung

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♦♦ Human herpes virus 8 (HHV8) ♦♦ Low power −− Single or multiple nodules, or extensive replacement of lymph node −− Capsular/subcapsular involvement ♦♦ High power −− Fascicles of spindle cells with vascular slits containing extravasated red blood cells −− Mitoses common −− +/− lymphocytes, plasma cells, histiocytes, and hemosiderin deposits −− Eosinophils hyalin globules (PAS-D+) often seen within spindle cells or histiocytes

Immunophenotype ♦♦ CD31+, CD34+, Factor VIII+/− ♦♦ Actin−

Differential Diagnosis ♦♦ Vascular transformation of lymph node sinuses −− Capsule spared, distinct vascular channels, no PAS+ hyaline globules ♦♦ Inflammatory pseudotumor of lymph node −− No vascular slits, no PAS+ hyaline globules −− Follicular hyperplasia and plasmacytosis are prominent ♦♦ Palisaded myofibroblastoma −− No vascular slits, no PAS+ hyalin globules −− Actin+, Factor VIII− ♦♦ Epithelioid hemangioma/hemangioendothelioma ♦♦ Bacillary angiomatosis −− No spindle cell fascicles; bacilli Warthin–Starry + −− Positive for Bartonella DNA by PCR

Palisaded Myofibroblastoma Synonym ♦♦ Hemorrhagic spindle cell tumor with amianthoid fibers

Clinical ♦♦ Age: wide age range

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♦♦ Sex: M > F (slight) ♦♦ Location: inguinal lymph nodes most common; cervical, mediastinal nodes rare ♦♦ Clinical course: benign; no local recurrences or metastases

Microscopic ♦♦ Short fascicles of bland spindle cells (+/− perinuclear vacuoles), palisaded nuclei ♦♦ Intersitial hemorrhage and/or hemosiderin ♦♦ Stellate foci of collagen (amianthoid-like fibers) ♦♦ Periphery of tumor often hemorrhagic, with compressed rim of residual lymph node ♦♦ Mitoses rare

♦♦ Follicular dendritic cell sarcoma −− Nests of plumper cells; no amianthoid-like fibers or hemorrhage; CD21, CD35+

Inflammatory Pseudotumor of Lymph Node Clinical ♦♦ Age: young adults ♦♦ Presentation: lymphadenopathy (superficial or deep), often with constitutional symptoms ♦♦ Treatment: excision of node is often curative

Macroscopic

Immunophenotype

♦♦ Enlarged lymph node(s), may be matted

♦♦ Actin+, Vimentin+ ♦♦ Desmin−, S-100−, Factor VIII−

Microscopic

Differential Diagnosis ♦♦ Kaposi sarcoma −− Lymph node capsule based −− Red cells within vascular slits; PAS+ hyaline globules common; CD31, CD34+ ♦♦ Intranodal schwannoma −− Distinct Antoni A and B areas; S-100+ ♦♦ Vascular transformation of lymph node sinuses ♦♦ Inflammatory pseudotumor of lymph nodes

♦♦ Proliferation of spindle cells (histiocytes and fibroblasts) and blood vessels, with acute and chronic inflammation and sclerosis ♦♦ Primarily involves hilum, trabeculae, and capsule

Differential Diagnosis ♦♦ Kaposi sarcoma −− Vascular slits and PAS+ hyaline globules present −− Sclerosis less prominent ♦♦ Castleman disease ♦♦ Hodgkin lymphoma

SUGGESTED READING General Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361–1392. Jaffe ES, Harris NL, Stein H, Isaacson PG. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood 2008;112:4384–4399. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer, 2008 Warnke RA, Weiss LM, Chan JKC, Cleary ML, Dorfman RF. Atlas of tumor pathology: tumors of the lymph nodes and spleen. Washington, DC: Armed Forces Institute of Pathology, 1994.

Lymphoid Hyperplasia Abbondanzo SL, Irey NS, Frizzera G. Dilantin-associated lymphadenopathy: spectrum of histopathologic patterns. Am J Surg Pathol 1995;19:675–686. Campbell JAH. Cat-scratch disease. Pathol Annu 1977;12:277–292. Childs CC, Parham DM, Berard CW. Infectious mononucleosis: the spectrum of morphologic changes simulating lymphoma in lymph nodes and tonsils. Am J Surg Pathol 1987;11:122–132.

Dorfman RF, Warnke R. Lymphadenopathy simulating the malignant lymphomas. Hum Pathol 1974;5:519–549. Epstein JI, Ambinder RF, Kuhajda FP, Pearlman SH, Reuter VE, Mann RB. Localized herpes simplex lymphadenitis. Am J Clin Pathol 1986;86:444–448. Ewing EP, Chandler FW, Spira TJ, Brynes RK, Chan WC. Primary lymph node pathology in AIDS and AIDS-related lymphadenopathy. Arch Pathol Lab Med 1985;109:977–981. Frizzera G. Castleman’s disease and related disorders. Semin Diagn Pathol 1988;5:346–364. Hartsock RJ. Postvaccinial lymphadenitis: hyperplasia of lymphoid tissue that simulates malignant lymphomas. Cancer 1968;21: 632–649. Miller-Catchpole R, Variakojis D, Vardiman JW, Loew JM, Carter J. Cat scratch disease: identification of bacteria in seven cases of lymphadenitis. Am J Surg Pathol 1986;10:276–281. Nosanchuk JS, Schnitzer B. Follicular hyperplasia in lymph nodes from patients with rheumatoid arthritis: a clinicopathologic study. Cancer 1969;24:343–354. Pinder SE, Colville A. Mycobacterial cervical lymphadenitis in children: can histological assessment help differentiate infections caused by non-tuberculous mycobacteria from Mycobacterium tuberculosis? Histopathology 1993;22:59–64.

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De Bruin PC, Kummer A, van der Valk P, van Heerde P, Kluin PM, Willemze R, Ossenkoppele GJ, Radaszkiewicz T, Meijer JLM. Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localization. Blood 1994;84:3785–3791.

Stanley MW, Frizzera G. Diagnostic specificity of histologic features in lymph node biopsy specimens from patients at risk for the acquired immunodeficiency syndrome. Hum Pathol 1986;17:1231–1239. Turner RR, Levine AM, Gill PS, Parker JW, Meyer PR. Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome. Am J Surg Pathol 1987;11:625–632. Wood GS, Garcia CF, Dorfman RF, Warnke RA. The immunohistology of follicle lysis in lymph node biopsies from homosexual men. Blood 1985;66:1092–1097.

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Lymph Node

Knowles DM. Etiology and pathogenesis of AIDS-related non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am 1996;10:1081–1109. Knowles DM, Chamulak GA, Subar M, Burke JS, Dugan M, Wernz F, Slywotzky C, Pelicci P-G, Dalla-Favera R, Raphael B. Lymphoid ­neoplasia associated with the acquired immunodeficiency syndrome (AIDS): the New York University Medical Center experience with 105 patients (1981–1986). Ann Intern Med 1988;108:744–753. Lowenthal DA, Straus DJ, Campbell SW, Gold JWM, Clarkson BD, Koziner B. AIDS-related lymphoid neoplasia: the Memorial Hospital experience. Cancer 1988;61:2325–2337. Macon WR, Williams ME, Greer JP, Stein RS, Collins RD, Cousar JB. T-cell-rich B-cell lymphomas: a clinicopathologic study of 19 cases. Am J Surg Pathol 1992;16:351–363. Martin AR, Weisenburger DD, Chan WC, Ruby EI, Anderson JR, Vose JM, Bierman PJ, Bast MA, Daley DT, Armitage JO. Prognostic value of cellular proliferation and histologic grade in follicular lymphoma. Blood 1995;85:3671–3678. Mollejo M, Menarguez J, Lloret E, Sanchez A, Campo E, Algara P, Cristobal E, Sanchez E, Piris MA. Splenic marginal zone lymphoma: a distinctive type of low-grade B-cell lymphoma. Am J Surg Pathol 1995;19:1146–1157. Nathwani BN, Kim H, Rappaport H. Malignant lymphoma, lymphoblastic. Cancer 1976;38:964–983.

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Nathwani BN, Metter GE, Miller TP, Burke JS, Mann RB, Barcos M, Kjeldsberg CR, Dixon DO, Winberg CD, Whitcomb CC, Jones SE. What should be the morphologic criteria for the subdivision of follicular lymphomas? Blood 1986;68:837–845.

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Ng CS, Chan JKC, Hui PK, Lau WH. Large B-cell lymphomas with a high content of reactive T cells. Hum Pathol 1989;20:1145–1154.

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16 Spleen Dennis P. O’Malley, md Attilio Orazi, md, frcpath (engl.)

Contents

I. General Considerations......................16-3 Examination and Evaluation of the Spleen.................................................16-3 Splenomegaly....................................................16-4 Splenic Rupture................................................16-4 Splenic Ectopia.................................................16-5

II. Lymphoid Neoplasms.........................16-5 Lymphomas Presenting Predominantly in White Pulp...............................................16-5 Splenic B-Cell Marginal Zone Lymphoma.........................................16-5 Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma.......16-6 Lymphoplasmacytic Lymphoma/ Waldenstrom Macroglobulinemia...16-6 Follicular Lymphoma............................16-7 Mantle Cell Lymphoma.........................16-8 Nodal Marginal Zone Lymphoma........16-8 Burkitt Leukemia/Lymphoma..............16-8 Lymphoid Neoplasms Presenting Predominantly in Red Pulp........................16-9 Hairy Cell Leukemia.............................16-9 Splenic B-Cell Lymphoma, Unclassifiable.....................................16-9 Prolymphocytic Leukemia..................16-10 Acute Lymphoblastic Leukemia.........16-10 Hepatosplenic T-Cell Lymphoma.......16-11 Large Granular Lymphocytic Leukemia..........................................16-11 Other Patterns of Splenic Involvement........16-12 Classic Hodgkin Lymphoma...............16-12

Nodular Lymphocyte-Predominant Hodgkin Lymphoma.......................16-12 Diffuse Large B-Cell Lymphoma........16-13

III. Myeloid and Related Disorders........16-13 Extramedullary Hematopoiesis.....................16-13 Acute Myeloid Leukemia...............................16-14 Myeloproliferative Neoplasms.......................16-14 Myelodysplastic Syndromes..........................16-15 Systemic Mastocytosis....................................16-15 Hemophagocytic Syndrome...........................16-16

IV. Nonhematopoietic Lesions...............16-16 Cysts................................................................16-16 Hamartoma.....................................................16-16 Inflammatory Pseudotumor..........................16-17 Dendritic Cell Tumors...................................16-17 Inflammatory Myofibroblastic Tumor.........16-18 Vascular Lesions.............................................16-18 Peliosis...................................................16-18 Hemangioma.........................................16-18 Lymphangioma.....................................16-19 Littoral Cell Angioma..........................16-19 Hemangioendothelioma.......................16-20 Angiosarcoma.......................................16-20 Metastatic Disease..........................................16-21

V. Reactive Lesions Including Hyperplasias, Infections, Autoimmune, and Immunodeficiency....................16-21 Hyperplasias...................................................16-21

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_16, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Essentials of Anatomic Pathology, 3rd Ed.

Vascular/Congestive Disorders.....................16-22 Red Blood Cell Disorders..............................16-22 Infections.........................................................16-23 Storage Diseases.............................................16-24 Other Systemic Disorders..............................16-25

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Autoimmune Conditions................................16-26 Congenital Immunodeficiency-Related Splenic Disorders.......................................16-26

VI. Suggested Reading...........................16-26

Spleen

16-3

GENERAL CONSIDERATIONS Examination and Evaluation of the Spleen ♦♦ The spleen as a specimen in anatomic pathology has several unusual features −− It is only rarely biopsied; it is almost always removed completely either intact or as multiple fragments −− Pathology findings are typically incidental because of removal secondary to trauma or are seen because of symptoms of splenomegaly associated with known disease −− Only occasionally is a spleen removed with pathology that is a significant diagnostic challenge due to its rarity, its overlap with other pathologic entities or an unusual histologic appearance that requires ancillary studies for diagnosis −− The pattern of involvement of splenic pathology can be divided into four general categories: white pulp lesions, red pulp lesions, focal lesions, or a combination of these types (Fig. 16.1) −− Normal spleen has small white flecks in a background of purple-red, representing the white and red pulp, respectively −− The gross presentation of white pulp lesions is a caricature of the normal splenic appearance; the small white flecks expand in size and become readily visible small white nodules, which is described as a miliary pattern (Fig. 16.2) −− In red pulp lesions, the spleen takes on a beefy red appearance, with the white pulp becoming inapparent −− Focal lesions can vary in size, consistency, and circumscription of their boundaries; these may represent cystic or solid masses. In masses, color and density depend on their cellular composition, although many focal lesions in spleen evoke a fibrosclerotic response from the splenic stroma, imparting a firm, yellow tan appearance (Fig. 16.3) ♦♦ The spleen as an organ is unique in its combination of functions −− The spleen functions as part of both the immune system and the hematopoietic system −− As an immune organ, one of its functions is to serve as a very large lymph node, with immunologic responses comparable to those found in other lymphoid organs −− Its immunologic function also includes phagocytosis of cells or materials that are recognized as “foreign”

Fig. 16.1. Approach to examination of the spleen.

−− In a similar manner, the spleen serves to cull effete red blood cells as they pass through splenic sinuses into cords; red blood cells lacking appropriate membrane deformability will be repaired or destroyed as they transit through the acidotic environment −− The splenic architecture is composed of a fibrous capsule with an interconnected complex of support trabeculae, a network of arteries and arterioles, a complex arrangement of vascular sinuses with associated macrophages, and a complex arrangement of lymphoid tissue −− Because of this combination of tissues and functions, the spleen presents with diseases that are expressions of its

Fig. 16.2. White pulp: The miliary pattern is an accentuation of the normal splenic architecture. The white pulp components are enlarged and prominent.

Fig. 16.3. Splenic infarction: The firm, tan wedge shaped mass is a splenic infarction. Microscopically, it is composed of macrophages, fibroblasts, and benign vascular elements.

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s­ imilarities to other sites (lymphomas) and its abundance of certain types of tissues (vascular tumors) but also related to its functions (extramedullary hematopoiesis, acute leukemias) and its unique anatomy (littoral cell angiomas) −− Because of its filtering function, it is not uncommon for the spleen to be a site of infection. The microenvironment of the spleen is somewhat inhospitable, so the organisms that are present must be particularly good at evading immunologic destruction (e.g., encapsulated bacteria, fungi)

Splenomegaly ♦♦ Splenomegaly may result from a variety of causes, both benign and malignant. Some of the most common causes of splenomegaly are systemic disorders that merely represent hyperfunction of normal splenic activities, stromal proliferation, and/or vascular congestion ♦♦ Splenomegaly may results in clinical symptoms including early satiety, abdominal fullness, and pain ♦♦ Splenic enlargement is not an uncommon manifestation of systemic hematologic disease; however, the spleen is rarely removed as a diagnostic specimen. Spleen may be removed as a result of intractable symptoms, including patient discomfort or cytopenias. Only rarely is the spleen removed for evaluation of an unknown cause of splenomegaly or a mass of uncertain etiology

Splenic Rupture (Fig. 16.4) ♦♦ There are a wide variety of both nonneoplastic and neoplastic causes associated with splenic rupture. The spleen is typically enlarged in these cases, sometimes massively. But the rapidity of enlargement may also play a role with acute processes rupturing while the spleen is smaller ♦♦ Hemoperitoneum as a result of splenic rupture often leads to serious consequences including shock and death, if not treated appropriately

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Trauma is the most common cause of splenic rupture. So-called spontaneous splenic rupture is better termed “atraumatic” rupture, which has some underlying cause. Spontaneous splenic rupture should be reserved for cases where there is no known etiology. A list of causes associated with splenic rupture can be seen in Table 16.1. In cases with an underlying neoplasm, atraumatic splenic rupture is ­associated with a high mortality rate. One notable cause of

Table 16.1  Atraumatic (“Spontaneous”) Splenic Rupture: Associations and Etiologies I.    Infectious a.  Bacterial i. Typhoid fever ii.   Q Fever iii. Infectious endocarditis (various species) iv.  Tuberculosis and other mycobacteria v.  Numerous others b.  Viral i. Epstein–Barr virus ii. CMV iii. HIV iv. Others c.  Parasitic/Protozoal i. Malaria ii. Others II.   Hematopoietic diseases a.  Acute leukemias b.  Lymphoma c. Myeloma/plasma cell neoplasms/amyloidosis (esp. plasma cell leukemia) d. CML and other myeloproliferative neoplasms (PMF, ET, PV) III.  Vascular lesions a.  Benign (e.g., peliosis, hemangioma) b.  Neoplastic (e.g., littoral cell angioma, angiosarcoma) IV. 

Cysts

V.   Infarction VI.  Autoimmune disorders including collagen-vascular diseases VII.  Hamartoma VIII.  Medications a.  Anticoagulants and thrombolytics b.  Cytokines including G-/GM-CSF IX.  Metastatic malignancy (carcinoma, melanoma, etc.) X.   Storage diseases XI.  Coagulation Abnormalities a.  Factor VIII deficiency b.  Congenital dysfibrinogenemia XII.  Pregnancy-related a.  Postpartum b.  Ectopic pregnancy (“splenic” pregnancy)

Fig. 16.4. Splenic rupture: This gross photograph shows several ruptures in the splenic hilum and with small amounts of adherent blood clot.

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XIII.  Miscellaneous a.  Sarcoidosis b.  Acute pancreatitis c.  Cirrhosis of liver from any cause d.  Mechanical (after vomiting, coughing)

Spleen

16-5

atraumatic splenic rupture is infectious mononucleosis/acute Epstein–Barr virus infection

Splenic Ectopia ♦♦ Accessory spleens are not uncommon findings at autopsy (20–30% of population) and are typically located in the splenic region but can be located at more distant sites. Accessory spleens have the normal architecture of spleen and are typically small

♦♦ Splenic–gonadal fusion is a rare developmental anomaly with portions of the spleen attaching to the left gonad +/− tissue connecting the normally located spleen with the wandering fragment ♦♦ Splenosis refers to the presence of multiple small foci of splenic tissue, which are present throughout the abdominal cavity. Splenosis usually arises after rupture of the spleen and seeding of the abdominal cavity with small fragments of splenic parenchyma

LYMPHOID NEOPLASMS Lymphomas Presenting Predominantly in White Pulp Splenic B-Cell Marginal Zone Lymphoma Definition ♦♦ B-cell lymphoma, thought to be derived from splenic marginal zone cells ♦♦ Splenic involvement is predominant, although marrow and peripheral blood involvement are present in virtually all cases ♦♦ Formerly known as “splenic lymphoma with villous lymphocytes” ♦♦ Splenic B-cell marginal zone lymphoma (SMZL) is a relatively common diagnosis made in spleens removed for undetermined causes of splenomegaly

Clinical ♦♦ Patients most often present with asymptomatic splenomegaly

Fig. 16.5. Splenic marginal zone lymphoma: Expansion of the white pulp by pale-appearing lymphocytes.

Laboratory ♦♦ Leukocytosis may be present. Lymphocytes in peripheral blood may have cytoplasmic projections, referred to as villous lymphocytes

Macroscopic (Figs. 16.5 and 16.6) ♦♦ Spleens are typically enlarged, often massively, with prominent expansion of the white pulp in a miliary pattern

Microscopic ♦♦ The white pulp is expanded and replaced by a population of predominantly small lymphocytes. These are typically round, with a relative increase in pale cytoplasm giving them a pale appearance; rare larger, transformed lymphocytes are also present. Occasionally there is plasma cell differentiation. In early involvement, they will expand the normally present marginal zone ♦♦ Another diagnostic feature is replacement of the periarteriolar lymphoid sheaths with B-cells. As the disease ­progresses, they will invade and replace the mantle zone and follicle centers. Small nodules of B-cells will be seen in the red pulp

Fig.  16.6. Splenic marginal zone lymphoma: Predominantly small lymphocytes with moderate amounts of clear or pale cytoplasm.

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♦♦ High grade transformation is uncommon but occurs. In cases of high grade transformation, the morphology will appear similar to diffuse large B-cell lymphoma and may have ­evidence of residual, low grade lymphoma ♦♦ Bone marrow involvement may be subtle and have an intravascular pattern

Additional Studies ♦♦ Flow: SMZL is positive for B-cell markers (CD19+, CD20+) and typically does not express CD5 or CD10, CD23, or annexin A1 ♦♦ IHC: SMZL will be positive for B-cell markers (CD20, CD79a, PAX-5) and negative for markers associated with other specific lymphoma types: CD5, CD10, bcl-6, Cyclin D1. Overexpression of p53 is associated with transformation to higher grade tumor and a poor prognosis ♦♦ Molecular: IgH gene rearrangements are typically positive. Allelic loss of 7p21–32 is seen in up to 40%. Trisomy 3q and other cytogenetic abnormalities can also be seen

Differential Diagnosis

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Clinical ♦♦ Patients are typically >50 years old. The disease is often asymptomatic but patients may have anemia, fatigue, ­infections, or symptomatic splenomegaly ♦♦ Splenic involvement can vary depending on presentation of disease. Most often splenic red pulp is more prominently involved (CLL-like presentation), in addition to white pulp involvement. Rarely, the predominant involvement is in the white pulp (SLLlike presentation) with minimal red pulp involvement

Laboratory ♦♦ Peripheral blood and bone marrow involvement is common. The usual presentation is isolated elevated WBC composed of small, mature lymphocytes

Macroscopic ♦♦ Prominent white pulp involvement leads to miliary pattern grossly. Red pulp involvement leads to beefy appearance of spleen. In some cases both patterns may be seen

Microscopic

♦♦ Benign: Splenic marginal zone hyperplasia ♦♦ Malignant: Other “small B-cell” lymphomas with splenic involvement including follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, and lymphoplasmacytic lymphoma (LPL)

♦♦ White pulp nodules are enlarged in size, with inconspicuous germinal centers. The predominant cell is small, round lymphocyte with scant cytoplasm and condensed chromatin. Rare larger cells with large open chromatin, prominent central nucleolus, and moderate cytoplasm (prolymphocytes, paraimmunoblasts) are present

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Fig. 16.7) Definition

Additional Studies

♦♦ Neoplastic proliferation of predominantly small, matureappearing B-cells that coexpress CD5 and CD19. Typically there is peripheral blood involvement (chronic lymphocytic leukemia [CLL]) and occasionally predominant nodal involvement (small lymphocytic lymphoma [SLL])

♦♦ Flow: CLL/SLL is positive for B-cell markers (CD19, CD20) with coexpression of CD5 and CD23. CD10 is not expressed. Some features that are typical are dim expression of CD20, no expression of FMC-7 and dim expression of surface light chains ♦♦ IHC: CLL/SLL has similar findings by IHC including expression of CD5, CD20, and CD23. Coexpression of CD43 and expression of bcl-2 are typical. CD10, Cyclin D1, and bcl-6 are not expressed ♦♦ Genetics: FISH studies for genetic abnormalities are key prognostic findings in CLL/SLL. Deletions are seen at 13q14 (50%), trisomy 12 (20%), and deletions of 11q22 and 17p ♦♦ Molecular: Hypermutation of the IgH genes is associated with a relatively good prognosis. Those with unmutated IgH genes appear to have a worse prognosis

Differential Diagnosis ♦♦ Malignant: other “small B-cell” lymphomas with splenic involvement including follicular lymphoma, marginal zone, mantle cell lymphoma, and LPL ♦♦ Benign: white pulp hyperplasias

Lymphoplasmacytic Lymphoma/ Waldenstrom Macroglobulinemia (Fig. 16.8) Definition Fig.  16.7. CLL/SLL: Expansion of the white pulp with small satellite nodules. The cells are predominantly small, round lymphocytes with occasional prolymphocytes.

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♦♦ LPL is an indolent form of B-cell lymphoma composed of IgM-secreting cells with lymphoid and plasmacytic features. Waldenstrom macroglobulinemia is defined as LPL with bone marrow involvement and IgM monoclonal gammopathy.

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Fig. 16.8. Lymphoplasmacytic lymphoma: Red pulp infiltration by a combination of neoplastic lymphocytes, lymphoplasmacytic cells, and plasma cells.

Fig.  16.9. Follicular lymphoma: Expansion and increase of white pulp/nodules with homogeneous, neoplastic lymphocytes that retain a follicular architecture.

Clinical

Follicular Lymphoma (Fig. 16.9) Definition

♦♦ Some patients have symptoms of hyperviscosity caused by large amounts of serum monoclonal IgM protein. Bone marrow and peripheral blood involvement are typical. Splenic involvement is not uncommon, but spleen is rarely removed for diagnostic purposes ♦♦ LPL is considered a diagnosis of exclusion; other possible diagnoses including marginal zone lymphoma, CLL/SLL, plasma cell dyscrasias must be ruled out to make a diagnosis of LPL

Macroscopic ♦♦ Dependent on type of microscopic involvement; the patterns may be diffuse or focal with a miliary or red pulp pattern

Microscopic ♦♦ Most common infiltration of both white and red pulp by a mixture of small lymphocytes, lymphoplasmacytic cells, and plasma cells. Dutcher bodies and Russell bodies are not uncommon within plasma cells. Rarely, LPL may have involvement of white pulp without prominent red pulp involvement

Additional Studies ♦♦ Flow: LPL is positive for B-cell markers (CD19, CD20) with surface light chain restriction of the lymphocytes. FMC-7 is often positive. Typically CD5, CD10, and CD23 are negative. Plasmacytic cells will express plasma cell markers (CD38, CD138) and will have cytoplasmic light chain restriction ♦♦ IHC: LPL expresses B-cell markers (CD20, PAX-5, CD79a). The lymphoplasmacytic cells are variably positive of plasma cell markers (CD138) while the plasma cells are positive for CD138. Cyclin D1, CD5, and CD10 are negative ♦♦ Molecular: IgH gene rearrangement are typically present

Differential Diagnosis ♦♦ Differentiation from splenic marginal zone lymphoma can be difficult

♦♦ A lymphoma derived from neoplastic follicle center cells. Splenic involvement is frequent

Clinical ♦♦ Low grade follicular lymphomas (FI) (grade 1 or 2) are typically indolent diseases with relentless growth. Grade 3 follicular lymphoma has a more aggressive clinical course and is more similar in behavior to diffuse large B-cell lymphoma. Follicular lymphoma often presents in stage IV

Macroscopic ♦♦ Typical white pulp involvement with a miliary pattern is seen. Larger nodules (possibly with necrosis or hemorrhage) may represent sites of higher grade transformation

Microscopic ♦♦ Increase in the size and density of white pulp nodules is the most prominent low power manifestation. Relatively uniform nodules are present and they are composed of predominantly small, cleaved lymphocytes (grade 1); large numbers of large lymphocytes with centroblastic features (grade 3); or only occasional large cells combined with small, cleaved cells (grade 2)

Additional Studies ♦♦ Flow: FL is positive for B-cell markers (CD19, CD20) with expression CD10 and restricted surface light chains ♦♦ IHC: Neoplastic lymphocytes express CD20, CD10, bcl-2 (75%), bcl-6 and are negative for CD5, CD23, and Cyclin D1 ♦♦ Molecular: Rearrangement of bcl-2 gene is seen in most cases ♦♦ t(14;18) can be detected by FISH studies and supports a diagnosis of FL

Differential Diagnosis ♦♦ Benign: Follicular hyperplasia

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♦♦ Malignant: Other “small B-cell” lymphomas with splenic involvement including small lymphocytic lymphoma, mantle cell lymphoma, and LPL

Mantle Cell Lymphoma (Fig. 16.10) Definition ♦♦ A neoplastic proliferation of typically small lymphocytes, which over express the Cyclin D1 gene product due to the presence of t(11;14). Splenic involvement is common

Clinical ♦♦ Often presents at high clinical stage

Laboratory ♦♦ Peripheral blood involvement is not uncommon

Macroscopic ♦♦ Miliary pattern; is most common with expansion of the white pulp

Microscopic ♦♦ Expansion of the splenic white pulp by small lymphocytes with irregular nuclear borders. Rarely, these may be confined to an expanded mantle zone ♦♦ More often, they replace the normal germinal centers, making uniform nodules. It is not uncommon for there to be “spill-over” into the red pulp with clusters of neoplastic mantle cells ♦♦ There is a variant termed blastoid mantle cell lymphoma, which encompasses two subtypes: one with blastic nuclear chromatin, the other, termed “pleomorphic,” which has larger cells size and more irregular nuclei. Blastoid variant is associated with a more aggressive clinical course and similar patterns of involvement or may occasional have more diffuse involvement of the spleen

Essentials of Anatomic Pathology, 3rd Ed.

Additional Studies ♦♦ Flow: B-cells coexpressing CD19 and CD5, which are negative for CD23, show light chain restriction (more often lambda), bright CD20, and sIg (compared to CLL/SLL with dim CD20 and sIg) and are positive for FMC7 ♦♦ IHC: Neoplastic lymphocytes express CD5, CD20, bcl-2, CD43, and Cyclin D1. p53 is often positive and Ki67 often increased in blastoid variant. There is typically no expression of CD10, CD23, or bcl-6 ♦♦ Karyotype: t(11;14) ♦♦ Molecular: Translocation of the bcl-1 gene and the Ig heavy chain gene; t(11;14). This leads to overexpression of Cyclin D1, a cell cycle regulator

Differential Diagnosis ♦♦ Benign: Mantle cell hyperplasia ♦♦ Malignant: Other “small B-cell” lymphomas with splenic involvement including follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, and LPL

Nodal Marginal Zone Lymphoma Definition ♦♦ A B-cell lymphoma arising from cells with characteristics of marginal zone cells, but not those primary to the spleen

Differential Diagnosis ♦♦ Splenic involvement by nodal or extranodal marginal zone lymphomas is quite rare compared to “primary” splenic marginal zone lymphoma ♦♦ Although there are some subtle immunophenotypic differences, most cases with splenic involvement are of the splenic-type

Burkitt Leukemia/Lymphoma Definition ♦♦ An aggressive, high grade malignancy of B-cells

Clinical ♦♦ There are three clinical settings: (1) endemic type, (2) sporadic type, (3) immunodeficiency-related. Typically occurs in young patients (<20 years) except in immunodeficiencyrelated group ♦♦ Splenic involvement is not common and is present in high stage disease

Macroscopic ♦♦ Miliary pattern; may have larger expansive nodules or diffuse disease, due to rapidity of cell growth

Microscopic

Fig.  16.10. Mantle cell lymphoma: Expansion of white pulp nodules with spill-over of lymphocytes into red pulp. Cytologically, the neoplastic mantle cells are small, with irregular nuclei and condensed chromatin.

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♦♦ Intermediate-sized lymphocytes expanding and replacing white pulp structures. Nuclei are generally round with small amounts of deeply staining cytoplasm. Mitotic figures and apoptotic bodies are common. Tingible-body macrophages may be present, imparting classic “starry sky” appearance. Subtle cytoplasmic vacuoles may be seen in cytologic preparations

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Additional Studies

Macroscopic

♦♦ Flow: Neoplastic lymphocytes express CD19, CD10, CD20+ with surface light chain restriction. TdT and CD5 are not expressed ♦♦ IHC: Abnormal lymphocytes are positive for CD20, CD10, with a proliferation rate by Ki67 near 100%. There is no expression of CD5, Cyclin D1, bcl-2, or TdT ♦♦ Karyotype: t(8;14) most common, t(2;8) or t(8;22) less common ♦♦ Molecular: Translocation of C-MYC gene at 8q24

♦♦ Massive splenomegaly is common and may be presenting sign ♦♦ The spleen typically has a beefy appearance from expansion of the red pulp

Differential Diagnosis ♦♦ Blastic or blastoid appearing neoplasms including ALL, blastoid mantle cell, blastoid NK leukemia/lymphoma, hepatosplenic T-cell lymphoma

Lymphoid Neoplasms Presenting Predominantly in Red Pulp Hairy Cell Leukemia (Fig. 16.11) Definition ♦♦ An uncommon B-cell neoplasm that prominently involves spleen, bone marrow, and peripheral blood

Clinical ♦♦ Usually indolent clinical behavior ♦♦ Present with symptoms related to marrow replacement (anemia) or symptoms associated with splenomegaly

Laboratory ♦♦ Increased circulating lymphocytes with characteristic “hairy” cytoplasmic projections ♦♦ These cells are positive for tartrate-resistant acid phosphatase (TRAP), which is not seen in normal lymphocytes ♦♦ Monocytopenia is common

Microscopic ♦♦ The red pulp is expanded by a population of abnormal cells ♦♦ These cells have round, centrally placed nuclei with moderate amounts of clear-to-pale cytoplasm ♦♦ Blood lakes (small pockets of blood in spaces surrounded by elongated hairy cells) are seen in red pulp in most cases

Additional Studies ♦♦ Flow: Abnormal B-cells are positive for CD20, CD11c, CD22, CD25, and CD103 with light chain restriction. Annexin A1 and CD123 are also expressed. Rare examples will express CD10 ♦♦ IHC: The lymphoid cells will express CD20, DBA.44, and TRAP. There may be some weak expression of cyclin D1 ♦♦ Molecular: IgH rearrangements present

Splenic B-Cell Lymphoma, Unclassifiable Definition ♦♦ A newly described entity which is a diagnosis of exclusion, and includes two diagnoses, splenic diffuse red pulp small B-cell lymphoma and hairy cell leukemia-variant (HC-V). This category applies to poorly defined B-cell lymphoma which does not meet the criteria of other better defined B-cell lymphomas

Diffuse Red Pulp Small B-Cell ♦♦ This disorder characteristically has a leukemic presentation with massive splenomegaly. There are villous lymphocytes in the peripheral blood smears ♦♦ The spleen shows diffuse involvement by small B-cells, which involve the cords and sinuses but spare follicular structures ♦♦ Immunophenotypic studies express CD20, DBA.44. They are negative for annexin A1, CD25, CD5, CD103, CD123, and CD11c

Hairy Cell Leukemia-Variant

Fig. 16.11. Hairy cell leukemia: Red pulp infiltration by lymphocytes with moderate amounts of cytoplasm and relatively open chromatin.

♦♦ This diagnosis accounts for approximately 10% of cases of HCL. These cases are increased in Asian populations ♦♦ These cases are associated with marked leukocytosis. Cases have involvement of peripheral blood, bone marrow, and spleen. Splenomegaly and Cytopenias are seen ♦♦ By morphology, these cases have hybrid features of prolymphocytic leukemia (PLL) (see below) and hairy cell leukemia (above). The bone marrow involvement may be subtle and predominantly sinusoidal in pattern ♦♦ Immunophenotype shows TRAP staining to be weak or negative. The cells will express CD20, CD103, FMC7, DBA.44, and CD11c. There is no expression of CD25, Annexin A1, or CD123

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Acute Lymphoblastic Leukemia Definition ♦♦ A neoplasm of lymphoid precursor cells (lymphoblasts) of either B-cell origin (~90%) or T-cell origin (~10%)

Clinical ♦♦ Most often occur in pediatric patients. B-cell type has prominent bone marrow involvement, +/− blood involve­ ment ♦♦ T-cell type often is associated with a mediastinal mass, +/− blood/bone marrow involvement ♦♦ Splenic involvement is common, but significant splenomegaly is rare

Laboratory Fig. 16.12. Prolymphocytic leukemia: In this case there is extensive red pulp infiltration by intermediate-sized lymphocytes with prominent central nucleoli.

Prolymphocytic Leukemia (Fig. 16.12) Definition ♦♦ Most cases are T-cell-derived leukemias; less commonly B-cell-derived malignancies. Both are aggressive diseases and can have prominent splenic involvement

Clinical ♦♦ Patients present with high WBC, often over 100,000

Macroscopic ♦♦ Often both white and red pulp involvement

Microscopic ♦♦ A uniform population of intermediate to large lymphocytes. They have round nuclei with prominent central nucleoli

Additional Studies ♦♦ Flow: T-cell: Immunophenotype is positive for CD3, CD2, and CD7 with most cases positive for CD4, coexpress CD4 and CD8 (25%), and the remainder expressing CD8 ♦♦ B-cell: Immunophenotype is positive for CD20 with bright surface immunoglobulin. There is variable expression of CD5, CD23, and FMC7 ♦♦ IHC: Immunohistochemistry in T-cell type are positive for CD3, CD2, and CD7 with variable expression of CD4 and CD8 (as above) ♦♦ Immunohistochemistry in B-cell type is positive for CD20 with variable expression of CD5 and CD23 and negativity for Cyclin D1 negative ♦♦ Karyotype: T-cell type: Abnormalities of 14q11 are common

Differential Diagnosis ♦♦ Need to consider variants of mantle cell lymphoma with leukemic/splenic presentation; Cyclin D1 stain is necessary to evaluate the possibility of mantle cell lymphoma

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♦♦ Elevated WBC with blasts

Macroscopic ♦♦ Expansion of red pulp by neoplastic lymphoblasts in sinuses; rarely, white pulp involvement

Microscopic ♦♦ Intermediate-sized lymphocytes with blastic chromatin and little cytoplasm

Additional Studies ♦♦ Flow: Immunophenotype of B-cell type is positive for CD19 and CD10, with expression of TdT and variable ­positivity for CD34 ♦♦ Immunophenotype of T-cell type is positive for CD3, CD2, CD5, and CD7. CD10 is variable. CD4 and CD8 are often both negative. TdT and CD1a are positive in some cases ♦♦ Aberrant expression of myeloid markers may be observed in both B and T-cell types ♦♦ Karyotype −− In the T-cell type some recurrent abnormalities include involvement of 14q11.2, 7q35, and 7p14-15 (T-cell receptor genes) −− In B-cell types, recurrent abnormalities are more common and better characterized −− Abnormalities include (a) t(9;22)(q34;q11.2); BCR/ABL1 (b) (v;11q23); MLL rearranged (c) t(12;21)(p13;q22); TEL/AML1 (d) t(1;19)(q23;p13.3); PBX/E2A (e) Hypodiploid (f) Hyperdiploid > 50 (g) t(5;14)(q31;q32); IL3-IGH (h) t(1;19)(q23;p13.3); E2A-PBX1

Differential Diagnosis ♦♦ Other blastic and blastoid neoplasms in splenic red pulp

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Fig.  16.13. Hepatosplenic T-cell lymphoma: This lymphoma shows extensive infiltration of the red pulp, predominately in sinuses. The malignant lymphocytes can range from small cells with condensed chromatin to intermediate or large cells with more blastic chromatin.

Fig. 16.14. Large granular lymphocytosis: These small, irregular T-cells infiltrate the red pulp and expand the PALS in the white pulp.

Hepatosplenic T-Cell Lymphoma (Fig. 16.13) Definition

♦♦ IHC: Staining shows a T-cell phenotype with CD3 expression, variable CD56, CD4, and CD8 negative, loss of CD5, and expression of TIA-1 ♦♦ Karyotype: Isochromosome 7q is found in almost all cases ♦♦ Molecular: Clonal rearrangement of T-cell receptor is ­typically seen

♦♦ Neoplasm of T-cells that characteristically affects spleen, liver, and bone marrow. This lymphoma often has surface expression of gamma/delta T-cell receptor, which ­normally accounts for only a very small percentage of normal T-cells

Clinical ♦♦ Usually occurs in adolescents and young adults with a male predominance. It is increased in incidence in posttransplant setting and in association with azathioprine and infliximab treatment for Crohn disease ♦♦ Bone marrow involvement is generally present and will most often show characteristic intrasinusoidal pattern of involvement. Peripheral blood involvement is subtle but is increased later in disease course

Laboratory ♦♦ Often thrombocytopenia and anemia

Macroscopic ♦♦ Spleen is usually markedly enlarged, with typical expanded red pulp appearance, but focal lesions are not seen. Liver is also diffusely enlarged

Microscopic ♦♦ Marked increase in lymphocytes in the red pulp. Infiltration is most prominent in the sinusoids. Cytology can vary from small, mature-appearing lymphocytes to larger more blastic appearance

Additional Studies ♦♦ Flow: Flow shows expression of T-cell markers (CD3+, CD56+/−, typically CD4−/CD8−). Most cases express surface gamma/delta T-cell receptor, although rare cases express alpha/beta

Differential Diagnosis ♦♦ Histologic evaluation includes several disorders including splenic involvement by leukemias, B-cell lymphomas involving the red pulp, and other T-cell lymphomas

Large Granular Lymphocytic Leukemia (Fig. 16.14) Definition ♦♦ A proliferation of cytotoxic T lymphocytes (85% of cases) or more rarely NK cells ♦♦ In many cases, these proliferations are nonneoplastic and associated with autoimmune diseases such as rheumatoid arthritis ♦♦ Occasionally, these proliferations are neoplastic

Clinical ♦♦ There is a strong association with autoimmune disease. Among the more common associations are Felty syndrome, rheumatoid arthritis, Sjogren syndrome, and SLE

Laboratory ♦♦ Review of the peripheral blood often reveals neutropenia ♦♦ There is an increase in large granular lymphocytes ♦♦ If LGL count is less than 2.0 × 109/L, the diagnosis requires confirmation of clonality by molecular techniques

Macroscopic ♦♦ Enlarged spleen. Red pulp expansion

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Microscopic

Macroscopic

♦♦ Increased lymphocytes and expansion of the red pulp, ­typically with relative sparing of the white pulp

♦♦ These most often present as focal, fibrotic nodules of varying sizes. Rarely, they can be massive or very small-sized

Additional Studies

Microscopic

♦♦ LGL disease of cytotoxic lymphocytes (T-LGL) most often positive for pan-T-cell markers (CD2, CD3, CD5, CD7), CD8, cytotoxic markers (e.g., TIA-1), CD57; CD56 usually negative ♦♦ LGL disease of NK cells are positive for CD56; CD57 usually negative ♦♦ Molecular: Increases in CD8-positive LGL disease is associated with clonal T-cell receptor gene rearrangements ♦♦ NK-types do not have clonal rearrangements of the T-cell receptor; clonality can be assessed by X-linked gene analysis or cytogenetics

♦♦ Neoplastic cells are large, often binucleate (Reed–Sternberg cells), with large nucleoli. The background cells may consist of a mixture of small lymphocytes, eosinophils (often prominent), plasma cells, macrophages, and neutrophils. Fibrosis may also be a prominent microscopic feature

Differential Diagnosis ♦♦ It is possible to confuse LGL of the spleen with other T-cell disorders involving the splenic red pulp ♦♦ Among these would be involvement by mycosis fungoides, hepatosplenic T-cell lymphoma, and other T-cell lymphomas

Other Patterns of Splenic Involvement Classic Hodgkin Lymphoma (Fig. 16.15) Definition ♦♦ A malignancy of “crippled” B-cells which produce large characteristic malignant cells, Reed–Sternberg and Hodgkin cells. The malignant cells are typically rare but are associated with a characteristic background

Clinical ♦♦ Patients may have “B” symptoms: fever, night sweats, weight loss. Prognosis depends on stage but is generally excellent. Splenic involvement usually implies at least Stage II disease

Additional Studies ♦♦ Flow: Typically noncontributory in the diagnosis of Hodgkin lymphoma, although specialized techniques can identify Hodgkin cells ♦♦ IHC: Hodgkin and R–S cells stain for CD15, CD30, with characteristic weak nuclear staining for PAX5. They are negative for CD45 and are typically negative for both Oct.2 and BOB1

Differential Diagnosis ♦♦ Macroscopic differential diagnosis includes other focal processes in the spleen both benign and malignant ♦♦ Microscopic differential includes other neoplasms with rare, large malignant cells with a polymorphous background including considerations that include T-cell/histiocyte-rich B-cell lymphoma, anaplastic large cell lymphoma, and others

Nodular Lymphocyte-Predominant Hodgkin Lymphoma Definition ♦♦ A neoplasm of B-cells, with a characteristic background, composed of small lymphocytes. The neoplastic cells, referred to as L&H cells, are large and share some features with Hodgkin and R–S cells, but Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct disease from “classic” Hodgkin lymphoma. Spleen involvement is very rare

Macroscopic ♦♦ Grossly, NLPHL presents as focal disease with variablesized nodules

Microscopic ♦♦ Malignant cells are large, pale lymphocytes, usually in the center or periphery of nodules of reactive, small, round, dark blue lymphocytes. The L&H cells or “popcorn” cells have delicate nuclear chromatin and sometimes lobated nuclei

Additional Studies ♦♦ Flow: Flow cytometry is noncontributory in the diagnosis of nodular lymphocyte-predominant Hodgkin lymphoma ♦♦ IHC: The L&H cells are strongly positive for CD20 and CD45 (LCA), in contrast to classic Hodgkin lymphoma. The L&H cells are often surrounded by a collar of T-cells which often are positive for CD57

Differential Diagnosis Fig. 16.15. Hodgkin lymphoma: A diagnostic Reed–Sternberg cell is seen in the splenic red pulp.

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♦♦ The differential diagnosis includes classic Hodgkin lymphoma and other B-cell lymphomas such as T-cell/histiocyterich large B-cell lymphoma

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Clinical ♦♦ Primary diagnosis of DLBCL is rarely made in spleen. Prognosis is dependent on clinical stage. Of all lymphomas seen in spleen, DLBCL is relatively common

Macroscopic ♦♦ Most often presents as focal disease (nodules or mass). Rarely may have diffuse involvement

Microscopic ♦♦ Usually diffuse sheets of large lymphoid cells. There may be considerable variation in specific cytologic details. Some cases may have more centroblastic appearance (more irregular nuclear contours, coarse chromatin, inconspicuous nucleoli, scant pale cytoplasm) or immunoblastic appearance (round nuclei, more open chromatin, prominent nucleoli, variable deeply staining cytoplasm) Fig. 16.16. Diffuse large B-cell lymphoma: Lymphoma (lower left) is composed of large lymphocytes. This mass is compressing the normal splenic structures.

Diffuse Large B-Cell Lymphoma (Fig. 16.16) Definition ♦♦ A heterogeneous category inclusive of several malignancies of large B-cells. There are a variety of methods for subtyping such as cell derivation, immunophenotype, and distinctive clinical features. Diffuse Large B-cell lymphoma (DLBCL) may be de novo or arise as a transformation of a low grade B-cell lymphoma

Additional Studies ♦♦ Flow: Flow cytometry is positive for B-cell markers (CD19/ CD20), often with surface light chain restriction (some cases do not express surface light chain). Some cases express CD10 (40%), while other cases express CD5 (10%) ♦♦ IHC: CD20+, variable for other markers (see lymph node chapter) ♦♦ Karyotype: Various abnormalities are present including abnormalities of 3q27(bcl-6), t(14;18) (IgH/bcl-2), and others ♦♦ Molecular: IgH gene rearrangements are typically present. IgH/bcl-2 rearrangements are present in subset of cases

MYELOID AND RELATED DISORDERS Extramedullary Hematopoiesis (Fig. 16.17) Definition ♦♦ Proliferation of neoplastic or nonneoplastic bone marrow elements in the spleen. Some authors prefer to restrict the use of Extramedullary Hematopoiesis (EMH) to benign proliferations of hematopoietic cells, and use the term “neoplastic myeloid proliferations” for those seen in association with myeloid neoplasms

Clinical ♦♦ Can occur in a variety of clinical settings but most often seen in myeloproliferative neoplasms or severe anemias (e.g., hemoglobinopathies). May also be seen as a consequence of treatment with marrow stimulating cytokines such as G-CSF or GM-CSF (Fig. 16.18)

Microscopic ♦♦ Trilineage EMH: Clusters of maturing erythroid, granulocytic precursors, and megakaryocytes in red pulp ♦♦ Unilineage EMH: Most often a single lineage in reactive cases (e.g., erythroid in thalassemia). No excess of immature elements (e.g., blasts) or dysplastic forms is seen

Fig. 16.17. Extramedullary hematopoiesis – benign: This spleen shows a cluster of hematopoietic elements (erythroid and megakaryocyte) in a sinus. There is no cytologic atypia seen, in ­contrast to MPD or MDS.

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Fig. 16.18. G-CSF effect: The splenic red pulp is expanded by massive increase in maturing granulocytic elements.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 16.19. Acute myeloid leukemia: Intermediate-sized blastic cells characterize AML, which preferentially infiltrates the red pulp.

Additional Studies ♦♦ IHC: No increase in CD34 or CD117 positive cells seen

Differential Diagnosis ♦♦ If marrow elements are markedly increased or dysplastic, myeloproliferative neoplasms, myelodysplastic disorders, or acute leukemias should be considered

Acute Myeloid Leukemia (Fig. 16.19) Definition ♦♦ Neoplastic proliferation of myeloid progenitor/early precursor cells. Most often with blasts of granulocytic lineage. Several subtypes based on cytogenetic findings, lineage, and phenotypic variation (see Chap. 17)

Clinical ♦♦ Findings are variable, but symptoms are usually associated with cytopenias or anemia. WBC is usually elevated with circulating blasts. Splenic involvement is not unusual but significant splenomegaly is quite rare

Macroscopic ♦♦ Red pulp involvement imparting a “beefy” appearance

Microscopic ♦♦ Red pulp sinuses are expanded by blastic-appearing intermediate-sized cells. Occasionally more mature forms, with cytoplasmic granules (promyelocytes) or eosinophils and eosinophilic precursors may be seen as well

Additional Studies ♦♦ Flow: Positive for a variety of myeloid antigens, depending on subtype including CD117, CD13, CD33, cytoplasmic myeloperoxidase, CD34+/− ♦♦ IHC: Variably positive for CD34, CD117, myeloperoxidase, lysozyme ♦♦ Karyotype: Characteristic abnormalities may be seen in ­several subtypes of Acute Myeloid Leukemia (AML). Cytogenetic subtypes include cases with t(8;21), inv(16), t(15;17), and 11q23 abnormalities

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Fig. 16.20. Extramedullary hematopoiesis, neoplastic: In this case of chronic idiopathic myelofibrosis, these are numerous hematopoietic elements, predominantly megakaryocytic and granulocytic. The megakaryocytes showed marked cytologic atypia.

Myeloproliferative Neoplasms (Fig. 16.20) Definition ♦♦ Neoplastic proliferations of hematopoietic stem cells, typically producing increased numbers of one or more of the myeloid lineages in the blood and bone marrow ♦♦ Subtypes include chronic myelogenous leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). Mastocytosis is now considered an MPN (Myeloproliferative Neoplasms) (see below)

Clinical ♦♦ Splenic enlargement is common in all MPNs except ET. Splenomegaly is typically massive in PMF. Sudden increase in spleen size in any MPN may herald an accelerated phase/ blast transformation

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Macroscopic

Clinical

♦♦ CML/PV: Enlargement with expansion of the red pulp, with typical “beefy” appearance ♦♦ PMF: As above but may also have distinct, purple nodules (so-called plums)

♦♦ Cytopenias common

Microscopic ♦♦ CML: Typically massive expansion of red pulp cords and sinuses by maturing granulocytes. Eosinophils may be prominent. In chronic phase CML, blasts are not numerous. Erythroid and megakaryocytic elements may be seen, but are not usually prominent ♦♦ PMF: Massive expansion of red pulp by a variety of trilineage marrow elements. Megakaryocytes, in particular, may be increased and present in clusters or large nodules. The megakaryocytes are cytologically atypical with large, bizarre nuclei

Additional Studies ♦♦ IHC: Increased blasts may be highlighted in cases of accelerated phase/blast transformation by myeloperoxidase, CD117, or rarely CD34 ♦♦ Cytogenetics: Cytogenetic progression in spleen may herald disease progression in the bone marrow

Myelodysplastic Syndromes Definition ♦♦ A group of clonal disorders of hematopoietic stem cell, associated with ineffective hematopoiesis, peripheral cytopenias, and increased risk of progression to AML

Differential Diagnosis ♦♦ Splenic enlargement rare ♦♦ Expansion of red pulp by immature, dysplastic marrow elements ♦♦ Acute transformation may occur

Systemic Mastocytosis (Fig. 16.21) Definition ♦♦ Abnormal clonal proliferation and accumulation of mast cells in multiple sites. Systemic types are clonal disorders

Clinical ♦♦ Constitutional symptoms may be prominent as well as mast cell cytokine-mediated symptomatology ♦♦ Mastocytosis can also be seen in association with other hematopoietic malignancies including myeloproliferative disorders, myelodysplastic syndromes (MDS), acute ­myeloid leukemias

Laboratory ♦♦ Elevated serum tryptase levels are almost always seen but are not entirely specific for mastocytosis ♦♦ Splenomegaly is common in systemic mastocytosis (~70%)

Macroscopic ♦♦ Variable findings, but varying degrees of fibrosis can be seen

Fig. 16.21. Mastocytosis: A fibrous lesion composed of spindled mast cells with other inflammatory elements including eosinophils and plasma cells. These lesions are common in spleen trabecular, perivascular, and perifollicular areas. An immunohistochemical stain for tryptase highlights the mast cells.

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Microscopic

Clinical

♦♦ Mastocytosis may involve any compartment in the spleen and present as diffuse or focal disease. Trabecular involvement is common. On routine H&E stains, mast cells are inconspicuous. Mast cells are round with moderate amounts of cytoplasm or occasionally unremarkable spindle cells. Cytoplasmic granules may be inapparent. Polychromatic stains (Giemsa, toluidine blue) will highlight mast cells and their granules ♦♦ Mast cell infiltrates are associated with polymorphous infiltrates of inflammatory cells including lymphocytes, plasma cells, and often prominent eosinophils. Fibrosis is common

♦♦ Often patients are very ill due to profound cytopenias ♦♦ Bone marrow is also a prominent site of involvement of these disorders ♦♦ Splenic involvement and enlargement is common

Macroscopic ♦♦ Congestion of the red pulp

Microscopic

♦♦ Flow: Often noncontributory due to associated fibrosis. However, if circulating mast cells are present they will be seen to have bright CD117 expression, express CD33 and CD45. Abnormal mast cells will sometimes express CD2 and/or CD25 ♦♦ IHC: Positive staining is seen for tryptase, CD117, CD43, and in some cases CD2 and CD25. Other histiocytic markers are also positive including CD68 and CD163, but these lack specificity

♦♦ Expanded red pulp cord and sinuses ♦♦ Macrophages with ingested blood elements are often numerous ♦♦ Erythrophagocytosis most common, but all circulating blood elements can be seen within macrophages ♦♦ Clusters of histiocytes may be seen ♦♦ In cases of T-cell lymphoma-associated Hemophagocytic Syndrome (HPS), infiltrate of cytologically abnormal T-cells may be appreciated

Hemophagocytic Syndrome

Additional Studies

Additional Studies

♦♦ EBV may be positive and is a common etiologic agent

Definition ♦♦ Consumption of hematopoietic elements by macrophages, secondary to a variety of causes ♦♦ Etiologies including congenital disorders, infection-associated, and those associated with other malignancies, especially T-cell lymphomas

Differential Diagnosis ♦♦ HPS needs to be distinguished from the exceptionally rare true histiocytic sarcoma (malignant histiocytosis) ♦♦ Some lymphomas, especially T-cell types can be associated with hemophagocytosis

NONHEMATOPOIETIC LESIONS Cysts Definition ♦♦ Space occupying lesions of spleen, typically fluid filled. True cysts have an epithelial lining, usually of flattened, bland epithelium. This lining is keratin positive. Others that lack epithelial linings are termed “false cysts” and often represent resolution of splenic hematomas. Some may be caused by infectious etiologies

Differential Diagnosis ♦♦ Lymphangioma or other vascular tumors

Hamartoma (Fig. 16.22) Definition ♦♦ A nonneoplastic mass lesion composed of normal red pulp components

Clinical ♦♦ Often incidental findings by imaging or at splenectomy for other causes

Macroscopic ♦♦ Usually well-circumscribed nodule, which resembles red pulp

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Fig.  16.22. Splenic hamartoma: The lesions are usually wellcircumscribed, but not encapsulated. They are composed ­predominately of benign red pulp elements.

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Microscopic

Dendritic Cell Tumors

♦♦ Histologic appearance resembles red pulp, and typically lacks white pulp or trabecular components. Narrow vascular spaces are lined by typical, plump littoral type endothelial cells. Occasionally, macrophages or fibrosis may be prominent

♦♦ Including follicular dendritic cell tumor, interdigitating dendritic cell tumor, inflammatory pseudotumor-like follicular dendritic cell tumor

Additional Studies ♦♦ IHC: Vascular spaces lined by CD8+/CD68+/CD34− endothelial cells

Differential Diagnosis ♦♦ Inflammatory pseudotumor, vascular lesions, capillary hemangioma with prominent sclerosis, in particular

Inflammatory Pseudotumor (See Table 16.2) Definition ♦♦ A nonneoplastic nodular proliferation of benign-appearing spindle cells with a mixture of inflammatory components including lymphocytes, macrophages, neutrophils, and plasma cells

Definition ♦♦ Neoplasms of immune accessory cells, follicular dendritic cells, or interdigitating dendritic cells

Clinical ♦♦ They are very rare in the spleen. The inflammatory pseudotumor-like follicular dendritic cell tumor (IPTLFDCT) is a neoplasm that has only been described in the spleen. This group of disorders have variable prognosis. Locally aggressive behavior has been reported in a significant percentage of cases but metastases are rare

Macroscopic ♦♦ Typically present as focal mass lesions that are firm, tan, and usually have well-defined borders

Clinical

Microscopic

♦♦ Typically present as mass lesion. Often an incidental finding during radiologic examinations for other conditions. Rarely, a specific history of previous infection (bacterial, fungal, etc.) may be elicited ♦♦ These are focal lesions which are firm and fibrotic. The borders may be well- or ill-defined

♦♦ Follicular dendritic cell tumor (FDCT) and interdigitating dendritic cell tumor (IDCT) are composed of masses of blunt-ended spindle cells. Spindle cells will often form whorls and fascicles. FDCT may often mimic a nodular/ follicular growth pattern, including infiltrating lymphocytes. IPTLFDCT has spindle cells with large numbers of infiltrating inflammatory elements including lymphocytes, granulocytes, and polyclonal plasma cells

Microscopic

Additional Studies

♦♦ These masses are a combination of fibrotic stromal elements (spindle cells), acellular sclerosis, and varying degrees of mixed inflammatory elements including lymphocytes, granulocytes. and polyclonal plasma cells

♦♦ IHC −− FDCT: CD21+, CD35+, CD23+/− −− IDCT: S100+, CD68+/− −− IPTLFDCT: CD21+, EBV+

Macroscopic

Differential Diagnosis ♦♦ Lesions that closely mimic IPT include inflammatory pseudotumor-like (IPT) follicular dendritic cell tumor, inflammatory myofibroblastic tumor, and occasional vascular lesions including hamartoma and capillary hemangioma with prominent sclerosis

Differential Diagnosis ♦♦ Other spindle cell lesions should be considered including infectious etiologies, true inflammatory pseudotumor, and inflammatory myofibroblastic tumor

Table 16.2. Differential Diagnosis of Splenic Inflammatory Pseudotumor Etiology

Distinguishing features

Inflammatory pseudotumor

Reactive, most probably secondary to infectious causes

Prominence of inflammatory and/or sclerotic changes. Clinical history

Inflammatory pseudotumor-like follicular dendritic cell tumor

Neoplasm of follicular dendritic cells; EBV-associated

Spindle cells are CD21/CD35 positive. EBV positive

Inflammatory myofibroblastic tumor

Neoplasm of myofibroblastic cells

Increased smooth muscle actin/HHF-35 positive spindle cells. Occasionally ALK positive. Cytogenetic abnormalities may be present

Capillary hemangioma with prominent sclerosis

Benign neoplasm of vascular components

Simulates IPT but with prominent vasculature. Lobular nature of involvement is a diagnostic clue. Vascular markers highlight prominent capillaries (CD34+)

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Inflammatory Myofibroblastic Tumor (See Table 16.2)

Hemangioma

Definition

Definition

♦♦ Neoplastic proliferation of bland-appearing spindle cells of myofibroblastic derivation, often with associated inflammatory elements

♦♦ Vascular neoplasms which occur in diverse sites throughout the body ♦♦ Cavernous hemangiomas are composed of large, thickwalled vascular spaces ♦♦ Capillary hemangiomas are composed of proliferation of small caliber, thin-walled elements

Clinical ♦♦ Often incidental findings by imaging or at splenectomy for other causes

Macroscopic ♦♦ Usually appear as well-circumscribed tan nodules or varying sizes

Microscopic

♦♦ Cavernous, capillary (Figs. 16.23 and 16.24)

Clinical ♦♦ Cavernous type may be associated with cytopenias, especially thrombocytopenia, due to trapping of blood elements in the distended vascular spaces

♦♦ Inflammatory Myofibroblastic Tumor (IMT) is composed of bland spindle cells, often in sheets or fascicles. There are varying degrees of mixed inflammatory elements including histiocytes, lymphocytes, neutrophils and plasma cells

Additional Studies ♦♦ IHC: Spindle cells are strongly positive for actin and may be ALK protein positive ♦♦ Cytogenetics: Although rarely obtained prospectively, it is likely that clonal rearrangements would be seen

Vascular Lesions (See Table 16.3) Peliosis Definition ♦♦ A rare vascular lesion composed of ectatic sinusoids and blood-filled cysts. Cysts are lined by CD8+ sinusoidal endothelium. Peliosis is associated with a variety of conditions and is presumed to be nonneoplastic

Fig. 16.23. Cavernous hemangioma: Large blood-filled spaces. Examination at higher magnification reveals these spaces to be lined with flattened, bland endothelial cells.

Table 16.3. Vascular Disorders of the Spleen Diagnosis Nonneoplastic

Benign neoplasms

Malignant neoplasms

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Features

Immunos

Peliosis

Rare. Unknown etiology. Ectatic sinusoids and blood-filled spaces

Endothelial lining positive for CD31/ FVIII/Ulex

Hamartoma

Red pulp, very little or no white pulp seen

CD31+, FVIII+, CD8+

Hemangioma

Most common vascular neoplasm of spleen. Cavernous or capillary types. Single or multiple. Similar features to other body sites

CD31+, FVIII+, CD34+

Lymphangioma

Thin lining, not keratin positive. Filled with proteinaceous fluid. Rarely single, more often part of multisystem lymphangiomatosis

Must rule out mesothelial cyst which are keratin+. Lined by D2−40+, CD31+, FVIII+ cells

Littoral cell angioma

Neoplasm of sinus lining cells. Larger, plump cells. May have papillary features and form cystic spaces. Focal hemophagocytosis

CD31+, FVIII+, CD34−, CD68+, often CD21+

Angiosarcoma

Vascular malignancy. May have solid areas. Anaplasia, mitoses, necrosis not uncommon

CD31, FVIII, Ulex variably positive. CD34+ in 50%. CD8 variable

Spleen

Fig. 16.24. Capillary hemangioma: Note the bland cytology of the endothelial cells and narrow vascular spaces.

Macroscopic ♦♦ Focal or diffuse lesions that are red pulp based. Cavernous types are composed of large-caliber blood-filled spaces. Capillary types appear as spongy, bloody masses but may appear occasionally more fibrotic

Microscopic ♦♦ Spaces are lined by unremarkable endothelial cells. Rarely, capillary hemangiomas may have extensive sclerotic changes, histiocytic infiltrates, and mimic IPT

Additional Studies ♦♦ IHC: Positive for CD31/CD34/Factor VIII/FLI-1. Negative for CD8

Differential Diagnosis ♦♦ Other benign and malignant vascular proliferations are the most common considerations (refer to Table 16.3)

Lymphangioma Definition

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Fig. 16.25. Littoral cell angioma: This distinctive-appearing vascular neoplasm of spleen has patent, interconnected vascular spaces lined by plump endothelial-derived cells (i.e., littoral cells).

Differential Diagnosis ♦♦ Often confused with mesothelial-derived cysts, which are lined by keratin positive cells

Littoral Cell Angioma (Fig. 16.25) Definition ♦♦ Neoplastic vascular proliferation, unique to the spleen, likely derived from specialized cells which line splenic sinuses. These tumor cells express both features of endothelial cells and some features of the macrophage lineage

Clinical ♦♦ These lesions are benign and often present clinically as an asymptomatic mass or a multinodular lesion found on imaging. Rarely, they present with mass symptoms or unusually with rupture. These masses are benign and are cured by excision. Malignant versions of littoral cell neoplasms have been described (see description of “Angiosarcoma”). There is some association with second malignancies (carcinomas, lymphomas); although the nature of the association is not clear

♦♦ A rare, benign proliferation of lymphatic-lined spaces, which is most often as part of a systemic disorder of diffuse lymphangiomatosis

Macroscopic

Macroscopic

Microscopic

♦♦ Cysts contain clear, watery fluid. They may be smooth or have papillary projections

Microscopic ♦♦ Lining cells are flattened and cytologically bland. Occasionally papillary projections of lining cells into lumen. Foamy macrophages and cholesterol clefts are not uncommon

Additional Studies ♦♦ IHC: Positive for vascular markers and negative for keratin. Lymphatic associated marker D2–40 is positive

♦♦ Most common presentation is multiple, spongy, cystic masses in red pulp ♦♦ Endothelial cells lining cysts are plump and cuboidal. There may be papillary projections of the sinus lining cells into the lumens of cysts often associated with luminal desquamation. Interstitial spaces contain varying amounts of sclerosis and fibrosis

Additional Studies ♦♦ IHC: Stains positive for CD31, Factor VIII, and FLI-1 but negative for CD34. CD8 and CD21 are variably positive

Differential Diagnosis ♦♦ Other vascular neoplasms

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Hemangioendothelioma (Fig. 16.26) Definition ♦♦ A vascular tumor of intermediate or uncertain malignant potential

Essentials of Anatomic Pathology, 3rd Ed.

Clinical ♦♦ Typically asymptomatic and discovered incidentally, like many other vascular lesions

Macroscopic ♦♦ Likely to be poorly circumscribed lesions. May appear spongy or solid (more common in epithelioid types)

Microscopic ♦♦ Vascular elements with solid or spindled areas are seen. Tumors are lacking in clear features of malignancy (numerous mitoses, necrosis, bizarre atypia) but may have some focal features suggestive of malignancy

Additional Studies ♦♦ IHC: Hemangioendotheliomas are variably positive for ­vascular markers CD31, CD34, Factor VIII, and FLI-1

Differential Diagnosis ♦♦ Other vascular neoplasms are important considerations. Specifically, distinguishing angiosarcoma with minimal malignant features can be very difficult

Angiosarcoma (Fig. 16.27) Definition ♦♦ A malignancy composed of vasoformative elements Fig.  16.26. Hemangioendothelioma: Irregular, interconnected vascular spaces are lined by plump, spindled cells.

Clinical ♦♦ Older adults who are typically severely ill

Fig.  16.27. Splenic angiosarcoma: Malignancy of vasoformative elements. The cells are markedly pleomorphic with irregular, randomly arranged vascular spaces.

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Macroscopic ♦♦ Angiosarcomas are usually large tumor masses, often with extensive hemorrhage and necrosis. There is usually diffuse splenic involvement

Microscopic ♦♦ Solid or spindled areas may be seen. Anastomosing vascular channels lined with pleomorphic endothelial cells are a characteristic feature. This feature may be less prominent in epithelioid variants but more classical areas are typically present. Mitoses and pleomorphism are variable but usually present at least focally

Additional Studies ♦♦ IHC: Angiosarcomas are variably positive for vascular markers CD31, CD34, Factor VIII, and Fli-1 ♦♦ Rare cases may be littoral cell-derived and are positive for CD8, with variable expression of CD68, and are termed “littoral cell angiosarcoma”

Metastatic Disease (Fig. 16.28)

Fig.  16.28. Metastases: Metastases are rarely identified in the spleen. Metastatic tumors often induce significant stromal fibrosis.

Definition ♦♦ Metastatic tumors from a variety of sites

Clinical ♦♦ Metastases to the spleen are uncommon and typically occur late in the course of disease. This is due to the fact that the spleen lacks afferent lymphatics, and also because of the acidotic, hypoxic environment of the spleen. Prognosis depends on the type and stage of tumor

Macroscopic ♦♦ Usually form grossly visible mass lesions

Microscopic ♦♦ These features are dependent on the type of tumor. Most often, there is a characteristic fibrotic stromal response to metastatic epithelial malignancies

REACTIVE LESIONS INCLUDING HYPERPLASIAS, INFECTIONS, AUTOIMMUNE, AND IMMUNODEFICIENCY Hyperplasias ♦♦ Follicular hyperplasia −− An expansion and increase in the reactive germinal centers in the spleen due to a variety of immunologic stimuli −− As in lymph nodes, features of benign follicles include: polarization, tingible-body macrophages, variation in size and shape, and well-formed mantle zones ♦♦ Localized (nodular) hyperplasia (Fig. 16.29) −− A rare, benign process that consists of a focal nodule(s) that grossly mimic lymphoma but are composed of benign follicular elements microscopically. ♦♦ Marginal zone hyperplasia (Fig. 16.30) −− An expansion of the “third” layer of the follicle, which surround the mantle zone −− These cells often have a monocytoid appearance but lack features of marginal zone lymphoma (see Table 16.4) −− Marginal zone hyperplasia can be associated with a variety of immunologic stimuli

Fig. 16.29. Localized (nodular) lymphoid hyperplasia: Nodules may grossly mimic lymphoma but have microscopic features of benign follicles.

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Fig. 16.30. Marginal zone hyperplasia: Atypical, three-layered follicle of spleen with an expanded marginal zone. Marginal zone hyperplasia can be difficult to distinguish from marginal zone lymphoma.

Fig.  16.31. Vascular congestion: In this case of hereditary spherocytosis, there is severe congestion of the red pulp. Red pulp congestion can be the result of a variety of conditions.

Expanded MZ (>12 cell layers)

Yes

Yes

♦♦ T-cell hyperplasia −− Characterized by an expansion of the PALS that often includes a mixture of large and small cells, with some intermixture of plasma cells −− It can be associated with a variety of etiologies including congenital immunodeficiencies, drug reactions (e.g., phenytoin), and other causes

Numerous B-cells in PALS

No

Yes

Vascular/Congestive Disorders

Follicles

3 layers

Loss of layers; often uniform single layer

Red Pulp

No increase in red pulp B-cells

Often has clusters of red pulp B-cells

Kappa/lambda

Polyclonal

Monoclonal

Ki67

Normal secondary follicles with high proliferation

Colonized follicles have low proliferation in neoplastic cells

IgH Rearrangements

No

Yes

Table 16.4. Marginal Zone Hyperplasia vs. Marginal Zone Lymphoma Features

MZH

MZL

MZH marginal zone hyperplasia, MZL marginal zone lymphoma

Definition ♦♦ Red blood cell congestion of the spleen is due to vascular disturbances of various etiologies

Clinical ♦♦ Vascular congestion may cause moderate splenomegaly depending on duration of vascular disturbance. Common etiologies include portal hypertension, splenic vein obstruction, hepatic vein obstruction, congestive heart failure, and liver disease

Microscopic ♦♦ Red pulp shows increase in red blood cells. Stromal elements may proliferate as a result of chronic congestion and causes splenic fibrosis. Gamna-Gandy bodies (nodules of iron deposition) may be present

Red Blood Cell Disorders (Fig. 16.31) ♦♦ Nonfollicular or immunoblastic hyperplasia −− Characterized by a proliferation of large transformed lymphocytes −− It can be seen in both the white pulp (PALS) and red pulp and may mimic large cell lymphoma −− It is most commonly seen in association with viral etiologies

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Definition ♦♦ Defects of red blood cells can result in splenic changes due to increases in modification and destruction of red blood cells. Several types of red blood cell disorders can induce splenomegaly and congestion including: membrane defects (e.g., hereditary elliptocytosis), enzyme defects (ex. G6PD), as well as qualitative (hemoglobin SS – sickle cell disease) and quantitative (e.g., thalassemias) hemoglobin abnormalities

Spleen

Fig. 16.32. Sickle cell disease: Note the sickled red blood cells distending the cords and sinuses. ♦♦ Similar changes can be seen due to excessive destruction of “normal” red blood cells with antigen-driven destruction such as transfusion and autoantibodies

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Fig. 16.33. Infectious mononucleosis/EBV: There is an increase in lymphocytes and immunoblasts with characteristic infiltration of vascular walls and trabeculae.

Clinical ♦♦ Symptomatology varies with type of disorder

Differential Diagnosis ♦♦ Sickle cell disease (Fig. 16.32) −− Some specific findings are associated with hemoglobin SS disease −− Loss of marginal zones is an early occurrence in the spleen −− As the disease progresses, splenic micro-infarcts are common −− Gamna-Gandy bodies are frequently seen; these are areas of necrotic cells and condensed residual DNA and iron deposition −− Eventually, the spleen becomes a small, fibrotic, nonfunctional mass due to repeated infarction ♦♦ Occasionally, children may present with an enlarged, painful spleen that is acutely infarcted (known as sickle cell crisis) ♦♦ Other types of red blood cell disorders may have erythrophagocytosis in splenic cords

Infections Definition ♦♦ A variety of infectious organisms may be present in the spleen. Several of these are discussed briefly below −− “Septic spleen” is a nonspecific descriptive term describing the spleen of patients with systemic infections. Grossly the spleen may be congested and soft but no specific microscopic findings are seen. The use of this term is discouraged −− Infectious mononucleosis/acute EBV infection (Fig.  16.33) can be seen in the spleen fairly frequently. EBV is associated with splenomegaly fairly commonly. Acute EBV infection may make the spleen especially

Fig.  16.34. Mycobacterium avium-intracellulare: Granulomas composed of macrophages filled with granular material that represents numerous organisms. M. avium-intracellulare is positive for both AFB and PAS. susceptible to rupture. Microscopically, there is an increase in immunoblasts, especially in PALS, invasion of vessel walls, trabeculae, and capsule by lymphocytes (a key microscopic feature) −− Tuberculosis may have miliary involvement in disseminated disease. Characteristic granulomas, with or without caseation are seen. Organisms are typically quite rare, and are identified by special stains including AFB and immunohistochemistry −− Mycobacterium avium-intracellulare (Fig.  16.34) is a mycobacterial infection that can be seen in the spleen. It is not uncommon in HIV/AIDS patients. Microscopically, there is a focal or diffuse increase in plump histiocytes filled with granular material (mycobacteria) that stains positively for AFB and PAS and may mimic a storage disease

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Fig. 16.35. HIV: This spleen shows some of the changes associated with HIV. In this late-stage case, the follicle (center) is depleted of lymphocytes. Plasmacytosis is also prominent.

−− Malaria is frequently associated with splenomegaly. Often this is due to a combination of red pulp congestion and increased macrophages. Prominence of parasitized red blood cells, malarial pigment, and follicular and marginal zone hyperplasia may also be seen −− Tropical splenomegaly is progressive massive splenomegaly associated with malaria or other infections by unknown, but likely immunologic, mechanism −− Leishmaniasis is a systemic infection by a protozoan. Involvement of spleen is not uncommon. Granulomas and histiocytic aggregates can be seen. Organisms can be seen within macrophages and are especially prominent using a Giemsa stain −− HIV/AIDS (Fig.  16.35) has variable splenic pathology, dependent on stage of disease. The early phase may have florid follicular hyperplasia, while late stage may have lymphoid depletion and regressed follicles. Opportunistic infections are increased in all stages of HIV/AIDS infection and should be considered in all cases −− Echinococcus (Fig. 16.36) infection in the spleen is characterized by cysts of variable size filled with debris and fragments of “hydatid sand.” Portions of the tapeworms can be seen. Most characteristic are the “head” portion or scolex, which has prominent hooklets −− Bartonella henselae (bacillary angiomatosis): Seen in HIV/AIDS and other immunocompromised patients this infection is characterized by formation of granulomatous nodules in red pulp. Numerous bacterial organisms can be demonstrated by Warthin–Starry stain or an immunohistochemical stain from the organism −− Fungi (including histoplasmosis, blastomycosis, coccidioidomycosis): Splenic involvement as part of disseminated disease; granulomas +/− caseation are present; organisms may be common or difficult to find; GMS and PAS stains may be of benefit

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Fig.  16.36. Echinococcal cyst: Contents with the cyst may include fragments of organisms. In this case, prominent hooklets are seen.

Fig. 16.37. Gaucher disease: High magnification showing macrophages filled with excess metabolic product.

Storage Diseases (Figs. 16.37 and 16.38) Definition ♦♦ Abnormal products accumulate due to inherited biochemical abnormalities (e.g., Gaucher, Niemann–Pick, ceroid histiocytosis, mucopolysaccharidoses), neoplasms (e.g., primary amyloidosis), or other causes (ex. secondary amyloidosis)

Clinical ♦♦ Findings are variable depending on the primary cause. Splenomegaly may be initial or primary manifestation of adult-type of storage disorders

Macroscopic ♦♦ Amyloidosis is associated with classic gross findings. Sago spleen refers to accumulation of amyloid which appears as focal, solid waxy nodules in the spleen. Lardaceous spleen

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Fig.  16.38. Niemann–Pick: Expansion of red pulp by numerous macrophages. These engorged macrophages lead to splenomegaly. refers to diffuse deposition of amyloid throughout the spleen giving the entire organ a solid, waxy appearance

Microscopic ♦♦ The microscopic appearance depends on type of accumulated product. Both Gaucher disease and Niemann–Pick disease have massive accumulations of engorged macrophages in the red pulp with compression of white pulp structures. In Gaucher disease, the classic “folded tissue paper” appearance is seen in macrophages. In Niemann–Pick disease, macrophages will appear to have numerous small cytoplasmic vacuoles ♦♦ Amyloidosis shows accumulation of glassy, acellular pink matrix, initially most prominent in walls of vessels. In primary amyloidosis, plasma cells are often quite rare

Additional Studies ♦♦ Positive staining for PAS diastase-resistant material can be seen in many storage disorders ♦♦ Amyloid will stain positive for Congo red, with classic applegreen birefringence on polarization

Differential Diagnosis ♦♦ Deposition of material in macrophages can also be seen in several infectious disorders including Mycobacterium aviumintracellulare, fungal infections, etc

Other Systemic Disorders ♦♦ Sarcoidosis (Fig. 16.39) −− Splenic involvement by sarcoidosis is not uncommon

Fig. 16.39. Sarcoidosis: Well-defined granulomas composed of epithelioid macrophages. −− Varying degrees of involvement are described −− Typically, well-circumscribed, “hard” granulomas composed of epithelioid histiocytes are the characteristic histologic feature −− No organisms are identified, and the cases are negative for AFB/GMS stains ♦♦ Castleman Disease (Fig. 16.40) −− Splenic involvement is rare; both hyaline-vascular type and plasma cell/systemic type have been reported, with the latter more common

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Fig.  16.40. Castleman disease: Although quite rare, splenic involvement by Castleman Disease shares the same histologic features seen in lymph nodes. −− The histologic findings are similar to those seen in lymph nodes

Autoimmune Conditions ♦♦ Immune thrombocytopenic purpura (ITP) −− The pathophysiology is based on autoimmune destruction of platelets −− Significant splenomegaly is uncommon −− Reactive follicular hyperplasia, increase of cordal macro­ phages, with occasional foamy histiocytes are typical histologic findings −− Occasionally findings include EMH, follicular hyperplasia, and marginal zone hyperplasia ♦♦ Autoimmune hemolytic anemia −− Morphologic findings include reactive follicular hyperplasia and vascular congestion of red pulp with plasmacytosis ♦♦ Systemic lupus −− Lupus can be associated with prominent splenomegaly with red pulp expansion, white pulp hyperplasias, and vasculitis −− Vasculitis, with onion-skin fibrosis of vessels, is common and nearly pathognomonic of lupus in the spleen

Fig. 16.41. Autoimmune lymphoproliferative syndrome: Spleen shows expansion by T-cells (CD4−/CD8−) and polyclonal plasma cells. Follicular and marginal zone hyperplasia may be seen. ♦♦ Felty syndrome (rheumatoid arthritis, splenomegaly, neutropenia) −− Felty syndrome may present with massive red pulp polyclonal plasmacytosis −− Other connective tissue diseases, such as polyarteritis nodosa, hyperthyroidism, and juvenile rheumatoid arthritis may all present with splenomegaly −− Follicular hyperplasia and polyclonal plasmacytosis may be seen in these disorders

Congenital Immunodeficiency-Related Splenic Disorders Definition ♦♦ Several primary immunodeficiencies may present with prominent splenic findings or splenomegaly

Clinical ♦♦ Disorders with prominent splenic involvement include autoimmune lymphoproliferative syndrome (ALPS), common variable immunodeficiency, selective IgA deficiency, hyperIgM syndrome, etc ♦♦ ALPS (Fig. 16.41) is characterized by an expansion of PALS and red pulp by CD4− CD8− T-cells. Variable plasmacytosis and follicular/marginal zone hyperplasias are present

SUGGESTED READING Abbott RM, Levy AD, Aguilera NS, Gorospe L, Thompson WM. From the archives of the AFIP: primary vascular neoplasms of the spleen: radiologic–pathologic correlation. Radiographics 2004;24:1137–1163.

Arber DA, Stricker JG, Chen Y-Y, Weiss LM. Splenic vascular tumors: a histologic, immunophenotypic, and virologic study. Am J Surg Pathol 1997;21:827–835.

Arber DA, Strickler JG, Weiss LM. Splenic mesothelial cysts mimicking lymphangiomas. Am J Surg Pathol 1997;21:334–338.

Burke JS. Splenic lymphoid hyperplasias versus lymphomas/leukemias: a diagnostic guide. Am J Clin Pathol 1993;99:486–493.

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Chadburn A. The spleen: anatomy and anatomical function. Semin Hematol 2000;37 (Suppl 1):13–21. Chan JK. Splenic involvement by peripheral T-cell and NK-cell neoplasms. Semin Diagn Pathol 2003;20:105–120. Colovai AI, Giatzikis C, Ho EK, Farooqi M, Suciu-Foca N, Cattoretti G, Orazi A. Flow cytometric analysis of normal and reactive spleen. Mod Pathol 2004;17:918–927. Dogan A, Isaacson PG. Splenic marginal zone lymphoma. Semin Diagn Pathol 2003;20:121–127. Farhi DC, Ashfaq R. Splenic pathology after traumatic injury. Am J Clin Pathol 1996;105:474–478. Farley DR, Zietlow SP, Bannon MP, Farnell MB. Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc 1992;67: 846–853. Franco V, Florena AD, Iannitto E. Splenic marginal zone lymphoma. Blood 2003;101:2464–2472. Garvin DF, King FM. Cysts and nonlymphomatous tumors of the spleen. Pathol Ann 1981;16:61–80. Hsu JT, Chen HM, Lin CY, Yeh CN, Hwang TL, Jan YY, Chen MF. Primary angiosarcoma of the spleen. J Surg Oncol 2005;92:312–316. Kansal R, Ross CW, Singleton TP, Finn WG, Schnitzer B. Histopathologic features of splenic small B-cell lymphomas. Am J Clin Pathol 2003;120:335–347. Kraus MD. Splenic histology and histopathology: an update. Semin Diagn Pathol 2003;20:84–93. Krishnan J, Frizzera G. Two Splenic lesions in need of clarification: hamartoma and inflammatory pseudotumor. Semin Diagn Pathol 2003;20:94–104. Kroft SH, Singleton TP, Dahiya M, et al. Ruptured spleens with expanded marginal zones do not reveal occult B-cell clones. Mod Pathol 1997;10:1214–1220.

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Kutok JL, Pinkus GS, Dorfman DM, et al. Inflammatory pseudotumor of lymph node and spleen: an entity biologically distinct from inflammatory myofibroblastic tumor. Hum Pathol 2001;32:1382–1387. Kutok JL, Fletcher CD. Splenic vascular tumors. Semin Diagn Pathol 2003;20:128–139. Mollejo M, Patrocino A, Mateo MS, et al. Large B-cell lymphoma presenting in the spleen: identification of different clinicopathologic conditions. Am J Surg Pathol 2003;27:895–902. Neiman RS, Orazi A. Histopathologic manifestations of lymphoproliferative and myeloproliferative disorders involving the spleen. In: Diagnostic Hematopathology, 2nd Edition. Edited by Knowles DM. Philadelphia, Lippincott, Williams & Wilkins; 2001;1881–1914. Neuhauser TS, Derringer GA, Thompson LDR, et al. Splenic angiosarcoma: a clinicopathologic and immunophenotypic study of 28 cases. Mod Pathol 2000;13:978–987. O’Malley DP, George TI, Orazi A, Abbondanzo S. Armed Forces Institute of Pathology. Benign and Reactive Conditions of Lymph Node and Spleen. American Registry of Pathology Press, Washington DC; 2009. Osuji N, Matutes E, Catovsky D, Lampert I, Wotherspoon A. Histopathology of the spleen in T-cell large granular lymphocyte leukemia and T-cell prolymphocytic leukemia: a comparative review. Am J Surg Pathol 2005;29:935–941. Sandler SG. The spleen and splenectomy in immune (idiopathic) thrombocytopenic purpura. Semin Hematol 2000;37 (Suppl 1):10–12. Shurin SB. The spleen and its disorders. In: Hematology: Basic Principles and Practice, 4th edition. Edited by Hoffman R, Benz EJ Jr, Shattil SJ, et al. New York, Churchill Livingston; 2005;901–909. Vasef MA, Neiman RS, Meletiou SD, et al. Marked granulocytic proliferation induced by granulocyte colony-stimulating factor in the spleen simulating a myeloid leukemia infiltrate. Mod Pathol 1998;11: 1138–1141.

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17 Bone Marrow Dennis P. O’Malley, md

Contents

I. General Considerations......................17-3 Sampling............................................................17-3 Evaluation.........................................................17-3

II. Myeloproliferative Neoplasms...........17-3 Myeloproliferative Neoplasm (MPN): General.........................................................17-3 Chronic Myelogenous Leukemia: BCR/ABL1 Positive, Stable Phase..............17-3 CML: Accelerated Phase/Blast Phase............17-4 Polycythemia Vera............................................17-5 Primary Myelofibrosis.....................................17-5 Essential Thrombocythemia............................17-6 Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, or FGFR1............17-7 Chronic Eosinophilic Leukemia......................17-7 Chronic Neutrophilic Leukemia.....................17-7 MPN, Unclassifiable.........................................17-8 Mastocytosis......................................................17-8

III. Acute Myeloid Leukemia...................17-9 AML: General..................................................17-9 AML with Recurrent Cytogenetic Abnormalities..............................................17-9 Acute Promyelocytic Leukemia...........17-10 AML (and MDS), Therapy-Related.............17-11 AML with Gene Mutations...........................17-11 AML with Myelodysplasia-Related Changes......................................................17-12 AML, Not Otherwise Categorized................17-12 AML: Myeloblastic...............................17-12 AML: Monocytic/Monoblastic............17-12 AML: Myelomonocytic........................17-13

Acute Megakaryoblastic Leukemia....17-13 Acute Erythroid Leukemia..................17-14 Acute Panmyelosis with Myelofibrosis....................................17-15 Other Forms of AML...........................17-15 Acute Leukemias of Ambiguous Lineage.....17-15 Blastic Plasmacytoid Dendritic Cell Neoplasm............................................17-16

IV. Acute Lymphoblastic Leukemia........17-16 B-Cell Lymphoblastic Leukemia/ Lymphoma.................................................17-16 Burkitt Leukemia/Lymphoma......................17-17 T Lymphoblastic Leukemia/ Lymphoma.................................................17-19

V. Myelodysplastic Syndromes.............17-19 Myelodysplastic Syndromes (MDS): General.......................................................17-19 Refractory Cytopenia with Unilineage Dysplasia....................................................17-20 Refractory Anemia with Ringed Sideroblasts................................................17-21 Refractory Cytopenia with Multilineage Dysplasia..............................17-21 Refractory Anemia with Excess Blasts.........17-22 MDS with Isolated Del(5q)............................17-22 MDS, Unclassifiable.......................................17-22

VI. Myelodysplastic/ Myeloproliferative Diseases.............17-23 Chronic Myelomonocytic Leukemia.............17-23 Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative..................................17-24 Juvenile Myelomonocytic Leukemia............17-24

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_17, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Myelodysplastic/Myeloproliferative Disease, Unclassifiable..............................17-24

VII. B-Cell Lymphoproliferative Disorders.........................................17-25 Monoclonal B-Cell Lymphocytosis...............17-25 Chronic Lymphocytic Leukemia...................17-25 B-Cell Prolymphocytic Leukemia.................17-26 Lymphoplasmacytic Lymphoma/ Leukemia/Waldenstrom Macroglobulinemia...................................17-27 Marginal Zone Lymphoma............................17-27 Follicular Lymphoma.....................................17-28 Mantle Cell Lymphoma.................................17-29 Hairy Cell Leukemia......................................17-29 Diffuse Large B-Cell Lymphoma..................17-30

X. Plasma Cell Disorders......................17-37 Reactive Plasmacytosis..................................17-37 Plasma Cell Myeloma....................................17-37 Monoclonal Gammopathy of Undetermined Significance.......................17-39 Primary Amyloidosis.....................................17-39 Plasma Cell Leukemia...................................17-40

XI. Histiocytic and Macrophage Disorders.........................................17-40 Langerhans Cell Histiocytosis.......................17-40 Hemophagocytic Syndrome...........................17-40 Storage Diseases.............................................17-41

XII. Metastases.......................................17-42 Metastatic Disease..........................................17-42

VIII. T- and NK-Cell XIII. Infections.........................................17-42 Lymphoproliferative Disorders.........17-31 T-Cell Prolymphocytic Leukemia.................17-31 XIV. Anemias...........................................17-43 Anaplastic Large Cell Lymphoma................17-31 Sezary Syndrome/Mycosis Fungoides..........17-32 Adult T-Cell Leukemia/Lymphoma..............17-32 Hepatosplenic T-Cell Lymphoma.................17-33 T-Cell Large Granular Lymphocytic Leukemia....................................................17-34 Other Types of T-Cell Lymphoma (Peripheral T-Cell Lymphoma, Angioimmunoblastic T-Cell Lymphoma, etc.)........................................17-35 Natural Killer Leukemias and Lymphomas................................................17-35

IX. Hodgkin Lymphoma.........................17-36 Classic Hodgkin Lymphoma.........................17-36 Nodular Lymphocyte-Predominant Hodgkin Lymphoma.................................17-36

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Iron Deficiency Anemia.................................17-43 Anemia of Chronic Disease............................17-43 Megaloblastic Anemia....................................17-44 Paroxysmal Nocturnal Hemoglobinuria.........................................17-44 Congenital Dyserythroblastic Anemias......................................................17-44

XV. Reactive Conditions, Treatment Changes, Miscellaneous...................17-44 Aplastic Anemia..............................................17-44 Cytokine Effects.............................................17-45 Granulomas....................................................17-45 Immune Thrombocytopenic Purpura (ITP)............................................17-45

XVI. Suggested Reading...........................17-46

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GENERAL CONSIDERATIONS Sampling ♦♦ Peripheral blood smear with associated CBC results is critical in adequately evaluating hematologic disorders ♦♦ Aspirate smears allow for examination of cytomorphology; differential counts of at least 200 cells (500 cells is recommended by WHO 2008) should be routinely performed on marrow aspirates ♦♦ Touch preparations of core biopsies should be performed in all cases of inaspirable bone marrows ♦♦ Core biopsies are necessary to evaluate the architecture of bone marrows; in some cases, fibrosis prevents aspiration and the core biopsy may be the only pathologic specimen available. Some focal pathology, such as paratrabecular lymphoid aggregates, is not typically observed in marrow aspirates ♦♦ Clot sections are fixed specimens made from aspirate smears. Although they are not decalcified, they lack some architectural information present in core biopsy

Evaluation ♦♦ Bone marrow examination should include all of the following elements when possible: adequate clinical history (including presence of previous hematologic disease or indication for biopsy), CBC results, other pertinent laboratory results (e.g., SPEP), peripheral blood smear, aspirate smear, clot section, core biopsy. Ancillary studies may be performed on these samples (see below) ♦♦ Similar to gynecologic cytology, bone marrow reports should include statement of specimen adequacy. If the specimen is inadequate, the reason for this should be stated (e.g., sample too small, sample crushed, etc.). A core biopsy is considered adequate if it is: a minimum of 1.5 cm in length and has at least ten partially preserved intertrabecular areas (WHO 2008) ♦♦ Standard staining for peripheral blood and aspirate smears are Wright–Giemsa or other Wright stain derivatives

♦♦ Prussian blue stains of aspirate smears are used to evaluate iron stores and the presence of ringed sideroblasts. More than rare ringed sideroblasts are indicative of a pathologic condition. They are considered significant if they represent 15% or more of erythroid precursors. Iron stains can be performed on core biopsy or clot sections, but are less sensitive than those performed on the aspirate ♦♦ H&E staining is the standard for core biopsies and clot sections. PAS staining (which highlights erythroid precursors) or Giemsa stains are used occasionally ♦♦ Reticulin staining is commonly performed on core biopsies to evaluate reticulin fibrosis. Reticulin fibrosis of the bone marrow is a common finding in pathologic conditions, but is not specific for any entity

Ancillary Studies ♦♦ Flow cytometry is often performed on bone marrow aspirates to evaluate for the presence of disease. Flow is most useful for establishing clonality and immunophenotype in lymphoproliferative disease and in evaluating the presence, immunophenotype, and amount of a blast population in acute leukemias. It can also detect abnormal maturation or antigen expression in myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) ♦♦ Genetic abnormalities are often critical in the diagnosis of several neoplastic bone marrow disorders. If a neoplastic diagnosis is considered, cytogenetics or other appropriate genetic testing should be performed on the bone marrow ♦♦ FISH studies are becoming more important in hematologic disease. Testing bone marrows for appropriate FISH probes allow rapid, efficient testing of specific cytogenetic abnormalities in hematologic disease ♦♦ Molecular testing for specific hematologic disorders (JAK2 in myeloproliferative neoplasms (MPN), PCR for quantitation of BCR/ABL1) is critical for diagnostic, prognostic and therapeutic decisions in selected hematologic disorders

MYELOPROLIFERATIVE NEOPLASMS Myeloproliferative Neoplasm (MPN): General Definition Neoplastic proliferations of hematopoietic stem cells, typically producing increased numbers of one or more of the myeloid lineages in the blood and bone marrow ♦♦ Clinical ♦♦ Splenic enlargement is common in MPN (see Chapter 16)

Chronic Myelogenous Leukemia: BCR/ABL1 Positive, Stable Phase (Fig. 17.1) Definition ♦♦ MPN associated with the BCR/ABL1 gene fusion of marrow stem cells, leading most often to blood and marrow expansion of predominantly granulocytic elements

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This is an increase in the amount of immature myeloid elements seen at the bone, an extending into the intertrabecular space. Dwarf (small, hypolobated) megakaryocytes common. Marrow sinuses are often dilated, and frequently have intrasinusoidal hematopoiesis

Additional Studies ♦♦ Flow: The role of flow cytometry is increasing. Abnormalities of myeloid antigen expression and maturation (e.g., myeloid expression of CD56) can be seen. These findings tend to occur in all cases, but are not entirely specific for CML ♦♦ IHC: Rarely used. CD34 staining may highlight increased blasts (see accelerated phase, below)

Cytogenetics/Molecular Fig.  17.1. Chronic myelogenous leukemia. Peripheral blood smear with increased granulocytes with left shift, including increased basophils.

Clinical ♦♦ Clinical presentation: fatigue (anemia), fullness/LUQ pain (splenomegaly), fever, and malaise are common findings ♦♦ Chronic myelogenous leukemia (CML) is a disease of adults, most often in their sixth decade. CML very rarely occurs in children, but should be distinguished from juvenile myelomonocytic leukemia (see below)

Diagnosis ♦♦ Peripheral blood −− Leukocytosis, often >100 × 109/L, composed of neutrophils and immature forms (predominantly neutrophilic) but <10% blasts, is seen. Often has prominent basophilia , which is a characteristic finding when present. Eosinophilia may also be prominent. Immature erythroid elements (nucleated red blood cells) and thrombocytosis are variably present −− Leukocyte alkaline phosphatase (LAP) score is markedly decreased, although rarely performed due to lack of specificity ♦♦ Aspirate smear −− Hypercellular smears consisting of numerous maturing granulocytic elements are characteristic. The M:E ratio is usually greater than 20:1. Dysplasia of the myeloid series is not typically present. Blasts number <10% in stable or chronic cases of CML. Megakaryocytes often increased and many have a distinctive morphology. These are socalled dwarf forms, which have small hypolobated nuclei and small amounts of mature cytoplasm. Pseudo-Gaucher cells (macrophages with sea-blue cytoplasm) may be seen ♦♦ Biopsy −− Cores are hypercellular, with the cellularity often approaching 100%. Numerous myeloid precursors (M:E >10:1). Often a paratrabecular expansion of immature myeloid elements is seen, causing a “myeloid bulge.”

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−− Characteristic translocation between chromosomes 9 and 22, leading to formation of Philadelphia chromosome (Ph1) −− t(9;22)(q34;q11). Transposition of BCR/ABL1 genes leading to overactive tyrosine kinase −− p210 gene product: most common (95%) – typical CML −− p190 gene product: rare (~5%) – morphology similar to CMML (also seen in ALL) −− p230 gene product: very rare (<1%) – morphology essential thrombocythemia (ET)-like or very rarely CNL-like

Differential Diagnosis ♦♦ Leukemoid reaction: reactive increase of granulocytes, without cytogenetic change; normal or increased LAP ♦♦ Chronic neutrophilic leukemia (see later), chronic eosinophilic leukemia (see later section), atypical CML (lacks cytogenetic AND molecular evidence of BCR/ABL1 translocation)

Treatment and Prognosis ♦♦ Family of tyrosine kinase inhibitors (e.g., imatinib) has proven to be very effective in the treatment of CML ♦♦ Effectiveness of therapy often followed by PCR studies of BCR/ABL1 expression in peripheral blood ♦♦ BMT may be therapy of choice in some patients

CML: Accelerated Phase/Blast Phase Definition ♦♦ Aggressive forms of cml, with associated worse prognosis −− Accelerated phase (AP): advancement of clinical and labo­ ratory features associated with a worsening prognosis −− Blast phase (blast crisis): clinical characteristics similar to poor prognosis acute leukemia, with >20% blasts in blood or bone marrow; approximately 30% of blast phase transform to lymphoblastic leukemias

Clinical ♦♦ Features of accelerated phase include any of the following: (1) 10–19% blasts in blood or marrow, (2) blood basophils >20%, (3) persistent thrombocytopenia or thrombocytosis in spite of therapy, (4) increasing spleen size and WBC count in spite of therapy, (5) cytogenetic evidence of clonal evolution

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♦♦ Criteria for blast phase include any of the following: (1) >20% blasts in blood or marrow, (2) extramedullary blast proliferation (e.g., spleen), and (3) large clusters or aggregates of blasts in bone marrow (often identified by immunohistochemistry)

♦♦ Postpolycythemic myelofibrosis (post-PV-MF) is characterized by marrow fibrosis, splenic enlargement, and leukoerythroblastic peripheral blood. It is considered to be a late stage of the disease. Splenomegaly with marked extramedullary hematopoiesis common

Diagnosis

Diagnosis

♦♦ Peripheral blood −− As in criteria above, there are increased blasts (10–19%) or increased basophils (>20%). The presence of dysplastic features in granulocytic elements is a sign of CML-AP ♦♦ Aspirate smear −− The aspirate smears show similar features to peripheral blood including increased blasts (>10%) and dysplastic features of marrow elements ♦♦ Biopsy −− Clusters and aggregates of increased blasts are seen. If present, significant reticulin fibrosis may suggest accelerated phase. Increased numbers of megakaryocytes or large clusters of megakaryocytes may also indicate CML-AP

♦♦ Peripheral blood −− Leukocytosis and thrombocytosis are common. Basophilia may be present. Red cell abnormalities are usually not striking, although microcytosis may be seen ♦♦ Aspirate smear −− Increase in all marrow elements (panmyelosis) lacking dysplasia. Stainable iron is absent ♦♦ Biopsy −− Normo- to hypercellular; and if hypercellular, typically has increased erythroid elements. Megakaryocytes may be increased and have dysplastic appearance. Postpoly­ cythemia myelofibrosis is a late development in polycythemia vera (PV) with extensive fibrosis that has a morphologic appearance indistinguishable from PMF (see below)

Additional Studies

Additional Studies

♦♦ Flow: Myeloid blasts (CD13, CD33, CD34, CD117) or lymphoid blasts (CD19, CD10, TdT) may be seen. Often mixed lineage leukemias with combination of myeloid and lymphoid antigens may be seen ♦♦ IHC: CD34/CD117 may highlight clusters of blasts ♦♦ Cytogenetics: In addition to t(9;22) additional abnormalities are often present. Most common findings include double Philadelphia chromosome; iso(17q); trisomy 8

♦♦ Cytogenetics/molecular: JAK2 mutations (especially V617F) are seen in essentially “all” cases of PV. Recurring cytogenetic defects are also seen in many cases. Common cytogenetic changes include: trisomy of chromosome 8 and 9, deletions of 20q, 13q and 9p

Differential Diagnosis ♦♦ Reactive erythrocytosis, other MPN

Polycythemia Vera

Primary Myelofibrosis (Fig. 17.2)

Definition

Definition

♦♦ Clonal MPN with predominant expression of erythroid proliferation

♦♦ Clonal MPN characterized by proliferation of megakaryocytes with significant associated marrow fibrosis

Clinical

Clinical

♦♦ The M:F ratio is 1–2:1 ♦♦ Diagnostic criteria (both major criteria and one minor criteria, or one major criteria and two minor criteria) ♦♦ Major criteria −− Hemoglobin >18.5 g/dL (men) or 16.5 g/dL (women) or other evidence of increased red blood cell mass −− Presence of JAK2 mutation or other functionally similar mutation ♦♦ Minor criteria −− Hypercellular bone marrow with panmyelosis −− Low serum erythropoietin −− In vitro endogenous erythroid colony formation ♦♦ Other clinical findings that are common, but do not count as specific criteria are: splenomegaly, thrombocytosis >400 × 109/L, and WBC >12 × 109/L. Thrombotic symptoms are relatively common

♦♦ Splenomegaly and hepatomegaly due to extramedullary proliferation of myeloid elements. “Prefibrotic stage” lacks splenomegaly and characteristic peripheral blood findings, lacks marrow fibrosis but has hypercellularity and megakaryocyte morphologic abnormalities. It accounts for up to 30% of cases of primary myelofibrosis (PMF) ♦♦ In PMF, transformation to acute myeloid leukemia (AML) occurs in 5–30% of patients

Diagnosis ♦♦ Peripheral blood −− Findings in peripheral blood include: leukoerythroblastosis (immature myeloid and erythroid elements), teardrop red blood cells (dacrocytes), immature neutrophilic elements (including rare blasts), and increased platelets (including abnormal hypogranulated or giant platelets). Rarely, circulating megakaryocytes or megakaryoblasts can be seen

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Fig. 17.2. Primary myelofibrosis. Note the clusters of morphologically atypical megakaryocytes. Extensive fibrosis would be seen on reticulin staining (not shown).

Fig. 17.3. Essential thrombocythemia. Note increased megakaryocytes. In contrast to PMF, fibrosis is rare.

♦♦ Aspirate smear −− Most cases inaspirable due to marrow fibrosis ♦♦ Biopsy −− Increased abnormal megakaryocytes are seen, usually in tight clusters with enlarged, hyperchromatic nuclei. Marrow sinuses are dilated. Intrasinusoidal hematopoiesis is commonly seen within the sinuses. Blasts account for <10% of the marrow cellularity. Reticulin fibrosis is typically present and moderate or severe; cases often have trichrome (mature collagen) positive fibrosis. Bone changes including osteosclerosis and abnormal trabeculae are common findings

Essential Thrombocythemia (Fig. 17.3)

Additional Studies ♦♦ Flow: Flow examination is typically not performed due to lack of aspirate ♦♦ IHC: CD34 may highlight increased blasts and also highlights intravascular hematopoiesis ♦♦ Cytogenetics/molecular: Approximately 50% of PMF patients will have JAK2 mutation. Cytogenetic abnormalities occur in up to 30% of patients with the most common being del(13q), del(20q), der(6)t(1;6), partial trisomy (1q), trisomy 8, or trisomy 9

Differential Diagnosis ♦♦ Acute panmyelosis with myelofibrosis, a rare subset of acute myeloid leukemia ♦♦ Polycythemia vera/post-PV-MF ♦♦ AML or MDS with fibrosis ♦♦ Autoimmune myelofibrosis: seen typically in young women with other autoimmune manifestations, lacks megakaryocytic abnormalities

Treatment and Prognosis ♦♦ Median survival 3–7 years from diagnosis

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Definition ♦♦ A neoplastic proliferation of marrow elements, with a predominance of megakaryocytes; these abnormal megakaryocytes produce large numbers of circulating platelets

Clinical ♦♦ Patients are often asymptomatic (>50%) or present with consequences of thrombocytosis; these can include either bleeding (hypofunctional platelets) or thrombosis. In contrast to other MPN, transformation to AML is rare

Diagnosis ♦♦ Peripheral blood −− A sustained platelet count >450 × 109/L is a diagnostic criteria (Note: this is decreased from WHO 2001 criteria, which was a platelet count of >600 × 109/L). Platelets are typically morphologically abnormal including variation in size, shape and granulation. There is typically a lack of elevated white blood cell count or basophilia ♦♦ Aspirate smear −− Increased megakaryocytes are seen and are typically large in size with large nuclei and abundant cytoplasm. Myeloid and erythroid elements are typically normal in appearance and maturation. Large clumps of platelets may occasionally be seen in aspirate smear ♦♦ Biopsy −− Often normocellular, there is a notable increase in number of megakaryocytes, which are present in loose clusters. The dysplastic megakaryocyte morphology includes very large size, with “cloud-like” nuclei and large amounts of mature, granular cytoplasm. Myeloid and erythroid elements are normal-appearing. Reticulin fibrosis is absent or minimal in extent

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Additional Studies ♦♦ Flow/IHC: Occasional dysmaturation of myeloid elements can be seen. However, the findings are not specific ♦♦ Cytogenetics/Molecular: An abnormal JAK2 is seen in 40–50% of cases. Abnormal cytogenetics are rare, but include del(20q) trisomy 8 and abnormalities of 9q in a small percentage of cases

Differential Diagnosis ♦♦ Reactive thrombocytosis lacks morphologic abnormalities in megakaryocytes. Also there are no abnormal cytogenetic findings ♦♦ Lacks features of other MPN (including CML, PMF, PV) and MDS

Treatment and Prognosis ♦♦ Indolent disorder, transformation to AML quite rare (<5%)

Myeloid and Lymphoid Neoplasms with Eosinophilia and Abnormalities of PDGFRA, PDGFRB, or FGFR1 ♦♦ The 2008 WHO Classification has placed this group of disorders together as a separate class of entities. Within this group are several rare entities including: chronic myelomonocytic leukemia (CMML) with eosinophilia, most cases of chronic eosinophilic leukemia and cases of T-cell lymphoblastic leukemia with eosinophilia. This group of disorders is characterized by molecular evidence of abnormalities of three genes PDGFRA, PDGFRB, or FGFR1. One of the more common abnormalities is the translocation of the FIP1L1/PDGFRA, which can be tested by FISH studies (by testing for deletions of CHIC2). However, abnormalities of PDGFRB and FGFR1 are often cryptic and can only be evaluated by molecular methods. Many of these disorders are responsive to antityrosine kinase mediations such as imatinib, making their identification as a unique clinical subset important.

Chronic Eosinophilic Leukemia (Fig. 17.4) Definition ♦♦ Autonomous proliferations of eosinophils with associated end-organ damage. Chronic eosinophilic leukemia (CEL) has proven clonality or cytogenetic abnormality; a subset of these cases are classified within the group of disorders with PDGFRA, PDGFRB, or FGFR1 abnormalities

Fig. 17.4. Chronic eosinophilic leukemia. This bone marrow core biopsy shows a massive increase in eosinophils and precursors.

granulation, hyperlobated), but these findings can be seen in reactive eosinophilia ♦♦ Aspirate smear −− Increased eosinophils and precursors are seen. Blasts are <20% (or a diagnosis of AML is made). Charcot–Leyden crystals (condensed aggregates of eosinophilic proteins in a large crystalline shape) may be seen. Dysplastic features of other cell lineages may be seen. Eosinophils may be abnormally chloroacetate esterase positive ♦♦ Biopsy −− Marrow biopsies are hypercellular, predominantly due to increased eosinophils

Additional Studies ♦♦ Cytogenetics/molecular: 5q33 abnormalities associated with PDGFB; +8; 8p11 associated with FGFR1; t(8;13), t(6;8). Cryptic del (4)(q12) resulting in FIP1L1/PDGRFA gene fusion (note: this abnormality is tested for by deletion of the CHIC2 gene which is lost in the process)

Differential Diagnosis ♦♦ AML inv(16) – differentiate by cytogenetics and blast count; other MPN

Clinical

Prognosis and Treatment

♦♦ CEL is a diagnosis of exclusion; other causes of eosinophilia (allergy, parasites, drug effects, secondary to neoplasms) must be excluded. The M:F ratio is 9:1. Eosinophilic infiltration may lead to damage in lungs, heart, skin, and GI tract. Constitutional symptoms such as diarrhea and pruritis are common

Chronic Neutrophilic Leukemia

Diagnosis

Definition

♦♦ Peripheral blood −− Eosinophilia of greater than 1.5 × 109/L is seen. Eosinophils may be dysplastic in appearance (abnormal

♦♦ Very rare disorder which consists of sustained, clonal proliferation of mature neutrophils that lacks BCR/ABL1 and other causes of neutrophilia (e.g., paraneoplastic)

♦♦ Imatinib, most often used in CML, has activity in some cases of CEL, including some with abnormalities of PDGFRA, PDGFRB and FGFR1

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Clinical ♦♦ There is a possible association with plasma cell myeloma (PCM). Hepatosplenomegaly is seen in almost all cases. It is an exceedingly rare disorder

Diagnosis ♦♦ Peripheral blood −− Numerous mature neutrophils (>25 × 109/L) are seen. Immature granulocytes number <10%. Dysplastic features of neutrophils are not seen. Blasts are not increased and are <1% of the white blood cell count ♦♦ Aspirate smear −− Increased neutrophils are seen. No dysplasia of neutrophils or other lineages is seen. Blasts are not increased and account for <5% of the marrow cellularity ♦♦ Biopsy −− The core biopsy is hypercellular, with sheets and ­aggregates of neutrophils and precursors. The M:E ratio is typically >20:1. Fibrosis is uncommon

Additional Studies ♦♦ Cytogenetics/Molecular: No specific genetic abnormalities have been identified. Most cases (>90%) have no abnormalities by routine cytogenetics. However, a subset of cases have been identified which have JAK2 mutations. It should be noted that there are no findings of abnormalities associated with other myeloid disorders such as BCR/ABL1, PDGFRA, etc

Differential Diagnosis ♦♦ CML, CMML, MDS

MPN, Unclassifiable Definition ♦♦ Cases that have clinical or morphologic features of a MPN, but lack features of a specific entity OR have significant overlap between more than one entity AND lack evidence of BCR/ABL1

Other ♦♦ Features are variable ♦♦ May represent very early stages of PV or PMF ♦♦ Features of MDS are lacking

Mastocytosis (Fig. 17.5) Definition ♦♦ Abnormal clonal proliferation and accumulation of mast cells in multiple sites. Disorders included within this diagnosis include: cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic disorder, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. Cutaneous mastocytosis and extracutaneous mastocytoma will not be discussed further in this section. The reader is referred to appropriate sections in this text

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Fig. 17.5. Mastocytosis. This core biopsy shows a classic paratrabecular aggregate of fibrosis with mast cells. Tryptase, CD117, Giemsa, or toluidine blue stains would highlight the mast cells. ♦♦ Mast cell leukemia is a very rare manifestation of mastocytosis with >10% mast cells in peripheral blood and diffuse infiltration of marrow by >20% mast cells

Clinical ♦♦ Constitutional symptoms may be prominent as well as mast cell cytokine-mediated symptomatology. Elevated serum tryptase levels are almost always seen, but are not entirely specific for mastocytosis. Other common sites of involvement in systemic mastocytosis include spleen, skin, and GI tract. Hepatosplenomegaly is a common clinical finding. Skeletal abnormalities with osteolytic lesions or pathologic fractures are not uncommon ♦♦ Mastocytosis can be seen in association with other hematopoietic malignancies including myeloproliferative neoplasms, MDS, acute myeloid leukemias, lymphomas, or other hematologic disorders

Diagnosis ♦♦ Peripheral blood −− Circulating mast cells are rarely seen except in mast cell leukemia. When seen they may appear similar to monocytes (when degranulated) or may have a more typical mast cell appearance ♦♦ Aspirate smear −− Mast cells are seen in increased numbers. In comparison to normal mast cells, neoplastic mast cells may be hypogranular or spindle-shaped. Increased numbers of eosinophils, lymphocytes, or plasma cells may be seen adjacent to or associated with mast cells. Because of the association with other hematopoietic disorders, care must be taken when evaluating other marrow elements ♦♦ Biopsy −− Mast cells are round with moderate amounts of cytoplasm or occasionally appear as unremarkable spindle cells. On H&E stains, mast cells are inconspicuous; cytoplasmic granules may be inapparent. Giemsa or toluidine blue

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stains may highlight metachromatic granules of mast cells. Mast cell infiltrates are associated with polymorphous infiltrates of inflammatory cells including lymphocytes, plasma cells and often prominent eosinophils −− Fibrosis is common and the classic appearance is of fibrotic paratrabecular aggregates with mast cells and mixed inflammatory cells

♦♦ IHC: Mast cells are positive for tryptase, CD117, CD43, CD2, and CD25 ♦♦ Note: CD2 and CD25 Expression is seen in neoplastic mast cells and not normal mast cells ♦♦ Cytogenetic/molecular: activating mutations of the KIT gene can be identified in many cases

Additional Studies

Differential Diagnosis

♦♦ Flow: Often noncontributory due to associated fibrosis, mast cells are positive for CD117, CD45, CD11c, CD33, CD43, CD2, and CD25

♦♦ Although there may be overlap, disorders with PDGFRA, PDGRFB, and FGFR1 should be considered separately from cases of mastocytosis

Acute Myeloid Leukemia AML: General (Fig. 17.6)

Clinical Findings

Classification

♦♦ AML is most often a disease of adults, 60 years and older. Contributing etiologies include: certain viruses, ionizing radiation, cytotoxic chemotherapy, benzene, and cigarette smoking

♦♦ Malignancy of myeloid progenitor/early precursor cells. Several subtypes exist which are based on cytogenetic findings, cellular lineage, and phenotypic variation. The current WHO classification divides acute myeloid leukemia (AML) into four general groups: AML with recurrent cytogenetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms (including AML and MDS), and AML not otherwise categorized ♦♦ AML, not otherwise categorized includes several clinical and/or morphologic entities, which make up the majority of cases of AML ♦♦ WHO terminology is used in this section, with the outdated FAB (French–American–British) classification system ­terminology included in parentheses for historical purposes

Diagnosis ♦♦ Auer rods are a fusion of primary granules, seen in the cytoplasm of blasts of granulocytic lineage; they are seen exclusively in a subset of cases of AML or high grade MDS. Cytochemical stains provide information on lineage of some AML types (See Table 17.1); for myeloperoxidase (MPO) or nonspecific esterase (NSE) to be considered positive, at least 3% of the neoplastic cells (e.g., blasts) must stain positively. While of some benefit, many of the results of cytochemical stains can be less important than genetic or immunophenotypic findings

AML with Recurrent Cytogenetic Abnormalities ♦♦ In cases with recurrent cytogenetic abnormalities, even if blasts percentages do not reach 20%, they should still be diagnosed at AML rather than an MDS

AML with t(8;21)(q22;q22)

Fig.  17.6. Acute myeloid leukemia. This core biopsy shows extensive infiltration by myeloid blasts.

♦♦ Translocation results in fusion of RUNX1/RUNX1T1 (AML1/ ETO) genes. Represents 5–10% of cases of AML. Patients are typically younger than in other types of AML ♦♦ Morphology is most often large blasts, most often with numerous cytoplasmic granules and frequent Auer rods. Maturing neutrophilic elements with or without dysplasia may be seen. Strong cytoplasmic positivity for myeloperoxidase is usually seen ♦♦ Flow: typically positive for CD34, CD13, CD33 (often weak), often coexpress CD19, with variable CD56 ♦♦ Prognosis is good, compared to other types of AML

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Table 17.1.  Cytochemical Stains Useful in the Diagnosis of Hematopoietic Disorders Stain

Disorder

Staining Pattern

Comment

Myeloperoxidase (MPO)

AML, myeloblastic AML, myelomonocytic APML

>3% blasts stain positive

Sudan black B (SBB)

AML, myeloblastic AML, myelomonocytic APML

Results similar to those of MPO

Nonspecific esterase (NSE)

AML, monocytic AML, myelomonocytic AMKL

>3% of monoblasts or promonocytes stains positive

Chloroacetate esterase (CAE)

AML, myeloblastic APML

Less sensitive than MPO

PAS

ALL Erythroleukemia

Block positivity Perinuclear globules

TRAP a

Hairy cell leukemia

Abnormal lymphocytes are positive

Some SMZL may also be positive

LAP b

CML

Low LAP score

PNH may also have low LAP score

a

Highlights Auer rods

Tartrate resistant acid phosphatase Leukocyte alkaline phosphatase, test is performed by scoring 100 granulocytes 0–4, and adding scores

b

AML with inv(16)(p13.1q22) or t(16;16) (p13.1;q22) ♦♦ Most commonly results in fusion of CBFB/MYH11 genes. Accounts for 10–12% of cases of AML and often has features of myelomonocytic leukemia. Most cases have atypical eosinophil precursors with heavy granulation and abnormally large granules. Eosinophilia may or may not be present in the peripheral blood. Cytochemistry for myeloperoxidase is typically positive in blasts (at least 3%), and a component of monoblasts/promonocytes that are positive for NSE (See Table 17.1) ♦♦ Flow: component of myeloid blasts positive for CD13, CD117, CD15, CD33, and myeloperoxidase. The monocytic elements are variable positive for CD11b, CD4, CD14, and CD64. CD2 is often aberrantly expressed on myeloid component ♦♦ Prognosis is good, compared to other types of AML

AML with t(9;11)(p22;q23) ♦♦ Translocation of MLLT2/MLL genes. Occur more frequently in AML in infants (9–12%) and fewer adults AMLs (2%). It is also seen in association with therapy-related AML (see later section). Monocytic morphology is typical, or less commonly, myelomonocytic features are seen. Increased incidence of extramedullary involvement (e.g., myeloid sarcoma) is seen ♦♦ NSE positivity by cytochemistry is seen in most cases

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♦♦ Flow: There are no specific flow findings for AML with 11q23 abnormalities, but monocytic lineage markers (CD11b, CD4, CD14, CD64) are often positive ♦♦ Prognosis of t(9;11) is poor

Aml with Alternate Mll Translocations ♦♦ Translocation of MLL genes with several other partner genes including MMLT3, MLLT1, MLLT10, ELL, and others. [t(11;19); t(4;11), etc] ♦♦ Occur more frequently in therapy-related AML (see later section) ♦♦ Monocytic morphology is typical. ♦♦ Prognosis of MLL gene translocations in AML is typically poor.

Acute Promyelocytic Leukemia (Fig. 17.7) Definition ♦♦ An acute myeloid leukemia with a predominance of neoplastic promyelocytes. There are two morphologic variants: hypergranular or “typical” type, and the microgranular or hypogranular type

Clinical ♦♦ Clinically can be associated with disseminated intravascular coagulation, making this diagnosis a potential medical emergency. This subtype represents 5–8% of all cases of AML ♦♦ (FAB: AML-M3)

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Prognosis and Treatment ♦♦ Favorable prognosis AML ♦♦ Treatment includes use of all-trans-retinoic acid (ATRA), which effects differentiation on neoplastic cells. t(11;17) variant appears to be resistant to ATRA

AML with t(6;9)(p23;q34) ♦♦ Translocation of DEK/NUP214 genes. Represents 0.7–1.8% of AML and occurs in both children and adults. Monocytic morphology is typical, and basophilia and multilineage dysplasia are also frequently seen ♦♦ AML with t(6;9) is associated with a poor prognosis

AML (and MDS), Therapy-Related Fig.  17.7. Acute promyelocytic leukemia. This aspirate smear shows a large cluster of abnormal, granular promyelocytes.

Diagnosis ♦♦ Peripheral blood −− Microgranular variant typically has few cells with identifiable granules (Granules are present, but smaller than that can be resolved by eye – they can be seen by electron microscopy). Typical acute promyelocytic leukemia (APML) has hypergranular promyelocytes, often numerous in peripheral blood smear. Neoplastic promyelocytes are intermediate in size with irregular nuclei. Nuclei often have a “figure eight” or “dumbbell” shape. Auer rods may be seen; cells with numerous Auer rods are termed “faggot cells” ♦♦ Aspirate smear −− Abnormal promyelocytes account for at least 20% of cells. Promyelocytes are intermediate-sized cells with moderate amounts of cytoplasm and numerous granules; Auer rods may be present. Nuclear irregularities are common. Myeloperoxidase cytochemistry strongly stains abnormal promyelocytes ♦♦ Biopsy −− The core biopsies are typically hypercellular. Normal marrow elements are replaced by promyelocytes. These neoplastic promyelocytes often have irregular, folded nuclear contours, and moderate amounts of pink cytoplasm

Additional Studies ♦♦ Flow: Immunophenotype is characteristic but not entirely specific for APML. Phenotype is positive for myeloid markers CD13, CD33, and often weak CD117. They are almost always negative for CD34 and HLA-DR (in contrast to most other AML). About 20% of cases express CD56 ♦♦ Cytogenetics/molecular: classic translocation t(15;17) (q22;q12) – PML/RARA; other translocations can occur but are rare – t(11;17); t(5;17)

Differential Diagnosis ♦♦ Other types of AML

Alkylating Agent-Related AML ♦♦ Latency is usually 5–6 years after treatment. This type of AML often arises from a previous MDS or is associated with significant dysplastic features. Morphology may be myeloid, monocytic, myelomonocytic, or other AML types. Marrow fibrosis is not uncommon ♦♦ Flow: Abnormal blast population will be present and often expresses CD34, other myeloid markers (CD13, CD33), possibly monocytic markers (CD64, CD14), with variable expression of CD56 and CD7 ♦♦ Genetics: These cases often have complex cytogenetics and may include MDS-like changes including deletions/monosomies of chromosomes 5 and 7 ♦♦ Prognosis: Poor

Topoisomerase Type II Inhibitor-Related AML ♦♦ Latency is approximately 3 years after treatment. Drugs associated with this type of leukemia include epipodophyllotoxins, etoposide, and teniposide. Usually there is no preceding MDS phase. Morphology almost always is monocytic or has a monocytic component ♦♦ Cytogenetics: In this AML there are typically abnormalities that involve the MLL gene at 11q23 including translocations t(11;19), t(9;11), and t(4;11)

AML with Gene Mutations ♦♦ Specific gene mutations have been identified that are both associated with chromosomal translocations and independent of those changes. Mutations in FLT-3, NPM1, CEBPA, C-KIT, and WT1 are all associated with AML. Each change may be associated with specific prognostic implications. Most importantly, individual prognosis and therapy of AMLs will likely be based on these and other molecular subclassifications in future −− NPM1: Normal cytogenetics. Favorable prognosis −− CEBPA: Normal cytogenetics. Favorable prognosis −− FLT-3: Normal cytogenetics. Most common abnormality, internal tandem repeats (ITD) are associated with an adverse prognosis

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AML with Myelodysplasia-Related Changes

Additional Studies

♦♦ AML with a prior history of MDS or morphologic features of dysplasia. There is also an absence of previous cytotoxic therapy or findings associated with specific genetic changes of another AML type ♦♦ Morphologic features are those of MDS with >20% blasts in peripheral blood or bone marrow ♦♦ Prognosis is poor

♦♦ Flow −− Minimally differentiated cases are positive for at least one panmyeloid antigen such as CD13, CD33, or CD117. They are negative for B or T antigens. TdT is positive in about one-third of cases. Flow methods for myeloperoxidase are more sensitive than cytochemistry and are positive even in cases with negative cytochemistry −− In AML without and with maturation the immunophenotype is typically positive for CD34, CD13, and CD33 with variable CD117 ♦♦ IHC: These cases are often positive for CD34, but this marker lacks lineage specificity

AML, Not Otherwise Categorized ♦♦ Listed below, these leukemias are classified based on morphologic, immunophenotypic, or clinical findings, and lack features of other types of leukemias ♦♦ This large group accounts for the majority of cases of de novo AML

AML: Myeloblastic Definition ♦♦ As a group, these are acute leukemias with varying degrees of granulocytic lineage differentiation ♦♦ Acute myeloblastic leukemia, with minimal differentiation (FAB:AML-M0) ♦♦ Acute myeloblastic leukemia, without maturation (FAB: AML-M1) ♦♦ Acute myeloblastic leukemia, with maturation (FAB: AML-M0)

Prognosis ♦♦ AML with minimal differentiation is associated with a poor prognosis ♦♦ The prognosis is variable in AML with and without maturation. Their prognosis is dependent on underlying molecular and cytogenetic abnormalities present

AML: Monocytic/Monoblastic (Fig. 17.8) Definition ♦♦ An acute leukemia where >80% of the leukemic cells are of monocytic lineage; this includes monoblasts, promonocytes and mature monocytes. Neutrophils and precursors should be <20% (see AML, myelomonocytic)

Clinical

Clinical

♦♦ Combined, these groups account for 45–60% of AMLs. Typical symptoms of AML are often present

♦♦ AML monocytic or monoblastic represent 3–6% of all cases of AML. Extramedullary disease is common including gum infiltrates, cutaneous, and CSF involvement ♦♦ (FAB:AML-M5a monoblastic; FAB: AML-M5b – mono­ cytic)

Diagnosis ♦♦ Peripheral blood −− Varying numbers of blasts are seen. Blasts may be undifferentiated or have unequivocal features of myeloblasts including cytoplasmic granules occasionally with Auer rods ♦♦ Aspirate smear −− Blasts comprise at least 20%, but are often more numerous. Cytochemistry in minimally differentiation has no positivity for myeloperoxidase. In cases without maturation and with maturation, myeloperoxidase is positive in at least 3% (but usually more) blasts. (See Table 17.1) −− Minimally differentiated: Blasts are intermediate to large in size with open, delicate chromatin and small amounts of agranular cytoplasm −− Without maturation: Blasts account for >90% of the nonerythroid cells present; no myeloid maturation is identified −− With maturation: Blasts account for at least 20% of the cells present, at least 10% of the cells present display neutrophilic maturation, with <20% monocytic lineage cells; dysplastic features may be present in the neutrophilic series ♦♦ Biopsy −− Typically hypercellular with a prominent component of blasts present

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Fig.  17.8. AML, with monocytic/monoblastic differentiation. This peripheral blood smear illustrates monocytic differentiation in circulating blasts of AML.

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Diagnosis ♦♦ Peripheral blood −− Blasts are often present and varying from poorly differentiated to those with a clear monocytic appearance. Blasts of monocytic lineage often have nuclear folds or irregularities, increased amount of blue or blue-gray cytoplasm and lack cytoplasmic granules ♦♦ Aspirate smear −− Blasts or blast equivalents (promonocytes) in aspirate (or PB) are greater than 20%. Monocytic differentiation may be less apparent in aspirate than in peripheral blood. Promonocytes (immature monocytic forms) are counted as blasts, but may be difficult to distinguish from other cells types unless numerous. By cytochemistry, nonspecific esterase is typically positive in monoblasts and promonocytes (see Table 17.1) ♦♦ Biopsy −− Biopsy is usually hypercellular. The infiltration of blasts usually apparent. Promonocytes have somewhat folded irregular appearance of blast nuclei

Additional Studies ♦♦ Flow: Blasts population variably expresses monocytic/myeloid antigens including CD11b, CD14, CD4, CD64. CD117 expression is not uncommon. CD34 is less commonly positive in the neoplastic population ♦♦ IHC: Monocyte/macrophage markers (e.g., CD68, CD163, lysozyme) may be negative in less differentiated forms of leukemia ♦♦ Cytogenetics/molecular: cytogenetics abnormalities vary

Differential Diagnosis ♦♦ AML with monocytic differentiation and 11q23 abnormalities should be classified with “AML with recurrent cytogenetic abnormalities” group

Fig. 17.9. AML, myelomonocytic. This core biopsy is infiltrated by blasts, some with irregular folded nuclei, suggesting monocytic differentiation. −− By cytochemistry distinct populations of myeloperoxidase-positive and nonspecific esterase-positive blasts are present, representing the myeloblastic and monoblastic components, respectively (see Table 17.1) ♦♦ Biopsy −− The core biopsy is typically hypercellular. Blasts population is often large and easily identifiable

Additional Studies ♦♦ Flow: Immunophenotype by flow will typically show a component of myeloblasts (CD13, CD33, CD34) and monoblasts (CD11b, CD4, CD64, CD117) ♦♦ Cytogenetics/molecular: abnormalities are often present but nonspecific

AML: Myelomonocytic (Fig. 17.9) Definition

Differential Diagnosis

♦♦ An acute leukemia with proliferation of both monocytic and neutrophil precursors

Acute Megakaryoblastic Leukemia (Fig. 17.10) Definition

Clinical ♦♦ This subtype accounts for 15–25% of cases of AML. Myelomonocytic may have extramedullary manifestations similar to monocytic/monoblastic leukemias ♦♦ (FAB:AML-M4)

Diagnosis ♦♦ Peripheral blood −− Often large numbers of circulating monocytes are seen. Circulating (undifferentiated) blasts are commonly seen ♦♦ Aspirate smear −− At least 20% blasts (or blasts + promonocytes) are seen. In addition, there must be at least 20% monocytes and monocytic precursors, and at least 20% neutrophils and precursors

♦♦ AML with inv(16)

♦♦ Leukemic proliferation of blasts, with > 50% being of megakaryocytic lineage

Clinical ♦♦ This represents 3–5% of all cases of AML. Increased incidence seen in patients with Down syndrome (trisomy 21) ♦♦ (FAB:AML-M7)

Diagnosis ♦♦ Peripheral blood −− Circulating blasts often present. Abnormal or bizarre platelets or micromegakaryocytes may be seen ♦♦ Aspirate smear

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Fig. 17.10. Acute megakaryoblastic leukemia. The core biopsy is infiltrated by large, undifferentiated blasts. Inset: A single megakaryoblast, with cytoplasmic blebs.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  17.11. Erythroleukemia. This aspirate smear shows the severe erythroid dysplasia often seen in erythroleukemia.

Clinical −− Blasts are of medium-large size and the classic appearance of megakaryoblasts includes deep blue “blebs” of cytoplasm (ineffective formation of platelets) ♦♦ Biopsy −− The core biopsies are hypercellular. The cellularity is often composed of a uniform population of poorly differentiated, relatively large blasts. Severe reticulin fibrosis is common. Rarely, the presence of more mature, identifiable megakaryocytic forms are present

Additional Studies ♦♦ Flow: Megakaryoblasts express CD41 and/or CD61. Other myeloid markers vary ♦♦ IHC: Useful markers for identification of megakaryoblasts include Factor VIII, CD61, and CD42b ♦♦ Cytogenetics/molecular: Trisomy 21 and inv(3) can be seen, but no changes are specific for acute megakaryoblastic leukemia (AMKL). iso(12p) is seen exclusively in patients with mediastinal germ cell tumors

Differential Diagnosis ♦♦ Transient myeloproliferative disorder of Down syndrome (TMPD): immature cells and blasts in peripheral blood of Down syndrome patients; most cases remit spontaneously, while others progress to leukemia

Acute Erythroid Leukemia (Fig. 17.11) Definition ♦♦ Very rare acute leukemia that consists of two main subtypes −− Erythroleukemia is characterized by the presence of >50% erythroid precursors of all nucleated cells AND >20% myeloblasts of all nonerythroid cells present −− Pure erythroid leukemia is characterized by a marrow consisting of >80% immature erythroid cells without significant numbers of myeloblasts

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♦♦ Profound anemia is common. There is considerable diagnostic overlap with AML with myelodysplasia-related changes. It represents <5% of all types of AML. Pure erythroid ­leukemia is extremely rare (<1%) ♦♦ (FAB:AML-M6)

Diagnosis ♦♦ Peripheral blood −− Severe RBC anisopoikilocytosis is not uncommon. A component of circulating blasts may be present ♦♦ Aspirate smear −− Severe erythroid dysplasia is almost always present. Erythroid dysplasia includes: megaloblastoid chromatin, multinucleation, nuclear fragmentation, giant erythroblasts, cytoplasmic vacuolation. Immature erythroid cells are increased. More common type (erythroleukemia) includes component of typical myeloblasts (often with myeloperoxidase positivity) −− Cytochemistry in acute erythroid leukemia may highlight vacuoles in abnormal erythroid precursors with strong, abnormal PAS positivity. An iron stain may highlight ringed sideroblasts ♦♦ Biopsy −− The marrow cores are hypercellular, with increased ­erythroid elements. The amounts and distribution of blasts is variable depending on the type of acute erythroid leukemia. Core biopsy morphology of immature erythroid elements can mimic other disorders and should be confirmed by smear morphology or immunophenotypic confirmation

Additional Studies ♦♦ Flow: Prominent populations of erythroid cells are present (markers such as bright CD71 may confirm erythroid lineage). Myeloblasts, with typical myeloid markers (CD13, CD33, CD34, CD117) are variably positive

Bone Marrow

♦♦ IHC: Anti-hemoglobin or anti-glycophorin antibodies are often useful in identifying immature erythroid cells ♦♦ Cytogenetics/molecular: Complex karyotypes are common. Abnormalities of chromosomes 5 and/or 7 are fairly frequent

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Immature hematopoietic cells are present and represent immature myeloid, erythroid, and megakaryoblastic elements (as identified by IHC). Severe fibrosis is present in all cases

Prognosis

Additional Studies

♦♦ Often aggressive disease with a poor prognosis

♦♦ Flow: Not usually available due to lack of aspirate, if present may highlight increased myeloblasts ♦♦ IHC: CD34 is positive in subpopulation of blasts, mostly the myeloblasts. Some immature cells of erythroid lineage are identified by staining for hemoglobin or glycophorin. A component of immature cells of the megakaryocytic/blastic lineage can be identified by staining for Factor VIII, CD31, CD61, and CD42b

Acute Panmyelosis with Myelofibrosis (Fig. 17.12) Definition ♦♦ AML subtype with proliferation of multilineage blasts and significant bone marrow fibrosis

Clinical ♦♦ APMF is very rare account for <1% of all cases of AML. There is no or minimal splenomegaly, in contrast to PMF, an important differential diagnostic consideration. This entity is distinct from AMKL (see above) although historically cases may have been misclassified. This disorder is often associated with a rapid course and dismal prognosis. Previous names include acute myelofibrosis or acute myelosclerosis

Diagnosis ♦♦ Peripheral blood −− Often pancytopenia is seen, although occasional circulating blasts may be seen. Typically there is a lack of anisopoikilocytosis of red blood cells ♦♦ Aspirate smear −− Aspirates are typically hypocellular and hemodilute, as well as inaspirable due to reticulin fibrosis ♦♦ Biopsy −− The cores are hypercellular, with a proliferation of all lineages. Dysplasia of all cell lineages is typically present, but may be most prominent in megakaryocytes.

Differential Diagnosis ♦♦ AMKL, AML with fibrosis or MDS with fibrosis

Prognosis ♦♦ Very poor prognosis is noted, despite treatment

Other Forms of AML ♦♦ Acute basophilic leukemia: very rare, blasts >20% with evidence of basophilic differentiation

Acute Leukemias of Ambiguous Lineage Definition ♦♦ Acute leukemias which have morphologic, cytochemical, or immunophenotypic features that either: (1) lack clear features of either myeloid or lymphoid origin, or (2) have characteristics of both myeloid and lymphoid lineage or both B-cell and T-cell lineage ♦♦ Myeloid lineage is defined as either evidence of myeloperoxidase expression (by flow, IHC, or cytochemistry) or monocytic differentiation (cytochemical expression of NSE, or phenotypic expression of CD11c, CD14, CD64, or expression of lysozyme) ♦♦ T-cell lineage is defined as expression of cytoplasmic CD3 (by flow, or other methods) or surface CD3 expression (which is rare in leukemias of ambiguous lineage) ♦♦ B-cell lineage is characterized as expression of strong CD19 with strong expression of other B-cell antigens, such as CD79a, cytoplasmic CD22, or CD10 expression or weak expression of CD19 with strong expression of at least two additional antigens (CD79a, cytoplasmic CD22, or CD10)

Acute Undifferentiated Leukemia ♦♦ Lacks no more than one lineage specific markers for B-ALL, T lymphoblastic leukemia/lymphoma (T-ALL), and AML

Fig. 17.12. Acute panmyelosis with myelofibrosis. This core biopsy is hypercellular, with abnormal-appearing megakaryocytes, and a population of blasts. Extensive fibrosis is present, and the lineage of the blasts is usually characterized by immunohistochemistry.

Mixed Phenotype Acute Leukemia with t(9;22) (q34;q11.2) ♦♦ This diagnosis is observed in patients with an acute leukemia and no known previous history of CML. These will typically have a dimorphic blast population with typical appearing myeloblasts and lymphoblasts

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Mixed Phenotype Acute Leukemia with t(v;11q23) MLL Rearranged ♦♦ Has other criteria of mixed phenotype leukemia with translocations of the MLL gene ♦♦ Dimorphic population of blasts is seen

Mixed Phenotype Acute Leukemia, B/Myeloid, NOS ♦♦ Associated with a poor prognosis

Mixed Phenotype Acute Leukemia, T/Myeloid, NOS ♦♦ Associated with a poor prognosis

Blastic Plasmacytoid Dendritic Cell Neoplasm Definition ♦♦ A clinically aggressive neoplasm of cells derived from a precursor of plasmacytoid dendritic cells

Clinical ♦♦ Patients will often have both leukemic disease and cutaneous tumors. Most patients are elderly, and this neoplasm occurs in males more frequently. There is some association with CMML. Some cases will evolve from CMML, and BPDC is a “blast transformation” event

Diagnosis ♦♦ Peripheral blood −− Frequently peripheral blood appearance is of nonspecific blasts, with open chromatin, scant cytoplasm, prominent nucleoli and no or rare cytoplasmic granules ♦♦ Aspirate smear −− Aspirates may show numerous blasts or the infiltrates of neoplastic cells may be subtle ♦♦ Biopsy −− Involvement in the bone marrow can be subtle, or massive

Additional Studies ♦♦ Flow: Immunophenotype of these cells shows coexpression of CD4 and CD56, with expression of CD123. Other markers are variable, but often cases will express CD33, CD7, with fewer cases expressing CD2 and CD38. There is typically no expression of CD3, CD5, CD13, CD16, CD19, or CD20. CD34 and CD117 are negative and TdT is positive in a subset of cases ♦♦ IHC: Staining for CD4 and CD56 is of benefit, but expression of CD123 is very helpful as both a specific and sensitive stain for this neoplasm

Differential Diagnosis ♦♦ Chronic myelomonocytic leukemia

Prognosis ♦♦ Very poor prognosis is noted, despite treatment

ACUTE LYMPHOBLASTIC LEUKEMIA B-Cell Lymphoblastic Leukemia/Lymphoma (Fig. 17.13) Definition ♦♦ A neoplasm of lymphoid precursor cells (lymphoblasts) of B-cell origin which accounts for approximately ~90% of cases of ALL. There are two main subtypes of B-cell lymphoblastic leukemia/lymphoma (B-ALL), (1) those with recurrent cytogenetic abnormalities and (2) those without recurrent genetic abnormalities (referred to specifically as B lymphoblastic leukemia, NOS)

Clinical ♦♦ Common pediatric malignancy and is relatively rare in adults. Initial presentation may present as infection, due to underlying hematologic abnormalities. Extramedullary involvement (CSF, skin, gonads) is common ♦♦ Lymphoblastic lymphoma is tissue-based disease with no significant blood or bone marrow involvement. If bone marrow involvement is >25%, then lymphoblastic leukemia is the more appropriate terminology

Diagnosis ♦♦ Peripheral blood

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−− Anemia, and/or thrombocytopenia, and/or neutropenia are common. Circulating blasts are common ♦♦ Aspirate smear −− Blasts are often numerous, usually small-intermediate in size, with delicate chromatin and variably prominent nucleoli. The amount of cytoplasm varies, but is usually scant and agranular. Rarely, B-ALL may have some cytoplasmic granules, but has immunophenotypic evidence of B-ALL and lacks cytochemical positivity for myeloperoxidase or NSE −− Cytochemistry in many cases does not provide any specific diagnostic information in B-ALL. When used, there are small, paranucelar dots and blobs of PAS-positive material in many cases. These cases are negative for myeloperoxidase and NSE (see Table 17.1) ♦♦ Biopsy −− Cores are usually hypercellular. The marrow cellularity is often replaced by a homogeneous population of poorly differentiated blasts

Additional Studies ♦♦ Flow: Immunophenotyping is a mainstay of B-ALL diagnosis with frequent expression of CD19, CD10, and TdT,

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Fig. 17.13. Precursor B-cell acute lymphoblastic leukemia. This composite photo shows (left to right) core biopsy, TdT staining, CD79a staining in precursor B-ALL. variable positivity for CD34, no expression of surface immunoglobulin and also expression of cytoplasmic CD22+ and cytoplasmic CD79a ♦♦ IHC: In paraffin, staining for B-ALL is comparable to immunophenotype by flow with expression of CD19, CD22, CD10, TdT, CD79a, and variable positivity for CD34 ♦♦ Karyotype: Genetic information in B-ALL is important for prognostication, whether obtained by classical cytogenetics, panels of FISH probes, or other techniques. Recurrent genetic abnormalities that are defined by the 2008 WHO classification include −− t(9;22)(q34;q11.2); BCR/ABL (very unfavorable prognosis) * Aberrant expression of myeloid antigens is relatively common −− (variable;11q23); MLL rearranged (unfavorable prognosis) * Occasionally will see combination of CD15 expression and lack of CD10 −− t(12;21)(p13;q22); TEL/AML1 (ETV6/RUNX1) (very favorable prognosis) −− t(1;19)(q23;p13.3); PBX/E2A (neutral prognosis) −− Hypodiploid (unfavorable prognosis) −− Hyperdiploid >50 (very favorable prognosis) −− t(5;14)(q31;q32); IL3/IGH (neutral prognosis)

some may be larger and more immature; flow cytometry of hematogones can be similar to B-ALL, but has important differences in maturation and intensity of antigen expression (Fig. 17.14)

Prognosis ♦♦ General prognosis of pediatric ALL is excellent ♦♦ Adult ALL typically has a poor prognosis

Burkitt Leukemia/Lymphoma (Fig. 17.15) Definition ♦♦ An aggressive, high grade malignancy of B-cells (Although not a precursor lesion like ALL, this topic is discussed in this section for convenience) ♦♦ Previously referred to as a type of ALL in the FAB classification (so-called FAB-ALL-L3)

Clinical ♦♦ There are three clinical settings: (1) endemic type, (2) sporadic type, and (3) immunodeficiency-related. Typically occurs in young patients (<20 years) except in immunodeficiencyrelated group. Usually present with tissue masses (lymphomatous presentation) although rarely present as a leukemic form, which is seen more commonly in males

Differential Diagnosis

Diagnosis

♦♦ Hematogones: Benign B-cell precursors, which are frequently present in pediatric bone marrows; when numerous, may mimic ALL; often are smaller than ALL blasts, but

♦♦ Peripheral blood −− Circulating abnormal lymphocytes are variably present. Various cytopenias may be seen

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Fig.  17.14. Hematogones. Although there is some variation in size, the majority of the hematogones are small with condensed chromatin. −− Although only rarely performed cytochemistry may highlight cytoplasmic vacuoles which are PAS negative (in contrast to B-ALL) but stain positively for lipid stains including Oil Red O ♦♦ Biopsy −− Core biopsies are often hypercellular. Involvement by Burkitt leukemia/lymphoma (BL) is often extensive. Rarely, in diffuse areas of involvement, a classic “starry sky” appearance is seen in marrow

Additional Studies

Fig. 17.15. Burkitt leukemia. Extensive marrow infiltration by a monomorphic population of intermediate-size lymphocytes in an AIDS patient.

♦♦ Aspirate smear −− When there is marrow involvement, numerous abnormal lymphocytes are seen. Abnormal lymphocytes are intermediate in size with round-to-irregular nuclear contours, and small to moderate amounts of vacuolated cytoplasm. The chromatin is often more condensedappearing than ALL

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♦♦ Flow: By immunophenotyping, BL will have expression of CD19, CD10, and CD20 with expression of restricted surface light chains. TdT is negative, as is CD5 ♦♦ IHC: Staining of the core will shows positivity for CD20, bcl-6, and CD10, and light chain restricted is sometimes demonstrable. Proliferation rate by Ki67 is near 100%. There is no expression of TdT, CD5, cyclin D1, or bcl-2 ♦♦ Cytogenetics/molecular: t(8;14) is most common, but t(2;8) or t(8;22) are seen in 15–20% of cases. The translocation of c-MYC gene at 8q24 can be illustrated by FISH probes

Differential Diagnosis ♦♦ Blastic or blastoid-appearing neoplasms including ALL, blastoid mantle cell, blastic plasmacytoid dendritic cell neoplasm

Prognosis ♦♦ Prognosis of BL is considerably worse than ALL. Bone marrow involvement is associated with poor prognosis

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T Lymphoblastic Leukemia/Lymphoma Definition ♦♦ A neoplasm of lymphoid precursor cells (lymphoblasts) of T-cell origin which accounts for 10–15% of cases of pediatric ALL

Clinical ♦♦ T-ALL often associated with a mediastinal mass (precursor T-cell lymphoblastic lymphoma), but in almost all cases, there is bone marrow involvement. Peripheral blood involvement is more variable. T-ALL is more common in adolescents or older children and occurs more commonly in males compared to females

Diagnosis ♦♦ Peripheral blood −− High WBC count with numerous blasts is common ♦♦ Aspirate smear −− Blasts are similar to B-ALL; they are intermediate size, blastic chromatin, scant cytoplasm. T-ALL often has more nuclear irregularity than B-ALL, but this is not a strong diagnostic criterion. Cytochemistry is not commonly used, however, cytochemical staining for acid phosphatase may show dot-like cytoplasmic positivity, which can be seen in T-ALL, but is not entirely specific

♦♦ Biopsy −− The degree of bone marrow involvement varies. Associated eosinophilia may be rarely seen

Additional Studies ♦♦ Flow: Immunophenotype is an important diagnostic tool with expression of CD3 common, variable expression of pan-T-cell antigens CD2, CD5, and CD7. CD4 and CD8 are often both positive. TdT is typically positive, as is CD1a. CD10 is variable but is less commonly positive than in B-ALL ♦♦ IHC: Staining in T-ALL will be positive for CD3, variably positive for CD2, CD5, and CD7, often positive for CD1a, CD4 and CD8 often both positive, TdT is positive, and CD10 variable ♦♦ Cytogenetics: Genetic rearrangements will often involve the T-cell receptor genes at 14q11 and 7q35

Differential Diagnosis ♦♦ B-ALL, AML, and other “small blue cell tumors” of childhood. All of these diagnoses must be distinguished by Immunophenotype

Prognosis ♦♦ Worse prognosis than B-ALL, but often this is due to higher stage disease presentation

MYELODYSPLASTIC SYNDROMES Myelodysplastic Syndromes (MDS): General Definition

♦♦ Dysgranulopoiesis includes: nuclear hypolobation (bilobed neutrophils, pseudo Pelger–Huet), hypersegmentation (rare), hypogranulation, abnormal granules, donut or ring-shaped granulocytes/precursors, and increased blasts

♦♦ A group of clonal disorders of hematopoietic stem cell, associated with ineffective hematopoiesis, peripheral cytopenias and increased risk of progression to AML

Clinical ♦♦ Usually seen in older adults. MDS are very rare in children. Cytopenias are common

Diagnosis ♦♦ Marrow elements involved are often increased in number in the marrow spaces but do not circulate (e.g., ineffective hematopoiesis). Aspirate is most useful in assessing dysplastic features ♦♦ Dyserythropoiesis includes: megaloblastoid changes (lack of nuclear maturation with abnormal chromatin clumping relative to maturing cytoplasm), multinucleation, nuclear fragmentation (karyorrhexis), nuclear budding, cytoplasmic vacuolation (typically PAS positive), internuclear bridges (Fig. 17.16)

Fig. 17.16. Myelodysplastic syndrome. Dyserythropoiesis in MDS.

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Table 17.2. Cytogenetics in Myelodysplastic Syndromes Relative prognosis Cytogenetic abnormalities Good Poor Intermediate

Fig.  17.17. Myelodysplastic syndrome. A dysplastic megakaryocyte in MDS.

Normal, −Y, del(5q), del(20q) Complex (>3 abnormalities), −7, or other abnormalities of chromosome 7 All other abnormalities

not obtained or did not yield a result, or when morphologic findings are limited and the presence of clonal abnormalities may clarify results. Typical panels for MDS FISH would include probes for 5q, chromosome 7, 20q, and chromosome 8. Deletions of these first three are common findings in MDS. Trisomy 8 is a common abnormality in many myeloid disorders

Prognosis ♦♦ Dysmegakaryopoiesis includes: small or large size, hypolobated or monolobated nuclei, separated nuclear lobes, abnormalities in cytoplasmic granulation (Fig. 17.17) ♦♦ ALIP or abnormal localization of immature precursors can be seen. In normal marrows, immature granulocytes tend to be adjacent to bone trabeculae. In ALIP there are clusters of immature cells (blasts, promyelocytes) in interstitial spaces, not adjacent to bone ♦♦ MDS with fibrosis represents about 10% of cases of MDS. Most cases of MDS with fibrosis are associated with increased blasts and often have an aggressive clinical course. Since aspirate smears are often not obtained, much of the diagnostic information must be obtained from core biopsy. CD34 staining of the core can provide important information on the number of blasts present ♦♦ Hypocellular MDS is rare and represents about 10% of all cases of MDS. Hypocellularity has no specific impact on prognosis, but can create diagnostic difficulties. Extra care must be taken to evaluate for other causes of marrow hypercellularity

Ancillary Studies ♦♦ Flow: Flow cytometry has become an important tool in establishing a diagnosis of MDS in bone marrow. Although sensitivity varies depending on antigen panels, technique, and operator experience, reproducible abnormalities of myeloid (and erythroid) immunophenotype can be seen in flow cytometry of MDS cases. While it is not prudent to diagnose MDS solely based on flow cytometric results, these abnormal findings can strongly support a diagnosis, especially in cases where morphologic findings are equivocal or technically compromised ♦♦ FISH: The use of panel of FISH studies may provide valuable adjunctive information in the diagnosis of MDS. The advantages of FISH studies are that they may provide results even in cases where a sample for routine cytogenetics was

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♦♦ Prognosis depends on specific diagnosis, percentage of blasts, and cytogenetic defects (see Table 17.2).

Refractory Cytopenia with Unilineage Dysplasia Definition ♦♦ An MDS characterized by symptoms and morphologic changes limited primarily to a single marrow lineage. The most common of these is refractory anemia (RA), with dysplasia of the erythroid lineage with a relatively low rate of progression to AML. Rare entities, refractory neutropenia (RN) and refractory thrombocytopenia (RT) are exceedingly rare and the biologic behavior has not been well defined

Clinical ♦♦ These entities accounts for 10–20% of all cases of MDS. Specific clinical features depend on the specific cytopenia. In RA, symptoms related to anemia, including fatigue and weakness are typical

Diagnosis ♦♦ Peripheral blood −− In RA, red blood cells are normocytic or slightly macrocytic. Anisocytosis and poikilocytosis may be present, as well as dimorphic red blood cell populations ♦♦ Aspirate smear −− In RA, there are increased numbers of erythroid elements (a result of ineffective erythropoiesis) with dyserythropoiesis in at least 10% of the erythroid elements. Blasts account for <5% of marrow cellularity −− In RN and RT, respectively, dysplastic features are seen in the granulocytic or megakaryocytic lineages in at least 10% of their respective lineages. Importantly, dysplasia is limited to only a single lineage and blasts

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are not increased, or other specific MDS diagnoses would be made ♦♦ Biopsy −− Often hypercellular due to increased ineffective erythropoiesis, dysplastic neutrophil precursors or abnormal megakaryocytes, but only a single of these lineages are involved

Additional Studies ♦♦ Cytogenetics/molecular: Clonal abnormalities present in up to 50% of cases. Some cases may have del(20q), trisomy 8; and deletion or monosomy of chromosomes 5 or 7

Differential Diagnosis ♦♦ Causes of anemia or other cytopenias due to specific vitamin deficiencies (iron, B12, folate) need to be excluded ♦♦ Dyserythropoiesis or other lineage dysplasia from other causes including postchemotherapy, medications, toxins, etc ♦♦ Should be differentiated from refractory anemia with ringed sideroblasts (RARS, below), which would have the presence of ringed sideroblasts

Prognosis ♦♦ Progression to AML is rare (approximately 2–5%)

Refractory Anemia with Ringed Sideroblasts Definition ♦♦ An MDS characterized by symptoms and morphologic changes limited primarily to the erythroid lineage, at least 15% ringed sideroblasts, and a relatively low rate of progression to AML

Clinical ♦♦ Chronic anemia that is either macrocytic or normocytic. Occasionally there are symptoms associated with iron overload

Diagnosis ♦♦ Peripheral blood −− Mild anisopoikilocytosis, sometimes with a dimorphic red blood cell population ♦♦ Aspirate smear −− The presence of ringed sideroblasts is primary to the diagnosis −− Ringed sideroblasts are erythroid precursors with granules of stainable iron that surround at least one-third of nuclear circumference (Fig. 17.18). Iron stain shows at least 15% of erythroid cells are ringed sideroblasts −− Dysplastic features of erythroid elements are seen ♦♦ Biopsy −− Marrows are normo- to hypercellular. There are increased erythroid elements. Blasts are not increased (<5%). Megakaryocytes are normal in number and morphology. Rarely, Prussian blue stain on core or clot section may reveal numerous ringed sideroblasts

Fig. 17.18. Refractory anemia with ringed sideroblasts. This iron stain illustrates several ringed sideroblasts in a case of RARS.

Differential Diagnosis ♦♦ Other causes of ringed sideroblasts include: excessive alcohol intake, certain drugs (esp. anti-tubercular medications, chloramphenicol), excess of minerals (lead, copper, zinc), or rare inherited sideroblastic anemias

Prognosis ♦♦ Relatively good prognosis with only 1–2% of RARS eventually evolving into AML

Refractory Cytopenia with Multilineage Dysplasia Definition ♦♦ An MDS characterized by dysplasia of two or more cell lineages with bi- or pancytopenia

Clinical ♦♦ Accounts for 15% of cases of MDS

Diagnosis ♦♦ Peripheral blood −− Less than 1% blasts are seen. Monocytes are <1 × 109/L (to eliminate CMML as a possible diagnosis). Dysplastic features are commonly seen in granulocytes anisopoikilocytosis of red blood cells is common ♦♦ Aspirate smear −− Less than 5% blasts are seen. Dysplasia of myeloid, erythroid and megakaryocytic cell lines may be seen. Dysplastic changes are present in at least 10% of two cell lineages. If >15% ringed sideroblasts seen on iron stain, diagnosis would be “refractory cytopenia with multilineage dysplasia (RCMD) and ringed sideroblasts” ♦♦ Biopsy −− Marrow cores are hypercellular. Dysplastic features of megakaryocytes may be prominent

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Additional Studies ♦♦ Cytogenetics/molecular: Karyotypic changes or FISH abnormalities correlate with prognosis (see Table 17.2)

Prognosis ♦♦ Approximately 10% of cases progress to AML

Refractory Anemia with Excess Blasts Definition ♦♦ MDS with dysplasia of multiple lineages and 5–19% blasts in bone marrow ♦♦ Refractory anemia with excess blasts (RAEB)-1: 5–9% blasts in bone marrow, <5% blasts in PB ♦♦ RAEB-2: 16–19% blasts in bone marrow, 5–19% blasts in peripheral blood or presence of Auer rods in cases with <20% blasts

Clinical

Fig. 17.19. 5q- Syndrome. Note the small, hypolobated megakaryocyte, which are common in this subtype of MDS.

♦♦ Anemia is a common finding

Diagnosis

Clinical

♦♦ Peripheral blood −− Dysplastic features common in granulocytes; anisopoikilocytosis in RBC. Circulating blasts may be seen. There is frequently thrombocytopenia. In some cases, platelets may have morphologic abnormalities ♦♦ Aspirate smear −− Blasts are increased; the count, based on an aspirate smear, is critical to specific diagnosis, classification, and prognosis. Multilineage dysplastic features are common. ♦♦ Biopsy −− Cores are hypercellular and clusters or aggregates of blasts or immature myeloid forms are often seen. Dysplasia of megakaryocytes is common

♦♦ Anemia is common. Occasionally thrombocytosis is present (unusual for an MDS which are most often associated with cytopenias)

Additional Studies ♦♦ IHC: CD34 may be useful in identifying clusters of blasts in core biopsies ♦♦ Cytogenetics/molecular: Common karyotypic abnormalities include trisomy 8, monosomy of chromosome 5 or del(5q), monosomy of chromosome 7 or del(7), and del(20q) (see Table 17.2)

Prognosis ♦♦ Median survival in RAEB-1 is 16 months, with a progression to AML within 2 years of 25%. Median survival in RAEB-2 is 9 months, with a progression to AML within 2 years of 33%

Diagnosis ♦♦ Peripheral blood −− Macrocytosis of red blood cells. Occasionally blasts may be seen (<5%). Platelets are normal or increased in number ♦♦ Aspirate smear −− Less than 5% blasts are seen. Normal to increased numbers of megakaryocytes. These megakaryocytes are typically relatively small in size with hypolobated or unilobated nuclei ♦♦ Biopsy −− Hypercellular core biopsies are seen. Increased numbers of hypolobated megakaryocytes are noted and these may be in clusters

Additional Studies ♦♦ Cytogenetics/molecular: Deletion of long arm of ­chromosome 5 involving bands q31–33. If additional abnormalities are present, then case would be classified as another type of MDS

Prognosis ♦♦ Lenalidomide therapy has shown significant benefit in patients with MDS with isolated del(5q)

MDS with Isolated Del(5q) (Fig. 17.19) Definition

MDS, Unclassifiable

♦♦ MDS associated with an isolated deletion of 5q, abnormal megakaryocytes, and a relatively good prognosis

♦♦ Similar to other MDS, but lacks features to make a diagnosis of a specific subtype

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Clinical ♦♦ Similar to other MDS ♦♦ Cytopenias

−− Lacks erythroid dysplasia (or consider a diagnosis of A) ♦♦ Biopsy −− Usually hypercellular

Diagnosis

Differential Diagnosis

♦♦ Peripheral blood −− No blasts are seen ♦♦ Aspirate smear

♦♦ Typically a diagnosis of exclusion ♦♦ Must rule out other reactive conditions, MDS/MPD disorders, or specific types of MDS

MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES Chronic Myelomonocytic Leukemia (Fig. 17.20) Definition ♦♦ CMML is a clonal stem cell disorder with a predominant proliferation of mature monocytic elements in the peripheral blood and bone marrow ♦♦ Features of dysplasia may be present or proliferative features without dysplasia may be seen ♦♦ CMML-1: blasts <5% in blood, <10% in marrow ♦♦ CMML-2: blasts 5–19% in blood or 10–19% in marrow

Clinical ♦♦ Monocytosis is >1 × 109/L. WBC is often found (~50% of patients) ♦♦ Fever, weight loss, fatigue, night sweats are not uncommon. Splenic enlargement is not uncommon

Diagnosis ♦♦ Peripheral blood

−− Monocytosis including immature forms (promonocytes), almost always >10% of all circulating WBCs. May see dysgranulopoiesis of WBCs (hypolobation, hypogranulation) ♦♦ Aspirate smear −− Less than 20% blasts are present. Blast counts include myeloblasts and immature monocytic forms (monoblasts and promonocytes). Monocytic elements may be difficult to appreciate by morphology alone; cytochemical (e.g., NSE) or immunohistochemical stains (CD68, CD163) may be of benefit −− Dyserythropoiesis (megaloblastoid changes, ringed sideroblasts, nuclear fragmentation, etc.) may be seen ♦♦ Biopsy −− Bone marrow is typically hypercellular. Consists of a predominant proliferation of granulocytic and monocytic elements, although monocytic elements may be difficult to appreciate by morphology alone. Dysplastic features may be seen in megakaryocytes −− Variable degrees of fibrosis may be seen

Additional Studies ♦♦ Flow: Increased monocytic elements are identified. These are positive for CD13, CD33, variable expression of CD11b, CD64, and CD14; presence of CD34 or CD117 suggests immature cells are present ♦♦ IHC: CD34 may highlight blasts; clusters or >20% may suggest transformation to AML ♦♦ Cytogenetics/molecular: +8; −7/del(7q); 12p abnormalities; point mutations of RAS gene are seen in many patients

Differential Diagnosis ♦♦ CML – differentiated by cytogenetics ♦♦ AML with monocytic or myelomonocytic differentiation: blasts or blasts + promonocytes >20% ♦♦ MDS/MPN with presence of t(5;12) – morphology is similar to CMML but is now categorized with hematologic disorders with PDFGR/FGFR abnormalities Fig. 17.20. Chronic myelomonocytic leukemia. Peripheral blood that shows increased monocytes and granulocytes.

Treatment and Prognosis ♦♦ Progression to AML in 15–30% of cases

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Atypical Chronic Myeloid Leukemia, BCR/ABL1 Negative Definition ♦♦ Proliferative disorder of bone marrow elements, with a predominance of granulocytic forms in peripheral blood; lacks features of other MPNs or MDS, and lacks cytogenetic and molecular evidence BCR/ABL1

Clinical ♦♦ Anemia is often present ♦♦ Splenomegaly is common

Diagnosis ♦♦ Peripheral blood −− WBC is increased to varying degrees. Increased mature and immature neutrophils are present. Monocytosis should be minimal and account for <10% of total white blood cells. Basophilia should be minimal or absent ♦♦ Aspirate smear −− Blasts account for <20% of cells. Increased M:E ratio is typical (often >10:1). Dysgranulopoiesis is common including pseudo Pelger–Huet changes, abnormal nuclear lobation, or abnormal cytoplasmic granulation ♦♦ Biopsy −− Marrow is hypercellular. Increased granulocytes and precursors are present. <20% blasts are present (or diagnose as AML) −− Reticulin fibrosis may be present

Additional Studies ♦♦ Flow/IHC: May show an increase in myeloid blasts, but as above, if >20%, then a diagnosis of AML should be made ♦♦ Cytogenetics/molecular: +8, del(20q), iso(17q), del(12p) can be found but are not specific for atypical chronic myeloid leukemia (aCML). JAK2 mutation has been reported in a subset of cases. NRAS or KRAS mutations have also been reported in approximately 30% of cases

Differential Diagnosis ♦♦ CML: presence of BCR/ABL1 translocation differentiates CML from aCML ♦♦ MDS: typically have cytopenias rather than leukocytosis ♦♦ CMML: degree of monocytosis is a critical distinction for diagnosis of CMML

Treatment and Prognosis ♦♦ Prognosis is poor compared to CML

Juvenile Myelomonocytic Leukemia Definition ♦♦ Clonal hematopoietic disorder of children with proliferation of monocytes and granulocytes lacking BCR/ABL1 ♦♦ Should have all major criteria (M) and at least two minor criteria (m) for diagnosis (see below)

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Clinical ♦♦ May present with constitutional symptoms such as fever, pallor, and weakness. Often presents as infection including bronchitis or tonsillitis. Bleeding may be a presenting sign. Leukemic infiltrates in tissues (esp. skin) can be seen

Diagnosis ♦♦ Peripheral blood −− Monocytosis >1 × 109/L (M) −− Hemoglobin F increased for age (m) −− Immature granulocytes may be present in blood (m), but blasts are <20% (M) −− WBC count >10 × 109/L (m) −− Anemia (often macrocytic) and thrombocytopenia are common −− Eosinophilia and basophilia may be seen ♦♦ Aspirate smear −− Blasts (+ promonocytes) <20% (M) −− Monocytes may be increased. Usually only minimal dyspoiesis is present. Cytochemical stains (NSE) may be useful in identifying monocytic elements ♦♦ Biopsy −− Hypercellular marrow. Increase in granulocytic and monocytic elements present. Megakaryocytes are often decreased

Additional Studies ♦♦ Cytogenetics/molecular: clonal chromosome abnormalities may be present including monosomy 7 (25%) (m); in vitro test shows myeloid progenitors hypersensitive to GM-CSF (m)

Differential Diagnosis ♦♦ CML: pediatric cases of CML exist, but are rare. They do have BCR/ABL1 translocation

Treatment and Prognosis ♦♦ Prognosis is poor, but better when patients are <1 year at time of presentation ♦♦ Bone marrow transplantation is currently the treatment of choice

Myelodysplastic/Myeloproliferative Disease, Unclassifiable Definition ♦♦ A default diagnosis of a marrow disorder that shares features of both MDS and MPD, but lacks specific features for a diagnosis of a specific entity, such as CMML ♦♦ RARS and thrombocytosis is a provisional entity in the WHO classification. It is characterized by: persistent anemia, numerous ringed sideroblasts, dysplasia of granulocytic elements, marked thrombocytosis with abnormal-appearing platelets, with or without leukocytosis, and with or without basophilia. The majority of cases are associated with the presence of JAK2 mutations. Because of its rarity, clinical behavior of this entity is uncertain

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B-CELL LYMPHOPROLIFERATIVE DISORDERS Monoclonal B-Cell Lymphocytosis Definition ♦♦ Monoclonal or oligoclonal expansions of B-cells with a ­phenotype of chronic lymphocytic leukemia (CLL, see below). These occur in older patient. At present, the natural history of this disorder is unclear. What appears to be true is that not all cases progress to overt lymphoid leukemia (e.g., CLL), but some of the cases will progress

Chronic Lymphocytic Leukemia (Fig. 17.21) Definition ♦♦ Neoplastic proliferation of predominantly small, matureappearing B-cells that coexpress CD5 and CD19; it is the blood and bone marrow counterpart to small lymphocytic lymphoma (SLL)

Clinical ♦♦ Patients are typically >50 years old. They are often asymptomatic but may have anemia, fatigue, infections or symptomatic splenomegaly

Diagnosis ♦♦ Peripheral blood

−− Clinical presentation is often isolated elevated WBC composed of small, mature lymphocytes −− Lymphocytes may have characteristic clumped chromatin with “cracked earth” or “soccer ball” pattern. Smudge or basket cells are often seen −− Lymphocytes are typically round with little cytoplasm, although rare cases may have irregular nuclear contours or, more rarely, plasmacytoid differentiation. Those with less condensed nuclear chromatin or irregular nuclei are referred to as “atypical CLL” −− Rare prolymphocytes (larger lymphocytes, with prominent single central nucleoli and increased amounts of amphophilic cytoplasm) are seen, but usually number less than 10% of lymphocytes ♦♦ Aspirate smear −− Increased number of small, round, mature-appearing lymphocytes are seen; variable numbers of prolymphocytes are also seen ♦♦ Biopsy −− Degree and pattern of lymphocytic infiltration varies. Infiltration may nodular, interstitial or diffuse. Degree of involvement varies widely. Rarely, vague nodules, with increased large cells (pseudofollicles) similar to those in lymph nodes are seen

Fig. 17.21. Chronic lymphocytic leukemia. Peripheral blood in CLL (left) and nodular infiltration of bone marrow (right).

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Additional Studies

B-Cell Prolymphocytic Leukemia (Fig. 17.22)

♦♦ Flow: Lymphocytes have a characteristic immunophenotype with coexpression of CD5 and CD19. These lymphocytes also express dim CD20, CD23, and lack FMC7, and CD10 expression. CD38+ and ZAP-70+ cases may have a more aggressive clinical course ♦♦ IHC: Expression of CD5, CD20, CD23, CD43, and bcl-2 are typical. CD10, cyclin D1, and bcl-6 are negative ♦♦ Cytogenetics: The most characteristic genetic abnormalities are tested for by FISH studies. Deletion of 13q is common (~80%) and is associated with a good prognosis. Deletions of 11q (4–27%) are associated with a poor prognosis. Trisomy 12 is (15–19%) is associated with a poor prognosis. Deletion of 17p is associated with a poor prognosis ♦♦ Molecular: Immunoglobulin heavy chain mutation status (IGCH) is prognostic. Unmutated CLL (corresponding to a pregerminal center origin) are associated with a poor prognosis. In contrast, mutated CLL (postgerminal center origin) is associated with a relatively good prognosis

Definition

Differential Diagnosis ♦♦ Other “small B-cell” lymphomas with splenic involvement including follicular lymphoma (FL), marginal zone, mantle cell lymphoma (MCL), and lymphoplasmacytic lymphoma

♦♦ B-cell neoplasm consisting of predominantly prolymphocytes (>55% in blood); some cases are derived from preexisting cases of CLL while other occur de novo

Clinical ♦♦ Patients present with high WBC, often >100 × 109/L. Splenomegaly is usually present. Lymphadenopathy is rare

Diagnosis ♦♦ Peripheral blood −− Numerous intermediate-large size lymphocytes, with mature chromatin, small-moderate amounts of amphophilic cytoplasm and a single, prominent, central nucleolus ♦♦ Aspirate smear −− Cells similar to those in peripheral blood are seen ♦♦ Biopsy −− Typically hypercellular, the marrow has interstitial or nodular aggregates of lymphocytes. Marrow infiltrated by population of intermediate-large size lymphocytes, many with prominent nucleoli

Additional Studies ♦♦ Flow: By flow cytometry typical findings include CD20+ and bright expression of surface Ig. FMC-7, CD23, and CD5 expression are variable

Fig. 17.22. B-Prolymphocytic leukemia. Peripheral blood (left) showing two prolymphocytes (large size, prominent central nucleolus) and bone marrow infiltrated by B-PLL (right).

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♦♦ IHC: PLL expresses CD20. Cyclin D1 is negative

Diagnosis

Differential Diagnosis

♦♦ Peripheral blood −− Increased numbers of small lymphocytes, plasma cells, and lymphoplasmacytoid cells are seen. Rouleaux formation may be severe due to paraprotein in blood ♦♦ Aspirate smear −− Increased numbers of lymphocytes, lymphoplasmacytic cells, and plasma cells seen. Dutcher bodies (intranuclear Ig inclusions) and Russell bodies (intracytoplasmic Ig inclusions) not uncommon; inclusions are often PAS positive ♦♦ Biopsy −− Nodular or interstitial infiltrates of lymphocytes, plasmacytoid cells and plasma cells. The aggregates are often paratrabecular in location

♦♦ Need to consider variants of MCL with leukemic presentation; cyclin D1 stain is necessary to evaluate the possibility of MCL ♦♦ CLL: The number of prolymphocytes in peripheral blood may be the only distinguishing criteria, making distinction from B-Cell prolymphocytic leukemia (B-PLL) difficult occasionally

Prognosis ♦♦ Poor prognosis

Lymphoplasmacytic Lymphoma/Leukemia/ Waldenstrom Macroglobulinemia (Fig. 17.23) Definition ♦♦ An indolent form of B-cell lymphoma composed of lymphocytes, plasmacytoid lymphocytes, and plasma cells with bone marrow and blood involvement

Clinical ♦♦ Weakness and fatigue due to anemia are common symptoms. The majority of patients have serum monoclonal protein of IgM type. Some patients (30%) have symptoms of hyperviscosity, caused by large amounts of serum monoclonal IgM protein ♦♦ Waldenstrom macroglobulinemia (WM) is currently defined as lymphoplasmacytic lymphoma/leukemia (LPL) with bone marrow involvement and a serum IgM monoclonal gammopathy of any concentration ♦♦ Serum protein may result in autoimmune symptoms ­(hemolytic anemia, neuropathy), coagulopathy or have ­cryoglobulin properties. Less common findings include cryoglobulinemia, neuropathies, deposition of IgM protein in skin or GI tract, or coagulopathies

Additional Studies ♦♦ Flow: Clonal B-cells which express CD19, with light chain restriction and lack of CD5, CD10, and CD23; Plasma cell population will express CD38, CD138 and monotypic cytoplasmic light chain expression. Lymphoplasmacytic cells may combine features of B lymphocytes (CD20 expression, surface immunoglobulin) with features of plasma cells (CD38, CD138) ♦♦ IHC: Findings are similar to flow. B-cells are positive for CD20, and plasma cells are positive for CD138. Both have monotypic light chain expression. Cyclin D1, CD5, and CD10 are not expressed ♦♦ Cytogenetics/molecular: Deletion 6, contrary to previous reports, is rare in LPL. Other rare cytogenetic changes include trisomies of 3, 4, and 18

Differential Diagnosis ♦♦ LPL is considered a diagnosis of exclusion. The differential diagnoses include marginal zone lymphoma (MZL), CLL/ SLL (with plasma cell differentiation), plasma cell dyscrasias ♦♦ Amyloidosis

Marginal Zone Lymphoma Definition ♦♦ B-cell lymphoma, thought to be derived from marginal zone cells ♦♦ Different subtypes of MZL include splenic MZL (SMZL), nodal MZL (NMZL), and extranodal (MALT-type) MZL (EMZL) ♦♦ SMZL with peripheral blood involvement formerly known as “splenic lymphoma with villous lymphocytes”

Clinical Fig. 17.23. Lymphoplasmacytic lymphoma. Marrow infiltrated by LPL. A mixture of lymphocytes, plasma cells, and lymphoplasmacytic cells are seen. Dutcher bodies (intranuclear immunoglobulin pseudoinclusions) can be seen.

♦♦ Degree of blood and bone marrow involvement varies with type; SMZL almost always has bone marrow involvement with variable peripheral blood involvement. In EMZL and NMZL, blood and bone marrow involvement is rare

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Diagnosis ♦♦ Peripheral blood −− Circulating abnormal lymphocytes, often with increased amounts of cytoplasm, nuclear irregularities, plasmacytoid features, or villous projections (SMZL) may be seen ♦♦ Aspirate smear −− Varying numbers of abnormal lymphocytes including small mature forms, plasmacytoid lymphocytes, plasma cells, and larger transformed lymphocytes may be seen ♦♦ Biopsy −− Degree of involvement varies from subtle to extensive involvement −− Pattern of involvement may be nodular, interstitial, or diffuse. SMZL often has subtle intrasinusoidal infiltration (seen best by IHC)

Additional Studies ♦♦ Flow: Positive for CD19, CD20, and FMC7 with variable expression of CD23; CD5, and CD10 are negative. CD103 is not expressed (in contrast to hairy cell leukemia) ♦♦ IHC: Abnormal lymphocytes express CD20 but lack expression of CD10, CD5, bcl-6, and cyclin D1 ♦♦ Cytogenetics/molecular: IgH gene rearrangements are positive. Allelic loss of 7p21–32 is seen in up to 40% of cases. Trisomy 3q and other abnormalities can be seen rarely

Differential Diagnosis ♦♦ Hairy cell leukemia: differential expression of CD103 can be helpful ♦♦ Follicular lymphoma: lack of CD10 and bcl-6 expression can help distinguish involvement. However, examination of tissue biopsy is the most reliable method of distinction ♦♦ Other “small cell” B-cell lymphomas

Follicular Lymphoma (Fig. 17.24) Definition ♦♦ A lymphoma derived from neoplastic follicle center cells with frequent marrow involvement (40%)

Clinical ♦♦ Low grade FL (Grade 1 or 2) are typically indolent diseases with relentless growth. Grade 3 FL has a more aggressive clinical course and is more similar in behavior to diffuse large B-cell lymphoma (DLBCL)

Diagnosis ♦♦ Peripheral blood −− Significant numbers of circulating cells are seen in follicular lymphoma in about 10% of cases. Morphology is typically small lymphocytes, with cleaved or notched nuclei and small amounts of cytoplasm ♦♦ Aspirate smear −− Because of associated fibrosis, neoplastic lymphocytes may be rare or absent in aspirate smears. Large clumps or

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Fig.  17.24. Follicular lymphoma. Classic paratrabecular lymphoid aggregate of follicular lymphoma in bone marrow biopsy.

aggregates of lymphocytes may be present in aspirate. Cytology depends on grade, but is typically small- to intermediate-sized lymphocytes with irregular nuclei and scant cytoplasm ♦♦ Biopsy −− Bone marrow cellularity varies with degree of involvement. Lymphoid aggregates in FL are typically paratrabecular, hugging the contours of the bone. Although typically small irregular lymphocytes are most common, large cells may be present in varying numbers −− Marrow may have discordant morphology compared to other sites of involvement; often marrow has low grade appearance, with higher grade lymphoma at other site. Less often, marrow has higher grade lymphoma (e.g., diffuse large B-cell lymphoma) with low grade lymphoma present in nodal sites

Additional Studies ♦♦ Flow: Because of fibrosis, flow cytometry may be negative. When present, FL cells are positive for CD19, CD20, and CD10 with light chain restriction. CD5 is typically negative although exceedingly rare CD5 positive FL is seen ♦♦ IHC: CD20 highlights B-cell aggregates in the marrow. Aggregates may show expression of bcl-6 and CD10, although expression may be decreased in decalcified specimens. Bcl-2 staining in bone marrow is less specific, as it is positive in most B-cell lymphomas. Cyclin D1 is negative ♦♦ Cytogenetics/molecular: Evidence of t(14;18)(q32q21) IgH/bcl-2 translocation is seen in the majority of cases of FL

Differential Diagnosis ♦♦ Paratrabecular aggregates are seen typically in FL, but this finding is not specific for FL and can be seen in a number of other lymphoma types

Bone Marrow

Mantle Cell Lymphoma (Fig. 17.25) Definition ♦♦ A neoplastic proliferation of typically small B lymphocytes which overexpress the cyclin D1 gene product and or have the characteristic t(11;14) and express CD5. Usually a tissuebased disease, peripheral blood and bone marrow involvement are not uncommon ♦♦ Blastoid variant of MCL are characterized by: (1) blastic chromatin or (2) larger pleomorphic nuclei. Blastoid MCL is associated with a more aggressive clinical course

Clinical ♦♦ Typically seen in older male patients. Disseminated disease is common at presentation

Diagnosis ♦♦ Peripheral blood −− Nonblastoid MCL lymphocytes in PB are small, with condensed mature chromatin and cleaved or notched nuclear contours and scant amounts of cytoplasm −− Blastoid MCL involvement in the peripheral blood is characterized by intermediate to large lymphocytes with open, blastic chromatin ♦♦ Aspirate smear −− Increased numbers of small lymphocytes with cleaved or irregular nuclei. Rarely large atypical, pleomorphic cells or intermediate- to large-sized-blastoid lymphocytes ♦♦ Biopsy −− Infiltrates are nodular or diffuse, with varying degrees of marrow involvement

Additional Studies ♦♦ Flow: Flow cytometry is characteristic, but not diagnostic of MCL. Abnormal lymphocytes express CD19, CD5, with bright surface light chain (more often lambda), and bright CD20 and FMC7 expression. (This is in contrast to CLL/

Fig. 17.25. Mantle cell lymphoma. Diffuse infiltration of bone marrow by MCL.

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SLL, which typically has dim CD20 and surface light chain and is negative for FMC7). CD23 is usually negative, but up to 25% of cases of MCL may have dim or partial expression of CD23 ♦♦ IHC: CD5+, CD20+, bcl-2+, CD43+, Cyclin D1+ (p53 often positive and Ki67 often increased in blastoid variant), CD10−, CD23−, bcl-6− ♦♦ Cytogenetics/molecular: t(11;14); translocation of the bcl-1 gene and the IgH gene leading to overexpression of cyclin D1, a cell cycle regulator

Differential Diagnosis ♦♦ Other small B-cell lymphomas: Expression of cyclin D1 or presence of t(11;14) will typically distinguish MCL from other types ♦♦ Acute lymphoblastic leukemia: can be confused with blastoid MCL. The expression of surface Ig light chains, CD20, and coexpression of CD5 will distinguish these entities

Treatment and Prognosis ♦♦ Because of its uniquely poor prognosis, MCL therapy is often more intensive than therapies for other small B-cell lymphomas

Hairy Cell Leukemia (Fig. 17.26) Definition ♦♦ An uncommon B-cell neoplasm that prominently involves spleen, bone marrow, and peripheral blood with distinctive “hairy” appearance in peripheral blood

Clinical ♦♦ Usually exhibits indolent clinical behavior. Splenomegaly is characteristic. Clinical findings are usually related to marrow replacement (anemia) or symptoms associated with splenomegaly

Diagnosis ♦♦ Peripheral blood −− Increased small-medium sized lymphocytes with homogeneous, mature chromatin, inconspicuous nucleoli and characteristic “hairy” cytoplasmic projections. Lymphocytes are positive for tartrate-resistant acid phosphatase (TRAP), which is not seen in normal lymphocytes −− Cytopenias are common; monocytopenia is most characteristic ♦♦ Aspirate smear −− These are often unavailable due to “dry tap.” Touch preparations are beneficial. Lymphocytes with round, centrally placed nuclei, with moderate amounts of clearto-pale cytoplasm are seen ♦♦ Biopsy −− Variable degrees of infiltration by abnormal lymphocyte population are seen. Almost invariably this disease is associated with severe reticulin fibrosis. Abnormal lymphocytes are often present in subtle interstitial infiltrates, with small, centrally-placed nuclei and moderate amounts of clear cytoplasm (“fried egg” appearance)

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Fig. 17.26. Hairy cell leukemia. Bone marrow with “fried egg” appearance of HCL (left) and TRAP immunostain (right).

Additional Studies

Diagnosis

♦♦ Flow: Typical findings of a B-cell lymphoma including positivity for CD19 and bright CD20 with light chain restriction. Other more characteristic findings include expression of CD11c, CD22, CD25, and CD103. CD10 expression is seen in a subset of cases. Annexin A1 is positive in HCL and is a very specific finding ♦♦ IHC: Staining in the lymphocytes includes positivity for CD20, CD123, T-bet, DBA.44, and TRAP. Cyclin D1 expression is seen in some cases of HCL ♦♦ Cytogenetics/molecular: No specific cytogenetic abnormalities are found. Clonal IgH rearrangements present ♦♦ 2-chlorodeoxyadenosine (2-CDA) is an effective therapy ♦♦ Typically excellent prognosis with current therapies

♦♦ Peripheral blood −− Rarely seen but when present, there are circulating large, atypical lymphoid cells ♦♦ Aspirate smear −− Marrow fibrosis often prevents DLBCL being present in aspirate. Touch preparation may be of benefit. Large lymphoid cells, occasionally with immunoblastic features may be seen in some cases ♦♦ Biopsy −− Degree of marrow involvement varies widely. Cells are large in size, but may be intermixed with smaller lymphocytes (either reactive or low grade component of lymphoma). Distribution may be paratrabecular, interstitial, or diffuse in pattern

Diffuse Large B-Cell Lymphoma

Additional Studies

Definition

♦♦ Flow: B-cells which express CD19 and CD20, with light chain restriction, although occasionally there is a complete lack of surface light chain expression. CD10 is positive in 40%, and CD5 is positive in approximately 5–10% of cases ♦♦ IHC: CD20 is positive in almost all cases. Other markers are variably positive depending on type ♦♦ Cytogenetics/molecular: Abnormalities of 3q27 are a relatively common; t(14;18) can be seen in a subset of cases; IgH rearrangements are positive

Treatment and Prognosis

♦♦ A heterogeneous category inclusive of several malignancies of large B-cells. There are a variety of methods for subtyping such as cell derivation, immunophenotype, and distinctive clinical features. DLBCL may be de novo or arise as a transformation of a low grade B-cell lymphoma

Clinical ♦♦ Primary diagnosis rarely made in bone marrow. Prognosis is mostly dependent on stage

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T- and NK-CELL LYMPHOPROLIFERATIVE DISORDERS T-Cell Prolymphocytic Leukemia (Fig. 17.27)

Additional Studies

Definition

♦♦ Anemia and thrombocytopenia are common. Splenomegaly is always present, and sometimes massive. Clinically patients may present with splenic infarct or rupture. Cutaneous involvement is not uncommon

♦♦ Flow: Abnormal lymphocytes are positive for CD3, CD4, and CD7, and are typically negative for CD8 and CD56. Rarely T-cell prolymphocytic leukemia (T-PLL) is CD4 negative and CD8 positive ♦♦ IHC: Stains for T-cell markers (CD3, etc.) are positive ♦♦ Cytogenetics/molecular: TCR are clonally rearranged. Cytogenetic abnormalities include inv 14(q11;q32) or t(14;14)(q11;q32) may be seen. Clonal T-cell receptor studies are present

Diagnosis

Differential Diagnosis

♦♦ Aggressive T-cell leukemia with prominent involvement of blood, bone marrow, and spleen

Clinical

♦♦ Peripheral blood −− Lymphocyte counts are usually >100 × 109/L. Most often the lymphocytes are large sized with single, prominent central nucleolus, round-to-irregular nuclear contours, condensed chromatin and a small-to-moderate amount of pale cytoplasm ♦♦ Aspirate smear −− Typically large populations of fairly uniform large-sized lymphocytes with mature chromatin, irregular nuclei, and prominent nucleoli are seen ♦♦ Biopsy −− Marrows are often hypercellular. There are interstitial or diffuse infiltrates of monotonous lymphoid cells

♦♦ T-cell CLL, a proliferation of small more mature-appearing neoplastic T-cells, is controversial and not included as a separate entity in WHO classification but is considered a morphologic subtype of T-PLL

Anaplastic Large Cell Lymphoma (Fig. 17.28) Definition ♦♦ T-cell lymphoma with a wide spectrum of morphologic appearances, although most commonly consisting of large, pleomorphic cells which are, by definition, positive for CD30 ♦♦ Two main types: ALK + and ALK−

Fig. 17.27. T-Prolymphocytic leukemia. Peripheral blood (left) and bone marrow aspirate (right) in T-PLL. Note differences from B-PLL see in Fig. 17.22.

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Treatment and Prognosis ♦♦ ALK + cases have better prognosis (compared to ALK−) although leukemic forms have a worse prognosis ♦♦ ALK − cases have poor prognosis similar to PTCL

Sezary Syndrome/Mycosis Fungoides Definition ♦♦ Mycosis fungoides (MF) is a usually indolent, cutaneous neoplasm of T-cells. Sezary syndrome (SS) is a similar disorder to MF, but has systemic involvement including lymph nodes, frequent blood and bone marrow involvement (leukemia), and an aggressive clinical course

Clinical ♦♦ SS occurs exclusively in adults. Erythroderma is common Fig. 17.28. Anaplastic large cell lymphoma. Large, pleomorphic cells with multilobated nuclei infiltrating bone marrow.

Clinical ♦♦ Marrow is involved in 15–25% of cases

Diagnosis ♦♦ Peripheral blood −− Leukemic forms are rare; circulating tumor cells are typically large with irregular nuclei and may have blastic chromatin ♦♦ Aspirate smear −− Unless marrow involvement is extensive, tumor cells are only rarely seen in aspirate smears ♦♦ Biopsy −− Degree and pattern of involvement varies. Rare isolated tumor cells with extensive fibrosis may be present. Large clusters of lymphoma cells may be present −− In small cell variant/leukemic forms, marrow may be diffusely involved with pleomorphic blast-like cells. Immunohistochemistry should be used in cases for staging, as marrow involvement may be subtle

Additional Studies ♦♦ Flow: Often difficult to diagnose as a specific neoplasm, although findings do support abnormal T-cells. Neoplastic cells are only occasionally CD3 positive (25–50%), positive for CD4 and CD2, usually CD7 negative and are variable for CD45 ♦♦ IHC: By definition, anaplastic large cell lymphoma (ALCL) is positive for CD30. CD3 is positive in 25–50%. ALK1 is positive in subset of cases. Rare cases with “null” phenotype lack most T-cell markers, but are often positive for CD43 ♦♦ Cytogenetics/molecular: ALK + will have t(2;5) – NPM/ ALK; or variants t(1;2), t(2;3), t(2;17), t(2;19) or other translocations involving ALK gene. Clonal T-cell gene rearrangements are found in 90% of cases

Differential Diagnosis ♦♦ Other T-cell lymphomas or Hodgkin lymphoma may have similar morphology

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Diagnosis ♦♦ Peripheral blood −− Diagnostic criteria vary for SS; however, most agree that at least 1.0 × 109/L neoplastic lymphocytes are the minimum. Lymphocytes are often small with condensed chromatin and folded, cerebriform nuclei. Nuclear folds can be accentuated by using H&E or Pap stain on blood smear ♦♦ Aspirate smear −− Increased numbers of small-medium sized lymphocytes with irregular nuclear contours are seen ♦♦ Biopsy −− Hyper- or normocellular marrows are seen with diffuse interstitial or nodular aggregates of lymphocytes. Infiltrates may be subtle and can be highlighted by immunohistochemistry

Additional Studies ♦♦ Flow: The preferred method for evaluating PB involvement in SS; Abnormal lymphocytes are positive for CD3, CD4, and CD5 with loss of CD7 expression ♦♦ IHC: T cell markers including CD3 are positive. CD7 is typically negative ♦♦ Cytogenetics/molecular: Clonal rearrangements of T-cell receptor are seen

Differential Diagnosis ♦♦ Infiltration of bone marrow by other T-cell lymphomas

Treatment and Prognosis ♦♦ SS is an aggressive disease with poor (10–20%) 5-year survival ♦♦ Transformation to large T-cell lymphoma has an especially grave prognosis

Adult T-Cell Leukemia/Lymphoma (Fig. 17.29) Definition ♦♦ T-cell lymphoproliferative disorder associated with the HTLV-1 virus infection. There are several clinical variants based on clinical presentation including: acute; lymphomatous; chronic; smoldering

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Differential Diagnosis ♦♦ Other T-cell lymphoid proliferations with leukemic involvement

Treatment and Prognosis ♦♦ Depends on clinical variant. Leukemic and lymphomatous variants tend to have a poor prognosis

Hepatosplenic T-Cell Lymphoma (Fig. 17.30) Definition ♦♦ Neoplasm of T-cells that characteristically affects spleen, liver, and bone marrow. Often have surface expression of gamma/delta T-cell receptor, which normally accounts for only a very small percentage of normal T-cells

Clinical Fig.  17.29. Adult T-cell leukemia/lymphoma. This peripheral blood illustrates the classic “flower-like” appearance of lymphocytes in ATLL.

Clinical ♦♦ Associated with infection by HTLV-1, patients are typically from Japan, Caribbean, or Central Africa. The median age is 55 years, with a M:F = 1.5:1. Hypercalcemia is a common finding (~70%). Lytic bone lesions and skin lesions are common. All patients present with disseminated disease of varying degrees. Opportunistic infections are frequent due to T-cell immunodeficiency

Diagnosis ♦♦ Peripheral blood −− Medium to large-sized lymphocytes with mature, clumped chromatin are seen. Lymphocyte nuclei often have a characteristic polylobated or “flower” shape. Rarely, lymphocytes are more blast-like in appearance ♦♦ Aspirate smear −− Cell similar to those in PB are seen, but marrow involvement may be less extensive than expected from degree of blood involvement ♦♦ Biopsy −− Infiltrates vary in amount and involvement may be subtle. Infiltrates are composed of small- to intermediate-sized lymphocytes with moderate amounts of nuclear pleomorphism. Bone changes, including prominent osteoblasts may be seen

Additional Studies ♦♦ Flow: Abnormal T-cells express CD3, CD2, CD5, CD4, and lack expression of CD7 and CD8 ♦♦ IHC: CD3 staining may be necessary to appreciate subtle infiltrates in bone marrow ♦♦ Cytogenetics/molecular: T-cell receptors are clonally rearranged. HTLV-1 is present in all cases. Clonal cytogenetic abnormalities are almost always seen, but no changes are specific for adult T-cell leukemia/lymphoma (ATLL)

♦♦ Most commonly in adolescent and young adult males. Increased in incidence in posttransplant setting. Spleen and liver involvement are always present. Spleen often shows characteristic intrasinusoidal/red pulp pattern of involvement

Diagnosis ♦♦ Peripheral blood −− Typically small- to intermediate-sized lymphocytes with mature-appearing chromatin, irregular nuclei and small amounts of chromatin. Rarely, lymphocytes with more blastic-appearing with less condensed chromatin and larger size are seen ♦♦ Aspirate smear −− Increased numbers of atypical lymphocytes are seen ♦♦ Biopsy −− Marrow is typically hypercellular, with prominent infiltrates of neoplastic lymphocytes. The abnormal lymphocytes have an intrasinusoidal distribution. Infiltration may be subtle on H&E sections; immunohistochemistry is important to identify degree of infiltration

Additional Studies ♦♦ Flow: The lymphocytes are positive for CD3, with variable CD56, and are typically “double negative” for CD4 and CD8. Most cases express surface gamma/delta T-cell receptor, although some rare cases express alpha/beta ♦♦ IHC: In marrow abnormal lymphocytes can be highlighted by staining for CD3 and TIA-1. HSTCL cells are variably positive for CD56, and are negative for CD4, CD8, and CD5. EBV is typically negative ♦♦ Cytogenetics/molecular: Isochromosome 7q is found in almost all cases. Clonal rearrangement of T-cell receptor is seen in all cases

Differential Diagnosis −− Other T-cell leukemias/lymphomas −− Leukemic forms of NK malignancies – cytogenetics and clinical findings should differentiate ♦♦ Prognosis −− Aggressive disease with poor prognosis −− Median survival <2 years

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Fig. 17.30. Hepatosplenic T-cell Lymphoma. Bone marrow shows infiltration by abnormal lymphocytes (left), with an intrasinusoidal distribution, illustrated by CD2 stain (right).

T-Cell Large Granular Lymphocytic Leukemia (Fig. 17.31) Definition ♦♦ A proliferation of cytotoxic T lymphocytes (85% of cases), or more rarely NK cells. In many cases, these proliferations are nonneoplastic and associated with autoimmune diseases such as rheumatoid arthritis. Occasionally, these proliferations are neoplastic and would be termed T-cell LGL leukemia, or less commonly NK cell LGL leukemia (also known as chronic lymphoproliferative disorder of NK cells; see below)

Clinical ♦♦ There is a strong association with autoimmune disease, such as Felty syndrome, rheumatoid arthritis, Sjogren syndrome, and SLE

Diagnosis ♦♦ Peripheral blood −− Review of the peripheral blood often reveals neutropenia or other cytopenias. Increased large granular lymphocytes are seen. If lymphocytes are less than 2.0 × 109/L, the diagnosis requires confirmation of clonality by molecular techniques. ♦♦ Aspirate smear

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Fig. 17.31. Large granular lymphocytic leukemia. Several abnormal lymphocytes, some with obvious cytoplasmic granules in the peripheral blood in a case of LGL leukemia. −− May see increased small-medium sized lymphocytes with irregular nuclear contours with or without cytoplasmic granules ♦♦ Biopsy

Bone Marrow

−− Often hypercellular marrows with interstitial infiltrates, and occasional aggregates of small-medium sized lymphocytes

Additional Studies

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Differential Diagnosis ♦♦ Primary diagnosis of T-cell lymphoma in marrow can be ­difficult; correlation with a diagnostic tissue biopsy is recommended

♦♦ Flow: pan-T-cell markers (CD2, CD3, CD5, CD7) may be present; CD56 usually negative ♦♦ IHC: Lymphocytes may be positive for CD3, CD8, and cytotoxic markers (e.g. TIA-1), CD57 ♦♦ Cytogenetics/molecular: clonal T-cell receptor gene rearrangements in CD8-positive LGL disease; NK-types do not have clonal rearrangements of the T-cell receptor; clonality can be assessed by X-linked gene analysis or cytogenetics

Prognosis

Differential Diagnosis

♦♦ Two WHO entities are encompassed under this heading, Aggressive natural killer (NK) leukemia (ANKL); chronic lymphoproliferative disorder of NK cells (CLPD-NK)

♦♦ Other T-cell lymphomas including mycosis fungoides, hepatosplenic T-cell lymphoma and other T-cell lymphomas ♦♦ Oligoclonal proliferations of T cell may be seen in post-bone marrow transplant settings ♦♦ Distinction of reactive and leukemia forms of LGL proliferations may be difficult. Presence of clonal T cell receptor rearrangements supports a diagnosis of T-LGL leukemia, but this may behave as an indolent disease

Other Types of T-Cell Lymphoma (Peripheral T-Cell Lymphoma, Angioimmunoblastic T-Cell Lymphoma, etc.) Definition ♦♦ Marrow or blood involvement by T-cell lymphomas occurs in high stage disease. Marrow involvement is common in angioimmunoblastic T-cell lymphoma

Diagnosis ♦♦ Peripheral blood −− Variable involvement, although relatively rare. Atypical lymphocytes may be present ♦♦ Aspirate smear −− Variable degrees of atypical lymphocytes are seen ♦♦ Biopsy −− Involvement may be nodular, interstitial, or diffuse in pattern. Involvement may be associated with significant fibrosis. Neoplastic T-cells may also be seen associated with mixed infiltrates including plasma cells, eosinophils, or macrophages

Additional Studies ♦♦ Flow: Abnormal T-cells will typically express CD3, and other T-cell markers are variable in expression although often there is loss of pan-T-cell antigens such as CD7 ♦♦ IHC: Staining for CD3 will highlight T-cells, with variable positivity for other T-cell markers ♦♦ Cytogenetics/molecular: TCR are rearranged. No specific cytogenetic abnormalities although clonal abnormalities may be seen

♦♦ Most T-cell lymphomas are aggressive and have a poor prognosis. Bone marrow involvement usually implies high stage disease

Natural Killer Leukemias and Lymphomas Definition

Clinical ♦♦ Typically very poor prognosis in ANKL, with poor response to standard therapies. CLPD-NK cells has a more indolent clinical course

Diagnosis ♦♦ Peripheral blood −− In ANKL, blastic cells are seen in peripheral blood. These will rarely have fine cytoplasmic granules −− CLPD-NK will have increased large granular lymphocytes ♦♦ Aspirate smear −− In ANKL, blastic cells present in smears, but can be difficult to positively assign a lineage (e.g., myeloid versus lymphoid blasts, NK versus T) ♦♦ Biopsy −− Infiltration of marrow can be focal or diffuse

Additional Studies ♦♦ Flow: Most critical for characterization of these entities, flow findings include a lack of surface CD3 expression, expression of CD2 and CD56 with variable expression of CD16 (~75%) and less commonly CD57 ♦♦ IHC: CD43, CD56 are expressed and often CD3 (cytoplasmic) positive. EBV is almost always positive ♦♦ Cytogenetics/molecular: No clonal rearrangements of TCR

Differential Diagnosis ♦♦ It is unclear if this represents a leukemic form of extranodal NK/T cell lymphoma (nasal type), or represent a distinct pathologic or clinical entity ♦♦ Other blastic malignancies, such as AML or ALL ♦♦ Other T-cell lymphomas

Prognosis ♦♦ ANKL: Typically behaves as an aggressive disease with very poor prognosis

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HODGKIN LYMPHOMA Classic Hodgkin Lymphoma (Fig. 17.32) Definition ♦♦ A malignancy of “crippled” B-cells which produce large characteristic malignant cells, Reed–Sternberg (R–S), and Hodgkin cells and a characteristic background tissue reaction

Clinical ♦♦ Patients may have “B” symptoms: fever, night sweats, and weight loss. Marrow involvement implies Stage IV disease

Diagnosis ♦♦ Peripheral blood −− PB involvement is almost never seen in classic Hodgkin lymphoma (CHL) ♦♦ Aspirate smear −− Because of associated fibrosis, little or no evidence of CHL is present in aspirate smears. Touch preparations may show Hodgkin or R–S cells ♦♦ Biopsy −− Degree of involvement is variable. Identification of fibrotic background with classic Hodgkin or R–S cells is diagnostic, although immunohistochemical confirmation is prudent. The presence of fibrosis without atypical large cells, necrosis, granulomas, or cellular background (histiocytes, eosinophils, plasma cells) without classic

R–S cells should be considered suspicious for involvement by CHL

Additional Studies ♦♦ IHC: CD30 is useful in identifying R–S cells. CD15/CD45 may be less helpful because of staining of background marrow elements

Differential Diagnosis ♦♦ Microscopic differential includes other neoplasms with rare, large malignant cells with a polymorphous background including: T-cell/histiocyte-rich large B-cell lymphoma, ALCL and others

Treatment and Prognosis ♦♦ Prognosis is typically excellent but is related to stage; marrow involvement usually implies higher stage disease

Nodular Lymphocyte-Predominant Hodgkin Lymphoma Definition ♦♦ A neoplasm of rare, large, atypical B-cells, with a characteristic background composed of small lymphocytes. The neoplastic cells, termed L&H cells are large and share some features with Hodgkin cells. However, nodular lymphocytepredominant Hodgkin lymphoma (NLPHL) is a disease distinct from CHL. Marrow involvement is very rare

Diagnosis ♦♦ Peripheral blood −− PB involvement almost never seen ♦♦ Aspirate smear −− Because of fibrosis, aspirate smear is usually uninformative ♦♦ Biopsy −− Findings are similar to CHL. Fibrotic foci with large atypical cells. Immunohistochemistry is helpful to confirm phenotype

Additional Studies ♦♦ IHC: Large atypical cells are positive for CD20, CD45, and are negative for CD30 and CD15

Differential Diagnosis Fig.  17.32. Classic Hodgkin lymphoma. Bone marrow involvement by CHL, with several Hodgkin and Reed–Sternberg cells.

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♦♦ Differential includes CHL and other B-cell lymphomas such as T-cell/histiocyte-rich DLBCL

Bone Marrow

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PLASMA CELL DISORDERS Reactive Plasmacytosis (Fig. 17.33)

Clinical

Definition

♦♦ Twice as common in blacks as whites. Common clinical findings include: anemia, bone pain, renal failure, neurologic symptoms, etc ♦♦ Laboratory: Presence of monoclonal immunoglobulin protein in serum (90%) or urine (75%) is seen. Monoclonal immunoglobulin protein is detectable by protein electrophoresis, immunolelectrophoresis, or immunofixation. Isotypes are variable: IgG (55%), IgA (22%), light chain only (18%), IgD (2%), IgE (<1%), IgM (<1%) ♦♦ Radiologic evidence of lytic lesions is common. Increased B2-microglobulin and hypercalcemia are commonly seen

♦♦ Increases in benign bone marrow plasma cells that may simulate a neoplasm of plasma cells; rarely plasma cells may increase to 20% or higher in reactive conditions, simulating myeloma

Clinical ♦♦ Common associations of reactive increases of plasma cells include: alcoholism, autoimmune diseases, viral infections (esp. hepatitis viruses, HIV/AIDS), immune deficiency states, drugs, etc. Plasma cell proliferations in HIV/AIDS may be associated with human herpesvirus-8 (HHV-8) infection

Diagnosis ♦♦ Although increased in number, plasma cells are cytologically mature. Reactive plasma cells are polyclonal by kappa/ lambda light chain analysis. Patients do not have a monoclonal protein (M-protein) in serum or urine

Plasma Cell Myeloma (Figs. 17.34 and 17.35) Definition ♦♦ Neoplastic proliferation of plasma cells with systemic involvement

Diagnosis ♦♦ Peripheral blood −− Rouleaux may be present due to increased levels of serum immunoglobulin. Circulating plasma cells are rare ♦♦ Aspirate smear −− Plasma cells typically easily identified on Wright– Giemsa-stained aspirates. Plasmacytic myeloma is characterized by a predominance of mature plasma cells with eccentric round nuclei with condensed chromatin, and deep blue cytoplasm with a pale perinuclear hof. Immature morphology includes features such as prominent nucleoli, large nuclear size, and central placement of nuclei.

Fig. 17.33. Plasmacytosis. Polyclonal plasmacytosis in a patient with hepatitis.

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Fig. 17.34. Plasma cell myeloma. Marrow replacement by myeloma (left) and a CD138 stain, highlight plasma cells (right).

Fig. 17.35. Plasma cell myeloma. Marrow involvement may be patchy in myeloma (left); light chain stains may show clear evidence of monoclonality (right).

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Bone Marrow

Plasmablastic morphology is characterized by blastic chromatin with prominent nucleolus, small amounts of deep blue cytoplasm and large size; plasmablasts can be easily confused with erythroblasts. Anaplastic morphology includes wide variations in size, nuclear shape, and cytologic detail of plasma cells; it may be difficult to differentiate from carcinoma, melanoma, etc ♦♦ Biopsy −− Cellularity depends on degree of involvement. Involvement may be patchy or diffuse. Plasma cells are usually present in sheets and clusters. Thinned bone trabeculae, increased osteoblasts, and osteoclasts may be seen

Additional Studies ♦♦ Flow: Flow cytometric detection of clonal plasma cells using expression of CD138 or CD38 and cytoplasmic light chains can accurately identify clonal plasma cells. However, ­quantitation of marrow involvement by marrow involve­ ment by flow typically markedly underestimates degree of involvement ♦♦ IHC: Stains to identify/quantify plasma cells include CD138, CD38, and VS38c. Kappa and lambda light chains, either by immunohistochemistry or in situ staining, may be used to prove clonal nature of plasma cells. Ki67, p53, cyclin D1, CD117 may provide additional prognostic information in myeloma ♦♦ Cytogenetics/molecular: FISH studies for myeloma are frequently used, as routine cytogenetics may not yield satisfactory results. Typical panel for FISH studies for myeloma would include testing for deletion of 13q14 (common, associated with a better prognosis), del(17p) (less common, associated with a poor prognosis), translocations of IGH/bcl-1 (rare, associated with a better prognosis), and translocations of IGH/FGFR3 (rare, poor prognosis). Complex karyotypes are also relatively common

Differential Diagnosis ♦♦ Reactive plasmacytosis; monoclonal gammopathy of undetermined significance (MGUS); other lymphoproliferative disorders with plasma cell differentiation

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Diagnosis ♦♦ Peripheral blood −− No specific findings ♦♦ Aspirate smear −− <10% plasma cells that are morphologically mature ♦♦ Biopsy −− Plasma cell infiltrates are usually minimal in degree and scattered in distribution

Additional Studies ♦♦ IHC: CD138 or VS38c may be useful to enumerate plasma cells; kappa/lambda may show polyclonal or monoclonal plasma cells

Primary Amyloidosis (Fig. 17.36) Definition ♦♦ Primary amyloidosis is a disorder of abnormal deposition of monoclonal immunoglobulin protein in various tissues

Clinical ♦♦ Organ, vascular, or coagulation dysfunction may be present due to amyloid deposition

Diagnosis ♦♦ Peripheral blood −− Typically no significant PB findings ♦♦ Aspirate smear −− In aspirate, amyloid may appear as waxy, homogeneous nodules −− Plasma cells may be seen, but often in surprisingly low numbers ♦♦ Biopsy −− Amyloid deposition is seen most often in walls of vessels, later in interstitial spaces

Treatment and Prognosis ♦♦ Plasmablastic morphology (>2% plasmablasts) has been associated with a decidedly worse prognosis

Monoclonal Gammopathy of Undetermined Significance Definition ♦♦ Clinical entity with production of a monoclonal serum protein (IgG in 75% of cases) without evidence of myeloma or other systemic lymphoproliferative disorder

Clinical ♦♦ Incidence increases with age; rare before age 50. 25–30% of patients eventually develop myeloma, amyloidosis, or other lymphoproliferative disorders. Latency between MGUS and development of other disorders may be 10 years or more

Fig. 17.36. Amyloidosis. Amyloid deposition in marrow, as an acellular, pink material. Inset: positive Congo Red stain.

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−− Amyloid appears as glassy, homogenous pink material on H&E −− Congo red stains amyloid brick red, which shows characteristic apple-green birefringence on polarization

Additional Studies

Clinical ♦♦ Occurs in about 2% of cases of PCM and is more frequently seen in light chain, IgE, and IgD myeloma

Diagnosis

♦♦ IHC: Plasma cells may be highlighted by CD38, CD138, VS38c; plasma cells are monoclonal for kappa or lambda stains

♦♦ Peripheral blood −− Circulating plasma cells of at least 2 × 109/L ♦♦ Aspirate smear/biopsy −− Findings similar to PCM

Plasma Cell Leukemia

Additional Studies

Definition

♦♦ Findings similar to plasma cell myeloma

♦♦ Rare manifestation of plasma cell malignancy associated with circulating neoplastic plasma cells and dismal prognosis

Treatment and Prognosis ♦♦ Dismal prognosis, often a preterminal event in evolution of myeloma

HISTIOCYTIC AND MACROPHAGE DISORDERS Langerhans Cell Histiocytosis (Fig. 17.37) Definition ♦♦ Clonal proliferation of antigen-presenting type cell with a characteristic cellular background

Clinical ♦♦ Variants are based on degree of involvement: unifocal disease (solitary eosinophilic granuloma); multifocal, unisystem ­disease (Hand–Schuller–Christian disease); and multifocal, multisystem disease (Letterer–Siwe disease) ♦♦ Disease associations include Hodgkin and other lymphomas

Diagnosis ♦♦ Aspirate smear

−− May be “dry tap” due to marrow fibrosis. Langerhans cells are macrophages with folded nuclei and moderate amounts of pale cytoplasm. Eosinophils may be increased ♦♦ Biopsy −− Nodules of pale, macrophages with associated eosinophils are seen.

Additional Studies ♦♦ IHC: Langerhans cells are positive for S-100, Langerin, CD1a, and fascin and variably positive for CD68, CD45, and lysozyme ♦♦ Additional studies: Birbeck granules (characteristic pentilaminar lysosomes) are present by EM

Differential Diagnosis ♦♦ Involvement by Hodgkin lymphoma, histiocytic disorders, T-cell lymphomas should be considered

Treatment and Prognosis ♦♦ Excellent survival with limited involvement. Worse prognosis is expected with multisystem disease

Hemophagocytic Syndrome (Fig. 17.38) Definition ♦♦ Ingestion of hematopoietic elements by macrophages, secondary to a variety of causes. Etiologies including congenital disorders, infection-associated and those associated with other malignancies, especially T-cell lymphomas

Clinical Fig. 17.37. Langerhans cell histiocytosis (LCH). Marrow infiltration by LCH, with pale pink histiocytes, some with grooved nuclei, and associated eosinophils.

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♦♦ Often patients are very ill due to profound cytopenias. Bone marrow is a prominent site of involvement of these disorders. Splenic involvement and enlargement is also common

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Fig. 17.38. Hemophagocytic syndrome. Marrow core (left) and aspirate (right) showing hemophagocytosis.

Diagnosis ♦♦ Peripheral blood −− Atypical lymphocytosis may be present if infectionrelated or lymphoid malignancy ♦♦ Aspirate smear/core biopsy −− Macrophages with ingested blood elements are ­numerous. Erythrophagocytosis most common, but all marrow ­components can be seen within macrophages. Clusters of macrophages/granulomas may be seen. In cases of T-cell lymphoma-associated hemophagocytic syndrome (HPS), infiltrate of cytologically abnormal T-cells may be appreciated

−− In Niemann–Pick, macrophages will appear to have numerous small vacuoles

Additional Studies ♦♦ Positive staining for PAS diastase-resistant material can be seen in many storage disorders

Differential Diagnosis ♦♦ Deposition of material in macrophages can also be seen in several infectious disorders including Mycobacterium avium intracellulare, fungal infections, etc

Additional Studies ♦♦ IHC: EBV by in situ hybridization is often positive in ­infection-associated cases ♦♦ Molecular: Familial form may have perforin gene defects

Storage Diseases Definition ♦♦ Abnormal products accumulate in the marrow, most often in macrophages, due to inherited biochemical abnormalities (e.g., Gaucher, Niemann–Pick, ceroid histiocytosis, mucopolysaccharidoses, etc.)

Diagnosis ♦♦ Depends on type of accumulated product −− In Gaucher disease, the classic “folded tissue paper” appearance is seen in macrophages (Fig. 17.39)

Fig. 17.39. Storage disease. Gaucher disease, with numerous large, pink macrophages. Inset: Aspirate smear shows macrophage with pale blue color and “folded tissue paper” appearance in cytoplasm.

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METASTASES Metastatic Disease (Fig. 17.40)

Clinical

Definition

♦♦ Prognosis depends on the type of tumor, although marrow involvement typically suggests high stage disease (Stage IV) ♦♦ Metastases to the marrow are not uncommon, especially in certain disease types such as small cell carcinoma, prostate carcinoma, breast carcinoma, lung carcinoma, etc

♦♦ Metastatic tumors from a variety of sites involving the bone marrow

Diagnosis

Fig. 17.40. Metastatic disease. Cluster of breast carcinoma cells seen in bone marrow aspirate.

♦♦ Peripheral blood −− An exceedingly rare occurrence, the presence of circulating malignant nonhematopoietic cells is termed “carcinocythemia,” and is associated with high stage, aggressive disease ♦♦ Aspirate −− Marrows are often inaspirable due to associated marrow fibrosis −− Touch preparations may shows clumps and aggregates of tumor cells ♦♦ Biopsy −− Metastatic disease often replaces marrow cellularity in a haphazard, pushing manner. Severe, diffuse marrow fibrosis is common. Tumors may appear similar to primary site, but often appear less differentiated in marrow. Immunohistochemistry may provide information on the primary site of tumor

INFECTIONS Definition ♦♦ A variety of infectious organisms may affect the bone ­marrow. Several of these are discussed briefly below −− Tuberculosis: Marrow involvement is seen in disseminated disease. Characteristic granulomas are present, with or without caseation. AFB stains rare organisms −− Mycobacterium avuim intracellulare: Not uncommon in HIV/AIDS patients with focal or diffuse increase in plump histiocytes filled with granular material that stains positively for AFB and PAS. Mycobacterium avuim intracellulare infection may mimic a storage disease (Fig. 17.41) −− Leishmaniasis: Marrow involvement is not uncommon in systemic form. Organisms can be seen in macrophages, especially in aspirate smear (Fig. 17.42) −− HIV/AIDS: Marrow pathology dependent on stage of disease (Fig. 17.43); common changes include (a) Hypercellularity (b) Lymphoid aggregates, often with atypical lymphocytes (c) Plasmacytosis (rarely with HHV-8 infection)

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(d) Dyserythropoiesis, including megaloblastoid changes (e) Megakaryocyte abnormalities including increased numbers, naked megakaryocyte nuclei, and abnormally large or hyperchromatic megakaryocyte nuclei (f) Granulomas or histiocytic aggregates (g) Opportunistic infections including fungal, viral, parasitic/protozoal, etc (h) Increased incidence of neoplasia including high grade lymphoma (Burkitt), Hodgkin lymphoma, Kaposi sarcoma, etc −− Fungi (including histoplasmosis, blastomycosis, coccidioidomy­ cosis): Granulomas with or without caseation are present. Organisms may be common or difficult to find. Special stains including GMS and PAS stains may be of benefit −− Parvovirus B19: Viral infection seen predominantly in young or immunosuppressed patients leading to severe anemias due to red cell aplasia. Characteristic nuclear viral inclusions may be seen. Giant pronormoblasts are atypical early erythroid precursors with viral changes that are sometimes seen in parvoviral infections (Fig. 17.44)

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Fig.  17.41.  Mycobacterium avium intracellulare. Bone marrow infiltration showing granulomas composed of macrophages filled with M. avium intracellulare. Inset: AFB stain.

Fig. 17.43. HIV. Bone marrow of HIV patient, which is hypercellular, with increased megakaryocytes.

Fig. 17.42. Leishmaniasis. Aspirate smear showing organisms within macrophage.

Fig. 17.44. Parvovirus. Giant pronormoblast seen in parvovirusinfected erythroid precursor.

ANEMIAS Iron Deficiency Anemia

Anemia of Chronic Disease

Clinical

Diagnosis

♦♦ Iron/ferritin studies are helpful in diagnosis

♦♦ Peripheral blood −− Typically normochromic, normocytic mild-moderate anemia without significant changes in white blood cells or platelets ♦♦ Aspirate smear −− Stainable iron is typically increased but ringed sideroblasts are not seen

Diagnosis ♦♦ Peripheral blood −− Often microcytic, hypochromic anemia ♦♦ Aspirate smear −− Absence of iron in Prussian blue stain

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Megaloblastic Anemia (Figs. 17.45 and 17.46) Clinical ♦♦ Serum B12/folate testing is useful for diagnosis

Diagnosis ♦♦ Peripheral blood −− Macrocytic anemia is typical

−− Hypersegmented neutrophils are seen in peripheral blood −− In severe cases, immature erythroid, and rarely myeloid, elements may be seen in blood ♦♦ Aspirate smear −− Erythroid elements have characteristic nuclear/cytoplasmic dyssynchrony. Erythroid nuclear chromatin is less condensed and “ropy” compared to stage of development of cytoplasm. Other dyserythropoiesis including fragmentation, budding, multinucleation, etc., is seen −− Giant bands (late myeloid precursors) may be seen ♦♦ Biopsy −− Increases of immature erythroid elements may simulate blasts of leukemias

Paroxysmal Nocturnal Hemoglobinuria Definition ♦♦ Acquired clonal hematopoietic disorder, arising from mutation of gene leading to abnormal membrane proteins (PIGA), leading to increased complement-mediated red cell hemolysis and increased risk of development of aplastic anemia (AA), MDS, and AML

Clinical ♦♦ Cytopenias and hemolysis common Fig. 17.45. Megaloblastic anemia. Hypersegmented neutrophil.

Diagnosis ♦♦ Peripheral blood −− Varying degrees of anisopoikilocytosis may be present ♦♦ Marrow −− May be hypoplastic or have significant erythroid hyperplasia −− Varying degrees of dyserythropoiesis may be present; if severe, consider diagnosis of MDS

Additional Studies ♦♦ Flow: abnormal decrease or lack of expression of CD55 and/ or CD59 on surface of white blood cells is diagnostic test of choice

Congenital Dyserythroblastic Anemias Fig. 17.46. Megaloblastic anemia. Bone marrow aspirate with erythroid hyperplasia and megaloblastic changes. Inset: Nuclear features of megaloblastic anemia.

♦♦ Group of rare erythroid maturation disorders; dyserythropoiesis common; congenital dyserythroblastic anemias (CDA)-II associated with positive Ham test (AKA: HEMPAS); multinucleation and erythroid nuclear bridges may be seen

REACTIVE CONDITIONS, TREATMENT CHANGES, MISCELLANEOUS Aplastic Anemia (Fig. 17.47) Definition ♦♦ Pancytopenia with associated marrow hypoplasia; severe aplastic anemia is defined as <25% of age-normal marrow cellularity

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♦♦ Etiologies include: constitutional defects (Fanconi anemia, dyskeratosis congenital, Schwachman–Diamond syndrome), infection-associated (EBV, parvovirus, HIV, hepatitis viruses), medication-related (chemotherapy, antibiotics, etc.), toxins/exposures (benzene, insecticides, ionizing

Bone Marrow

radiation), and a variety of other causes, although many cases are idiopathic

Clinical ♦♦ Absolute neutrophil counts are typically <0.2 × 109/L ♦♦ Platelets counts typically <20 × 109/L ♦♦ Anemia is often severe

Diagnosis ♦♦ Peripheral blood −− Decreases in circulating blood cells ♦♦ Aspirate smear −− Hypocellular, often consists of only stromal elements, lymphocytes, plasma cells, and very rare hematopoietic elements ♦♦ Biopsy −− Hypocellular −− Cellularity consists of stromal elements (+/− fibrosis); lymphoid aggregates may be seen; hematopoietic elements are decreased in number

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mimic an acute leukemia due to increase of immatureappearing forms ♦♦ Erythropoietin (EPO): typically causes erythroid hyperplasia in bone marrow; some dyspoiesis may be seen including megaloblastoid changes

Granulomas (Figs. 17.48 and 17.49) ♦♦ Granulomas may be due to infections, neoplasms (Hodgkin lymphoma, other lymphomas, etc.), systemic/autoimmune disorders (sarcoid, ulcerative colitis, etc.), drug/therapyrelated, immune-deficiencies ♦♦ Lipogranulomas are poorly formed foci of disrupted adipocytes with some surrounding macrophages

Immune Thrombocytopenic Purpura (ITP) ♦♦ Autoimmune destruction of platelets, with thrombocy­topenia ♦♦ Marrow has increased numbers of megakaryocytes

Differential Diagnosis ♦♦ Hypoplastic MDS/AML: residual hematopoietic cells are immature, in hypoplastic AML and MDS CD34 is often positive, while it is absent/rare in AA

Prognosis and Treatment ♦♦ Recovery depends on underlying etiology of AA (if known) ♦♦ Treatment may include supportive therapy (transfusions, cytokines) or bone marrow transplant

Cytokine Effects ♦♦ G-CSF/GM-CSF: peripheral blood increase of granulocytes and sometimes monocytes with +/− immature forms, often with toxic granulation; marrow has increased M:E ratio, increased granulocytic and monocytic elements; may

Fig. 17.47. Aplastic anemia. Marked hypocellularity, with only rare hematopoietic elements.

Fig. 17.48. Granuloma. Sarcoid granuloma seen in bone marrow biopsy.

Fig. 17.49. Granuloma: Lipogranuloma.

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SUGGESTED READING Bellucci S, Michiels JJ. The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost 2006;32:381–398. Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica 2009;94:264–268.

ED, Salar A, Solé F, Stamatopoulos K, Thieblemont C, TraverseGlehen A, Wotherspoon A, Coiffier B, Piris MA. Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia 2008;22:487–495. Morice WG, Kurtin PJ, Hodnefield JM, Shanafelt TD, Hoyer JD, Remstein ED, Hanson CA. Predictive value of blood and bone marrow flow cytometry in B-cell lymphoma classification: comparative analysis of flow cytometry and tissue biopsy in 252 patients. Mayo Clin Proc 2008;83:776–785.

Boveri E, Arcaini L, Merli M, Passamonti F, Rizzi S, Vanelli L, Rumi E, Rattotti S, Lucioni M, Picone C, Castello A, Pascutto C, Magrini U, Lazzarino M, Paulli M. Bone marrow histology in marginal zone B-cell lymphomas: correlation with clinical parameters and flow cytometry in 120 patients. Ann Oncol 2009;20:129–136.

Nolte F, Hofmann WK. Myelodysplastic syndromes: molecular patogenesis and genomic changes. Ann Hematol 2008;87:777–795.

Cotelingam JD. Bone marrow biopsy: interpretive guidelines for the surgical pathologist. Adv Anat Pathol 2003;10:8–26.

Orazi A, Germing U. The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 2008;22:1308–1319.

Davis BH, Holden JT, Bene MC, Borowitz MJ, Braylan RC, Cornfield D, Gorczyca W, Lee R, Maiese R, Orfao A, Wells D, Wood BL, StetlerStevenson M. 2006 Bethesda International Consensus recommendations on the flow cytometric immunophenotypic analysis of hematolymphoid neoplasia: medical indications. Cytometry B Clin Cytom 2007;72 Suppl 1:S5–S13. Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M. Clinical relevance of bone marrow fibrosis and CD34positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol 2009;27:754–762. Dunphy CH, O’Malley DP, Perkins SL, Chang CC. Analysis of immunohistochemical markers in bone marrow sections to evaluate for myelodysplastic syndromes and acute myeloid leukemias. Appl Immunohistochem Mol Morphol 2007;15:154–159. Ho AK, Hill S, Preobrazhensky SN, Miller ME, Chen Z, Bahler DW. Small B-cell neoplasms with typical mantle cell lymphoma immunophenotypes often include chronic lymphocytic leukemias. Am J Clin Pathol 2009;131:27–32.

Orazi A. Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases. Pathobiology 2007;74:97–114.

Orazi A, Chiu R, O’Malley DP, Czader M, Allen SL, An C, Vance GH. Chronic myelomonocytic leukemia: The role of bone marrow biopsy immunohistology. Mod Pathol 2006;19:1536–1545. Pagnucco G, Giambanco C, Gervasi F. The role of flow cytometric immunophenotyping in myelodysplastic syndromes. Ann N Y Acad Sci 2006;1089:383–394. Peterson LC, Agosti SJ, Hoyer JD. Hematology clinical Microscopy Resource Committee; Members of the Cancer Committee, College of American Pathologists. Protocol for the examination of specimens from patients with hematopoietic neoplasms of the bone marrow: a basis for checklists. Arch Pathol Lab Med 2002;126:1050–1056. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds.). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2008.

Inamdar KV, Medeiros LJ, Jorgensen JL, Amin HM, Schlette EJ. Bone marrow involvement by marginal zone B-cell lymphomas of different types. Am J Clin Pathol 2008;129:714–722.

Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092–1097.

Matutes E, Oscier D, Montalban C, Berger F, Callet-Bauchu E, Dogan A, Felman P, Franco V, Iannitto E, Mollejo M, Papadaki T, Remstein

Veillon DM, Cotelingam JD. Pathologic studies useful for the diagnosis and monitoring of plasma cell dyscrasias. Contrib Nephrol 2007;153:25–43.

Inamdar KV, Bueso-Ramos CE. Pathology of chronic lymphocytic leukemia: an update. Ann Diagn Pathol 2007;11:363–389.

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18 Neoplasms of the Skin and Immunodermatology Daniel P. Vandersteen, md, Melanie Triffet-Treviño, md, and Chris H. Jokinen, md

Contents

I. Cutaneous Neoplasms and Developmental Anomalies.................18-3

Epithelial Neoplasms and Developmental Anomalies.....................................................18-3 Cystic Lesions: Neoplastic or Developmental...............................18-3 Epidermal Tumors and Proliferations..............................18-5 Pilar and Pilosebaceous-Derived Tumors................................................18-9 Eccrine-Derived Tumors and Proliferations............................18-13 Apocrine-Derived Tumors and Proliferations............................18-19 Neuroendocrine-Derived Tumors........18-20 Soft Tissue Neoplasms and Developmental Anomalies...................................................18-21 Adipocyte-Derived Tumors and Proliferations....................................18-21 Neural-Derived Tumors and Proliferations............................18-22 Smooth Muscle-Derived Tumors and Proliferations....................................18-25 Fibrohistiocytic, Histiocytic, and Langerhans Cell-Derived Proliferations....................................18-27 Fibrous Proliferations and Tumors.....18-31 Vascular Proliferations, Malformations, and Tumors................................................18-35 Reactive, Nonneoplastic Vascular Proliferations, and Telangiectasias..........................18-35

Benign Vascular Neoplasms.................18-38 Vascular Tumors of Low Grade Malignancy.......................................18-40 Malignant Vascular Tumors................18-40 Tumors of Perivascular Cells...............18-41 Melanocytic Proliferations and Pigmentary Disorders........................18-42 Pigmentary Disorders of the Skin.......18-42 Benign Melanocytic Proliferations......18-43 Malignant Melanoma...........................18-47 Lymphoproliferative Disorders and Leukemias...........................................18-48

II. Immunodermatology.......................18-54 Methods, Terminology and Techniques........18-54 Direct Immunofluorescence (DIF)......18-54 Indirect Immunofluorescence (IIF)...................................................18-54 Western Immunoblotting.....................18-55 ELISA....................................................18-55 Immunobullous Diseases................................18-55 Patterns of Antibody Deposition.........18-55 Linear Deposition Along the Basement Membrane Zone........................................18-55 Bullous Pemphigoid (BP).....................18-55 Cicatricial Pemphigoid.........................18-56 Herpes Gestationis (Pemphigoid Gestationis).......................................18-56 Epidermolysis Bullosa Acquisita (EBA)...............................18-57 Bullous Systemic Lupus Erythematosus (BSLE)....................18-58

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_18, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Linear IgA Bullous Dermatosis (Chronic Bullous Disease of Childhood)....................................18-59 Deposition in Intercellular Spaces................18-60 Pemphigus.............................................18-60 Granular Deposition Along the Basement Membrane Zone: Lupus Erythematosus...........................................18-67 Discoid Lupus Erythematosus (DLE)................................................18-67 Subacute Cutaneous Lupus Erythematosus (SCLE)...................18-68 Bullous Systemic Lupus Erythematosus ................................18-68 Systemic Lupus Erythematosus..........18-69 Granular Deposition in the Dermal Papillae.......................................................18-69 Dermatitis Herpetiformis (DH)...........18-69 Clumped Cytoid Bodies and Shaggy Deposition of Fibrinogen Along the Basement Membrane Zone................18-70 Lichen Planus........................................18-70 Lupus Erythematosus..........................18-71 Dermatomyositis...................................18-71 Erythema Multiforme..........................18-71 Paraneoplastic Pemphigus...................18-71

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Lichenoid Dermatitis............................18-71 Lichenoid Drug Reaction.....................18-71 Graft Versus Host Disease...................18-71 Weak Thick Linear Deposition Along the Basement Membrane Zone and Perivascular Deposition.....................18-71 Porphyrias.............................................18-71 Deposition on Eosinophils and Diffuse Deposition on Connective Tissue..............18-72 Urticaria................................................18-72 Deposition in Blood Vessels...........................18-73 Vasculitis................................................18-73

III. Tnm Classification of Malignant Melanoma of the Skin (2010 Revision)................................18-74 IV. Tnm Classification of Cutaneous Squamous Cell Carcinoma (Cscc) and Other Cutaneous Carcinomas (2010 Edition, Ajcc)........................18-75 V. Tnm Classification of Merkel Cell Carcinoma (2010 Edition, Ajcc)......18-75 VI. Suggested Reading...........................18-76

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CUTANEOUS NEOPLASMS AND DEVELOPMENTAL ANOMALIES Epithelial Neoplasms and Developmental Anomalies Cystic Lesions: Neoplastic or Developmental Epidermoid Cyst (Infundibular Cyst) Clinical

Cysts Associated with Branchial Cleft Deformities Clinical

♦♦ Dome-shaped lesions with central punctum; multiple lesions may be associated with Gardner syndrome

Microscopic

Microscopic ♦♦ Dermal cyst with/without an epidermal connection lined by stratified squamous epithelium with a granular layer; cyst contains laminated keratin debris

Comedonal Cyst Microscopic ♦♦ Similar to the epidermoid cyst, but characterized by follicular plugging and hyperkeratosis; may be more superficial and typically has a larger epidermal ostia or punctum

♦♦ Cystic lesions may be formed in and around the ear in association with branchial cleft deformities. These differ from the branchial cleft cyst of the neck by their location and their microscopic characteristics ♦♦ May be similar to an epidermoid cyst except for their tendency to collapse and assume a multiloculated appearance. Other forms, in addition to the above, have adnexal structures and even cartilage within their walls

Branchial Cleft Cyst Clinical ♦♦ A developmental anomaly presenting as a cyst in the lateral aspect of the neck

Milia Clinical ♦♦ Small white-yellow papules which may occur sporadically or in association with blistering diseases (epidermolysis bullosa, porphyria cutanea tarda, pemphigoid, etc.) which disrupt or occlude the eccrine ducts or hair follicles

Microscopic ♦♦ A small epidermoid-like cyst located in the superficial dermis

Steatocystoma (Fig. 18.1) Clinical ♦♦ May occur in a solitary form (simplex) or as multiple lesions inherited in an autosomal dominant fashion (multiplex)

Microscopic ♦♦ An irregular, collapsed, intradermal cyst lined by a ­stratified squamous epithelium with an irregular, corrugated internal cuticle. Sebaceous glands are usually evident in the duct walls, and the cyst contains proteinaceous debris but no keratin

Dermoid Cyst Clinical ♦♦ An embryonic closure defect that typically involves the skin lateral to the eye, the scalp, the neck or near the mastoid process. Usually detected early in life

Microscopic ♦♦ A unilocular dermal or subcutaneous cyst lined by stratified squamous epithelium and having hair follicles, glands and, sometimes, smooth muscle in the cyst wall

Fig. 18.1. Steatocystoma (A, B).

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Microscopic

Microscopic

♦♦ A lymphoepithelial cyst characterized by a stratified squamous or a pseudostratified ciliated lining with a dense lymphocytic infiltrate with germinal centers in the wall

♦♦ The cyst may be lined by cuboidal, columnar or stratified squamous epithelium ♦♦ The cyst wall contains thyroid follicles with or without skin appendages and lymphocytic inflammation ♦♦ Smooth muscle and cartilage are absent

Eruptive Vellus Hair Cyst Clinical ♦♦ Small flesh-colored papules in children and young adults

Microscopic ♦♦ An epidermoid-like cyst that contains numerous, small vellus hairs

Pigmented Terminal Hair Cyst Microscopic

Cutaneous Ciliated Cyst Clinical ♦♦ Usually found on the lower extremities or buttocks of reproductive aged women

Microscopic

♦♦ An epidermoid-like cyst containing numerous pigmented, terminal hairs

♦♦ Ciliated, cuboidal to columnar lined, multiloculated cyst surrounded by fibrous tissue ♦♦ No endometrial or fallopian tube type stroma is evident within the cyst walls

Trichilemmal (Pilar) Cyst Clinical

Endometriosis and Endosalpingiosis Clinical

♦♦ Dome-shaped papules/nodules found predominantly on the scalp; may be single or multiple

♦♦ Blue-red cysts/nodules most commonly seen in the vulvar or periumbilical regions of reproductive aged females

Microscopic ♦♦ A dermal or subcutaneous cyst lined by an eosinophilic stratified squamous epithelium that lacks a granular layer. The cyst contents are composed of solid, nonlaminated keratin

Proliferating Trichilemmal Cyst/Tumor (Fig. 18.2) Clinical ♦♦ Multinodular scalp lesion more common in females

Microscopic ♦♦ Well-defined, multilobular tumor with trichilemmal keratinization; dense fibrous tissue surrounds the individual lobules; cystic areas may be inconspicuous ♦♦ Malignant forms occur but are rare ♦♦ More marked infiltration, cytologic atypia, and mitotic activity characterize the malignant variants

Bronchogenic Cyst Clinical ♦♦ A developmental cyst usually found near the precordium early in life

Microscopic ♦♦ This cystic lesion attempts to recapitulate the bronchi with a cyst lined by respiratory epithelium and a cyst wall with smooth muscle, glands and/or cartilage

Thryoglossal Duct Cyst Clinical ♦♦ A developmental cyst found in the midline of the neck, near the hyoid bone

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Fig. 18.2. Proliferating trichilemmal tumor (A, B).

Neoplasms of the Skin and Immunodermatology

Microscopic ♦♦ Similar to the cutaneous ciliated cyst, except that the cyst wall contains endometrial/fallopian tube type stroma with or without hemosiderin deposition

Hidrocystoma Microscopic ♦♦ Unilocular or multilocular cysts lined by either apocrine or eccrine epithelium −− Apocrine: decapitation secretion (apical snouts) and a myoepithelial layer; may have papillary projections −− Eccrine: a two-layered cuboidal epithelium with no myoepithelial layer or decapitation secretion

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♦♦ There is no true epidermal lining, and the cystic spaces may be multiloculated

Oral Mucocele Clinical ♦♦ A translucent, blue nodule usually found on the lower lip

Microscopic ♦♦ A cystic space containing varying degrees of central mucin and lined by chronic inflammatory cells with numerous foamy histiocytes ♦♦ There is no true epithelial lining

Hybrid Cyst Microscopic

Epidermal Tumors and Proliferations Actinic Keratosis (Senile, Solar) Clinical

♦♦ A cystic lesion combining the histologic features of more than one cyst type, usually trichilemmal and epidermoid cysts

♦♦ White-yellow, erythematous, and scaly patches or plaques on sun-damaged skin; some may be pigmented

Digital Mucous Cyst (Fig. 18.3) Clinical

Microscopic

♦♦ A fluctuant, sometimes tender, translucent nodule of the digits

Microscopic ♦♦ Dermal mucin deposited into a cyst-like space that may or may not also contain fibroblasts and collagen

♦♦ While a variety of histologic types exist, all have in common epidermal dysplasia, which may also involve the hair follicles ♦♦ Hyperplastic, atrophic, acantholytic, epidermolytic, lichenoid, pigmented, bowenoid, and clear cell categories exist and reflect additional alterations to the dysplastic epidermis (e.g., lichenoid variant = actinic keratosis with a band-like lymphocytic inflammatory infiltrate; bowenoid variant = actinic keratosis with full thickness dysplasia = carcinoma in situ)

Benign Lichenoid Keratosis (Fig. 18.4) (Lichen Planus-Like Keratosis) Clinical ♦♦ Solitary papule or plaque found primarily on the trunk or upper extremities

Microscopic ♦♦ Very similar to lichen planus with a dense band-like lymphocytic infiltrate at the dermal–epidermal interface with basilar vacuolar degeneration and cytoid bodies

Fig. 18.3. Digital mucous cyst.

Fig. 18.4. Benign lichenoid keratosis.

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♦♦ In contrast to lichen planus, eosinophils and parakeratosis may be seen ♦♦ In contrast to a lichenoid actinic keratosis, there is no keratinocyte dysplasia

Seborrheic Keratosis Clinical ♦♦ Brown, elevated, and sharply demarcated lesions which occur most commonly on the face, trunk, and upper extremities ♦♦ These benign tumors often have a “stuck-on” appearance and are more common in middle-aged and older adults ♦♦ The sudden appearance of numerous seborrheic keratosis in association with visceral malignancy is referred to as the Leser–Trelat sign

Microscopic ♦♦ An epidermal proliferation of bland basaloid and polygonal keratinocytes associated with prominent keratin cyst formation ♦♦ The lesion is sharply delineated at its base and appears to grow up from the epidermis ♦♦ Irritated forms demonstrate more endophytic growth and form numerous squamous eddies ♦♦ Acanthotic, adenoid, clonal, pigmented, and hyperkeratotic variants exist

Essentials of Anatomic Pathology, 3rd Ed.

Inverted Follicular Keratosis (Fig. 18.5) Microscopic ♦♦ An endophytic epidermal growth with numerous squamous eddies which, like seborrheic keratosis, is sharply delineated but is centered on the hair follicles ♦♦ Note: This entity is considered a variant of seborrheic kera­tosis by some experts and a viral-induced lesion by others

Warty Dyskeratoma (Fig. 18.6) Clinical ♦♦ A benign, solitary, umbilicated nodule or papule on sun-exposed skin

Microscopic ♦♦ A hair follicle centered, endophytic squamous proliferation which is sharply delineated ♦♦ The base of the lesion typically reveals elongated trabeculae with varying degrees of dyskeratosis that underlies broad areas of acantholytic dyskeratosis located immediately below a keratin-filled, central crater

Linear Epidermal Nevus Clinical ♦♦ Localized and systemic forms exist and are characterized by a linear arrangement of closely set papillomatous papules ♦♦ The systemic form may be associated with other defects, including skeletal and central nervous system abnormalities

Microscopic ♦♦ Both variants demonstrate epidermal papillomatosis, acanthosis, and hyperkeratosis ♦♦ Many histologic variants exist, but, importantly, the presence of epidermolytic hyperkeratosis may be associated with systemic involvement

Fig. 18.5. Inverted follicular keratosis.

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Fig. 18.6. Warty dyskeratoma.

Neoplasms of the Skin and Immunodermatology

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Nevus Comedonicus Clinical

Large Cell Acanthoma Clinical

♦♦ Comedo-like papules with a central keratin plug usually in a linear arrangement on the palms, soles, or other sites

♦♦ Erythematous patches on sun-exposed skin

Microscopic ♦♦ Deep epidermal invaginations with laminated keratin similar to a comedo ♦♦ Epidermolytic hyperkeratosis may be evident

White Sponge Nevus Clinical ♦♦ Extensive, white patches and plaques involving mucosal sites (chiefly oral but also vaginal, rectal, and esophageal) which are evident early in life and are inherited in an autosomal dominant pattern

Microscopic ♦♦ There is acanthosis and pallor of the mucosal lining due to prominent cytoplasmic clearing (intracellular edema) of the suprabasilar keratinocytes ♦♦ Similar changes are seen in leukoedema and pachyonychia congenita

Microscopic ♦♦ A sharply defined epidermal proliferation of enlarged, pale keratinocytes with mild dysplasia ♦♦ Comment: these lesions are aneuploid and are best considered to be a variant of actinic keratosis

Squamous Cell Carcinoma In Situ (Bowen Disease) Clinical ♦♦ Erythematous, irregular, scaly patches, and plaques that may involve any skin surface as well as the mucous membranes ♦♦ Bowen disease of the penis is often referred to as erythroplasia of Queyrat ♦♦ Sun exposure, arsenic, and other chemicals are associated with an increased risk of development of Bowen disease ♦♦ Approximately 5% of these lesions develop an invasive component

Leukoedema Clinical ♦♦ Patchy white plaques and patches of the oral mucosa with an adult onset ♦♦ These lesions remit and recur and are not inherited

Microscopic ♦♦ Similar to white sponge nevus from which it differs by clinical grounds

Geographic Tongue (Lingua Geographica) Clinical ♦♦ Irregular, erythematous patches with white borders on the tongue

Microscopic ♦♦ The erythematous areas show loss of the normal granular and horny layers while the white areas demonstrate acanthosis with neutrophilic inflammation

Clear Cell Acanthoma (Fig. 18.7) Clinical ♦♦ Solitary, slowly growing nodules or plaques with an oozing surface ♦♦ These lesions are most common on the lower extremities

Microscopic ♦♦ A plate-like epidermal thickening by a proliferation of clear, heavily glycogenated keratinocytes ♦♦ The tumors are sharply demarcated from the adjacent epidermis (eyeliner sign) and, characteristically, have neutrophils scattered throughout the proliferation, an important feature in separating this entity from other tumors with a plate-like growth pattern

Fig. 18.7. Clear cell acanthoma (A, B).

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Microscopic ♦♦ Epidermal acanthosis associated with full thickness epidermal dysplasia, which may involve the adnexa ♦♦ A dense lichenoid inflammatory infiltrate may also be present ♦♦ Intraepidermal spread (Borst–Jadassohn phenomena) may be prominent and should be differentiated from melanoma and Paget disease

Bowenoid Papulosis Clinical ♦♦ Red-brown papules or plaques on the external genitalia and perineum of young adults ♦♦ Lesions are frequently multiple, and there is a strong association with human papillomavirus (HPV) types 16 and 18 with other types occurring less frequently ♦♦ Unlike Bowen disease, these lesions may regress and are less likely to give rise to an invasive carcinoma

Microscopic ♦♦ Fairly discrete areas of epidermal acanthosis associated with varying degrees of epidermal dysplasia, koilocytosis, hypergranulosis, and parakeratosis ♦♦ In situ carcinoma may be present

Squamous Cell Carcinoma (Fig. 18.8) Clinical ♦♦ Indurated, hyperkeratotic nodules which may show ulceration or verruciform changes ♦♦ Currently, squamous cell carcinoma is the second most common cutaneous malignancy ♦♦ The incidence is increasing ♦♦ While most are related to sun exposure, other risk factors include fair complexion, chronic inflammation, immunosuppression, burns, HPV infection, and chemical exposure (e.g., arsenic)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The overall rate of metastases is approximately 5% but is >10% at mucosal sites and the ear

Microscopic ♦♦ Atypical nests of epidermoid cells invasive into the dermis and, usually, with overlying epidermal dysplasia ♦♦ Differentiation varies from poorly differentiated (minimal keratin production, marked nuclear pleomorphism, high mitotic rate) to well differentiated (abundant keratin pearl formation, minimal cytologic atypia, and few mitoses) ♦♦ The presence of keratin production, intercellular desmosomes (“spines”), and overlying epidermal dysplasia are useful features in separating this tumor from other entities ♦♦ Variants include clear cell, spindle cell, acantholytic, and verrucous tumors

Verrucous Carcinoma Clinical ♦♦ A variant of squamous cell carcinoma that typically appears as a large hyperkeratotic nodule ♦♦ All cutaneous surfaces may be involved but plantar, oral (oral florid papillomatosis). and anogenital lesions are particularly common ♦♦ These tumors frequently recur but have little metastatic potential

Microscopic ♦♦ An endophytic and exophytic growth of well-differentiated squamous epithelium with extensive keratinization ♦♦ The deep component shows a broad, pushing front at its advancing edge ♦♦ If any significant nuclear dysplasia is present, a diagnosis of squamous cell carcinoma should be made

Keratoacanthoma Clinical ♦♦ A rapidly growing, umbilicated nodule with a central keratin plug ♦♦ Multiple lesions may be present ♦♦ Typically, these tumors regress over the course of a few months, but they may recur ♦♦ These tumors are considered to be a variant of squamous cell carcinoma by some experts

Microscopic

Fig. 18.8. Squamous cell carcinoma.

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♦♦ A well-defined, sharply demarcated, craterform squamous proliferation with a central keratin plug ♦♦ The squamous epithelium frequently has a glassy ­appearance and lacks significant cytologic atypia ♦♦ A lichenoid inflammatory infiltrate may be present ♦♦ The presence of cytologic atypia, infiltrative borders, or atypical mitoses warrants a diagnosis of a squamous cell carcinoma

Neoplasms of the Skin and Immunodermatology

Pilar and Pilosebaceous-Derived Tumors Dilated Pore of Winer Clinical ♦♦ Flesh-colored papule or cyst with a central keratotic plug found chiefly on the head and neck

Microscopic ♦♦ A cone-shaped dilatation of the follicular infundibulum with a central keratin plug ♦♦ The wall of the pore is proliferative with finger-like projections extending into the adjacent dermis ♦♦ No secondary hair follicles are evident within the cyst wall

Pilar Sheath Acanthoma Clinical ♦♦ Small nodule with a central keratin-filled pore on the upper lip

Microscopic ♦♦ Similar in architecture to the dilated pore but with a more proliferative wall ♦♦ The epithelium of the wall is paler than that of the dilated pore and may have some degree of peripheral palisading suggesting abortive hair follicle development ♦♦ No well-developed secondary hair follicles with hair formation are evident

Trichofolliculoma (Fig. 18.9) Clinical ♦♦ Solitary, flesh-colored nodules with a central pore from which numerous white hairs emerge

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♦♦ If sebaceous glands are evident within the secondary follicles, then a diagnosis of a sebaceous trichofolliculoma is appropriate

Tumor of the Follicular Infundibulum (Fig. 18.10) Clinical ♦♦ Small, hyperkeratotic papules or plaques on the head and neck

Microscopic ♦♦ A plate-like expansion of the epidermis by interanastomosing and interweaving trabeculae of glycogenated squamous epithelium within the superficial dermis ♦♦ The trabeculae show multiple attachments to the epidermis and to the hair follicles ♦♦ The trabeculae may show some peripheral palisading but lack mucin deposition or stromal retraction ♦♦ Elastic fibers are often condensed at the base of the lesion

Differential Diagnosis ♦♦ Fibroepithelioma of Pinkus and eccrine syringofibro­ adenoma ♦♦ Fibroepithelioma of Pinkus has narrow trabeculae with more pronounced basaloid differentiation while eccrine syringofibroadenoma shows scattered eccrine ducts within its trabeculae

Basaloid Follicular Hamartoma Clinical ♦♦ Small, flesh-colored papules or plaques on the head and neck ♦♦ Solitary, multifocal, and inherited variants have been described

♦♦ Similar to the dilated pore, a central, elongated, and dilated infundibulum is present ♦♦ Numerous secondary hair follicles radiate peripherally from the central cavity that is filled with laminated keratin and numerous hairs

Microscopic

Fig. 18.9. Trichofolliculoma.

Fig. 18.10. Tumor of the follicular infundibulum.

♦♦ Small, starfish- or octopus-like proliferations of basaloid cells within the dermis arranged as anastamosing trabeculae with peripheral palisading and surrounding fibrosis

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Trichilemmoma (Fig. 18.11) Clinical ♦♦ Verrucous, hyperkeratotic papules usually found on the face ♦♦ Multiple trichilemmomas occur in the autosomal dominant disorder, Cowden disease

Microscopic ♦♦ A single lobule or, occasionally, a multilobular proliferation of round, clear (glycogen rich) squamous cells giving a platelike thickening to the epidermis ♦♦ There is usually a follicular accentuation to the proliferation with the pale cells growing down preexisting follicular structures ♦♦ The lobules are surrounded by a PASD positive basement membrane ♦♦ A desmoplastic variant exists which, in addition to typical trichilemmoma areas, has central trabeculae surrounded by a dense, hypocellular stroma

Trichoadenoma (Fig. 18.12) Clinical ♦♦ Yellow to flesh-colored papule on the face

Microscopic ♦♦ Numerous keratin-filled cysts lined by a stratified squamous epithelium are evident within the dermis ♦♦ A granular layer is present (epidermoid keratinization), and the cysts have a surrounding fibrous stroma ♦♦ Solid trabeculae are rare

Trichoepithelioma Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic ♦♦ An admixture of keratin-filled cysts and trabeculae of basaloid cells with peripheral palisading and a surrounding fibrous stroma ♦♦ Stromal retraction is not evident, and true hair bulb formation is rarely seen

Differential Diagnosis ♦♦ Keratotic basal cell carcinoma is different from trichoepithelioma by having stromal retraction, mucin deposition, individual cell necrosis, and numerous mitoses ♦♦ Microcystic adnexal carcinoma differs from desmoplastic trichoepithelioma by the presence of deeper infiltration with eccrine ducts lined by an eosinophilic cuticle. A layered appearance with cysts predominating superficially and trabeculae predominating at the deep aspect of the tumor are characteristic

Trichoblastoma Clinical ♦♦ A controversial entity having histologic and clinical overlap with trichoepithelioma and basal cell carcinoma

Microscopic ♦♦ A proliferation of germinative basaloid cells arranged in nests, sheets, or trabeculae ♦♦ Conspicuous hair bulb differentiation is seen at the edge of the nests or sheets but also as single, primitive hair folliclelike structures surrounded by a dense fibrous sheath ♦♦ Stromal clefting and extensive mucin deposition are typically absent

Differential Diagnosis ♦♦ Basal cell carcinoma shows stromal clefting, mucin deposition, single cell necrosis and lacks primitive hair bulb structures

♦♦ Small flesh-colored papules on the face of young- to middleaged adults ♦♦ Solitary, desmoplastic, and multiple (autosomal dominant inheritance) variants exist

Fig. 18.11. Trichilemmoma.

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Fig. 18.12. Trichoadenoma.

Neoplasms of the Skin and Immunodermatology

♦♦ Trichoepithelioma has admixed keratin-filled cysts and has few to no primitive hair bulbs

Trichodiscoma Clinical ♦♦ A hamartomatous proliferation of the hair disk which presents as multiple flesh-colored papules on the face and also elsewhere on the body

Microscopic ♦♦ A nodular mesenchymal proliferation surrounded by an epidermal collarette ♦♦ Centrally there are stellate fibroblasts embedded in collagen, reticulin, and elastic fibers with abundant mucin deposition ♦♦ Thin-walled vessels with prominent basement membranes are seen within the proliferation

Perifollicular Fibroma and Fibrofolliculoma Clinical ♦♦ Both occur as solitary and, more often, multiple flesh-colored papules on the face or neck

Microscopic ♦♦ Perifollicular fibromas show a loose, concentric proliferation of fibrous tissue around normal hair follicles while fibrofolliculomas show both a fibrous and a follicular proliferation centered on a dilated follicle ♦♦ The epithelial component of the latter consists of epithelial trabeculae that arise from the infundibulum and are surrounded by fibrous tissue

Pilomatricoma (Fig. 18.13) (Calcifying Epithelioma of Malherbe) Clinical ♦♦ Deep-seated, frequently calcified nodules on the head, neck, and upper extremities of children and young adults

Fig. 18.13. Pilomatricoma.

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♦♦ These lesions may be solitary or multiple (autosomal dominant inheritance) or may be a marker of a systemic disease (Gardner syndrome)

Microscopic ♦♦ A cystic or multinodular tumor with a biphasic epithelial growth pattern consisting of eosinophilic, ghosts or shadow cells centrally and basophilic, basaloid cells peripherally ♦♦ Granulomatous inflammation and calcification are frequent and may obscure the characteristic growth pattern

Basal Cell Carcinoma (Fig. 18.14) Clinical ♦♦ Well-delineated, pearly, translucent, pink-tan papules or nodules with telangiectasia ♦♦ Superficial, nodular/ulcerative, pigmented, diffuse, morpheaform, and fibroepitheliomatous variants exist ♦♦ Most are found on sun-exposed skin of the elderly, but occasional cases are evident on nonsun-exposed skin ♦♦ Basal cell carcinoma is currently the most common cutaneous malignancy, and the incidence is increasing ♦♦ Risk of developing basal cell carcinomas is related to sunexposure and skin type ♦♦ Multiple tumors are seen in Basex syndrome and basal cell carcinoma nevus syndrome (Gorlin syndrome), an autosomal dominant inherited disease also having odontogenic keratocysts, palmar-plantar pits, ectopic calcification, and skeletal abnormalities ♦♦ Basal cell carcinoma has little tendency to metastasize

Microscopic ♦♦ A proliferation of atypical basaloid cells in nests, trabeculae, and/or cysts within the dermis but often demonstrating multifocal epidermal attachment ♦♦ Peripheral palisading, stromal retraction, mucin deposition, single cell necrosis, and mitoses are characteristic and are useful in separating this tumor from other entities

Fig. 18.14. Basal cell carcinoma.

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Fig. 18.15. Fibroepithelioma of Pinkus.

Fig. 18.16. Nevus Sebaceous.

♦♦ Nodulocystic, metatypical (keratotic), pigmented, adenoidal, infiltrating, superficial, and morpheaform histologic variants exist, with the latter two having an increased risk of recurrence

Microscopic

Fibroepithelioma of Pinkus (Fig. 18.15) Clinical ♦♦ Polypoid or plaque-like lesions on the thigh or trunk ♦♦ Considered as a premalignant lesion by many experts

Microscopic

♦♦ The epidermis frequently demonstrates papillomatosis or verruciform change ♦♦ Numerous immature or abortive hair follicles are situated within the superficial dermis with a reduction in the number of mature terminal hairs ♦♦ The sebaceous glands appear haphazardly distributed within the dermis and may appear atrophic, hyperplastic, or relatively normal in size ♦♦ Apocrine glands are a frequent finding in the deep dermis

♦♦ Interanastomosing epithelial strands with multiple points of attachment to the epidermis and surrounded by a fibrous stroma ♦♦ The trabeculae are thinner than the tumor of the follicular infundibulum, being 2–3 epithelial cells in thickness

Sebaceous Hyperplasia Clinical

Malignant Pilomatricoma Clinical

♦♦ Enlarged, hyperplastic sebaceous glands emptying into a central hair follicle often situated in the superficial dermis

♦♦ A rare tumor occurring as tumors or nodules on the face

Microscopic ♦♦ Similar to a benign pilomatricoma but showing areas with infiltration, mitoses, and nuclear pleomorphism

Nevus Sebaceous (Fig. 18.16) Clinical ♦♦ Single or multiple, yellow papules to plaques with or without verruciform features on the head and neck of infants, adolescents, and young adults ♦♦ A linear form exists ♦♦ Nevus sebaceous with cerebral abnormalities is referred to as the nevus sebaceous syndrome ♦♦ Basal cell carcinoma is the most common malignancy associated with nevus sebaceous while syringocystadenoma papilliferum is the most common benign proliferation associated with this condition

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♦♦ Small yellow papules on the face and forehead of older adults

Microscopic Sebaceous Adenoma Clinical ♦♦ Pink to yellow papules on the face and neck of older adults ♦♦ Multiple lesions are often associated with visceral malignancy (Muir–Torre syndrome)

Microscopic ♦♦ A multilobulated tumor often showing attachment to or emptying through the overlying epidermis ♦♦ The lobules are composed of basaloid cells peripherally and multivacuolated cells centrally ♦♦ By definition, the basaloid cells comprise less than 50% of cells of the individual lobules ♦♦ Infiltration, necrosis, and frequent mitoses are absent

Sebaceous Epithelioma Clinical ♦♦ Similar to sebaceous adenoma

Neoplasms of the Skin and Immunodermatology

Microscopic ♦♦ A faintly lobular tumor similar to the sebaceous adenoma ♦♦ Basaloid cells comprise more than 50% of the cells in the individual lobules ♦♦ While occasional mitotic figures may be seen, abundant mitotic activity, infiltration, nuclear pleomorphism, or necrosis should lead to a consideration of sebaceous carcinoma or basal cell carcinoma with sebaceous differentiation

Sebaceous Carcinoma (Fig. 18.17) Clinical ♦♦ Ulcerated or nonulcerated nodules on the head and neck region of older adults ♦♦ The periocular region is a particularly common site where derivation from the meibomian gland occurs ♦♦ These tumors are associated with a high metastatic potential and increased mortality (~25%)

Microscopic ♦♦ These tumors may show irregular lobules or a diffuse infiltrating pattern ♦♦ Attachment to the overlying epidermis may be present, and pagetoid spread is common in the periocular variants ♦♦ These tumors show a spectrum of sebaceous differentiation varying from tumors composed predominantly of basaloid cells to tumors with numerous multivacuolated sebaceous cells ♦♦ Infiltration, necrosis, nuclear pleomorphism, nucleoli, and mitoses are usually readily evident ♦♦ Perineural and capillary-lymphatic space invasion may be seen

Immunophenotype ♦♦ Cytokeratin and EMA+; S-100 protein and CEA−

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Eccrine-Derived Tumors and Proliferations Syringoma-Like Proliferations Associated with Alopecia Clinical ♦♦ No specific clinical findings are associated with this lesion which presents simply as alopecia of any etiology

Microscopic ♦♦ This is a relatively rare, apparently, nonneoplastic proliferation of the eccrine ducts in response to alopecia ♦♦ The microscopic is that of the particular form of alopecia affecting the patient with the addition of a diffuse, haphazard proliferation of the eccrine ducts limited to the mid- and upper dermis ♦♦ Ducts, trabeculae, comma, and tadpole-shaped forms may all be seen ♦♦ No nuclear pleomorphism or perineural invasion is evident, but mitotic figures may be seen ♦♦ This proliferation may be seen throughout the scalp in cases of severe alopecia

Differential Diagnosis ♦♦ Syringoma is usually a more localized and circumscribed eccrine proliferation and lacks the haphazard appearance of the above ♦♦ Microcystic adnexal carcinoma and eccrine syringoid carcinoma are more infiltrative lesions that typically involve the lower dermis and the subcutis and show frequent perineural invasion

Eccrine Syringofibroadenoma (Fig. 18.18) Clinical ♦♦ Single or multiple papules or nodules with a wide age range and distribution ♦♦ The extremities are most commonly involved

Microscopic ♦♦ Interanastomosing cords and trabeculae of epithelial cells extending into the dermis with multiple points of attachment to the epidermis

Fig. 18.17. Sebaceous carcinoma.

Fig. 18.18. Eccrine syringofibroadenoma.

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Fig. 18.19. Syringoma.

Fig. 18.20. Chondroid syringoma.

♦♦ The cords are thin and surrounded by a fibrous stroma ♦♦ Scattered throughout the epithelial cords are areas of eccrine duct differentiation with prominent eosinophilic cuticles

Chondroid Syringoma (Benign Mixed Tumor, Fig. 18.20) Clinical

Differential Diagnosis ♦♦ Tumor of the follicular infundibulum and fibroepithelioma of Pinkus lack eccrine differentiation

Syringoma (Fig. 18.19) Clinical ♦♦ Multiple flesh-colored or faintly yellow papules on the eyelids or upper face ♦♦ Other sites may also be involved, and linear and eruptive variants occur ♦♦ Clear cell variants may be associated with diabetes

Microscopic ♦♦ A fairly well-circumscribed but unencapsulated neoplasm involving the mid- to upper dermis composed of eccrinederived cords and ducts ♦♦ The cords may show characteristic tadpole-shaped forms ♦♦ Two or more cell layers with an internal eosinophilic cuticle and varying degrees of clear cell change line the ducts ♦♦ In general, the tumor does not infiltrate the deep dermis or subcutaneous fat, lacks mitotic activity and necrosis, and has no significant pleomorphism

♦♦ A benign, slowly growing, typically solitary tumor nodule on the head and neck; other sites may be involved

Microscopic ♦♦ A well-circumscribed, biphasic tumor nodule located within the dermis and/or the subcutaneous fat ♦♦ Epithelial cords, trabeculae, and ducts are embedded in an abundant myxoid, fibromyxoid, or cartilaginous matrix ♦♦ The epithelial component lacks nuclear pleomorphism, infiltration, necrosis, and mitotic activity ♦♦ The ducts may show eccrine and/or apocrine differentiation

Differential Diagnosis ♦♦ Pleomorphic adenoma (benign mixed tumor of the salivary glands) should be differentiated from chondroid syringoma because of its tendency to recur and, possibly, malignant transformation ♦♦ As these tumors are similar histologically, location and the presence of adjacent normal salivary glands are the most reliable features used to separate these entities

Malignant Chondroid Syringoma Clinical

♦♦ Eccrine-derived tumors typically stain positively for the cytokeratins, EMA, and CEA, which highlights the luminal aspect of the eccrine ducts

♦♦ A rare, highly malignant tumor with a predilection for the distal extremities ♦♦ These tumors frequently recur and metastasize and are associated with increased mortality

Differential Diagnosis

Microscopic

Immunophenotype

♦♦ Desmoplastic trichoepithelioma has numerous keratotic cysts, frequent calcification and lacks eccrine duct formation ♦♦ Microcystic adnexal carcinoma is much more infiltrative and typically involves the deep dermis and subcutaneous fat

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♦♦ Malignant appearing, infiltrating epithelial cords, ducts and sheets that overgrow the benign mesenchymal matrix ♦♦ Necrosis, mitoses, and nuclear pleomorphism are present ♦♦ An adjacent benign mixed tumor is not typically seen

Neoplasms of the Skin and Immunodermatology

Differential Diagnosis ♦♦ Carcinosarcoma shows a malignant mesenchymal ­component in addition to an epithelial malignancy

Papillary Eccrine Adenoma Clinical ♦♦ A firm, pink to tan nodule on the distal extremities of adolescents and young adults with a female predominance ♦♦ Blacks are more commonly affected than whites

Microscopic ♦♦ A fairly well-circumscribed but unencapsulated proliferation of eccrine ducts and duct-like structures within the dermis ♦♦ The ducts are lined by a multilayered cuboidal epithelium without apical snouts ♦♦ Micropapillary projections and transluminal bridging may be seen ♦♦ The tumor stroma is fibrotic and frequently hyalinized. Cribiform structures, necrosis, mitotic activity, and nuclear pleomorphism are absent

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Nodular Hidradenoma (Clear Cell Hidradenoma, Solid-Cystic Hidradenoma and Eccrine Acrospiroma, Fig. 18.21) Clinical ♦♦ Solid or cystic, intradermal nodule 0.5–2.0 cm in diameter ♦♦ These tumors are usually solitary but may be multiple ♦♦ The head, neck, and extremities are most commonly involved ♦♦ Predominates in young adults with a slight female predominance

Microscopic ♦♦ A well-circumscribed and often pseudoencapsulated tumor composed of a single lobule or, more often, multiple lobules of eosinophilic to clear cells in the dermis ♦♦ Cystic change may be prominent ♦♦ Tubular structures lined by cuboidal to columnar cells with an eosinophilic cuticle are evident in most tumors and are important in proper classification ♦♦ Foci of squamous and/or mucinous differentiation may be seen

Differential Diagnosis ♦♦ Aggressive digital papillary adenoma/adenocarcinoma (see below)

Aggressive Digital Papillary Adenoma/ Adenocarcinoma Clinical ♦♦ Asymptomatic flesh-colored nodule on the digits of middleaged adults ♦♦ The recurrence rate is approximately 50% for these tumors, and the overtly malignant lesions have a metastatic rate of approximately 25–40%

Microscopic ♦♦ Generally, an unencapsulated and poorly circumscribed proliferation of eccrine ducts, tubules, cysts, and nests within the dermis and/or subcutaneous fat ♦♦ The ducts and cystic structures are lined by a multilayered epithelium with abundant micro- and macropapillae ♦♦ Cribiform structures are frequently identified ♦♦ Varying degrees of nuclear pleomorphism, mitotic activity, and necrosis may be seen ♦♦ Tumor grade correlates with metastatic potential, but all forms may metastasize ♦♦ Note: all of these lesions are best classified as ­adenocarcinomas due to their propensity for recurrence ♦♦ A histologic grade should be given as a prognostic indicator for the risk of metastases

Differential Diagnosis ♦♦ Papillary eccrine adenoma does not show the infiltration, nuclear atypia, mitotic activity, or the cribiforming of the aggressive digital papillary adenocarcinoma

Fig. 18.21. Nodular hidradenoma (A, B).

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♦♦ While this tumor is predominantly intradermal, occasional attachments may be seen to the overlying epidermis ♦♦ Necrosis, mitotic activity, and nuclear pleomorphism are absent or minimal in extent

Hidradenocarcinoma (Malignant Nodular Hidradenoma) Clinical ♦♦ Similar distribution to their benign counterparts but occur in older individuals (>50 years of age) ♦♦ Recurrence and metastatic rate is approximately 50%

Microscopic ♦♦ Like the hidradenoma, this tumor is composed of ­eosinophilic and/or clear cells forming lobules within the dermis ♦♦ The malignant variants, however, are asymmetrical, infiltrating, mitotically active and demonstrate nuclear pleomorphism and/or necrosis

Differential Diagnosis ♦♦ Clear cell squamous cell carcinoma, clear cell renal cell carcinoma, clear cell melanoma, and trichilemmal carcinoma ♦♦ Look for tubular structures with an eosinophilic cuticle to confirm eccrine differentiation; CEA may be useful in that it highlights the luminal border of eccrine-derived structures

Hidroacanthoma Simplex (Intraepidermal Poroma) Clinical ♦♦ A rare, benign variant of poroma typically involving the extremities of older individuals

Microscopic ♦♦ An intraepidermal proliferation (Borst–Jadassohn phenomenon) of round to faintly spindled cells with eosinophilic to faintly clear cytoplasm ♦♦ Intracytoplasmic glycogen is evident on PAS staining ♦♦ Rare eccrine ducts/tubules may be seen ♦♦ The individual cells are remarkably uniform and lack nuclear atypia ♦♦ The tumor cells are sharply demarcated from the squamous cells of the adjacent epidermis

Eccrine Poroma (Fig. 18.22) Clinical ♦♦ A red to flesh-colored tumor found most frequently on the sole of the foot or hand, but other sites may be involved ♦♦ These tumors may reach many centimeters in diameter and may be pedunculated ♦♦ While the majority of these tumors are solitary, multiple lesions may be seen (eccrine poromatosis)

Microscopic ♦♦ This tumor is composed of numerous cords or trabeculae of small rounded tumor cells which rain down form the epidermis into the dermis in a fairly circumscribed manner

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Fig. 18.22. Eccrine poroma. ♦♦ The epidermal component is similar to hidroacanthoma simplex while the dermal component often shows numerous wellformed lobules with frequently conspicuous duct formation ♦♦ Cystic change is typically less than that seen in hidradenoma while the degree of epidermal involvement is significantly greater ♦♦ The tumor cells show intercellular bridges and should not be confused with squamous cells that are larger and more polygonal ♦♦ Poromatous lesions that are entirely limited to the dermis are often called dermal duct tumors

Porocarcinoma (Malignant Eccrine Poroma) Clinical ♦♦ The malignant counterpart to the eccrine poroma affects similar sites but tends to occur in older individuals with a long history of progressive tumor growth ♦♦ The recurrence and metastatic rate approaches 25% ♦♦ Multiple cutaneous metastases are not uncommon

Microscopic ♦♦ Like their benign counterparts, epidermal, dermal, and mixed epidermal–dermal variants are seen ♦♦ The epidermal variants and the cutaneous metastases typically show frank pagetoidosis with scattered foci of ductal differentiation

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Fig. 18.23. Cylindroma. ♦♦ The mixed variants are by far the most common and have a similar architecture to their benign counterpart; however, these tumors are infiltrative, mitotically active and demonstrate nuclear pleomorphism, and occasionally perineural and capillary-lymphatic invasion

Cylindroma and Malignant Cylindroma (Fig. 18.23) Clinical ♦♦ Solitary or multiple, red to purple nodules on the head, neck, or scalp ♦♦ Multiple tumors (turban tumors) are inherited in an autosomal dominant fashion and may be associated with multiple trichoepitheliomas

Microscopic ♦♦ Multiple, dermal-based lobules are found in the dermis and have an interlocking or “jigsaw puzzle” appearance ♦♦ The individual lobules are surrounded by an eosinophilic basement membrane ♦♦ Two cell types are evident within the lobules: a lymphocytelike population of cells with hyperchromatic nuclei which predominate at the periphery of the lobules and a population of larger cells with oval, vesicular nuclei which predominate centrally ♦♦ Hylanizing basement membrane-like material is also frequently evident within the lobules ♦♦ Malignant variants demonstrate nuclear pleomorphism, mitotic activity, loss of the surrounding basement membrane, and infiltration of adjacent tissue ♦♦ Malignant variants are rare and may arise in the background of multiple benign cylindromas

Eccrine Spiradenoma and Malignant Eccrine Spiradenoma (Fig. 18.24) Clinical ♦♦ Usually solitary, blue to flesh-colored, intradermal nodules on the ventral aspect of the body

Fig. 18.24. Eccrine spiradenoma (A, B). ♦♦ These tumors are frequently painful. Rarely, multiple tumors may be seen in a linear or zosteriform distribution

Microscopic ♦♦ One or more, basophilic tumor lobules are evident in the dermis and are usually encapsulated ♦♦ The lobules are composed of two cell types similar to the cylindroma: a small, lymphocyte-like population and a larger cell type with oval, vesicular nuclei ♦♦ Ductal differentiation may be conspicuous within the lobules, and pseudovascular spaces may give a hemangiomatous quality to the lesion ♦♦ The intervening stroma often demonstrates lymphangiectasia ♦♦ The rare malignant variants require an adjacent benign focus of typical microscopy for confident diagnosis ♦♦ The malignant variants are characterized by infiltration, mitoses, nuclear pleomorphism, necrosis, and lymphatic invasion

Eccrine Duct Carcinoma Clinical ♦♦ A nodular and often ulcerated lesion of long-standing duration found most commonly on the head, neck, and extremities of older adults

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♦♦ Approximately 50% metastasize to lymph nodes or visceral sites

Microscopic ♦♦ An infiltrating dermal tumor composed of strands, trabeculae, and tubules with varying degrees of lumen formation ♦♦ The histologic pattern is very similar to ductal carcinoma of the breast, which should always be excluded clinically ♦♦ There is at least some degree of nuclear pleomorphism, and nucleoli are frequently prominent ♦♦ Mitotic figures and necrosis may also be identified

Syringoid Eccrine Carcinoma (Eccrine Epithelioma) Clinical ♦♦ Typically, a plaque or an ulcerated tumor of the scalp of middle-aged adults ♦♦ This tumor is locally aggressive with frequent recurrences, but metastases are rare

Microscopic ♦♦ A dermal-centered tumor showing extensive infiltration with involvement of the subcutaneous fat ♦♦ This tumor is composed of infiltrating cords and trabeculae with faint lumen formation and a dense, hyalinizing stroma ♦♦ Unlike microcystic adnexal carcinoma, keratocysts are rarely present ♦♦ The individual cells often have basaloid features but lack peripheral retraction ♦♦ Nuclear pleomorphism is mild, and mitotic figures are scarce ♦♦ Perineural invasion is frequent

Microcystic Adnexal Carcinoma (Fig. 18.25) Clinical ♦♦ A flesh-colored to yellow, slowly growing firm plaque or nodule involving the head, neck, or face of older adults ♦♦ Like syringoid eccrine carcinoma, this is a locally aggressive tumor with frequent recurrences but with no tendency to metastasize

Microscopic ♦♦ A dermal-centered tumor showing extensive infiltration of the deep dermis and subcutaneous tissues ♦♦ Keratocysts, trabeculae, and ductules are evident throughout the lesion, but keratocysts tend to predominate superficially while trabeculae predominate at the deeper aspect of the tumor ♦♦ The middle of the tumor shows an admixture of all forms giving this tumor a triphasic or trilayered look from superficial to deep ♦♦ The individual epithelial units are frequently invested by a dense fibrous stroma giving this tumor a sclerotic appearance ♦♦ Perineural invasion is common while nuclear pleomorphism and mitotic activity are rare

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Fig. 18.25. Microcystic adnexal carcinoma (A, B).

Mucinous Eccrine Carcinoma Clinical ♦♦ A flesh-colored to blue nodule on the head and neck region (particularly the eyelid) of older adults with a male predominance

Microscopic ♦♦ A dermal-based tumor showing islands of relatively bland epithelial cells floating in pools of mucin similar to colloid carcinoma of the breast

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Adenoid Cystic Carcinoma General

Hidradenoma Papilliferum Clinical

♦♦ A rare, primary cutaneous neoplasm showing a similar microscopic to its counterparts elsewhere but having a less aggressive course

♦♦ Typically a solitary, asymptomatic nodule present in the genital region of females ♦♦ Similar lesions have been described within the ear, nipple, and eyelid

Mucoepidermoid Carcinoma General ♦♦ A rare primary tumor of skin showing similar histologic features to its salivary gland counterpart

Apocrine-Derived Tumors and Proliferations Apocrine Nevus Clinical ♦♦ A rare lesion typically presenting as a papule in the axilla or on the scalp

Microscopic ♦♦ An increase in the number or size of mature-appearing apocrine glands

Syringocystadenoma Papilliferum (Fig. 18.26) Clinical ♦♦ Typically a solitary, verrucous to papillary lesion on the scalp, face. or neck, but other sites may be involved ♦♦ In children, this tumor frequently arises within a nevus sebaceous

Microscopic ♦♦ A partially cystic, dermal-centered tumor showing ­overlying epidermal invagination ♦♦ The cystic space contains abundant papillary structures lined by a bilayered epithelium with apical snouts, consistent with apocrine differentiation ♦♦ The fibrovascular cores contain abundant plasma cells

Microscopic ♦♦ A well-demarcated, dermal-based neoplasm showing no involvement of the overlying epidermis ♦♦ This tumor is also frequently cystic in areas and is characterized by numerous trabeculae, epithelial fronds, and papillary structures lined by a bilayered epithelium showing apocrine differentiation (apical snouts) ♦♦ The stroma is fibrovascular and lacks the plasma cells of syringocystadenoma papilliferum ♦♦ Occasional cases show a more pronounced fibrous stroma with a lobular architecture akin to fibroadenoma of the breast ♦♦ Rare cases show malignant transformation with high grade nuclear features, frequent mitoses, necrosis, and infiltration

Tubular Apocrine Adenoma (Fig. 18.27) Clinical ♦♦ A well-defined nodule occurring most commonly on the scalp of adults

Microscopic ♦♦ An unencapsulated, but well-demarcated proliferation of numerous ducts/glands lined by a bilayered to multilayered epithelium showing apocrine differentiation ♦♦ Small papillary structures and occasional cribiforming may be seen and resemble proliferative lesions in the breast ♦♦ These lesions may show some degree of nuclear atypia and mitotic activity but generally are not considered as carcinomas unless obvious infiltration of surrounding tissues is seen

Apocrine Carcinoma Clinical ♦♦ A rare primary tumor of skin that typically presents as an erythematous nodule with or without ulceration in older adults ♦♦ A variety of sites may be affected including the scalp, eye, ear, and anogenital regions amongst others ♦♦ Recurrences and metastases may occur

Microscopic

Fig. 18.26. Syringocystadenoma papilliferum.

♦♦ A variety of histologic appearances may be present including cystic, papillary, sheet-like, and ductal variants ♦♦ Infiltration of adjacent tissues is seen, and pagetoidosis may be evident ♦♦ Nuclear pleomorphism may be mild to marked, and varying degrees of mitotic activity and necrosis may be evident ♦♦ By definition, areas of apocrine differentiation should be identified, at least focally

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Fig. 18.27. Tubular apocrine adenoma.

Differential Diagnosis ♦♦ Apocrine carcinoma of the breast has similar histologic and immunophenotypic characteristics and should be excluded clinically

Neuroendocrine-Derived Tumors Merkel Cell Carcinoma (Fig. 18.28) Clinical ♦♦ An aggressive neoplasm typically presenting as a slowly growing nodule on the sun-exposed skin (head and neck region) of older adults ♦♦ The recurrence and metastatic rate is approximately 40–50%

Microscopic ♦♦ A variety of histologic forms may be seen and include sheetlike, ribboned, nested, trabecular, and organoid variants ♦♦ Pseudorosettes may be prominent ♦♦ These tumors are typically dermal based but frequently involve the subcutis and may show an intraepidermal growth pattern

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Fig. 18.28. Merkel cell carcinoma (A, B).

♦♦ Focal areas of squamous, eccrine, or sebaceous differentiation may be seen, and these tumors may arise in conjunction with another histologically distinct neoplasm ♦♦ The cytologic and immunophenotypic appearance is characteristic and common to all variants ♦♦ Cytologically, the tumor cells have very high nuclear/cytoplasmic ratios, indistinct cell borders, hyperchromatic, and finely granular nuclei with inconspicuous nucleoli and thin nuclear membranes ♦♦ Nuclear molding and mitoses are abundant

Neoplasms of the Skin and Immunodermatology

♦♦ Immunophenotypically, the tumor cells express low molecular weight cytokeratin (CAM 5.2) in a perinuclear dot-like pattern which may also be seen with neurofilament staining ♦♦ Cytokeratin 20 staining is generally positive, and these tumors express a variety of neuroendocrine markers including neuron-specific enolase, chromogranin, synaptophysin, and neurofilament, but are generally negative for S-100 protein and vimentin

Differential Diagnosis ♦♦ Merkel cell carcinomas must be differentiated from a variety of other neuroendocrine tumors of either metastatic or primary origin ♦♦ Small cell neuroendocrine carcinomas from visceral sites metastatic to skin have an essentially identical histologic appearance but have recently been reported to be ­cytokeratin 20 negative ♦♦ Cutaneous neuroblastoma generally shows a filamentous background and/or focal ganglion cell differentiation and is typically cytokeratin negative (except for the olfactory variant) ♦♦ Primitive neuroectodermal tumors/extraosseous Ewing sarcomas are usually cytokeratin negative and typically express MIC-2

Soft Tissue Neoplasms and Developmental Anomalies Adipocyte-Derived Tumors and Proliferations Lipoma Clinical ♦♦ A sporadic or multifocal tumor of the middle aged to elderly typically involving the trunk and/or extremities

Microscopic ♦♦ A thin encapsulated proliferation of mature adipose tissue ♦♦ The adipose tissue may be accompanied by a wide variety of other types of mesenchymal-derived tissue: fibrous (fibrolipoma), bone (osteolipoma), cartilage (chondroid lipoma), bone marrow (myelolipoma), mucoid substances (myxoid lipoma), smooth muscle (myolipoma). and smooth muscle and vessels (angiomyolipoma)

Angiolipoma Clinical ♦♦ A painful, subcutaneous nodule(s) involving the upper extremities of young adults

Microscopic ♦♦ Thin encapsulated proliferations of mature adipocytes and variably sized, thin-walled vessels ♦♦ Microthrombi are readily identified within the vessel lumina ♦♦ A cellular variant showing numerous small vessels with few adipocytes exists and must be differentiated from other vascular tumors that lack the proliferation of mature adipocytes

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Spindle Cell Lipoma Clinical ♦♦ A solitary, painless, subcutaneous nodule with a predilection for the base of the neck of middle aged to older adults

Microscopic ♦♦ An encapsulated proliferation of mature adipocytes and bland, bipolar spindle cells embedded in a myxoid matrix with collagen fibers ♦♦ The spindle cells may predominate and typically show bland, uniform features ♦♦ Lipoblasts and the plexiform capillary network of myxoid liposarcoma are absent ♦♦ Occasional cases show bizarre, multinucleated cells and merge with pleomorphic lipoma

Pleomorphic Lipoma Clinical ♦♦ Similar to spindle cell lipoma

Microscopic ♦♦ Similar to spindle cell lipoma with the addition of ­numerous, multinucleated (floret cells) cells with ­hyperchromatic, peripherally situated nuclei

Lipoblastoma and Lipoblastomatosis Clinical ♦♦ These are tumors of infants and young children and typically present as painless masses on the extremities in a localized (lipoblastoma) or diffuse (lipoblastomatosis) fashion ♦♦ The latter may recur with incomplete excision

Microscopic ♦♦ Multilobular proliferations of immature and mature adipocytes embedded in a myxoid matrix and separated by thin fibrous septae ♦♦ The adipocytes may show a wide spectrum of differentiation from spindle cells to multivacuolated lipoblasts to mature, univacuolated adipocytes ♦♦ These lesions tend to mature histologically with time

Lipofibromatous Hamartoma of Nerve Clinical ♦♦ A tumor-like condition that presents as a mass of the wrist and/or forearm ♦♦ Typically, these patients are young children, but adult presentations also occur ♦♦ Sensory defects, parathesias, pain, and macrodactyly may be prominent ♦♦ Due to the intimate association of this proliferation with nerves, surgical excision is contraindicated and may lead to permanent sensorimotor impairment

Microscopic ♦♦ A proliferation of benign fibroadipose tissue is evident in and around nerve fibers which show secondary degeneration, atrophy, and fibrosis

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Lipomatosis Clinical ♦♦ Multiple clinical forms exist including a diffuse variant typically involving the extremities or trunk of young children, a symmetrical variant (Madelung disease) involving the neck region of middle-aged adult males as well as visceral and pelvic variants

Microscopic ♦♦ All are unencapsulated proliferations of mature adipose tissue involving the subcutis, skeletal muscle and, occasionally, other structures

Nevus Lipomatosus Superficialis Clinical ♦♦ A hamartomatous proliferation typically presenting as multiple, polypoid papules or plaques on the buttocks, posterior trunk or thigh of children to young adults

Microscopic ♦♦ Small lobules of mature adipocytes are evident in the superficial and mid dermis and may be associated with keratin plugs and loss of adnexal structures

Hibernoma Clinical ♦♦ A slow-growing, asymptomatic mass of the chest or upper back of young to middle-aged adults ♦♦ Other sites may also be affected

Microscopic ♦♦ An encapsulated, multilobular tumor composed of an admixture of multivacuolated and univacuolated adipocytes and large cells with eosinophilic cytoplasm and distinct cell membranes

Liposarcoma Clinical

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The multiple or diffuse variant has a strong association with neurofibromatosis type 1 and may show extensive, cosmetically deforming lesions with a bag of worms appearance and feel ♦♦ The diffuse variant is seen more frequently in childhood and adolescence ♦♦ The diffuse variant has definite malignant potential while the sporadic variant lacks this characteristic

Microscopic ♦♦ A variety of histologic subtypes exist, but all are characterized by a proliferation of wavy, pointed spindle cells embedded in a variably collagenous to myxoid matrix ♦♦ These tumors are unencapsulated but are generally well circumscribed ♦♦ They do not infrequently incorporate dermal adnexal structures, but direct adnexal invasion is rare ♦♦ Plexiform, diffuse, myxoid, and pacinian variants exist ♦♦ The plexiform variant is thought to be diagnostic of neurofibromatosis while the diffuse variant may also be associated with this disease at an increased rate

Special Studies ♦♦ Neurofibromas are derived from nerve and, as such, demonstrate positive staining for axonal markers such as neurofilament and silver impregnation techniques ♦♦ Similar to other neural-derived tumors, these lesions are also positive for S-100 protein, CD57, and neuron-specific enolase

Schwannoma (Neurilemmoma, Fig. 18.29) Clinical ♦♦ A peripheral nerve sheath derived tumor that generally presents as a solitary nodule/mass on the head, neck, or extremities of adults ♦♦ Rarely, multiple tumors may be evident (schwanno-matosis), and at least some of these cases are associated with neurofibromatosis type 2 ♦♦ In general, schwannomas have little, if any, malignant potential

♦♦ These are rare tumors of skin that generally present as slowly growing subcutaneous masses in older adults

Microscopic ♦♦ The myriad of histologic types of liposarcoma are addressed in detail elsewhere ♦♦ Generally, the liposarcomas involving skin are of the welldifferentiated (atypical lipoma) or myxoid types ♦♦ The former has lipoma-like, sclerosing and spindle cell variants which may recur but typically do not metastasize

Neural-Derived Tumors and Proliferations Neurofibroma Clinical ♦♦ Solitary and multiple forms exist ♦♦ The solitary variant is typically a soft, polypoid, flesh-colored tumor occurring in adults

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Fig. 18.29. Plexiform schwannoma.

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Microscopic ♦♦ A well-circumscribed, encapsulated tumor within the subcutis or deeper tissues ♦♦ Occasionally, dermal involvement may be evident ♦♦ The tumor is composed of spindle cells with wavy, pointed nuclei embedded in a collagenous and highly vascular stroma ♦♦ Classically, cellular, Antoni A areas with palisading, Verocay bodies are admixed with paucicellular, myxoid, Antoni B areas ♦♦ Degenerative changes are frequent findings and include hyalinization, vascular thrombosis, dystrophic ­mineralization, and hemorrhage ♦♦ The ancient variants typically show some degree of nuclear pleomorphism and enlargement with a smudgy chromatin pattern ♦♦ Plexiform variants exist and typically present in childhood or adolescence ♦♦ These tumors are composed of multiple, cellular, Antoni A-like, encapsulated nodules that must be differentiated from plexiform neurofibroma and plexiform fibrohistiocytic tumor ♦♦ Cellular variants are moderately to markedly cellular and may have mitotic activity. Nuclear pleomorphism and necrosis, however, are absent. Melanotic variants also exist and must be differentiated from malignant melanoma

Special Studies ♦♦ Schwannomas are derived from the peripheral nerve sheath and, therefore, lack axonal differentiation; that is, they are neurofilament and silver staining negative ♦♦ Schwann cells are S-100 protein positive and are generally surrounded by type IV collagen-rich basement membrane ♦♦ Epithelial membrane antigen typically stains the capsule of schwannomas

Traumatic Neuroma Clinical ♦♦ Reactive, nonneoplastic proliferations of nerve in response to injury ♦♦ Typically present as small, often painful, nodules at sites of previous injury

Microscopic ♦♦ A well-localized but unencapsulated, haphazard proliferation of nerve fibers associated with dermal fibrosis (scar)

Palisaded and Encapsulated Neuroma (Solitary Circumscribed Neuroma, Fig. 18.30) Clinical ♦♦ Solitary, flesh-colored papule on the face of middle-aged to older adults

Microscopic ♦♦ A nodular to multinodular, often dumbbell-shaped proliferation of spindle cells embedded in a collagenous matrix

Fig. 18.30. Palisaded and encapsulated neuroma. ♦♦ These lesions are well circumscribed but only partially encapsulated ♦♦ The superficial component generally lacks a true capsule and tends to resemble a neurofibroma while the deep component is encapsulated and resembles a schwannoma ♦♦ The spindle cells demonstrate wavy, pointed nuclei and lack mitotic activity ♦♦ Contrary to its name, true nuclear palisading is rare in this lesion ♦♦ A nerve may be evident entering the base of the lesion

Special Studies ♦♦ Like neurofibroma, this lesion contains both axons and schwann cells and, hence, is S-100 protein and neurofilament positive

Granular Cell Tumor (Fig. 18.31) Clinical ♦♦ Slowly growing, sometimes painful, flesh-colored nodules with a predilection for the tongue, trunk, and extremities of adults ♦♦ While usually solitary, multiple and familial variants exist

Microscopic ♦♦ Irregular fascicles and/or sheets of large, round to polygonal cells with eosinophilic, granular cytoplasm ♦♦ Cell borders are indistinct giving this tumor a syncytial appearance

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Fig. 18.32. Neurothekeoma.

Microscopic ♦♦ Similar to granular cell tumor, but these lesions are S-100 protein negative

Nerve Sheath Myxoma (NSM) and Cellular Neurothekeoma (Fig. 18.32) Clinical Fig. 18.31. Granular cell tumor.

♦♦ Soft, mobile, flesh-colored papules on the face or upper extremities of young adults ♦♦ These tumors may recur with incomplete excision

Microscopic ♦♦ Nuclei are generally round to ovoid, central, and monomorphic ♦♦ Nuclear pleomorphism, mitotic activity, necrosis, and large tumor size may be associated with the rare malignant variants ♦♦ Prominent pseudoepitheliomatous hyperplasia of the epidermis is often seen overlying this tumor and must not be mistaken for squamous cell carcinoma

Special Studies ♦♦ While the cell of origin remains to be clarified, most authorities support a schwann cell derivation for these tumors ♦♦ Accordingly, these tumors are usually, but not always, S-100 protein and neuron-specific enolase positive

Differential Diagnosis ♦♦ Secondary granular cell change is not an uncommon finding in other tumor types (dermatofibroma, neurofibroma, etc.) which should be excluded prior to making the diagnosis of granular cell tumor ♦♦ This tumor should also be differentiated from congenital epulis discussed below

♦♦ NSM is a fascicular to lobular dermal tumor composed of spindle and stellate cells embedded in myxoid lobules which in turn are separated by fibrous septae ♦♦ Cellular neurothekeoma is composed of more uniform, epithelioid cells in nests and fascicles with minimal myxoid background material ♦♦ Mitotic activity and mild nuclear pleomorphism may be seen in both lesions

Special Studies ♦♦ NSM is typically S-100 protein+ and is likely derived from the peripheral nerve sheath ♦♦ Cellular neurothekeoma is S-100 protein– and its cell of origin is unclear ♦♦ The lack of S-100 protein positivity in the cellular variants allows these lesions to be readily distinguished from most melanocytic neoplasms

Perineurioma Clinical ♦♦ A benign tumor of perineural origin that typically presents as a subcutaneous mass on the trunk and limbs of adults

Congenital Epulis Clinical

Microscopic

♦♦ A polypoid gingival lesion in newborns that may spontaneously regress

♦♦ A well-circumscribed proliferation of bland spindle cells in fascicles with whorled and storiform areas

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Neoplasms of the Skin and Immunodermatology

Special Studies ♦♦ Like perineural cells, this tumor is S-100 protien– and EMA+

Malignant Peripheral Nerve Sheath Tumor General ♦♦ A rare, primary cutaneous malignancy frequently associated with neurofibromatosis type 1 when primary in the skin ♦♦ These lesions are discussed in detail in the chapter on soft tissue pathology

Cutaneous Meningothelial Heterotopias/Meningiomas (Fig. 18.33) Clinical ♦♦ Classic meningocele is typically a transilluminating mass along the lower spine and represents a congenital defect ♦♦ Rudimentary meningocele is thought to be a herniation of the meninges into the superficial tissues of the scalp with a subsequent loss of its intracranial attachment ♦♦ Cutaneous meningioma comes in three forms: type I is congenital lesion involving the head and paravertebral regions of children and is secondary to misplaced arachnoid cells during embryogenesis; type II occurs on the head and neck region of adults and is thought to be secondary to a proliferation of arachnoid cells through a cranial foramina; type III

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represents a metastasis or direct extension of tumor into skin form an intracranial primary

Microscopic ♦♦ Meningoceles are typically cyst-like structures lined by arachnoid cells and having surrounding dense fibrous tissue with occasional collections of meningothelial cells in whorllike structures ♦♦ Meningiomas are usually well-circumscribed deep dermal to subcutaneous proliferations composed of spindle cells arranged in fascicles and whorls with or without psammoma body formation ♦♦ Nuclear pleomorphism and mitotic activity may be seen, particularly in the type III variants ♦♦ Special studies ♦♦ Meningothelial proliferations are usually vimentin and EMA+ ♦♦ Cytokeratin and S-100 protein may also be expressed by these tumors

Heterotopic Glial Tissue (Nasal Glioma) Clinical ♦♦ Flesh-colored mass on the nasal bridge of infants to young adults. Intranasal involvement may also be present ♦♦ Radiographic studies should be performed to exclude an intracranial attachment

Microscopic ♦♦ Nodules of benign eosinophilic, fibrillar, glial tissue within the deep dermis and subcutis ♦♦ Rarely, neuronal cells may also be seen

Smooth Muscle-Derived Tumors and Proliferations Smooth Muscle Hamartoma Clinical ♦♦ A congenital, sometimes pigmented, indurated plaque on the trunk which typically presents in infancy

Microscopic ♦♦ A haphazard proliferation of smooth muscle fascicles in the dermis with or without basilar epidermal hyperpigmentation

Becker Nevus Clinical ♦♦ An acquired, organoid, hyperpigmented plaque with hypertrichosis on the back of young adults and in adolescents ♦♦ This lesion may be associated with other congenital abnormalities

Microscopic Fig. 18.33. Meningioma.

♦♦ Epidermal acanthosis and basilar hyperpigmentation occasionally associated with a mild haphazard proliferation of smooth muscle fascicles within the dermis

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Fig. 18.35. Angioleiomyoma.

Fig. 18.34. Piloleiomyoma.

Piloleiomyoma (Pilar leiomyoma, Fig. 18.34) Clinical ♦♦ Multiple, somewhat painful papules or nodules on the trunk or extremities of young adults ♦♦ May be inherited in an autosomal dominant fashion

Microscopic ♦♦ A fairly well-circumscribed yet irregular proliferation of smooth muscle fascicles within the dermis ♦♦ The individual cells have elongated eosinophilic cytoplasm and cigar-shaped nuclei ♦♦ No nuclear pleomorphism, mitotic activity, or necrosis is evident

Angioleiomyoma (Fig. 18.35) Clinical ♦♦ A solitary, sometimes painful nodule on the extremities of adults

Microscopic ♦♦ A nodular, well-circumscribed proliferation of smooth muscle in fascicles admixed with numerous, variably sized vessels ♦♦ Degenerative changes are frequent

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Fig. 18.36. Leiomyosarcoma.

Leiomyosarcoma (Fig. 18.36) Clinical ♦♦ Two clinical variants exist: a superficial or cutaneous variant and a deep or subcutaneous variant ♦♦ The former predominates on the limbs of young adults and is likely derived from the arrector pili muscle ♦♦ This variant may locally recur but generally does not metastasize ♦♦ The subcutaneous variant predominates on the limbs of the elderly and has both local recurrence and metastatic potential

Microscopic ♦♦ The cutaneous variant demonstrates an irregular, infiltrating, and haphazard proliferation of smooth muscle bundles reminiscent of piloleiomyoma ♦♦ However, unlike piloleiomyoma, this tumor has low-grade nuclear pleomorphism, mitotic activity, and, rarely, necrosis

Neoplasms of the Skin and Immunodermatology

♦♦ The deep or subcutaneous variant is akin to leiomyosarcomas arising elsewhere and consists of a nodular, at least focally infiltrating, proliferation of smooth muscle fibers in well-formed to ill-defined bundles with varying degrees of nuclear pleomorphism, mitotic activity and necrosis

Fibrohistiocytic, Histiocytic, and Langerhans Cell-Derived Proliferations Fibrous Histiocytoma (Dermatofibroma, Fig. 18.37) Clinical ♦♦ Usually single, occasionally multiple, slightly elevated, smooth, flesh-colored to hyperpigmented nodules on the extremities or trunk of adults

Microscopic ♦♦ Numerous subtypes have been described but all are generally made up of a proliferation of histiocytes, fibroblasts, and collagenous tissue in varying proportions ♦♦ The prototypical lesion (dermatofibroma) consists of a fairly well-circumscribed, unencapsulated, mid-dermal proliferation with feathery edges, an overlying Grenz zone and epidermal hyperplasia with basilar hyperpigmentation

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♦♦ The cellular component consists of spindled, fibroblast-like cells admixed with plump histiocytic cells in an irregular fashion ♦♦ Storiform areas may be evident, and there may be focal extension into the subcutis ♦♦ Chronic inflammatory cells, multinucleated giant cells, xanthomatized histiocytes, and hemosiderin-laden histiocytes are also frequently identified within these lesions ♦♦ Important variants include atypical dermatofibroma (dermatofibroma with monster cells), aneurysmal fibrous histiocytoma, and epithelioid cell histiocytoma, all of which may be mistaken for other more aggressive entities ♦♦ Atypical dermatofibroma is a lesion showing large, hyperchromatic, multinucleated giant cells in addition to typical dermatofibroma features and should be distinguished from atypical fibroxanthoma and malignant fibrous histiocytoma ♦♦ Aneurysmal fibrous histiocytoma is a fibrous histiocytoma with prominent intralesional hemorrhage and cystic, pseudovascular spaces ♦♦ This lesion should be distinguished from angiomatoid fibrous histiocytoma, a lesion of intermediate grade malignancy occurring in the pediatric population ♦♦ Epithelioid cell histiocytoma is composed of a polypoid well-circumscribed proliferation of angulated, epithelioid, histiocytic-appearing cells surrounded by an epidermal collarette ♦♦ This lesion should be distinguished from melanocytic tumors, both Spitz nevus and melanoma

Special Studies ♦♦ Most fibrous histiocytomas express FXIIIa but are negative for CD34 ♦♦ Dermatofibroma sarcoma protuberans tends to have the opposite staining pattern, but overlap and divergent staining patterns occasionally occur

Angiomatoid Fibrous Histiocytoma (Fig. 18.38) Clinical ♦♦ A fairly deep-seated, usually subcutaneous, nodule or mass within the extremities of children and adolescents ♦♦ This lesion is considered to be of borderline or intermediate malignancy and may recur and, rarely, metastasize

Microscopic

Fig. 18.37. Dermatofibroma.

♦♦ A circumscribed, partially cystic and lobular mass usually centered on subcutaneous tissue ♦♦ This tumor is composed of an admixture of cystic, bloodfilled pseudovascular spaces, myxoid lobules of histiocytic appearing cells, and peripheral lymphocytic inflammation and fibrosis ♦♦ The neoplastic cells are somewhat spindled to plump, epithelioid cells with eosinophilic to amphophilic cytoplasm and mildly pleomorphic nuclei ♦♦ Mitotic figures may be evident

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Fig. 18.39. Juvenile xanthogranuloma.

Fig. 18.38. Angiomatoid fibrous histiocytoma (A, B).

Special Studies ♦♦ The histiocytic-appearing cells often show expression of smooth muscle actin, desmin, and CD34, suggesting to some a myofibroblastic derivation to this tumor

Plexiform Fibrohistiocytic Tumor Clinical ♦♦ A slowly growing deep dermal to subcutaneous mass on the extremities of children to young adults ♦♦ This is a tumor of intermediate malignancy that may recur and rarely metastasizes

Microscopic ♦♦ An unencapsulated, irregular biphasic tumor consisting of short fibromatosis-like fascicles of plump spindle cells admixed with nodules of histiocytic and osteoclast-like giant cells with minimal nuclear pleomorphism ♦♦ The admixture of nodules and fascicles gives this tumor a plexiform appearance at low power

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Juvenile Xanthogranuloma (Fig. 18.39) Clinical ♦♦ Solitary to multiple, yellow to red papules on the head and neck region of infants is the most common presentation ♦♦ However, adolescents and adults may also be affected, and other body sites may be involved ♦♦ Visceral involvement may be evident with the eye being the most common extracutaneous site of involvement ♦♦ Typically, the cutaneous lesions regress over time

Microscopic ♦♦ Fairly well-circumscribed collection of histiocytes within the dermis admixed with Touton giant cells, xanthomatized histiocytes, and chronic inflammatory cells ♦♦ The epidermis is spared, but periadnexal involvement is common ♦♦ Spindle cell and inflammatory cell rich variants exist

Reticulohistiocytoma and Multicentric Reticulohistiocytosis Clinical ♦♦ Solitary and multicentric variants exist ♦♦ The former is usually a yellow to brown nodule on the upper body of adults while the latter shows multiple lesions associated

Neoplasms of the Skin and Immunodermatology

with a destructive arthritis and constitutional symptoms, also in adults ♦♦ Occasionally, the multicentric variant is associated with visceral neoplasia

Microscopic ♦♦ Both variants are characterized by fairly well-circumscribed proliferations of large, eosinophilic histiocytes with “glassy” cytoplasm ♦♦ The individual cells may contain more than a single nucleus but Touton giant cells are usually absent, and xanthomatized histiocytes are not generally present ♦♦ Mild nuclear pleomorphism and admixed inflammation with eosinophils and lymphocytes may be evident

Atypical Fibroxanthoma (Fig. 18.40) Clinical ♦♦ Typically a solitary, often ulcerated polypoid nodule on the sun-exposed skin (head and neck) of the elderly ♦♦ A less common variant occurs on the trunk and extremities of young adults ♦♦ These tumors, when limited to superficial tissues, may locally recur but have minimal metastatic potential

Microscopic ♦♦ A nodular, often well-circumscribed, proliferation of very pleomorphic epithelioid to spindle cells with frequent mitoses, often atypical ♦♦ These tumors are usually centered on the dermis and frequently about the dermal-epidermal junction where they stop abruptly ♦♦ Epidermal ulceration is common, but true epidermal involvement with pagetoid spread should raise concerns about malignant melanoma or squamous cell carcinoma ♦♦ Rarely, the tumor is composed of spindle cells in poorly defined fascicles and may be mistaken for leiomyosarcoma ♦♦ While occasional tumors may show superficial involvement of the subcutaneous tissues, extensive subcutaneous

Fig. 18.40. Atypical fibroxanthoma.

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involvement and/or prominent vascular invasion and necrosis should lead to an alternate diagnosis (e.g., malignant fibrous histiocytoma)

Special Studies ♦♦ This tumor is a diagnosis of exclusion; therefore, S-100 protein, cytokeratin, and desmin should be negative by immunoperoxidase technique to exclude malignant melanoma, carcinoma, and leiomyosarcoma, respectively ♦♦ Smooth muscle actin may be expressed by a subset of these tumors and is not indicative of smooth muscle differentiation (leiomyosarcoma) in the absence of desmin positivity

Malignant Fibrous Histiocytoma General ♦♦ These tumors are rarely primary cutaneous lesions and have overlapping histologic features with atypical fibroxanthoma ♦♦ The latter tumor is often considered to be a superficial variant of malignant fibrous histiocytoma with minimal metastatic potential ♦♦ The term malignant fibrous histiocytoma should be used for those tumors that demonstrate deep tissue involvement, vascular invasion, or extensive necrosis as detailed above ♦♦ The histologic subtypes and clinical distribution of this tumor are detailed in the chapter on soft tissue tumor

Xanthomas and Xanthelasma (Fig. 18.41) Clinical ♦♦ Numerous clinical and histologic subtypes exist, many of which are related to systemic lipid abnormalities and represent storage disorders ♦♦ Eruptive −− Yellow papules on the buttocks and other sites associated with type I hyperlipoproteinemia ♦♦ Tuberous −− Yellow papules and nodules on the extensor surfaces associated with hyperlipoproteinemia types II–IV ♦♦ Tendinous −− Nodules or masses on the tendons of the extremities associated most frequently with type II hyperlipoproteinemia −− Planar −− Yellow papules and plaques that may involve ­intertriginous sites, palmar creases, or more multiple sites in a diffuse fashion −− The intertriginous variant is associated with type II hyperlipoproteinemia, the palmar variant with type III hyperlipoproteinemia, and the diffuse variant is often associated with hematopoeitic disorders ♦♦ Xanthelasma −− Yellow plaques on the eyelids, which are associated with lipid abnormalities in only approximately 50% of patients (type III hyperlipoproteinemia) ♦♦ Xanthoma disseminatum −− Not a true storage disorder but, rather, a non-X histiocytosis that presents as yellow-red papules and plaques on

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Essentials of Anatomic Pathology, 3rd Ed.

intraepidermal neutrophils, and a subepidermal proliferation of markedly xanthomatized histiocytes

Special Studies ♦♦ Xanthomas and the non-X histiocytoses are S-100 protein−, CD1a−, macrophage markers+ (CD68) and Birbeck granule

Langerhans Cell Histiocytosis (LCH, Histiocytosis X, Fig. 18.42) Clinical ♦♦ Three clinical variants of this disease have historically been described ♦♦ Letterer–Siwe disease is an acute disseminated form characterized by numerous brown papules on the scalp or face of infants with visceral involvement ♦♦ Hand–Christian–Schuller disease is a chronic, multifocal variant with osseous and localized visceral involvement that affects older children and adults and only occasionally involves the skin ♦♦ Eosinophilic granuloma is a chronic, focal variant that typically involves osseous sites in adults but may involve skin ♦♦ Many cases of LCH do not fit into the above categories and can show a wide spectrum of manifestations

Microscopic Fig. 18.41. Verruciform xanthoma. the flexural surfaces and mucosal membranes of young adults −− There is no association between lipid abnormalities and this disorder ♦♦ Verruciform xanthoma −− Usually a solitary, yellow-red, papillomatous lesion of the mouth, this localized process may be seen at a number of cutaneous sites as a primary lesion or as a secondary phenomena in other disorders (e.g., squamous cell carcinoma, epidermal nevi, lupus erythematosus)

Microscopic ♦♦ All of the above lesions show an admixture of xanthomatized histiocytes, nonxanthomatized histiocytes, and chronic inflammatory cells in varying proportions depending on the age and evolution of the lesion ♦♦ These lesions are typically dermal limited but, occasionally, show more extensive cutaneous involvement ♦♦ Epidermal involvement is not evident ♦♦ Occasional cases will have numerous multinucleated giant cells and/or Touton giants cells and, hence, show overlap with juvenile xanthogranuloma ♦♦ This is particularly true of xanthoma disseminatum, which should be distinguished by clinical criteria ♦♦ Verruciform xanthoma is a special histologic variant characterized by epidermal acanthosis, papillomatosis, parakeratosis,

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♦♦ Nodular or loose aggregates of Langerhans cells within the dermis variably admixed with multinucleated cells, eosinophils, neutrophils, and chronic inflammatory cells ♦♦ Epidermal involvement is common and aids in distinguishing this lesion from the non-X histiocytoses and urticaria pigmentosa ♦♦ Proper diagnosis rests on identifying the Langerhans cell that is a histiocyte-like cell with abundant, eosinophilic to amphophilic cytoplasm and a reniform, sometimes twisted nucleus with occasional longitudinal grooves

Immunoperoxidase ♦♦ Langerhans cells are S-100 protein+ and CD1a+

Electron Microscopy ♦♦ Birbeck granules are considered diagnostic of Langerhans cell differentiation

Congenital Self-Healing Reticulohistiocytosis Clinical ♦♦ Single or multiple, sometimes ulcerated, papules or nodules on the face, trunk, and extremities of newborns ♦♦ Lesions are usually present at birth but occasionally will develop during the perinatal period ♦♦ Lesions typically regress within 2–4 months

Microscopic ♦♦ The histologic appearance of this lesion is similar to that of LCH, from which it cannot be reliably separated on histologic grounds alone ♦♦ In general, this entity has larger, more eosinophilic cells with “glassy” cytoplasm than LCH

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Differential Diagnosis ♦♦ This entity is best separated from LCH using clinical criteria; the electron microscopic findings may aid in this process

Indeterminate Cell Histiocytosis General ♦♦ Occasional histiocyte-like proliferations demonstrate S-100 protein+ and CD1a+ on immunoperoxidase studies but no Birbeck granules on electron microscopy ♦♦ These proliferations have no distinct clinical or histologic characteristics at present

Benign Cephalic Histiocytosis Clinical ♦♦ A non-X histiocytosis usually presenting as multiple yellow to red papules on the face of young children which completely regress with time

Microscopic ♦♦ A cellular, somewhat cohesive infiltrate of plump histiocytes often with admixed eosinophils is evident within the dermis ♦♦ The overlying epidermis may be attenuated or ulcerated, but epidermotropism is not evident ♦♦ Mild nuclear pleomorphism may be seen

Eruptive Histiocytoma Clinical ♦♦ A non-X histiocytosis characterized by numerous, fleshcolored to red papules occurring in crops on the trunk, proximal extremities and, occasionally, the mucosal membranes of adults ♦♦ Lesions may regress, persist, and/or recur

Microscopic ♦♦ A bland infiltrate of histiocytes with or without coin-filtration of other inflammatory cells within the dermis

Fibrous Proliferations and Tumors Hypertrophic Scar and Keloid Clinical Fig. 18.42. Langerhans cell histiocytosis (A, B). ♦♦ PASD positive intracytoplasmic inclusions may be seen in this tumor but are apparently not present in LCH ♦♦ Epidermal involvement may rarely be present

Immunoperoxidase ♦♦ S-100 protein+, CD1a+

Electron Microscopy ♦♦ In addition to Birbeck granules, dense, myelin-like bodies with lamination are evident in this entity and may allow distinction from LCH

♦♦ Hypertrophic scars are slightly raised, red, smooth, and firm lesions at sites of previous injury which have no tendency for recurrence and no racial predilection ♦♦ Keloids are raised to polypoid, red to flesh-colored lesions usually, but not always, occurring at sites of injury and growing beyond the limits of the injured site ♦♦ These lesions may recur and are more common in blacks

Microscopic ♦♦ A fairly cellular, often nodular proliferation of dermal fibroblasts in a variably collagenized stroma with only minimal hyalinization characterizes the hypertrophic scar ♦♦ Keloids show more extensive, and often, less cellular nodular fibroblastic proliferations with extensive hyalinization of collagen

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Nodular Fasciitis/Proliferative Fasciitis/ Proliferative Myositis Clinical ♦♦ Reactive, nonneoplastic proliferations presenting as rapidly growing, deep nodules or masses on the trunk or extremities of adults ♦♦ Virtually any site may be affected

Microscopic

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic ♦♦ A well-circumscribed, nodular to multilobular tumor composed of a proliferation of plump histiocyte-like cells admixed with multinucleated giant cells, spindle cells, foam cells, and hemosiderin-laden cells in a variably collagenized matrix ♦♦ Mitotic figures may be evident, but no cytologic atypia or necrosis is evident ♦♦ The latter aid in distinguishing this lesion from epithelioid sarcoma

♦♦ All are proliferations of bland, reparative, bipolar spindle cells embedded in a variably myxoid to collagenized stroma ♦♦ Most lesions are centered on the fascia/subcutaneous tissue interface, but dermal, vascular, and skeletal muscle variants are not uncommon ♦♦ The spindle cells have bland nuclear features, scattered normal mitotic figures and wispy, pointed cytoplasm giving these lesions a “tissue culture” appearance ♦♦ Extravasated erythrocytes and admixed chronic inflammatory cells are additional features ♦♦ The proliferative variants have, in addition to the above, a population of large, ganglion-like cells admixed within the spindle cells

♦♦ Polypoid, filiform or pedunculated flesh-colored lesions typically involving the groin, axilla, and neck region of adults

Fibroma of Tendon Sheath Clinical

Pleomorphic Fibroma Clinical

♦♦ Slowly growing, benign fibrous nodule firmly attached to the tendon sheath on the distal extremities of adults

Microscopic ♦♦ A well-circumscribed, lobulated proliferation composed of densely hyalinized, paucicellular collagen centrally and more cellular fibroblastic proliferations peripherally ♦♦ The individual lobules often have peripheral stromal clefting but lack nuclear pleomorphism, mitotic activity, or necrosis

Giant Cell Tumor of Tendon Sheath (Fig. 18.43) Clinical ♦♦ Similar to fibroma of tendon sheath (see above)

Acrochordons (Soft Fibroma, Skin Tags, Fibroepithelial Polyps) Clinical

Microscopic ♦♦ A polypoid lesion with epidermal acanthosis overlying a variably hyalinized fibrovascular core ♦♦ Adipocytes may be abundant in the central aspect of the lesion

♦♦ A benign polypoid to dome-shaped, flesh-colored lesion on the trunk or extremities of adults

Microscopic ♦♦ A paucicellular, polypoid proliferation of large, pleomorphic cells with hyperchromatic nuclei, small nucleoli, and scant cytoplasm embedded in a fibrous stroma ♦♦ Rare mitotic figures may be seen in these lesions and do not imply an aggressive course

Sclerotic Fibroma Clinical ♦♦ Usually a solitary, flesh-colored nodule in adult patients ♦♦ Multiple lesions may be associated with Cowden disease

Microscopic ♦♦ A well-circumscribed, nodular proliferation of hyalinized, paucicellular fibrous tissue with laminated, cleft-like stromal spaces

Angiofibroma (Fibrous Papule, Oral Fibroma, Acquired Digital Fibrokeratoma, Pearly Penile Papules) Clinical ♦♦ Papular to polypoid, flesh-colored lesions usually in adults

Microscopic

Fig. 18.43. Giant cell tumor of tendon sheath.

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♦♦ A faintly polypoid, well-circumscribed proliferation of fibrovascular tissue with scattered hyperchromatic, occasionally multinucleated, stellate cells within the upper dermis

Neoplasms of the Skin and Immunodermatology

♦♦ In the digital variant there is overlying epidermal acanthosis and hyperkeratosis with the dermal collagen fibers oriented parallel to the long axis of the lesion

Elastofibroma Clinical ♦♦ Typically a deep-seated, subscapular mass in older adults ♦♦ Occasionally other sites are involved

Microscopic ♦♦ An irregular, unencapsulated proliferation of paucicellular collagen admixed with enlarged and often globular elastic fibers best visualized with elastic stains

Dermatomyofibroma Clinical ♦♦ A benign, solitary, flesh-colored to hyperpigmented plaque on the shoulder region of young adults

Microscopic ♦♦ A well-circumscribed proliferation of spindled, bland myofibroblastic cells in thin fascicles within the dermis ♦♦ The fascicles are oriented parallel to the epidermis except near adnexal structures where they assume a perpendicular growth pattern relative to the epidermis ♦♦ No nuclear pleomorphism, necrosis or significant mitotic activity is evident

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Microscopic ♦♦ A moderately cellular, usually well-circumscribed proliferation of spindled myofibroblasts embedded in a collagenous stroma ♦♦ The spindle cells have characteristic actin-positive intracytoplasmic eosinophilic inclusions

Fibrous Hamartoma of Infancy (Fig. 18.44) Clinical ♦♦ A hamartomatous lesion typically presenting as a deep dermal to subcutaneous nodule or plaque on the trunk of young children (usually less than 3 years of age)

Microscopic ♦♦ A deep dermal to subcutaneous, irregular, triphasic proliferation that merges with adjacent tissue ♦♦ The proliferation is composed of an admixture of densely collagenized, fibromatosis-like fascicles of bland spindle cells, myxoid, myofibroblastic lobules, and adipocytes showing a range of differentiation from lipoblast-like to mature univacuolated cells

Myofibroma/Myofibromatosis Clinical ♦♦ Solitary and multifocal variants exist ♦♦ The solitary variants may be seen in infants, young children, and adults and typically present as a dermal or subcutaneous nodule on the head, neck, trunk, or extremities ♦♦ The multifocal variants are seen in infancy or as congenital lesions ♦♦ Multiple soft tissue lesions may be seen, and, if visceral involvement is present, there is increased morbidity and mortality ♦♦ The solitary variants in children, however, have a tendency to regress

Microscopic ♦♦ An unencapsulated, well-circumscribed, biphasic dermal and/or subcutaneous tumor composed of an admixture of peripheral smooth muscle-like fascicles admixed with more centrally located immature, mesenchymal-like spindle cells embedded in a myxoid background ♦♦ The latter component often has a hemangiopericytoma-like proliferation of blood vessels ♦♦ Mitotic figures and necrosis may be seen and usually do not herald an aggressive course

Infantile Digital Fibroma/Fibromatosis Clinical ♦♦ A benign, rapidly growing nodule on the fingers or toes of infants and young children ♦♦ Lesions may be multiple and typically regress over time

Fig. 18.44. Fibrous hamartoma of infancy (A, B).

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Fig. 18.45. Giant cell fibroblastoma. ♦♦ The collagenized fascicles frequently appear to arise from the deep dermis and “rain down” into the subcutaneous tissue

Fibromatosis General ♦♦ A variety of fibromatoses may present as cutaneous masses, and these are discussed within the chapter on soft tissue pathology

Giant Cell Fibroblastoma (Fig. 18.45) Clinical ♦♦ A tumor of intermediate grade malignancy occurring almost exclusively in children as a nodule or plaque on the torso or extremities ♦♦ This tumor shows a tendency to local recurrence but has minimal to no metastatic potential ♦♦ Giant cell fibroblastoma is frequently associated with dermatofibroma sarcoma protuberans (see below) and may precede, follow, or occur with this related lesion

Microscopic ♦♦ An infiltrative, dermal, and often subcutaneous tumor composed of mildly pleomorphic spindle cells embedded in a variably myxoid stroma ♦♦ The hallmark of this tumor is the presence of pseudovascular spaces lined by pleomorphic, hyperchromatic, and multinucleated-appearing cells that are not truly of endothelial origin

Special Studies

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 18.46. Dermatofibrosarcoma protuberans.

♦♦ Childhood variants also exist and may have coin-filtrating giant cell fibroblastoma ♦♦ This tumor has a significant local recurrence rate but rarely metastasizes ♦♦ When a fibrosarcoma component is present, the risk of metastases increases significantly

Microscopic ♦♦ An infiltrative, dermal, and subcutaneous proliferation of monotonous spindle cells in distinctly storiform pattern ♦♦ Unlike dermatofibroma, there typically is no epidermal hyperplasia, but basilar hyperpigmentation may be seen ♦♦ Tumor cells infiltrate the subcutaneous fat in a characteristic lace-like fashion ♦♦ The tumor cells are remarkably bland-appearing and monomorphic ♦♦ The mitotic rate is usually low ♦♦ Occasional tumors have a prominent myxoid background while others show transition to higher grade fibro­ sarcoma ♦♦ DFSP usually lacks the coinfiltration of inflammatory cells, giant cells, and xanthoma cells typically present in dermatofibroma ♦♦ A pigmented variant of DFSP, the Bednar tumor, exists and has in addition to the above, variable numbers of melaninladen, dendritic-appearing cells

♦♦ Similar to DFSP, these tumors may express CD34

Special Studies

Dermatofibroma Sarcoma Protuberans (DFSP, Fig. 18.46) Clinical

Fibrosarcoma Clinical

♦♦ An indurated, red to blue, plaque-like or multinodular lesion on the trunk or extremities of young to middle-aged adults

♦♦ Two clinical variants exist: an infantile (congenital) form and an adult form

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♦♦ DFSP is typically CD34+, S-100 protein−, and FXIIIa−

Neoplasms of the Skin and Immunodermatology

♦♦ The former typically presents as a large mass on the extremities of infants and has a relatively good prognosis compared to its adult counterpart ♦♦ The adult variant also typically involves the extremities but has a high recurrence and metastatic rate with subsequent increased mortality

Microscopic ♦♦ Both variants are characterized by a proliferation of mildly pleomorphic spindled cells embedded in a variably collagenized matrix ♦♦ The spindle cells are arranged in fascicles with a herringbone pattern that is more cellular than the fascicles of the fibromatoses ♦♦ Mitotic activity is always present but varies in quantity ♦♦ The infantile variant may have more immature rounded cells with a less prominent herringbone pattern ♦♦ Chronic inflammatory cells are frequently admixed within this variant

Special Studies ♦♦ Vimentin+, some are actin+ ♦♦ This tumor is a diagnosis of exclusion, and other sarcomas and the fibromatoses should be considered prior to diagnosis

Epithelioid Sarcoma Clinical ♦♦ A malignant tumor of uncertain origin typically presenting as firm, often ulcerated nodules on the hand, wrist, or forearm of adolescents and young adults ♦♦ This tumor frequently shows multiple recurrences as well as metastases

Microscopic ♦♦ Usually a multinodular tumor involving the dermis and/or subcutaneous tissue ♦♦ The nodules frequently are well demarcated and have central necrosis, simulating necrotizing epithelioid granulomas ♦♦ The lesional cells are plump, round, histiocyte-like cells with abundant eosinophilic cytoplasm, and relatively uniform ovoid nuclei ♦♦ An admixed spindle cell component may be evident ♦♦ There is usually a faint, collagenized stroma surrounding the individual cells ♦♦ Multinucleated giant cells are not typically seen in this tumor, a feature that aids in distinguishing this lesion from giant cell tumor of tendon sheath

Special Studies ♦♦ The lesional cells have a relatively unique immunophenotype being EMA+, vimentin+, and cytokeratin+

Synovial Sarcoma General ♦♦ Synovial sarcoma may rarely present as a cutaneous mass and is discussed in detail in the chapter on soft tissue pathology

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Vascular Proliferations, Malformations, and Tumors Reactive, Nonneoplastic Vascular Proliferations, and Telangiectasias Nevus Flammeus Clinical ♦♦ A congenital vascular telangiectasia/malformation with many clinical forms including the salmon patch and the portwine stain ♦♦ The former is a pink-red, macule/patch on the glabella that regresses during childhood ♦♦ The latter is a large, unilateral, red facial plaque that persists and may be associated with Sturge–Weber, Klippel– Trenaunay, or other vascular syndromes

Microscopic ♦♦ Dilated (telangiectatic), thin-walled vessels are present within the papillary and superficial reticular dermis

Phakomatosis Pigmentovascularis General ♦♦ A group of hamartomatous lesions consisting of nevus flammeus in combination with a variety of pigmented lesions (mongolian spot, nevus spilus, and nevus pigmentosus)

Eccrine Angiomatous Hamartoma Clinical ♦♦ An angiomatous, sometimes painful, nodular lesion on the acral regions of children

Microscopic ♦♦ A hamartomatous proliferation of mature eccrine glands and thin-walled vessels in the deep dermis or subcutaneous fat ♦♦ Occasionally, other mesenchymal elements, particularly adipocytes, may also be admixed with the above

Nevus Anemicus Clinical ♦♦ A solitary, circumscribed, pale, macule or patch on the torso thought to be secondary to vascular hyperreactivity to catecholamines

Microscopic ♦♦ No histologic abnormalities are evident within this clinical lesion

Lymphangioma Circumscriptum (Fig. 18.47) Clinical ♦♦ Grouped, vesicle-like lesions arranged in a plaque-like form on any cutaneous surface and appearing at birth or early in life

Microscopic ♦♦ Dilated, thin-walled lymphatic structures lined by flattened, bland endothelial cells are evident within the superficial

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Fig. 18.47. Lymphangioma. dermis and are intimately associated with an acanthotic, surrounding epidermis ♦♦ Occasional cases have a deeper dermal component, and these variants may recur if superficially excised

Cavernous Lymphangioma Clinical ♦♦ A congenital or infantile, doughy mass involving the head, neck, or extremities which may recur if incompletely excised

Microscopic ♦♦ Numerous, variably sized lymphatic spaces are evident within the dermis and subcutaneous tissues ♦♦ The lymphatic spaces are lined by flattened, bland endothelium and are variably filled with eosinophilic proteinaceous material ♦♦ Chronic inflammatory cells may be seen within the vessel walls or the stroma of this proliferation

Cystic Hygroma Clinical ♦♦ A large, cystic mass of the posterior neck of infants that is usually congenital and may be associated with Turner syndrome

Microscopic ♦♦ Numerous, large, and cystically dilated lymphatic spaces within the dermis and subcutaneous tissues are evident in this lesion ♦♦ Lymphoid aggregates are frequently present in the walls of these structures and aid in differentiating this lesion from other hemangiomatous processes

Lymphangiomatosis Clinical ♦♦ A rare, often fatal, congenital disease which typically presents as sponge-like masses involving the skin of the extremities along with bone and visceral involvement ♦♦ Rare cases are limited to the extremities and a have a better prognosis than their systemic counterparts

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 18.48. Angiokeratoma.

Microscopic ♦♦ Infiltrating, interanastomosing, and variably dilated lymphatic structures are evident in the dermis and underlying soft tissues in this entity

Spider Angioma (Nevus Araneus) Clinical ♦♦ A red papule with “spidery” red legs on any cutaneous surface in both children and adults ♦♦ These lesions occur with an increased incidence in pregnancy, liver disease, and thyrotoxicosis

Microscopic ♦♦ A central, dilated dermal arteriole is present and is interconnected to a superficial network of dilated capillaries

Venous Lake Clinical ♦♦ A dark blue papule on the sun-damaged skin of older adults, especially the ears, lips, and face

Microscopic ♦♦ A superficial, dilated venous structure is evident within the dermis

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) Clinical ♦♦ An autosomal dominant inherited disorder characterized by cutaneous and visceral telangiectasias beginning in childhood

Microscopic ♦♦ Telangiectatic superficial vessels are present in the dermis

Angiokeratoma (Fig. 18.48) Clinical ♦♦ Four clinical variants exist ♦♦ Fordyce ♦♦ Multiple, dark papules on the scrotum or vulva of the elderly

Neoplasms of the Skin and Immunodermatology

♦♦ Mibelli ♦♦ An autosomal dominant inherited disease characterized by warty papules on the extremities of children ♦♦ Angiokeratoma corporis diffusum ♦♦ Widespread cutaneous lesions with a bathing-trunk distribution and an association with Fabry disease (x-linked, a-galactosidase deficiency) ♦♦ Solitary

Microscopic ♦♦ The microscopy of all these variants is similar consisting of superficial, thin-walled, ectatic vessels closely associated with an acanthotic epidermis ♦♦ The Fabry-associated variant may show vacuolization of endothelial and smooth muscle cells which corresponds to glycolipid lamellar deposits on electron microscopy

Angiolymphoid Hyperplasia with Eosinophils (ALH, Epithelioid Hemangioma) Clinical ♦♦ Red-blue, papules, and nodules on the head of adults of uncertain etiology ♦♦ Occasional patients will have peripheral blood eosinophilia

Microscopic ♦♦ Well-circumscribed nodule or nodules are evident within the dermis and/or subcutaneous tissue and are composed of an admixture of variably sized vessels, a polymorphous lymphoid infiltrate, and a variable number of eosinophils ♦♦ Enlarged, often vacuolated, and hobnailed, endothelial cells line the vessels ♦♦ The lymphoid infiltrate is composed of an admixture of T- and B-lymphocytes on immunoperoxidase studies and, rarely, forms germinal centers

Differential Diagnosis ♦♦ ALH should be distinguished from Kimura disease, which it vaguely resembles clinically and histologically ♦♦ The latter is more common in adolescents and young adults of Asian descent and is characterized by cutaneous nodules with a wider cutaneous distribution associated with lymphadenopathy and peripheral eosinophilia ♦♦ Histologically, Kimura disease lacks the vascular proliferation of ALH and has more prominent lymphoid follicles with germinal center formation

Pyogenic Granuloma (Lobular Capillary Hemangioma) Clinical ♦♦ A hyperplastic, possibly neoplastic, lesion typically presenting as a solitary (occasionally multiple), polypoid, glistening red mass which may locally recur

Microscopic ♦♦ A polypoid, intradermal lesion frequently surrounded by an epidermal collarette and characterized by a lobular

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proliferation of bland capillaries and venules in a myxoid background ♦♦ Overlying ulceration and prominent inflammation are frequently present

Bacillary Angiomatosis Clinical ♦♦ An infectious disease mimicking a vascular neoplasm, this lesion is most commonly seen as an angiomatous lesion in immunosuppressed patients but may also affect the immunocompetent. Bartonella quintana and henselae are the responsible organisms

Microscopic ♦♦ A pyogenic granuloma-like vascular proliferation with the additional features of numerous neutrophils, leukocytoclasia and granular, basophilic, intracytoplasmic masses within the endothelial cells lining the vascular proliferation ♦♦ The masses prove to be clumps of bacteria that stain nicely by the Warthin–Starry technique

Differential Diagnosis ♦♦ Verruga peruana is a related disease that is endemic in Peru and caused by Bartonella bacilliformis

Intravascular Papillary Endothelial Hyperplasia (Masson Hemangioma) Clinical ♦♦ A proliferative/reorganizing thrombus that may involve any cutaneous or mucosal surface but is frequently seen in rectal tissue

Microscopic ♦♦ Typically a localized process involving a single vessel or occasionally multiple adjacent vessels and characterized by numerous, intraluminal, endothelial-lined papillary structures with hylanized connective tissue cores ♦♦ The endothelial cells lack nuclear atypia or significant mitotic activity and, generally, do not “pile up” or stratify

Pseudo-Kaposi Sarcoma Clinical ♦♦ A group of pseudoneoplastic lesions including acroangiodermatitis and Stewart–Bluefarb syndrome ♦♦ The former is a variant of severe stasis dermatitis that typically involves the lower extremities of older adults ♦♦ The latter is an arteriovenous malformation unilaterally involving a lower extremity in a young adult

Microscopic ♦♦ Acroangiodermatitis is characterized by a relatively superficial proliferation of small, bland vascular structures which are often thick walled and may be arranged in a lobular architecture ♦♦ There is associated chronic inflammation, dermal hemosiderin deposition, erythrocyte extravasation, and overlying epidermal acanthosis and hyperkeratosis

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♦♦ The Stewart–Bluefarb syndrome shows a transdermal proliferation of similar vessels and, occasionally, an arteriovenous malformation may identified in the deeper tissues

Differential Diagnosis ♦♦ These reactive proliferations should be distinguished from Kaposi sarcoma which is characterized by a more infiltrative vascular proliferation which surrounds adnexa, dissects dermal collagen and shows a vessel around vessel growth pattern (the promontory sign)

Benign Vascular Neoplasms Angioma Serpiginosum Clinical ♦♦ Multiple, gyrate papules on the extremities of children and young adults

Microscopic ♦♦ A clustered proliferation of thick-walled capillaries is evident within the papillae of the superficial dermis

Hemangiomas (Infantile, Cavernous, Capillary, Superficial, and Deep, Fig. 18.49) Clinical and General ♦♦ A variety of confusing terms have been utilized for hemangiomas rapidly developing in infancy, shortly after birth

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Traditionally, pathologists have classified these lesions as capillary or cavernous hemangiomas, with the thought that the former regress while the latter do not ♦♦ It is now clear that this division is erroneous and that, instead of representing distinct histologic entities, capillary and cavernous histologic changes are merely the histologic findings along points of time in the evolution of all infantile hemangiomas ♦♦ Dermatologists instead classify infantile hemangiomas as superficial or deep depending on whether the overlying skin surface is bright red or largely normal ♦♦ Further, almost all infantile hemangiomas experience some regression after their initial period of rapid growth, regardless of the histologic type

Microscopic ♦♦ Early lesions (“cellular hemangioma”) show a highly cellular, often lobular proliferation of endothelial cells with indistinct lumina and scattered mitosis ♦♦ These lesions may be dermal limited or extend into the underlying soft tissue ♦♦ As the lesions age, vascular lumina become more apparent being composed of small capillary-sized vessels (“capillary hemangioma”) which then progress to larger cavernoussized vessels (“cavernous hemangioma”)

Cherry Angiomas Clinical ♦♦ Acquired, small, red papules on the trunk of adults

Microscopic ♦♦ Dilated, mildly thickened capillary blood vessels in the papillary dermis

Acral A-V Tumor (Arteriovenous Hemangioma, Cirsoid Aneurysm) Clinical ♦♦ Small, red-blue, papules on the head, neck or extremities of adults

Microscopic ♦♦ Localized, mid to upper dermal proliferation of variably sized, thick-walled vessels having features of both arteries and veins

Tufted Angioma (Tufted Angioblastoma) Clinical ♦♦ Angiomatous appearing, red to brown, macules or plaques on the neck, torso, and shoulders of children and young adults

Microscopic

Fig. 18.49. Cavernous hemangioma.

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♦♦ Multiple, cellular lobules of endothelial cells with peripheral, slit-like spaces are evident within the dermis and superficial subcutaneous tissue giving this lesion a “cannonball”-like pattern

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Microvenular Hemangioma (Fig. 18.50) Clinical

Glomeruloid Hemangioma Clinical

♦♦ An acquired, slowly growing red-blue papule on the extremities of young adults

♦♦ An unusual vascular proliferation that occurs in the setting of POEMS syndrome, these lesions are typically red, domeshaped to flat, papules, and macules on the trunk and extremities of adults

Microscopic ♦♦ A poorly circumscribed, dermal proliferation of monomorphic, thin-walled, branching venules lined by bland endothelium ♦♦ The venules dissect through the collagen raising some concern for Kaposi sarcoma or low grade angiosarcoma, but the atypia associated with these two lesions is absent

Targetoid Hemosiderotic Hemangioma Clinical ♦♦ A red papule surrounded by clear and ecchymotic halos in succession on the trunk or extremities of adults

Microscopic ♦♦ Thin-walled, somewhat dilated vascular structures with intraluminal papillae and hobnailed endothelium characterize this lesion centrally ♦♦ The peripheral and deep aspects of this tumor show interanastomosing vascular spaces that dissect the dermal collagen in association with hemosiderin deposition and chronic inflammatory cells

Microscopic ♦♦ A glomerulus-like proliferation of tightly entwined capillarysized blood vessels is present in the upper dermis ♦♦ The endothelial cells have characteristic, intracytoplasmic, eosinophilic, PAS+ inclusions that represent absorbed immunoglobulin

Kaposiform Hemangioendothelioma Clinical ♦♦ A childhood neoplasm with a predilection for the retroperitoneum that rarely involves skin

Microscopic ♦♦ A multinodular, cellular neoplasm involving the dermis and underlying soft tissue ♦♦ The nodules are composed of fascicles of bland spindle cells, small congested capillaries, slit-like vascular spaces and epithelioid endothelial cells with hemosiderin, hyaline globules, and primitive cytoplasmic lumina ♦♦ No significant mitotic activity is evident ♦♦ The multinodularity, the lack of plasma cells and the lack of atypia all aid in distinguishing this lesion from the histologically similar Kaposi sarcoma

Spindle Cell Hemangioendothelioma Clinical ♦♦ Single or multiple, red-blue, often painful nodules on the extremities of children and young adults

Microscopic ♦♦ A fairly well-circumscribed, dermal and/or subcutaneous, nodular tumor composed of an admixture of large, cavernous vascular spaces admixed with a spindle cell to faintly epithelioid, cellular component ♦♦ The large vascular spaces frequently have thrombosis with intravascular papillary projections ♦♦ The spindle cells often have vacuole-like, intracytoplasmic lumina

Acquired Progressive Lymphangioma (Benign Lymphangioendothelioma) Clinical ♦♦ An acquired, slowly enlarging, bruise-like plaque on the extremities or trunk of young adults

Microscopic Fig. 18.50. Microvenular hemangioma.

♦♦ Thin-walled, anastomosing, irregular vascular channels are evident within the dermis and predominate superficially where they are oriented horizontally to the epidermis

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♦♦ The deeper dermis also has scattered irregular lumina that are oriented haphazardly or perpendicularly to the overlying epidermis ♦♦ The vascular lumina are lined by bland, flattened endothelium and lack any significant intraluminal contents

Angiomatosis Clinical ♦♦ A rare, benign, vascular proliferation of childhood characterized by an angiomatous growth involving a large area of the trunk and/or extremity with or without hypertrophy of the affected segment

Microscopic ♦♦ An irregular and haphazard proliferation of variably sized vessels and adipocytes is evident within the dermis and underlying soft tissues ♦♦ A characteristic finding is the presence of small vascular structures clustered near or within the wall of a large, thickwalled vein

Vascular Tumors of Low Grade Malignancy Epithelioid Hemangioendothelioma Clinical ♦♦ Solitary or multiple, cutaneous, and/or visceral masses with a wide age range and geographic distribution ♦♦ These lesions may recur and occasionally metastasize

Microscopic ♦♦ A proliferation of epithelioid to spindled endothelial cells as cords and nests in a myxoid to hylanized stroma ♦♦ Intracytoplasmic lumina with erythrocytes are evident within the epithelioid cells, but well-formed vascular structures are rarely identified ♦♦ The tumor often seems to arise from a large vessel wall, often preserving its vascular architecture

Retiform Hemangioendothelioma Clinical ♦♦ A plaque-like or nodular tumor on the extremities of young adults characterized by frequent recurrences and low metastatic potential

Microscopic ♦♦ An irregular proliferation of branching, angulated blood vessels lined by hobnailed endothelial cells is present within the dermis and has been likened to similar appearing structures within the rete testis ♦♦ A deeper, more solid component with spindled and epithelioid cells and papillary structures may also be evident

Dabska Tumor (Malignant Endovascular Papillary Angioendothelioma) Clinical ♦♦ A rare, tumor typically presenting as a mass on the head, neck, or extremities of children and adolescents

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Microscopic ♦♦ An irregular, dermal proliferation of vascular structures lined by hobnailed endothelium and having numerous papillary, intraluminal projections lined by atypical, hyperchromatic endothelial cells with occasional mitoses ♦♦ Admixed lymphocytes are also frequently present

Kaposi Sarcoma Clinical ♦♦ Five different clinical subtypes exist ♦♦ Classic −− Red-blue plaques on the lower extremities of elderly men of Mediterranean descent ♦♦ African, endemic variants −− A nodular, indolent variant affecting the limbs of young to middle-aged men −− A lymphoadenopathic, aggressive variant affecting young children ♦♦ Immunosuppression-associated variant −− Usually related to transplantation with a potentially aggressive course ♦♦ AIDS-related variant −− An aggressive variant that may involve any anatomic site ♦♦ Kaposi sarcoma has been recently linked to human herpes virus type 8 which may play an important role in its pathogenesis

Microscopic ♦♦ The microscopic is similar in all of the above variants ♦♦ In the patch stage, a few, irregular, and infiltrating small vessels are present predominantly within the superficial dermis ♦♦ The vessels infiltrate adnexa and frequently grow in a vesselaround-vessel pattern, the “promontory sign” ♦♦ Scattered lymphocytes, plasma cells and extravasated erythrocytes are evident within the dermis, and hemosiderin deposition is also frequently present ♦♦ The plaque stage shows, in addition to the above, a transdermal infiltrate with spindle cell areas arranged in irregular fascicles ♦♦ The spindle cell component has characteristic sieve-like spaces with extravasated erythrocytes, mild nuclear pleomorphism, occasional mitotic figures, and eosinophilic hyaline globules ♦♦ The nodular variant is composed almost exclusively of a fairly well-circumscribed, nodular, dermal, and/or subcutaneous proliferation of spindle cells in fascicles with similar features to the plaque stage

Malignant Vascular Tumors Angiosarcoma (Fig. 18.51) Clinical ♦♦ Three clinical variants exist

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Fig. 18.52. Glomus tumor.

♦♦ High grade lesions are typically more cellular and are composed of sheets or fascicles of polygonal, epithelioid, or spindle cells with nuclear pleomorphism, mitoses, and often prominent nucleoli ♦♦ Well-formed vascular structures may be scant, but intracytoplasmic lumina are often identified and aid in the differential diagnosis Fig. 18.51. Angiosarcoma.

♦♦ Idiopathic angiosarcoma of the face and scalp of the elderly −− This variant presents as multiple bruise like, infiltrating plaques, and nodules ♦♦ Postirradiation angiosarcoma −− Infiltrating, plaques, ulcers, or nodules occurring years after radiation to the involved site ♦♦ Lymphedema associated angiosarcoma (Stewart–Treves syndrome) −− Angiosarcomas arising in the setting of prolonged lymphedema, usually postmastectomy patients ♦♦ The overall survival for patients with cutaneous angiosarcoma is poor with frequent recurrences and early lymph node and visceral metastases characterizing their clinical course

Microscopic ♦♦ All three clinical variants of angiosarcoma show the same spectrum of histologic findings ♦♦ Well-formed, small, often slit-like, vessels that interanastomose and dissect the dermal collagen in an infiltrative fashion characterize the low grade variants ♦♦ The endothelial cell lining may be flattened and nondescript, but areas with nuclear hyperchromasia, mitotic activity, and stratification are usually evident ♦♦ A papillary network lined by atypical endothelial cells may be prominent

Special Studies ♦♦ CD31, CD34, FVIII, and Ulex europaeus I lectin stain, to a variable degree, endothelial-derived tumors ♦♦ CD31 is probably the most specific and sensitive endothelial cell marker amongst this group

Tumors of Perivascular Cells Glomus Tumor (Fig. 18.52) Clinical ♦♦ These tumors of specialized arteriovenous anastomoses (Sucquet-Hoyer canal) most often present as painful, redblue nodules on the fingers, but any cutaneous site may be involved ♦♦ A multicentric variant with autosomal dominant inheritance exists

Microscopic ♦♦ These tumors are characterized by a well-circumscribed, deep dermal proliferation of small vessels and a variable number of round to polygonal cells with eosinophilic cytoplasm and uniform, round to ovoid nuclei ♦♦ Rarely, mild, degenerative nuclear pleomorphism may be present ♦♦ The glomangioma, a common variant, has, in addition to the above, a component of large, cavernous vascular structures ♦♦ Tumors that also have a proliferation of smooth muscle, usually perivascular, have been called glomangiomyoma ♦♦ Rare malignant glomus tumors have also been described

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Special Studies

Microscopic

♦♦ The glomus cells are smooth muscle actin+, vimentin+ and may stain for desmin

♦♦ Basal keratinocyte hyperpigmentation without elongation of the rete ridges

Hemangiopericytoma General

Postinflammatory Hyperpigmentation Clinical

♦♦ A controversial neoplasm that rarely involves the skin; this tumor is a diagnosis of exclusion as its histologic pattern may be mimicked by a wide variety of neoplasms ♦♦ This tumor is discussed in more detail in the chapter on soft tissue pathology

♦♦ An acquired excess of melanin pigmentation in areas of preceding inflammation

Microscopic

PEComa General

Dowling–Degos Disease Clinical

♦♦ A rare benign cutaneous neoplasm with morphologic and immunohistochemical evidence of perivascular epithelioid cell (PEC) differentiation ♦♦ Like systemic PEComas (renal angiomyolipoma, lymphangiomyomatosis, etc.) show a female predilection ♦♦ No known association with tuberous sclerosis ♦♦ Most reported cases occur on the extremities

Microscopic

♦♦ Increased melanophages within the superficial dermis with/ without basilar keratinocyte hyperpigmentation

♦♦ An autosomal dominant disorder characterized by reticulated, pigmented macules of the flexural areas in combination with pitted, perioral, acneiform scars, and comedone-like lesions on the neck and back

Microscopic ♦♦ Filiform to antler-like epidermal downgrowths in association with basilar keratinocyte hyperpigmentation, dermal melanosis, and mild dermal lymphohistiocytic inflammation

♦♦ Dermal proliferation with neoplastic cells arranged in sheets, nests, or trabeculae, separated by thin capillaries; may extend into subcutis ♦♦ The lesional cells are epithelioid, spindled, or both and have a central round nucleus, and clear or granular eosinophilic cytoplasm ♦♦ Mitotic activity is usually absent

Kitamura Reticulate Hyperpigmentation Clinical

Special Studies

♦♦ Basilar hyperpigmentation with elongation of the rete ridges and epidermal atrophy

♦♦ The neoplastic cells variably express melanocytic (HMB45, Melan-A, MiTF) and muscle markers (desmin, actin) ♦♦ The cells are negative, or only focally positive for S-100 ♦♦ No expression of cytokeratins or epithelial membrane antigen

Melanocytic Proliferations and Pigmentary Disorders Pigmentary Disorders of the Skin Melasma Clinical ♦♦ An acquired, symmetrical, brown hypermelanosis of the face that is more common in women

Microscopic

♦♦ An autosomal dominant disorder characterized by reticulated, depressed pigmented macules on the dorsal hands and feet with pits and breaks on the palms and soles

Microscopic Vitiligo Clinical ♦♦ Acquired, depigmented, white patches surrounded by a normal or hyperpigmented border

Microscopic ♦♦ Absence of melanocytes within the depigmented areas

Albinism Clinical ♦♦ An inherited disorder of the tyrosinase gene characterized by the lack of ocular pigment (ocular albinism; X-linked recessive) or the lack of ocular, follicular, and cutaneous pigment (oculocutaneous albinism; autosomal recessive)

Microscopic

♦♦ An increase in melanin deposition within the basal epidermis and/or within dermal melanophages

♦♦ Normal-appearing epidermis containing a normal complement of melanocytes but a complete or markedly reduced amount of melanin production

Freckle (Ephelid) Clinical

Piebaldism Clinical

♦♦ Small, well-demarcated red-brown macules on sun-exposed areas. The lesions darken with sun exposure

♦♦ An autosomal dominant disorder with onset at birth characterized by a stationary hypomelanosis of the skin and hair

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involving the lateral trunk, arms, legs, and forehead (white forelock)

Microscopic ♦♦ Absence of melanocytes and melanin within affected regions

Nevus Depigmentosus Clinical ♦♦ A congenital, stable hypopigmented macule or patch on the trunk or extremities

Microscopic ♦♦ Normal number of melanocytes but reduced melanin production within the lesional areas

Idiopathic Guttate Hypomelanosis Clinical ♦♦ Numerous, small hypopigmented macules on the sun-exposed surface of the extremities

Microscopic ♦♦ Marked reduction of melanin granules within lesional skin in association with epidermal atrophy and flattening of the rete ridges

Café-au-Lait Spot Clinical ♦♦ Light brown, pigmented macule that may be found on any cutaneous surface and, if numerous, may be associated with neurofibromatosis

Microscopic ♦♦ Increased melanocytes and increased melanin production within the basal epidermis

Electron Microscopy ♦♦ Macromelanosomes

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Benign Melanocytic Proliferations Mongolian Spot Clinical ♦♦ A slate-blue patch on the lower back of newborns and infants, often of Asian or African descent ♦♦ The lesions typically regress over time

Microscopic ♦♦ Long, wavy, variably pigmented, individual melanocytes are present within the deep dermis and are oriented parallel to the overlying epidermis

Nevus of Ito and Ota Clinical ♦♦ Both of these lesions present as a slate-blue to mottled macule or patch which may be congenital or develop in adolescence ♦♦ The nevus of Ito typically involves the skin of the scapular, deltoid, or supraclavicular regions while the nevus of Ota involves the skin of the face, usually in a unilateral fashion ♦♦ The nevus of Ota may be associated with ipsilateral scleral, conjunctival, corneal, or retinal pigmentation ♦♦ The pigmentation persists ♦♦ These lesions may be present individually or in combination with one another or with the mongolian spot

Microscopic ♦♦ Both of these entities are characterized by the presence of pigmented, spindled, and dendritic, individual melanocytes within the mid and upper dermis

Blue Nevi (Figs. 18.53 and 18.54) Clinical ♦♦ Two subtypes exist −− A small, well-circumscribed blue to blue-black papule on the hands or feet characterizes the common blue nevus

Becker Nevus (Becker Melanosis) Clinical ♦♦ A hamartomatous lesion characterized by a hyperpigmented patch with hypertrichosis over the shoulder region or back

Microscopic ♦♦ Slight epidermal acanthosis/papillomatosis with basal keratinocyte hyperpigmentation and dermal melanosis ♦♦ A dermal, smooth muscle hamartomatous component may also be present

Mucosal Melanotic Macules Clinical ♦♦ A pigmented macule/patch on the mucosa of the oral or genital region

Microscopic ♦♦ Basilar keratinocyte pigmentation with or without dermal melanosis

Fig. 18.53. Common blue nevus.

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♦♦ Solar lentigines are frequently multiple and are markers of increased risk of melanoma development

Microscopic ♦♦ Elongation of the rete ridges with basilar keratinocyte hyperpigmentation and a mild to marked proliferation of basilar melanocytes in a lentiginous (single cell, nonnested) fashion

Lentigo Simplex Clinical ♦♦ A congenital or acquired, sharply demarcated, round to oval, macular area of hyperpigmentation, usually less than 5 mm in diameter ♦♦ Most lesions develop in childhood, but new lesions may form in adulthood ♦♦ Multiple lesions may be associated with the LEOPARD, NAME or Peutz–Jeghers syndromes ♦♦ The speckled lentiginous nevus (nevus spilus) is a variant characterized by a light brown patch with superimposed, darkly pigmented macules

Microscopic ♦♦ Mild to moderate elongation of the rete ridges in association with basilar and, often, suprabasilar keratinocyte hyperpigmentation and a lentiginous proliferation of bland nevomelanocytes ♦♦ Some lentigines show focal junctional nesting and, hence, overlapping features with a junctional nevus ♦♦ The term “jentigo” has, at times, been used for such lesions

Fig. 18.54. Cellular blue nevus (A, B). −− A 1–3 cm or larger blue to blue-gray plaque on the sacrum or buttocks typifies the cellular blue nevus

Microscopic ♦♦ Common blue nevus −− A symmetrical and fairly well-circumscribed proliferation of spindled to dendritic nevomelanocytes within the dermis −− The dermis frequently is sclerotic within the lesional area ♦♦ Cellular blue nevus −− Typically a large, dermal and/or subcutaneous, symmetrical nodule composed of an admixture of spindled, dendritic, and rounded nevomelanocytes −− The spindled and dendritic component predominates at the periphery of the lesion while nests of more rounded nevomelanocytes with melanophages are more common centrally ♦♦ Atypical variants may show nuclear pleomorphism, mitotic activity, an infiltrating architecture, and even necrosis

Solar Lentigo Clinical ♦♦ A uniformly pigmented macule/patch on areas chronically exposed to sunlight

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Common Melanocytic Nevi Clinical ♦♦ Benign, melanocytic proliferations that typically develop in childhood and adolescence ♦♦ The appearances of common melanocytic nevi vary from pigmented macules/papules to flesh-colored nodules to papillomatous lesions depending on the relative degree of junctional versus dermal activity and the site of origin ♦♦ These nevi are typically small (<1  cm), evenly pigmented, symmetrical and sharply bordered ♦♦ The presence of large numbers of nevi on a single individual is a marker of increased risk of melanoma

Microscopic ♦♦ Common melanocytic nevi are characterized by symmetrical and well-circumscribed proliferations of bland, round nevomelanocytes as nests along the dermal–epidermal junction and/or within the dermis ♦♦ The dermal component, if present, shows maturation and lacks significant mitotic activity or cytologic atypia ♦♦ The junctional component may show nevomelanocytic nests with or without an accompanying lentiginous melanocytic proliferation ♦♦ The nests within the junctional component are uniform in size and spacing and are typically limited to the basal epidermis

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Dysplastic Nevus (Clark Nevus, Atypical Nevus, B-K Mole) Clinical

Spitz Nevus (Spindle and Epithelioid Cell Nevus, Fig. 18.56) Clinical

♦♦ A tan-brown to black, irregularly and asymmetrically pigmented macule/papule, usually >5 mm in diameter ♦♦ Multiple lesions may be inherited as the B-K mole (dysplastic nevus) syndrome or the familial atypical mole syndrome ♦♦ This syndrome(s) is associated with a markedly increased risk of melanoma development. Most lesions are sporadic and are associated with a lesser risk of melanoma development

♦♦ Smooth-surfaced, round, sharply circumscribed, pink to red papule most commonly involving the face and/or the extremities of children to young adults

Microscopic ♦♦ Typically a compound nevomelanocytic proliferation showing a spectrum of architectural and cytologic features which include the following −− Junctional shouldering −− Lamellar dermal fibrosis −− Bridging of the rete ridges by melanocytic nests −− Melanocytic nuclear pleomorphism with nucleoli −− Early upward migration of melanocytes within the epidermis −− Perivascular chronic inflammation at the base of the lesion

Microscopic ♦♦ Spitz nevi are generally well-circumscribed and symmetrical proliferations which may be junctional, compound, or dermal ♦♦ The nuclear pleomorphism that is present within these lesions may be mistaken for malignant melanoma ♦♦ The prototypical Spitz nevus has the following histologic features −− Epidermal hyperplasia −− Hypergranulosis −− Kamino bodies (cytoid bodies) −− Large junctional nests of epithelioid to spindled melanocytes −− Clefting between the junctional nests and the epidermis

Pigmented Spindle Cell Nevus of Reed (Fig. 18.55) Clinical ♦♦ Sharply defined, heavily pigmented, symmetrical papule on the trunk or extremities of adolescents/young adults

Microscopic ♦♦ Symmetrical and well-circumscribed proliferation of monomorphic, spindled melanocytes along the dermal–epidermal junction and, usually, the papillary dermis ♦♦ The individual melanocytes may have nucleoli, and mitotic figures are commonly seen ♦♦ There may be prominent upward migration of melanocytes within the epidermis ♦♦ Coarse melanin is frequently seen within the melanocytes and associated melanophages

Fig. 18.55. Pigmented spindle cell nevus of Reed.

Fig. 18.56. Spitz nevus (A, B).

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−− Deep dermal maturation −− Nuclear pleomorphism with nucleoli −− Additional features that may be present and may mimic melanoma include the following (a) Brisk mitotic activity (b) Upward epidermal migration of melanocytes (c) Adnexal involvement

Congenital Nevus Clinical ♦♦ A variant of the melanocytic nevus which is present at birth ♦♦ Congenital nevi are often divided into three groups based on their size: small (<1.5 cm), medium (1.5–20 cm), and large (>20 cm) ♦♦ These nevi are typically brown to black and frequently show an irregular surface with hypertrichosis ♦♦ Congenital nevi are associated with an increased risk of melanoma development; the risk is the greatest for the large congenital nevi, which may show malignant transformation in up to 20% of cases

Microscopic ♦♦ Congenital nevi are similar to the common melanocytic nevi in that they are symmetrical, well-circumscribed proliferations with deep maturation ♦♦ They differ from common melanocytic nevi by having involvement of the deep reticular dermis/subcutis and by showing frequent involvement of adnexal structures

Deep Penetrating Nevus (Fig. 18.57) Clinical ♦♦ A darkly pigmented, uniform papule/nodule most often presenting on the trunk or extremities of young adults

Microscopic ♦♦ A distinctly, wedge-shaped proliferation of uniformly atypical melanocytes within the dermis and, occasionally, along the dermal–epidermal junction ♦♦ The nevomelanocytes are arranged into poorly formed nests and irregular fascicles which extend into the deep reticular dermis and/or subcutis without deep maturation ♦♦ These nevomelanocytes have nuclear pleomorphism and nucleoli, but mitotic figures are absent to scarce ♦♦ Dense melanin pigmentation is present throughout the lesion within the melanocytes and adjacent melanophages

Halo Nevus Clinical ♦♦ A typical melanocytic nevus with a surrounding zone of depigmentation

Microscopic ♦♦ A chronically inflamed nevus of any type ♦♦ The lymphocytes are densely arranged within the dermal component of the nevus and may completely obscure the underlying melanocytic lesion

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Fig. 18.57. Deep penetrating nevus (A, B).

♦♦ The remaining melanocytes may show some degree of atypia and disorganization, but the typical features of a regressing melanoma are absent

Pigmented Epithelioid Melanocytoma Clinical ♦♦ A heavily pigmented lesion that usually occurs in children and young adults but can affect any age or ethnic background, a wide variety of anatomic sites, and either gender

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♦♦ A controversial and provisional entity, considered as a “borderline” melanocytic neoplasm or low grade melanoma with a low risk of recurrence, but metastatic potential ♦♦ Nearly half of all patients have metastases in sentinel lymph node biopsies, but with only rare reports of spread to viscera. Some authors recommend lymph node biopsy in all cases ♦♦ No adverse outcomes in short-term data but long-term followup is currently unavailable ♦♦ There is no known association with Carney complex although microscopically it resembles epithelioid blue nevus

Microscopic ♦♦ A nonulcerative, circumscribed or infiltrative dermal mass composed of sheets of epithelioid or spindle cells. May extend into the subcutis along adnexa ♦♦ The epithelioid cells have large round nuclei with or without large nucleoli. Spindle cells may have long dendritic cytoplasmic processes ♦♦ Resembles epithelioid blue nevus of Carney complex, and so-called equine or animal-type melanoma based on heavily pigmented cells ♦♦ Marked cytoplasmic pigmentation may obscure nuclear details and bleached sections may be necessary to evaluate ♦♦ Mitotic activity is usually absent but may have up to 3/mm2 ♦♦ May be part of a combined nevus

Malignant Melanoma (Figs. 18.58 and 18.59) Clinical ♦♦ The majority of melanomas show a variegated, asymmetrical distribution of dark brown to black pigment within a lesion of greater than 0.5 cm in diameter ♦♦ However, amelanotic melanomas do exist and may mimic other neoplasms ♦♦ Melanomas are divided clinicopathologically into four basic subtypes −− Superficial spreading malignant melanoma (a) Accounts for approximately 60% of melanomas

Fig. 18.59. Nevoid malignant melanoma.

(b) Related to sun exposure (c) Shows both a macular and a nodular appearance clinically (d) May affect all age groups but predominates in adults −− Lentigo maligna melanoma (a) Accounts for approximately 10–15% of mela­ nomas (b) Related to sun exposure (c) Largely a disease of the elderly (d) Grows initially as dark macule or patch (lentigo ­maligna) and develops a papular or nodular component when invasive (lentigo maligna melanoma) (e) Head and neck region most commonly affected −− Nodular malignant melanoma (a) Accounts for approximately 10–20% of all melanomas (b) Nodular, often symmetrical appearance clinically (c) May be amelanotic −− Acral-lentiginous melanoma (a) Accounts for 5–10% of all melanomas (b) Tumors of the palms, soles, nails, and genitalia (c) Most common melanomas of dark-skinned races

Prognostic Factors

Fig. 18.58. Superficial spreading malignant melanoma.

♦♦ Tumor thickness is the most important prognostic factor at present, as measured by Clark level or Breslow depth ♦♦ Ulceration ♦♦ Lymphatic invasion ♦♦ Location of the primary melanoma ♦♦ Signs of regression ♦♦ Sex ♦♦ Age

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Microscopic ♦♦ Almost all melanomas begin as epidermal proliferations which, if left unchecked, may invade into the dermis and underlying tissues ♦♦ Melanomas have a constellation of atypical cytologic and architectural features that may be present in varying portions within a given lesion including the following −− Architectural asymmetry −− Poor circumscription −− Upward epidermal migration of melanocytes, nested or single −− Melanocytic nests vary in size, shape, and distribution −− No deep maturation of melanocytes −− Cytologic atypia in the form of nuclear pleomorphism, prominent nucleoli, and mitotic figures −− Invasion of lymphatic spaces and nerves −− Adnexal involvement ♦♦ The lentiginous variants of melanoma show a predominant single, nonnested proliferation of melanocytes within the epidermis with or without upward epidermal migration ♦♦ The invasive component may be nested or may show a distinct spindled appearance with or without neurotropism (desmoplastic melanoma) ♦♦ The superficial spreading variant of melanoma shows a nested epidermal component with prominent upward epidermal migration, and the invasive component is typically nested but may be spindled ♦♦ The nodular melanoma is largely a dermal tumor with a minor, overlying epidermal component

Staging (see TNM Classifications) ♦♦ Stage I −− Tumor thickness 1.5 mm or less ♦♦ Stage II −− Tumor thickness 1.51–4.00 mm ♦♦ Stage III −− Tumor thickness greater than 4 mm or nodal and/or satellite metastases ♦♦ Stage IV −− Tumor metastatic to distant sites

Essentials of Anatomic Pathology, 3rd Ed.

recognized that differences exist between cutaneous lymphomas and their systemic counterparts resulting in the WHO-EORTC classification for cutaneous lymphoma ♦♦ The following lymphoma discussion will focus on the WHOEORTC classification of lymphoma, and the reader is urged to refer to the systemic lymphoma chapter for comparison (Chapter 7)

WHO-EORTC Classification (2005) ♦♦ Cutaneous T-Cell and NK-cell lymphomas −− Mycosis fungoides (MF) −− MF variants and subtypes (a) Folliculotropic MF (b) Pagetoid reticulosis (c) Granulomatous slack skin −− Sézary syndrome −− Adult T-cell leukemia/lymphoma −− Primary cutaneous CD30+ lymphoproliferative disorders (a) Primary cutaneous anaplastic large cell lymphoma (b) Lymphomatoid papulosis −− Subcutaneous panniculitis-like T-cell lymphoma −− Extranodal NK-T-cell lymphoma, nasal type −− Primary cutaneous peripheral T-cell lymphoma, unspecified (a) Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) (b) Cutaneous g/d T-cell lymphoma (provisional) (c) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) ♦♦ Cutaneous B-Cell lymphomas −− Primary cutaneous marginal zone B-cell lymphoma −− Primary cutaneous follicle center cell lymphoma −− Primary cutaneous diffuse large B-cell lymphoma, leg type −− Primary cutaneous diffuse large B-cell lymphoma, other (a) Intravascular B-cell lymphoma ♦♦ Precursor hematologic neoplasm −− CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)

Primary Cutaneous Marginal Zone Lymphoproliferative Disorders and Leukemias B-Cell Lymphoma (Fig. 18.60) (Also See Chapter 15) Clinical ♦♦ Solitary or multiple tumors/nodules Classification of Cutaneous Lymphomas ♦♦ A variety of cutaneous lymphomas exist, many of which differ ­significantly from their systemic counterparts in terms of histologic features, behavior, and/or treatment ♦♦ In 1997, the European Organization for Research and Treatment of Cancer (EORTC) proposed a new, cutaneous lymphoma classification based on clinical, histologic, and immunophenotypic criteria with an emphasis on disease entities rather than histologic subgroups. In 2005, the WHO

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♦♦ Extremities most often involved ♦♦ Excellent long term survival ~100%

Microscopic ♦♦ Nodular or diffuse, often bottom-heavy infiltrates ♦♦ Benign germinal centers usually present ♦♦ Malignant small lymphocytes, plasmacytoid lymphocytes, plasma cells and centrocyte-like cells infiltrate diffusely

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Microscopic ♦♦ A tumor composed of follicular center cells either in the form of centrocytes (cleaved cells) or centroblasts ♦♦ Tumor cells are arranged into ill-defined nodules or diffuse sheets ♦♦ Germinal center formation may or may not be present

Immunophenotype ♦♦ CD20+, CD79a+, usually surface immunoglobulin (Sig)+ ♦♦ CD5−, CD10−, bcl-2−

Differential Diagnosis ♦♦ Marginal zone lymphoma ♦♦ Lymphoid hyperplasia ♦♦ Systemic follicular lymphoma (bcl-2+)

Primary Cutaneous Diffuse Large B-Cell Lymphoma of the Leg (Fig. 18.61) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Red to blue nodules/plaques involving one or both legs Typically affects older patients, >70 years old Frequently disseminates ~50% 5-year survival

Microscopic ♦♦ Diffuse, sheet-like proliferation of large atypical lymphocytes ♦♦ Epidermotropism is generally absent ♦♦ The large lymphocytes may have centrocytic, centroblastic, or immunoblastic features

Immunophenotype Fig. 18.60. Marginal zone lymphoma (A, B).

♦♦ CD20+, CD79a+, bcl2+, Sig+/−

Genotype outside of the germinal centers and may encroach upon the germinal centers ♦♦ Reactive T-cells, eosinophils, and histiocytes are frequently admixed throughout the neoplasm

Immunophenotype ♦♦ CD20+, CD79a+, CD43+/−, Sig+, cytoplasmic immunoglobulin (Cig)+ ♦♦ CD5−, CD23−, cyclinD1−

Differential Diagnosis ♦♦ Lymphoid hyperplasia ♦♦ Follicular lymphoma

Primary Cutaneous Follicle Center Cell Lymphoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Solitary or grouped papules, nodules, or plaques Head and neck region most commonly involved May be associated with annular erythemas Rarely disseminate but frequently recur

♦♦ No t(14,18) translocation

Intravascular Large B-Cell Lymphoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Violaceous, indurated plaques or patches Lower extremities most often involved Central nervous system involvement may also be present Poor prognosis

Microscopic ♦♦ Large atypical lymphocytes are present within dilated vessels of the dermis and/or subcutis ♦♦ Rarely, atypical lymphocytes may be present adjacent to the vessels

Immunophenotype ♦♦ CD20+, CD79a+, Sig+

Mycosis Fungoides (Fig. 18.62) Clinical ♦♦ Persistent, erythematous patches and/or plaques which may progress to tumors over the course of many years

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Fig. 18.62. Mycosis fungoides (A, B).

Fig. 18.61. Large B-cell lymphoma of the leg (A, B).

♦♦ Annular and serpiginous plaques may be present ♦♦ Trunk and extremities most commonly involved ♦♦ Generally an indolent disease with tumor formation and systemic spread occurring only after many years to decades

♦♦ The epidermotropic lymphocytes frequently populate the basal layer of the epidermis and are generally unassociated with spongiosis ♦♦ The epidermotropic lymphocytes may aggregate into intraepidermal microabscesses (Pautrier microabscesses) ♦♦ The epidermotropic lymphocytes are frequently larger than those within the dermis and display varying degrees of nuclear convolution and cerebriform change ♦♦ The tumor stage shows a more diffuse, often sheet-like, proliferation of atypical, often large, lymphocytes with or without epidermotropism

Immunophenotype ♦♦ CD3+, CD4+, CD7+/–, CD8–, CD30– ♦♦ Rare CD8+ variants exist

Microscopic

Folliculotropic Mycosis Fungoides Clinical

♦♦ A band-like, epidermotropic proliferation of variably sized lymphocytes is present in the superficial dermis

♦♦ Erythematous papules or plaques typically affecting the head and neck region

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♦♦ Hair loss within the affected regions ♦♦ Typically affects adult patients

Sézary Syndrome Clinical

Microscopic

♦♦ Generalized erythroderma in association with generalized lymphadenopathy and leukemic infiltration of the blood by malignant T-cells ♦♦ Alopecia, palmoplantar keratoderma, and leonine facies are common findings ♦♦ Poor prognosis with a 5-year survival of less than 50%

♦♦ Marked folliculotropism of atypical lymphocytes ♦♦ Mucinous degeneration of follicular epithelium ♦♦ Lymphocytes usually have the atypical nuclear features of mycosis fungoides, and epidermotropism may be evident ♦♦ Eosinophils are often present

Immunophenotype

Microscopic

♦♦ Similar to mycosis fungoides

♦♦ Similar to mycosis fungoides but epidermotropism may be absent

Differential Diagnosis

Immunophenotype

♦♦ Primary (idiopathic) variants of follicular mucinosis affect younger individuals and appear unrelated to mycosis fungoides ♦♦ Other systemic diseases may show secondary follicular mucinosis (e.g., lupus erythematosus)

♦♦ Similar to mycosis fungoides

Pagetoid Reticulosis Clinical ♦♦ Hyperkeratotic patches or plaques limited to a distal extremity (Woringer–Kolopp type) ♦♦ No systemic involvement present ♦♦ Excellent prognosis ♦♦ The systemic or disseminated form (Ketron–Goodman type) is best considered to be mycosis fungoides

Microscopic ♦♦ A distinctly epidermotropic proliferation of large atypical lymphocytes with irregular, often cerebriform, nuclei ♦♦ Minimal to no dermal component

Immunophenotype ♦♦ Similar to mycosis fungoides

Granulomatous Slack Skin Clinical ♦♦ Pendulous plaques involving the axilla and groin regions ♦♦ Probably a rare variant of mycosis fungoides ♦♦ Males are affected more often than females

Microscopic ♦♦ Dense, dermal, atypical lymphocytic infiltrate admixed with numerous multinucleated histiocytes ♦♦ Multinucleated cells often have a wreath-like arrangement of nuclei ♦♦ Elastolysis is frequently present ♦♦ Dermal lymphocytes are generally small and have cerebriform nuclear features

Immunophenotype ♦♦ Similar to mycosis fungoides

Adult T-Cell Leukemia/Lymphoma (ATLL) General ♦♦ A leukemia/lymphoma associated with the human T-cell leukemia virus (HTLV-1)

Clinical ♦♦ ATLL is endemic in Japan, South America, Central Africa, and the Caribbean ♦♦ ATLL generally develops many years (decades) after infection with HTLV-1 ♦♦ Preleukemic, smoldering, chronic, lymphomatous, and acute clinical variants exist ♦♦ The acute phase is characterized by leukemia, lymphadenopathy, organomegaly, hypercalcemia, and cutaneous lesions that may include erythroderma, plaques, papules, nodules, or macules

Microscopic ♦♦ Skin biopsies may resemble mycosis fungoides with an epidermotropic infiltrate of cerebriform lymphocytes or may be considerably more pleomorphic with medium to large-sized lymphocytes with tumor formation ♦♦ The peripheral blood contains pleomorphic lymphocytes with hyperlobated nuclei resembling a clover leaf

Immunophenotype ♦♦ The immunophenotype is similar to mycosis fungoides, and CD25 is frequently expressed

Genetic findings ♦♦ HTLV-1 genes are clonally integrated into the T-cell tumor DNA by Southern blot analysis

Primary Cutaneous CD30+ Lymphoproliferative Disorders Including Lymphomatoid Papulosis and Primary Cutaneous Anaplastic Large Cell Lymphoma (Fig. 18.63) General ♦♦ Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma are part of a spectrum of related clinicopathologic entities having in common a good prognosis

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Fig. 18.63. CD30+ large T-cell lymphoma.

Fig. 18.64. Subcutaneous, panniculitis-like T-cell lymphoma.

Table 18.1. Comparison of Lymphomatoid Papulosis (LyP) and CD30+ Cutaneous T-Cell Lymphoma (CTCL) LyP

CD30+CTCL

Clinical Lesion type Size of lesion(s) Distribution Remit Systemic spread 5-year survival Age

Multiple <1 cm Extremities/trunk 100% None 100% Any age

Single or grouped >1 cm Extremities/head/neck 25–50% 25% 90% Older adults

Microscopic Pattern Subcutis Inflammation Necrosis Epidermotropism

Wedge shaped Spared Marked Rare Common

Diffuse sheets Involved Sparse Common Rare

Immunophenotype and molecular genetics CD30+ pattern CD30+ clusters Immunophenotype CD3+, CD4+ TCR clonality 10–20% t(2,5) translocation + or −

CD30+ sheets CD3+/−, CD4+/− Usually + + or −

and numerous CD30+ large lymphocytes histologically (see Table 18.1)

Subcutaneous, Panniculitis-Like T-Cell Lymphoma (Fig. 18.64) Clinical ♦♦ Subcutaneous nodules or plaques typically involving the lower extremities ♦♦ Frequent, severe constitutional symptoms ♦♦ Hepatosplenomegaly may be present

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♦♦ Hemophagocytic syndromes are common ♦♦ Systemic dissemination is uncommon ♦♦ Often have an indolent clinical course

Microscopic ♦♦ A variably dense, polymorphous, panniculitis-like infiltrate is present with no or minimal dermal involvement ♦♦ The pleomorphic lymphocytes may be small, medium, or large T-cells which characteristically “ring” around the adipocytes ♦♦ Lipophages, plasma cells, eosinophils, neutrophils and, occasionally, lymphoid follicles may be present ♦♦ Necrosis, karyorrhexis, hemophagocytosis, and angiodestruction are common

Immunophenotype ♦♦ CD3+, CD8+, Tia-1+, porin+, a/b+, CD56−

Genotype ♦♦ Clonal T-cell receptor, alpha/beta genotype ♦♦ EBV negative

Extranodal NK/T-Cell Lymphoma, Nasal Type General ♦♦ An aggressive form of NK or cytotoxic T-cell lymphoma characterized by cutaneous and/or nasal involvement

Clinical ♦♦ This form of NK/T-cell lymphoma most frequently affects adults and is most common in East Asian and South American countries ♦♦ The trunk and extremities are most often involved by tumors, plaques, nodules, or ulcers ♦♦ There may be an associated hemophagocytic syndrome ♦♦ The prognosis is poor with survival rates typically less than a year

Microscopic ♦♦ A dense dermal and/or subcutaneous infiltrate is present with regions of angiocentricity and angiodestruction

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♦♦ The tumor cells vary from small- to large-sized cells with hyperchromatic to vesicular nuclei ♦♦ A background mixed inflammatory infiltrate is common

♦♦ Rarely multiple cutaneous lesions may be present ♦♦ This entity has a good prognosis, particularly when a single lesion is present

Immunophenotype

Microscopic

♦♦ CD2+, surface CD3−, cytoplasmic CD3+, CD56+, TIA-1+, EBV+, T-cell receptor−

♦♦ An aggressive form of cutaneous lymphoma characterized by disseminated papules, nodules, or ulcers ♦♦ Systemic involvement may occur, and the overall survival is poor (mean survival of 32 months)

♦♦ A dense dermal lymphocytic infiltrate with polymorphous features is evident ♦♦ Epidermotropism is generally minimal or absent ♦♦ The infiltrate frequently surrounds and may infiltrate adnexal structures, but no follicular mucinosis is evident. The bulk of the infiltrate is dermal based and not follicular ♦♦ The individual cells are small- to medium-sized lymphocytes that are frequently admixed with background histiocytes, reactive lymphocytes, eosinophils and, occasionally, plasma cells

Microscopic

Immunophenotype

♦♦ A pleomorphic infiltrate of small- to medium-sized atypical lymphocytes is present with marked epidermotropism ♦♦ The atypical lymphocytes frequently invade adnexal structures, and angioinvasion may also be present

♦♦ CD3+, CD4+, CD8−, CD30−

Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma Clinical

Immunophenotype ♦♦ CD3+, CD8+, TIA-1+, betaF1+, CD4−, CD7−, CD56−, EBV−

Cutaneous Gamma/Delta T-Cell Lymphoma Clinical ♦♦ An aggressive form of cutaneous lymphoma characterized by disseminated plaques, nodules, or ulcers typically involving the extremities and, frequently, the trunk ♦♦ Involvement of other sites (mucosa and other extranodal regions) is common, and a hemophagocytic syndrome may occur

Microscopic ♦♦ Epidermotropic, dermal, and subcutaneous infiltrative patterns occur and may coexist ♦♦ The individual lymphocytes are medium to large in size with pleomorphic nuclear features and a clumped chromatin pattern ♦♦ Individual cell necrosis and confluent necrosis may be prominent ♦♦ Angioinvasion and angiodestruction are frequent findings

Immunophenotype

Genetics ♦♦ The TCR is clonally rearranged. Molecular studies are generally needed for diagnosis to exclude reactive etiologies (lymphoid hyperplasia, florid rosacea, etc.)

Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified General ♦♦ A cutaneous T-cell lymphoma that does not meet the criteria of the previously defined cutaneous T-cell lymphomas

Clinical ♦♦ These tumors typically present with multiple tumors, nodules, or plaques without a site predilection ♦♦ The prognosis is generally poor with 5-year survival rates of less than 20%

Microscopic ♦♦ A diffuse, destructive dermal infiltrate is present without significant epidermotropism or folliculotropism ♦♦ The tumors are composed of at least 30% large ­lymphocytes, but sheets of large lymphocytes may be present

Immunophenotype ♦♦ CD3+, CD4+, CD30−, CD56−

Genetics

CD4+/CD56+ Hematodermic Neoplasm (Blastic NK-Cell Lymphoma) General

♦♦ The T-cells have a clonal rearrangement of the TCR gamma gene. EBV is typically negative

♦♦ An aggressive neoplasm thought to be derived from a plasmacytoid dendritic cell precursor

Pleomorphic Small/Medium-Sized Cutaneous T-Cell Lymphoma Clinical

Clinical

♦♦ CD3+, CD2+, CD5−, CD4−, CD8−, betaF1−

♦♦ A solitary nodule, plaque, or papule on the head and neck region is the most common presentation

♦♦ Patients may present with solitary or generalized cutaneous involvement in the form of tumor nodules or plaques ♦♦ There is typically concurrent or subsequent involvement of the bone marrow, peripheral blood, and lymph nodes

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♦♦ However, cutaneous disease may be the first manifestation of a leukemic process in evolution

Clinical ♦♦ Macules, papules, nodules, tumors, plaques, and ulcers may all be manifestations of leukemia cutis ♦♦ Any cutaneous surface may be involved ♦♦ Gingival involvement is particularly characteristic of acute myelogenous leukemia of the monocytic type (AML, M5)

Microscopic

Fig. 18.65. Leukemia cutis.

Microscopic ♦♦ A diffuse dermal and/or subcutaneous infiltrate of medium sized, blastic lymphocytes is present ♦♦ No significant angioinvasion or epidermotropism is evident

Immunophenotype ♦♦ CD4+, CD56+, CD123+, CD3−, CD8−, MPO−, TdT+/−, CD68+/−

Leukemia Cutis (Fig. 18.65) General

♦♦ The most common pattern of leukemic infiltration of skin is the diffuse dermal, reticular or splaying pattern where the neoplastic cells splay apart the dermal collagen fibers in a discohesive fashion ♦♦ Perivascular to angiocentric infiltrates are also seen frequently in chronic lymphocytic leukemia (CLL) and in AML ♦♦ Nodular patterns of infiltration are also common ♦♦ The cytologic features of a particular leukemic infiltrate reflect their systemic cell of origin −− CLL: Small, monotonous lymphocytes −− AML: Myeloblasts with or without eosinophilic myelocytes, differentiated monocytes, etc −− CML (chronic myelogenous leukemia): A spectrum of granulocytic cells and myeloblasts −− ALL (acute lymphoblastic leukemia): Medium sized, fairly monotonous lymphoblasts

Immunophenotype

♦♦ All forms of leukemia may involve the skin during the course of their evolution ♦♦ Most often, this occurs in patients with a known diagnosis of leukemia

♦♦ ♦♦ ♦♦ ♦♦

CLL: CD20+, CD23+, CD5+, CD43+/−, CD3− AML: CD3−, CD20−, CD43+, MPO+/−, CD68+/− CML: CD3−, CD20−, CD43+, MPO+ ALL: CD3 or CD20+, TdT+/−, MPO−

IMMUNODERMATOLOGY Methods, Terminology and Techniques Direct Immunofluorescence (DIF) ♦♦ A skin biopsy that has been snap frozen or placed in transport media (such as Michel media) is incubated with fluorescein conjugated antibodies against immunoglobulin and complement ♦♦ Standard panel of conjugates includes IgG, IgA, IgM, C3, and fibrinogen

Indirect Immunofluorescence (IIF) ♦♦ The patient’s serum is incubated with normal human skin that has been split at the level of the lamina lucida using 1.0 M NaCl (salt-split skin) ♦♦ Fluorescein conjugated antibodies to IgG are then added

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♦♦ If circulating antibody to basement membrane zone is present, the conjugate will localize to the epidermal side, the dermal side, or to both ♦♦ This pattern reflects the location of the immune deposits (for example hemidesmosome or sublamina densa) and allows distinction between certain immunobullous diseases ♦♦ The titer of the circulating antibody is determined by incubating the patient’s serum with fluorescein conjugated antibodies to IgG on an epithelial substrate, usually monkey esophagus ♦♦ Other substrates may be used in specific conditions, such as rat bladder epithelium for paraneoplastic pemphigus or guinea pig esophagus for Pemphigus foliaceus ♦♦ Progressively more dilute samples of patient serum are used (1:5, 1:10, 1:20, 1:40, 1:80, and so on)

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♦♦ The dilution at which fluorescence can no longer be subjectively identified is the antibody titer ♦♦ Indirect immunofluorescence can also be performed using fluorescein conjugated antibodies to IgA ♦♦ This is helpful for diseases involving IgA, such as linear IgA bullous dermatosis and dermatitis herpetiformis

Western Immunoblotting ♦♦ A more specific technique to identify the antigens that the patient’s antibodies are directed against

ELISA ♦♦ Enzyme-linked immunosorbant assays have recently been developed for a number of immunobullous diseases ♦♦ These allow rapid, sensitive, and specific identification of antibodies

Fig. 18.66. Bullous pemphigoid. Subepidermal separation with eosinophils and lympocytes.

Immunobullous Diseases Patterns of Antibody Deposition ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Linear deposition along the basement membrane zone Deposition in intercellular spaces Granular deposition along the basement membrane zone Granular deposition in the dermal papillae Cytoid bodies and shaggy deposition along the basement membrane zone ♦♦ Thick linear deposition along the basement membrane zone and perivascular deposition ♦♦ Deposition on eosinophils and diffuse deposition on connective tissue ♦♦ Deposition in blood vessels

Linear Deposition Along the Basement Membrane Zone Bullous Pemphigoid (BP) Clinical ♦♦ Most commonly occurs in the elderly but has been reported in children and neonates ♦♦ Clinical presentation characteristic for pruritic tense bullae (negative Nikolsky sign) that heal without scarring ♦♦ The primary lesion is often urticarial ♦♦ Brunsting–Perry pemphigoid is a clinical subtype with scarring ♦♦ Distribution is mainly flexural, lower extremities and trunk ♦♦ Mucous membrane lesions occur in 10–30%

Microscopic ♦♦ Typically shows subepidermal separation with ­inflammatory infiltrate of eosinophils and lymphocytes (Fig. 18.66) ♦♦ Eosinophilic spongiosis may be present ♦♦ Neutrophils may also be seen, but are not prominent ♦♦ Basal layer spongiosis without frank separation may be seen in early or perilesional biopsies

Fig. 18.67. Bullous pemphigoid. Linear deposition of IgG along with basement membrane zone.

Electron Microscopy ♦♦ Separation occurs within the lamina lucida

Immunopathology ♦♦ DIF on a perilesional skin biopsy specimen shows linear deposition of antibody (IgG > IgA) and complement at the basement membrane zone (Fig. 18.67) ♦♦ Eosinophils are often prominent ♦♦ IIF using salt-split human skin demonstrates localization of the antibody to the epidermal side of the split (Fig. 18.68) ♦♦ A combined pattern (epidermal and dermal) is occasionally seen ♦♦ Indirect immunofluorescence detects circulating IgG basement membrane zone antibodies in 50–70% of patients ♦♦ The antibody titer is not predictably correlated with disease activity or prognosis ♦♦ Implicated antigens −− Most commonly detected antigen is a 230-kD hemi-­ desmosomal cytoplasmic protein (BP antigen I) −− The second most commonly detected is a 180-kD hemidesmosomal transmembrane protein (BP antigen II)

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Fig. 18.68. Bullous pemphigoid. Antibody localizes to the epidermal side of salt-split skin.

Cicatricial Pemphigoid Clinical ♦♦ Characterized by inflammation and scarring of the mucosal membranes, most commonly conunctiva ♦♦ May also involve oral and genital mucosa ♦♦ Primary oral lesion is often desquamative gingivitis ♦♦ Skin lesions are less common, but can occur ♦♦ Ocular scarring may lead to synblepharon, decreased tear production, entropion, and blindness

Microscopic ♦♦ May see subepithelial separation but usually see nonspecific mucositis with inflammatory infiltrate of eosinophils, plasma cells, and lymphocytes ♦♦ Neutrophils may also be present, but are not prominent

Electron Microscopy ♦♦ Separation occurs at the level of the lamina lucida

Immunopathology ♦♦ DIF pattern is identical to that seen in bullous pemphigoid ♦♦ There is linear deposition of IgG, IgA, and C3 along the basement membrane zone ♦♦ Eosinophils are often present in the lamina propria ♦♦ IIF usually does not detect circulating antibodies ♦♦ When antibodies are present, IIF using salt-split skin localizes the antibodies to the epidermal side in some cases, and to the dermal side in others

Implicated Antigens ♦♦ Most commonly implicated antigens are the same as for bullous pemphigoid (230-kD and 180-kD hemi-­desmosomal proteins), corresponding to the epidermal pattern of binding on salt-split skin ♦♦ Some patients have antibodies to epiligrin (laminin 5), a component of the anchoring filaments ♦♦ This subset of patients has been associated with the dermal pattern of binding on salt-split skin

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Fig. 18.69. Herpes gestationis. Eosinophilic spongiosis and subepidermal separation with eosinophils.

Herpes Gestationis (Pemphigoid Gestationis) Clinical ♦♦ Occurs exclusively in women ♦♦ Characterized by pruritic tense bullae (negative Nikolsky sign) that heal without scarring ♦♦ Primary lesion is often urticarial ♦♦ May begin around the umbilicus ♦♦ Usually most prominent on abdomen and flexural skin ♦♦ Mucosal lesions are very rare ♦♦ Most commonly occurs during the second or third trimester of pregnancy and resolves after delivery ♦♦ Postpartum flares can occur ♦♦ In subsequent pregnancies, the eruption occurs earlier and is more severe ♦♦ May also occur with hormonal medication or menses in susceptible women ♦♦ Has been reported with molar pregnancy and gestational malignancy

Epidemiology ♦♦ Increased frequency of HLA-B8, DR3, and DR4

Microscopic ♦♦ Usually identical to bullous pemphigoid ♦♦ Typically see subepidermal separation with inflammatory infiltrate of eosinophils, lymphocytes and occasionally neutrophils ♦♦ Early or perilesional biopsies may not show frank separation ♦♦ Basal cell necrosis may be more prominent than in bullous pemphigoid ♦♦ Might see eosinophilic spongiosis and/or an inverted teardrop pattern of epidermal edema (Fig. 18.69)

Electron Microscopy ♦♦ Separation occurs within the lamina lucida

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−− Mucosal erosions with scarring (“cicatricial pemphigoidlike”) ♦♦ All three types of lesions may be present; considerable overlap exists ♦♦ Associated diseases include systemic lupus erythematosus, other diseases of autoimmunity (inflammatory bowel disease, Goodpasture syndrome, glomerulonephritis, rheumatoid arthritis, thyroiditis, diabetes), and malignancy (multiple myeloma, chronic lymphocytic leukemia) ♦♦ Prognosis is generally poor

Epidemiology ♦♦ Increased incidence of HLA-DR2 Fig.  18.70. Herpes gestationis. Linear deposition of complement along the basement membrane zone.

Immunopathology ♦♦ DIF shows linear deposition of complement along the basement membrane zone (Fig. 18.70) ♦♦ Linear deposition of IgG may also be present, but is less prominent than complement ♦♦ This pattern reflects the nature of the circulating antibody, referred to as “herpes gestationis factor” (HG factor) ♦♦ HG factor is an IgG antibody (usually IgG1) that avidly fixes complement ♦♦ It is often present in such low titers that DIF and IIF fail to identify it, but the complement it fixes can be detected ♦♦ IIF is usually negative ♦♦ Low titers of circulating IgG antibodies to basement membrane zone are identified in less than 20% of patients ♦♦ When present, salt-split skin localizes these antibodies to the epidermal side of the separation

Microscopic ♦♦ If a noninflamed mechanobullous lesion is biopsied, microscopic will show a subepidermal separation with minimal inflammation (Fig. 18.71) ♦♦ If clinical lesion is inflamed, biopsy will have subepidermal separation with neutrophils, eosinophils, and lymphocytes along the basement membrane and in the upper dermis

Implicated Antigens ♦♦ The majority of patients have antibodies that are directed against the minor bullous pemphigoid antigen, BP antigen II (180-kD transmembrane hemidesmosomal protein) ♦♦ A smaller group of patients have antibodies directed against the major bullous pemphigoid antigen, BP antigen I (230-Kd cytoplasmic hemidesmosomal protein)

Epidermolysis Bullosa Acquisita (EBA) Clinical ♦♦ Adults are affected more commonly than children ♦♦ Racial differences are seen, with blacks affected more frequently ♦♦ Three different clinical patterns are observed −− A mechanobullous eruption with noninflammatory blisters and increased skin fragility in an acral ­distribution, that heals with scarring and milia. This is the most frequent presentation −− An inflammatory (“bullous pemphigoid-like”) vesicobullous eruption that heals without scarring or milia

Fig. 18.71. Epidermolysis bullosa acquisita. Subepidermal separa­ tion wth minimal inflammation.

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♦♦ Neutrophils tend to predominate over eosinophils ♦♦ Basal layer spongiosis without frank separation may be seen in early or perilesional biopsies

Electron Microscopy ♦♦ Separation usually occurs at the level of the lamina densa/ sublamina densa ♦♦ Occasionally occurs in the lamina lucida

Immunopathology ♦♦ DIF has a pattern identical to bullous pemphigoid, with linear deposition of IgG and complement along the basement membrane zone ♦♦ IgA, IgM, and fibrinogen are less commonly present. Indirect immunofluorescence is necessary to distinguish EBA from pemphigoid ♦♦ IIF on salt-split skin shows a dermal pattern of binding (Fig. 18.72) ♦♦ Circulating IgG antibody to basement membrane zone is commonly present

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ They do not usually have other cutaneous manifestations of lupus ♦♦ Patients with systemic lupus can also have blistering for other reasons, such as concurrent primary bullous disease or severe medication or photosensitivity reaction

Epidemiology ♦♦ Increased incidence of HLA-DR2

Microscopic ♦♦ Typically shows subepidermal separation with inflammatory infiltrate of neutrophils and lymphocytes in the dermal papillae (as in dermatitis herpetiformis) and along the basement membrane zone (Fig. 18.73) ♦♦ Neutrophils predominate

Immunoelectron Microscopy ♦♦ IgG and complement are deposited in the sublamina densa ♦♦ Separation occurs at the level of the sublamina densa

Implicated Antigens ♦♦ The majority of patients have antibodies that are directed against the 290-Kd noncollagenous domain (NC-1) on the alpha chain of collagen type VII (anchoring fibrils) ♦♦ Rarely, antibodies to a 145-Kd noncollagenous globular domain on the alpha chain of collagen type VII have been identified

Bullous Systemic Lupus Erythematosus (BSLE) Clinical ♦♦ Patients with systemic lupus erythematosus may also develop autoimmunity to basement membrane zone ♦♦ These patients present with a blistering eruption, especially on sun-exposed skin ♦♦ They will also have other signs and symptoms of systemic lupus

Fig. 18.72. Epidermolysis bullosa acquisita. Antibody localizes to the dermal side of salt-split skin.

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Fig. 18.73. Bullous systemic lupus erythamatosus. Subepidermal separation wih neutrophils and lymphocytes in dermal papillae and along the basement membrane zone.

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Fig. 18.74. Bullous systemic lupus erythamatosus. Linear ­deposition of IgG along the basement membrane zone.

Immunopathology ♦♦ DIF shows either linear (Fig.  18.74) or granular to fibrillar deposition of IgG and complement along the basement membrane zone (Fig. 18.75) ♦♦ IgM and IgA are occasionally present ♦♦ IIF using salt-split skin demonstrates immune deposits on the dermal side of the separation ♦♦ Circulating IgG to basement membrane zone is present in some but not all patients ♦♦ Antinuclear antibodies are often seen

Implicated Antigens ♦♦ As in EBA, the majority of patients have antibodies that are directed against the 290-Kd noncollagenous domain (NC-1) on the alpha chain of collagen type VII (anchoring fibrils) ♦♦ Rarely, antibodies to a 145-Kd noncollagenous globular domain on the alpha chain of collagen type VII have been identified ♦♦ Antibody specificity is the same as that seen in epidermolysis bullosa acquisita ♦♦ In some cases, antibodies to type VII collagen cannot be detected ♦♦ Some authors propose two subtypes, BSLE 1 and BSLE 2, based on the presence (BSLE 1) or absence (BSLE 2) of antibodies to type VII collagen

Linear IgA Bullous Dermatosis (Chronic Bullous Disease of Childhood) Clinical ♦♦ Occurs in adults and children, probably more common in children and in women ♦♦ Clinically heterogeneous ♦♦ Clinical exam shows a vesiculobullous eruption on normal or erythematous skin ♦♦ May have a “cluster-of-jewels” appearance ♦♦ Commonly occurs on trunk and flexures in adults and on lower abdomen, groin, and periorificial in children

Fig.  18.75. Bullous systemic lupus erythamatosus. Linear to granular deposition of IgG along the basement membrane zone and epidermal ANA. ♦♦ Oral lesions occur in about 70% ♦♦ Other mucosal surfaces, including conjunctivae, may be involved ♦♦ Disease associations include −− Medications (captopril, vancomycin, lithium), gastrointestinal diseases (inflammatory bowel disease, gluten sensitive enteropathy) malignancy (hematogenous, carcinoma, melanoma) various ­infections, other diseases of autoimmunity ♦♦ Prognosis is generally good

Microscopic ♦♦ Usually shows subepidermal separation with inflammatory infiltrate of neutrophils, eosinophils, and lymphocytes (Fig. 18.76) ♦♦ Neutrophils predominate over eosinophils, especially in early lesions ♦♦ Basal layer spongiosis without frank separation may be seen in early or perilesional biopsies

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Fig. 18.77. Linear IgA bullous dermatosis. Linear deposition of IgA along the basement membrane zone. ♦♦ Several different antigens have been identified ♦♦ Most common is a 97-Kd component of the anchoring filaments termed LAD-1 ♦♦ Immune deposition here corresponds to an epidermal pattern of binding on salt-split skin ♦♦ Antibodies to a 290-Kd component of collagen type VII have also been identified ♦♦ Epitope is different than that of EBA ♦♦ Immune deposition here corresponds to a dermal pattern of binding on salt-split skin ♦♦ Other antibodies have also been identified ♦♦ LABD is likely a heterogeneous group of diseases, with a variety of autoantibodies Fig. 18.76. Linear IgA bullous dermatosis. Subepidermal separation with neutrophils greater in number than lymphocytes and eosinophils. ♦♦ May see neutrophilic microabscesses in dermal papillae, similar to dermatitis herpetiformis

Immunoelectron Microscopy ♦♦ Mixed findings occur ♦♦ In some cases, there is IgA deposition in the lamina lucida (beneath the hemidesmosomes) ♦♦ In others cases, IgA is found in the sublamina densa, in association with anchoring fibrils ♦♦ IgA may also be found deposited in both locations

Immunopathology ♦♦ DIF shows linear deposition of IgA along the basement membrane zone (Fig. 18.77) ♦♦ IgG, IgM, C3, and fibrinogen may be present but are of lower intensity than IgA ♦♦ IIF on salt-split skin may show an epidermal pattern (most common), a dermal pattern, or both ♦♦ Circulating IgA antibodies (usually IgA1) to basement membrane zone can be identified in 60–70% Implicated Antigens

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Deposition in Intercellular Spaces Pemphigus ♦♦ A group of diseases all characterized clinically by ­cutaneous and/or mucosal blistering or erosions and histologically by acantholysis ♦♦ Immunopathology −− Autoantibodies to epithelial cell surfaces giving an intercellular space pattern of antibody deposition (ICS pattern)

Variants ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Pemphigus vulgaris Pemphigus vegetans Drug-induced pemphigus Pemphigus foliaceus Pemphigus erythematosus IgA pemphigus Paraneoplastic pemphigus

Pemphigus Vulgaris Clinical ♦♦ Most commonly occurs in adults (mean age 50–60) but has been reported in children

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♦♦ Increased incidence with Ashkenazi Jewish or Mediterranean heritage, but no race is exempt ♦♦ Oral lesions (erosions) usually develop first ♦♦ Disease may be confined to the oral cavity ♦♦ Skin lesions are typically flaccid bullae that rupture easily leaving erosions and crusts ♦♦ Gentle pressure on the blister roof will cause extension of the bulla (positive Nikolsky sign) due to the fragility of the surrounding skin ♦♦ Any stratified squamous epithelial surface may be involved, including other mucosal surfaces ♦♦ Pemphigus vegetans is a clinical subtype characterized by chronic lesions that develop into hyperkeratotic plaques, often in intertriginous sites ♦♦ Most commonly implicated medications in drug-induced pemphigus are penicillamine and captopril

Microscopic ♦♦ Characteristic for suprabasilar separation with acantholysis (Fig. 18.78) ♦♦ Basal layer remains attached, with separation at the lateral and apical margins (“tombstoning”) (Fig. 18.79)

Fig. 18.79. Pemphigus vulgaris. “Tomb stoning” of basal layer. ♦♦ Acantholysis extending down hair follicles helps to distinguish pemphigus from other causes of acantholysis such as Hailey–Hailey and Darier disease ♦♦ Eosinophilic spongiosis may be present ♦♦ There is a mixed inflammatory infiltrate in the dermis ♦♦ Pemphigus vegetans has more acanthosis and eosinophilic spongiosis with relatively subtle suprabasilar separation and acantholysis

Electron Microscopy ♦♦ First sign is loss of attachment of cell membrane between adjacent keratinocytes, at the level of the desmosome ♦♦ Widening of intercellular spaces follows, as desmosomes pull apart ♦♦ Intracellular keratin filaments begin to show perinuclear clustering and the acantholytic cells then “round up” and float free

Immunopathology

Fig.  18.78. Pemphigus vulgaris. Suprabasilar separation with acantholysis.

♦♦ DIF shows IgG and C3 bound to the keratinocyte cell surface in an ICS pattern; also referred to as intercellular substance (Fig. 18.80) ♦♦ May be seen throughout the thickness of the epidermis or only in the deeper levels ♦♦ In active disease, IIF is nearly always positive for circulating IgG antibodies to ICS (Fig. 18.81) ♦♦ False negatives are more likely in drug induced and early disease ♦♦ Antibody titer correlates fairly well with disease activity ♦♦ False positive “pemphigus-like” antibodies are not uncommon and can be seen with medications (penicillin),

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Fig. 18.80. Pemphigus vulgaris. IgG bound to keratinocyte cell surface in an ICS pattern.

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♦♦ Clinical variants include a sporadic form, a drug-induced form, and an endemic form (Fogo selvagem) ♦♦ Fogo selvagem is seen in agricultural and poverty-stricken regions of Brazil and South America ♦♦ Familial cases are frequently seen ♦♦ Peak incidence in the second and third decade ♦♦ The black fly (Simulian pruinosum) has been epidemiologically implicated as a vector ♦♦ Sporadic form occurs in elderly patients with no family history ♦♦ No environmental factors have been implicated ♦♦ Drug-induced form most commonly linked to “thiol” drugs (penicillamine and captopril) but has also been seen with “masked thiols” (penicillins and cephalosporins) and nonthiols (enalapril) ♦♦ Other associations include myasthenia gravis and thymoma (benign and malignant)

Microscopic ♦♦ As in pemphigus vulgaris, but more superficially located ♦♦ Acantholysis occurs in a subcorneal or intraepidermal location (Fig. 18.82)

Electron Microscopy ♦♦ Acantholysis affects all layers, including the basal layer

Immunopathology

Fig.  18.81. Pemphigus vulgaris. Circulating IgG to ICS on ­ onkey esophagus. m infections (dermatophytes), and full thickness epidermal disruption (burns) ♦♦ The titer of false positive antibody is usually low (less than 1:80)

Implicated Antigen ♦♦ Autoantibodies (IgG4 > IgG1 and IgG3) are directed against desmoglein 3, a 130-kD transmembrane glycoprotein located in desmosomes ♦♦ It exists in a molecular complex with plakoglobin, an 85-kD intracellular protein

Pemphigus Foliaceus Clinical ♦♦ Characterized by superficial erosions and crusts, flaccid vesicles or bullae may be present ♦♦ Usually begins on head/neck (seborrheic distribution) and spreads acrally ♦♦ Mucosal lesions are rare ♦♦ May be exacerbated by sunlight

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♦♦ DIF and IIF have findings similar or identical to those seen in pemphigus vulgaris (Fig. 18.83) ♦♦ DIF cannot reliably distinguish pemphigus vulgaris from pemphigus foliaceus ♦♦ In active disease, IIF is nearly always positive for ­circulating IgG antibodies to ICS ♦♦ Antibody titer correlates fairly well with disease activity ♦♦ Guinea pig esophagus appears to be better than monkey esophagus as a substrate for the detection of antibodies

Implicated Antigen ♦♦ Autoantibodies are directed against desmoglein 1, a 160-kD transmembrane glycoprotein located in desmosomes ♦♦ Like desmoglein 3 (antigen in pemphigus vulgaris), desmoglein 1 exists in a molecular complex with plakoglobin

Pemphigus Erythematosus Clinical ♦♦ A rare disease characterized by facial lesions with features of both lupus erythematosus and pemphigus foliaceus (or seborrheic dermatitis) and lesions on the trunk more suggestive of pemphigus (flaccid bullae, erosions, and crusts) ♦♦ Usually photodistributed ♦♦ Mucosal lesions are rare ♦♦ May occur in any age; mean onset 40–60 years ♦♦ Clinical signs of lupus may be present, but usually are not ♦♦ When present, lupus is usually mild or localized only

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♦♦ Various autoimmune diseases (myasthenia gravis) and malignancies (bronchogenic carcinoma) have also been associated

Microscopic ♦♦ Superficial acantholysis (similar to pemphigus foliaceus) is the main feature (Fig. 18.84) ♦♦ A subcorneal separation or pustule may be present ♦♦ Lichenoid dermatitis may be seen, but changes ­characteristic of lupus are not usually found

Electron Microscopy ♦♦ Demonstrates findings similar to early pemphigus ♦♦ Most marked changes occur at the level of the stratum granulosum and upper stratum spinosum

Immunopathology ♦♦ DIF characterized by the combination of a typical ICS pattern with IgG and/or C3 (Fig. 18.85), as well as granular to linear deposition of IgM along the basement membrane zone (Fig. 18.86) ♦♦ A lupus band is usually NOT present ♦♦ As in pemphigus vulgaris and pemphigus foliaceus, IIF is usually positive for circulating antibodies against ICS

Fig. 18.82. Pemphigus foliaceus. Subcorneal acantholysis.

Fig. 18.83. Pemphigus foliaceus. IgG bound to keratinocyte cell surface in an ICS pattern. ♦♦ Antinuclear antibodies are present in 30–60% ♦♦ Most commonly associated medications are penicillamine and captopril

Fig. 18.84. Pemphigus erythematosus. Subcorneal acantholysis.

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Fig. 18.85. Pemphigus erythematosus. IgG bound to keratinocyte cell surface in an ICS pattern.

Fig.  18.86. Pemphigus erythematosus. Granular deposition of IgM along the basement membrane zone and cytoids.

Fig.  18.87. IgA Pemphigus. Subcorneal separation with neutrophils.

Implicated Antigen

Microscopic

♦♦ Unknown

♦♦ SPD-type has subcorneal separation with neutrophils (Fig. 18.87) ♦♦ IEN-type has an intraepidermal cleft with neutrophils (slightly deeper than the SPD-type) (Fig. 18.88) ♦♦ Suprabasilar separation may be seen ♦♦ In both types, acantholysis is sparse ♦♦ Neutrophilic microabscesses, as seen in dermatitis herpetiformis, have been reported

IgA Pemphigus ♦♦ Numerous synonyms: intraepidermal neutrophilic IgA dermatosis, atypical neutrophilic dermatosis, intercellular IgA vesicopustular dermatosis, and IgA Pemphigus foliaceus

Clinical ♦♦ A rare disease, only reported in caucasians ♦♦ Has been reported in children ♦♦ Clinical lesions include flaccid vesicles and pustules, sometimes in an annular or circinate pattern ♦♦ Distribution is often central ♦♦ Mucosal lesions do not occur ♦♦ The clinical course is fairly mild ♦♦ Two subtypes are IgA pemphigus of the subcorneal pustular dermatosis type (SPD) and IgA pemphigus of the intraepidermal neutrophilic type (IEN)

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Immunopathology ♦♦ DIF is characterized by deposition of IgA in an ICS pattern (Fig. 18.89) ♦♦ In general, deposition of C3 and other immunoglobulins does not occur ♦♦ Circulating IgA against ICS present in less than half of the reported cases ♦♦ Circulating anti-ICS IgG (lower titer than anti-ICS IgA) has been rarely reported

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♦♦ A 120-kD protein has been linked to the IEN-type ♦♦ Other antigens, including some linked to pemphigus vulgaris, have also been associated

Paraneoplastic Pemphgius Clinical ♦♦ Association between pemphigus and malignancy has long been recognized ♦♦ Described as a distinct entity in 1990 ♦♦ More common in older adults, but has been reported in children ♦♦ Malignancy usually presents first ♦♦ Prognosis is very poor; both malignancy and pemphigus are usually treatment resistant ♦♦ Hematopoeitic malignancies (CLL, Castleman tumor, Waldenstrom macroglobulinemia, and non-Hodgkin lymphoma) have been most commonly associated, but poorly differentiated sarcomas, adenocarcinoma, and even benign thymoma have been linked ♦♦ Clinically characterized by severe, painful, and recalcitrant erosions of mucosal surfaces ♦♦ Oral mucosa most commonly involved ♦♦ May also affect conjunctivae, genital mucosa, and respiratory epithelium ♦♦ Cutaneous eruption is polymorphous ♦♦ Initially may have a pruritic papulosquamous eruption ♦♦ Blisters may later develop, including on palms and soles (reminiscent of erythema multiforme) ♦♦ Chronic lichenoid changes have also been described Fig.  18.88. IgA Pemphigus. Subcorneal separation with intraepidermal neutrophils.

Fig.  18.89. IgA Pemphigus. IgA bound to keratinocyte cell ­surface in an ICS pattern.

Implicated Antigen(s) ♦♦ Most likely a heterogeneous group of diseases with antibodies directed against several different antigens ♦♦ Most strongly implicated antigen is desmocollin 1, a 115-kD protein found on the extracellular surface of the desmosome, which has been linked to the SPD-type

Microscopic ♦♦ In about half of the cases, a combination of histologic features is seen, including −− Suprabasilar separation and acantholysis (Fig. 18.90) −− Lichenoid changes (vacuolar degeneration, a band-like infiltrate, and exocytosis of inflammatory cells) (Fig. 18.91) −− Dyskeratotic and necrotic keratinocytes (as seen in erythema multiforme) ♦♦ Many cases will not have all of these features ♦♦ Eosinophilic infiltration is not typically seen ♦♦ Atypia of infiltrating cells also not seen

Immunoelectron Microscopy ♦♦ Immune complexes present in a variety of locations, including the hemidesmosomes, desmosomal plaques, keratinocyte plasma membrane, and extracellular regions of desmosomes

Immunopathology ♦♦ DIF has the characteristic combination of an ICS pattern with IgG +/− C3, and linear to granular deposition of C3 +/− IgG along the basement membrane zone (Fig. 18.92)

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Fig. 18.90. Paraneoplastic pemphigus. Mucosa with suprabasilar separation and acantholysis.

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Fig. 18.91. Paraneoplastic pemphigus. Another zone with lichenoid mucositis.

♦♦ Other lichenoid features, such as cytoids (dyskeratotic keratinocytes) and shaggy deposition of fibrinogen are variably present ♦♦ Circulating IgG against epithelial cell surfaces has been detected on many substrates, including stratified squamous (as in other forms of pemphigus) as well as transitional and columnar epithelium ♦♦ Best sensitivity/specificity profile in urinary bladder epithelium (rat and mouse)

Implicated Antigens ♦♦ Autoantibodies are directed against a complex of four antigens ♦♦ Most strongly and consistently detected are antibodies against −− A 190-kD protein (identity unknown) −− A 210-kD protein (desmoplakin 2) ♦♦ Also detected are antibodies against

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Fig.  18.92. Paraneoplastic pemphigus. Complement bound to cell surface in an ICS pattern and in a linear to granular pattern along the basement membrane zone. −− A 230-kD hemidesmosomal protein (bullous pemphgoid antigen 1) −− A 250-kD protein (desmoplakin 1)

Neoplasms of the Skin and Immunodermatology

Granular Deposition Along the Basement Membrane Zone: Lupus Erythematosus Lupus Variants ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Discoid lupus erythematosus Localized Disseminated Subacute cutaneous lupus erythematosus Systemic lupus erythematosus Bullous systemic lupus erythematosus

Discoid Lupus Erythematosus (DLE) Clinical ♦♦ DLE is a cutaneous disease, usually not accompanied by systemic signs of lupus ♦♦ It is photodistributed and thus typically affects the face, head and neck, chest, and upper back ♦♦ Disease may be localized or widespread (disseminated) ♦♦ More common in young women ♦♦ Increased incidence in blacks ♦♦ Clinical lesions are patches, papules, and plaques ♦♦ Characteristic features include telangiectasia, atrophy, scarring, and follicular plugging ♦♦ Scalp involvement results in scarring alopecia ♦♦ Response to treatment (photoprotection, topical steroids, and systemic antimalarials) is variable, but tends to be good

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Immunopathology ♦♦ On involved or sun-exposed skin, DIF shows granular deposition along the basement membrane zone with IgM, sometimes referred to as a lupus band (Fig. 18.94) ♦♦ The strict definition of a lupus band reserves the use of the term for the presence of granular IgM along the basement membrane zone in uninvolved and nonsun-exposed skin, as seen in systemic LE (Fig. 18.95) ♦♦ Granular deposition with other conjugates, including C3, IgA, and IgG, is usually present, which helps to confirm the diagnosis ♦♦ Fibrinogen often forms a shaggy band along the basement membrane zone, typical for a lichenoid reaction ♦♦ DIF may be negative (or only have minimal granular IgM deposition) in a biopsy from an old “burned-out” lesion or from the atrophic center of a lesion, making site selection for biopsy critical for the diagnosis ♦♦ DIF is negative in uninvolved and nonsun-exposed skin

Microscopic ♦♦ Epidermal atrophy, hyperkeratosis, and thickening of the basement membrane accompany basal liquifactive degeneration, pigment incontinence, and a variable degree of lichenoid inflammation (Fig. 18.93) ♦♦ Periadnexal and perivascular infiltrate is present in the upper and mid dermis ♦♦ Follicular infundibular plugging is often seen ♦♦ Dermal mucinosis often present

Fig. 18.93. Discoid lupus erythematosus. Interface dermatitis.

Fig. 18.94. Discoid lupus erythematosus. Granular deposition of IgM along the basement membrane zone and cytoids.

Fig. 18.95. Discoid lupus erythematosus. The “lupus band” of systemic lupus erythematosus is granular deposition of IgM along the basement membrane zone in nonsun-exposed skin.

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♦♦ May also see epidermal antinuclear antibodies, most commonly with IgG ♦♦ Indirect immunofluorescence is negative

Subacute Cutaneous Lupus Erythematosus (SCLE) Clinical ♦♦ SCLE is a photodistributed, symmetric, and often widespread eruption, most commonly seen in females ♦♦ Mean age of presentation is around 40, which is slightly older than other types of LE ♦♦ There is a strong association with the presence of anti-Ro (SS-A) antibodies and Sjögren syndrome ♦♦ Systemic lupus erythematosus is present in 50% ♦♦ ANA is positive in about half; other antibodies including anti-La (SS-B), anti-thyroid, and anti-cardiolipin are variably present ♦♦ Lesions are nonscarring and nonindurated ♦♦ May see annular/polycyclic plaques with central clearing or papulosquamous lesions (scaly pink-red papules) ♦♦ Lesions LACK atrophy, scarring, and follicular plugging ♦♦ Clinical course is usually relatively benign, but a subset of patients may go on to develop severe systemic disease

Epidemiology ♦♦ Increased incidence of HLA-DR3 and HLA-DR2 as well as inherited homozygous C2 and C4 deficiency

Microscopic (Fig. 18.96) ♦♦ Many features are similar to changes seen in discoid LE, but histologic distinction between the two can sometimes be made ♦♦ In general, SCLE has less −− Hyperkeratosis −− Basement membrane thickening −− Follicular involvement

Fig. 18.96. Subacute cutaneous lupus erythematosus. Interface dermatitis.

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−− Follicular plugging −− Dermal infiltrate, and it is more superficially located ♦♦ SCLE tends to have more −− Epidermal atrophy −− Liquifactive degeneration −− Cytoid bodies −− Pigment incontinence −− Satellite cell necrosis −− Lymphocyte exocytosis ♦♦ Exceptions to these rules are frequent, and in many cases, SCLE cannot be histologically distinguished from other types of LE

Immunopathology ♦♦ DIF has findings that are distinct from other types of LE ♦♦ There is a discrete “particulate” or speckled pattern of epidermal deposition with IgG that occurs predominantly in the basal layer, and is associated with the presence of anti-Ro (SS-A) antibodies (Fig. 18.97) ♦♦ Particulate dermal–epidermal deposition can be seen in other types of lupus and is not suggestive of SCLE ♦♦ Other DIF changes typical for LE (granular deposition along the basement membrane zone with IgM and other conjugates) may be present, but often are not ♦♦ May also see epidermal antinuclear antibodies, most commonly with IgG ♦♦ Circulating antinuclear antibodies are detected in 50% ♦♦ Indirect immunofluorescence is usually otherwise negative

Bullous Systemic Lupus Erythematosus ♦♦ DIF is characterized by linear or granular deposition along the basement membrane zone ♦♦ See description under the section “Linear deposition along the basement membrane zone”

Fig. 18.97. Subacute cutaneous lupus erythematosus. Speckled or “particulate” pattern of intercellular epidermal IgG deposition.

Neoplasms of the Skin and Immunodermatology

Systemic Lupus Erythematosus Clinical ♦♦ SLE is an autoimmune disease with a wide variety of possible systemic manifestations ♦♦ Over 75% of patients will have some form of cutaneous involvement, including malar erythema, photosensitivity, oral involvement (cheilitis, ulcers, petechiae, and gingivitis), or discoid lesions ♦♦ Nonspecific lesions may be seen in SLE, but may also be seen in a variety of other conditions or in normal patients ♦♦ These include vasculitis and vasculopathy, Raynaud phenomenon, livedo reticularis, perniosis, urticaria and urticarial vasculitis, nonscarring alopecia, and rheumatoid nodules ♦♦ Most common in women of childbearing age (F:M 9:1) and dark skinned patients (black, hispanic, and so on) ♦♦ Increased incidence of complement deficiency, both due to excessive consumption by immune complexes and an increased incidence of inherited deficiencies of complement components (most commonly homozygous C2 deficiency) ♦♦ Mean age of onset is in the thirties ♦♦ May be induced by medication ♦♦ Clinical course is variable; may be mild and controlled with medication or severe and recalcitrant ♦♦ Most commonly affected systems include joints (90%), kidneys (50%), lungs (40%), and the central nervous system (30%), but a wide variety of other organs may also be affected ♦♦ Constitutional signs are frequent and include fatigue, fever, weight loss, and malaise ♦♦ Most common cause of mortality is due to renal involvement

Microscopic ♦♦ Microscopic characteristics depends on the type of lesion biopsied ♦♦ No changes diagnostic for systemic LE exist ♦♦ Discoid lesions show changes as described for discoid LE ♦♦ Vasculitic lesions clinically associated with lupus anticoagulant syndrome show thrombotic microangiopathy, indistinguishable from other types of thrombotic microangiopathy (such as cryoglobulin associated microangiopathy) ♦♦ Biopsy of malar erythema is nonspecific, with telangiectasia and rarely liquifactive degeneration or interface dermatitis

Immunopathology ♦♦ As discussed above, the strict definition of a positive lupus band test is the presence of granular deposition of IgM (and other conjugates) along the basement membrane zone in a biopsy from nonsun-exposed and uninvolved skin (Fig. 18.95) ♦♦ The presence of a lupus band is correlated with a higher incidence of systemic disease ♦♦ Granular deposition with other conjugates (IgG, IgA, and C3) is usually seen ♦♦ Circulating antinuclear antibodies may be detected on indirect immunofluorescence, but IIF is otherwise negative

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Granular Deposition in the Dermal Papillae Dermatitis Herpetiformis (DH) Clinical ♦♦ DH is a chronic, intensely pruritic eruption with usual onset in the second to fourth decade, though it may occur at any age ♦♦ Primary lesions are pruritic urticarial papules that develop into small tense vesicles ♦♦ Due to the intense pruritus of the lesion, an excoriation is usually all that remains at the time of exam ♦♦ Most commonly affects extensor surfaces, particularly on pressure points, including the extensor surfaces of the forearms (elbows), knees, back, buttocks, and sacrum ♦♦ Associated with gluten-sensitive enteropathy which is clinically significant in 10% or less, but histologically detectable (by villous atrophy and increased lymphocytic infiltrate) in 60–70% of patients ♦♦ Cutaneous disease and small bowel disease both respond to gluten-free diet ♦♦ Also clinically characterized by a rapid (within 24–48  h) response to dapsone ♦♦ DH is also associated with an increased incidence of GI lymphoma and other malignancies ♦♦ Other organs with associated conditions include the thyroid (hyper and hypothyroidism, thyroid nodules and malignancy) and stomach (atrophy and hypochlorhydria) ♦♦ A variety of other autoimmune diseases have also been associated (Sjögren syndrome, insulin dependent diabetes, rheumatoid arthritis, myasthenia gravis, and SLE, among others)

Epidemiology ♦♦ Increased frequency of HLA haplotypes B8, A1, DR3 and DQw2

Microscopic ♦♦ Early lesions show neutrophils along the basement membrane zone and in the dermal papillae, accompanied by fibrin deposition, leukocytoclasis, and rare eosinophils ♦♦ Clefts appear at the sites of neutrophil accumulation, termed papillary microabscesses (Fig. 18.98) ♦♦ Perivascular lymphohistiocytic infiltrate is often present in the upper and middle dermis ♦♦ As vesicles or bullae develop, findings become nonspecific (subepidermal separation with neutrophils and eosinophils)

Immunopathology ♦♦ DIF characteristically has granular deposition of IgA in the dermal papillae and along the basement membrane zone (Fig. 18.99) ♦♦ Granularity is most pronounced in the dermal papillae ♦♦ Granular deposition with other conjugates (C3, IgG, and IgM) is rarely present, but has been reported ♦♦ These changes are found in perilesional (within 3–5  mm) normal-appearing skin

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♦♦ The patient’s titer of IgA anti-endomysial antibody, detected using monkey esophagus substrate, correlates with disease activity as well as patient’s compliance with the gluten-free diet

Implicated Antigen ♦♦ Unknown

Clumped Cytoid Bodies and Shaggy Deposition of Fibrinogen Along the Basement Membrane Zone Lichenoid Tissue Reaction ♦♦ Cytoid bodies are round, homogeneously fluorescent cells that appear scattered as single cells or clumped in groups along the basement membrane zone ♦♦ They can also be seen in the epidermis (erythema multiforme) or upper dermis ♦♦ They are thought to represent necrotic keratinocytes and/or fragments of basement membrane ♦♦ Scattered cytoids can be seen nonspecifically in many conditions ♦♦ Shaggy deposition of fibrinogen along the basement membrane zone gives a pattern that has been likened to “dripping paint” ♦♦ While neither of these two findings is specific, the combination of clumped cytoids and shaggy deposition of fibrinogen is seen in lichenoid tissue reactions ♦♦ The diagnosis in each of these entities is dependent on the appropriate histopathology being present

Variants Fig. 18.98. Dermatitis herpetiformis. Papillary microabscesses.

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Lichen planus Lupus erythematosus Dermatomyositis Erythema multiforme Paraneoplastic pemphigus Lichenoid dermatitis Lichenoid drug reaction Graft versus host disease Other dermatoses

Lichen Planus Immunopathology

Fig.  18.99. Dermatitis herpetiformis. Granular deposition of IgA in dermal papillae and along basement membrane zone. ♦♦ Several antibodies can be produced by patients with dermatitis herpetiformis and/or gluten sensitive enteropathy, including IgG and/or IgA anti-endomysial antibodies, antigliadin and anti-reticulin antibodies

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♦♦ The “classic” lichenoid tissue reaction is often seen, with clumped cytoid bodies along the basement membrane zone and shaggy deposition of fibrinogen along the basement membrane zone (Fig. 18.100) ♦♦ Mucosal lesions are less likely to have cytoid bodies; shaggy fibrinogen may be the only finding present ♦♦ Yeast (Candida) can sometimes be found in mucosal lesions ♦♦ Although clumped cytoids are quite characteristic of LP, LP cannot be diagnosed on immunopathology alone. Microscopic consistent with LP must also be present to make the diagnosis

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Lichenoid Dermatitis Immunopathology ♦♦ Dermatitis due to any number of causes may also demonstrate a lichenoid tissue reaction ♦♦ This pattern is more likely to be seen in chronic dermatitis

Lichenoid Drug Reaction Immunopathology ♦♦ In addition to lichenoid changes, drug reactions will also have eosinophils in the superficial and middle dermis

Graft Versus Host Disease Immunopathology Fig.  18.100. Lichen planus. Shaggy deposition of fibrinogen and clumped cytoids along the basement membrane zone.

Lupus Erythematosus ♦♦ See section above

Immunopathology ♦♦ The typical features seen in lupus erythematosus are listed above. In addition, lupus may also demonstrate lichenoid features on immunopathology, often in combination with typical granularity along the basement membrane zone ♦♦ Immunofluorescence of aged or “burned out” lesions may only have lichenoid changes

Dermatomyositis Immunopathology ♦♦ Although granularity along the basement membrane zone similar to that seen in lupus erythematosus (the lupus band) has been reported, immunofluorescence usually does not demonstrate these changes ♦♦ A lichenoid tissue reaction and nonspecific discontinuous granularity along the basement membrane zone are more commonly seen ♦♦ Subepidermal fibrin deposition may also be seen

Erythema Multiforme Immunopathology

♦♦ Lichenoid features can occasionally be seen in chronic graftversus-host disease ♦♦ Epidermal cytoids may also be observed ♦♦ Granular deposition of IgM along the basement membrane zone is observed in about 40% of patients with acute disease and around 85% of patients with chronic disease ♦♦ In addition, IgM and C3 can sometimes be found within dermal vessel walls

Weak Thick Linear Deposition Along the Basement Membrane Zone and Perivascular Deposition Porphyrias ♦♦ The porphyrias are a group of inherited or acquired diseases that result from deficiency in the activities of enzymes of the heme biosynthetic pathway ♦♦ The characteristic clinical appearance of each of the subtypes results from accumulation of intermediaries or their byproducts ♦♦ While the clinical appearance, course, and prognosis of the porphyrias with cutaneous manifestations varies from type to type, the microscopic and immunofluorescence are the same or very similar. The variants tend to vary by degree

Variants

♦♦ See section above

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Immunopathology

Clinical

♦♦ In addition to the characteristic features described above, clumped cytoids and shaggy deposition of fibrinogen along the basement membrane zone can also be seen

♦♦ The following discussion pertains to the porphyrias with cutaneous manifestations ♦♦ Cutaneous changes can either immediate or delayed

♦♦ Erythema multiforme is characterized by epidermal cytoid bodies and weak perivascular deposition of IgM in the superficial dermis ♦♦ Shaggy deposition of fibrinogen and cytoids in the dermis and at the dermal–epidermal junction may also be seen ♦♦ Granular deposition of IgM, C3, and fibrinogen along the dermoepidermal junction are occasionally present

Paraneoplastic Pemphigus

Aminolevulinic acid dehydratase porphyria (ALA) Acute intermittent porphyria (AIP) Congenital erythropoietic porphyria (CEP) Porphyria cutanea tarda (PCT) Hepatoerythropoietic porphyria (HEP) Hereditary coproporphyria (HCP) Variegate porphyria (VP) Erythropoietic protoporphyria (EPP) Pseudoporphyria (drug-induced) (PP)

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♦♦ An immediate reaction, as seen in EPP, includes erythema, pain, edema, and purpura ♦♦ The other types of cutaneous porphyria show delayed phototoxicity, presenting as fragility, blistering, scarring, and hypertrichosis ♦♦ Other reported clinical findings include sclerodermoid changes, alopecia, and hyperpigmentation ♦♦ In inherited homozygous PCT, abnormal enzyme levels are seen in the liver and the red blood cells ♦♦ In heterozygous PCT, where abnormal enzyme levels are expressed in the liver, disease expression usually requires a “second hit” to the liver such as concomitant infection (hepatitis or HIV), alcohol ingestion, estrogen therapy, or pregnancy ♦♦ Diagnosis and subtyping of porphyria is based in part on the clinical presentation, microscopic, and immunofluorescence. However, the porphyrin levels in the urine, stool, and red blood cells are the gold standard of diagnosis

Microscopic ♦♦ The subtypes demonstrate similar findings to varying degrees ♦♦ They are characterized by a pauci-inflammatory subepidermal separation with upward protrusion of the dermal papillae (“festooning”) (Fig. 18.101) ♦♦ There is homogeneous thickening of the blood vessels in the dermal papillae ♦♦ There is PAS positive deposition of material in and around the upper dermal blood vessels as well as along the basement membrane zone ♦♦ Actinic elastosis is usually present ♦♦ Thickening of the basement membrane zone, hyperkeratosis, acanthosis, and hypergranulosis are variably present ♦♦ Occasionally, PAS positive globules arranged in a linear fashion may be seen in the blister roof (“caterpillar bodies”) (Fig. 18.102)

Electron Microscopy ♦♦ EM shows extensive reduplication of the basal lamina of the upper dermal blood vessels and basement membrane zone ♦♦ There are widened perivascular spaces containing fibrillar material and small collagen fibrils ♦♦ In some cases there are irregular clumps of amorphous material embedded in the perivascular material ♦♦ The site of separation is the lamina lucida

Immunopathology ♦♦ Again, the subtypes demonstrate similar findings to varying degrees ♦♦ There is marked deposition of immunoglobulin and complement (IgG, IgM, C3, IgA, and fibrinogen) in and adjacent to the upper dermal blood vessels (Fig. 18.103) ♦♦ In addition, there is weak thick deposition of immunoglobulin and complement along the basement membrane zone ♦♦ In general, these changes are more pronounced in involved sun-exposed skin, and in active lesions ♦♦ EPP demonstrates changes more marked than PCT, VP or PP

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Fig. 18.101. Porphyria. subepidermal. Separation with minimal inflammation and “festooning”.

Deposition on Eosinophils and Diffuse Deposition on Connective Tissue Urticaria Clinical ♦♦ Referred to as hives or wheals, they are characterized by pruritic, erythematous or white, nonpitting edematous papules or plaques that change in size and shape over hours ♦♦ They vary in size from small papules to large plaques ♦♦ The depth of involvement varies from superficial to deep ♦♦ Episodes of urticaria are arbitrarily defined as either acute or chronic ♦♦ Chronic includes episodes persisting for longer than 6 weeks ♦♦ While the cause of acute urticaria is often established (usually food, drug, or contact), the cause of chronic urticaria is usually not identified ♦♦ There are many implicated etiologic factors and associations, including foods and food additives, medications and hormonal

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♦♦ Urticaria may be separated into a variety of subtypes based on the etiology

Clinical Subtypes ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Physical urticarias Dermatographism Pressure urticaria Cholinergic urticaria Exercise-induced urticaria Solar urticaria Cold urticaria Heat, water, and vibrational urticaria Aquagenic pruritus Angioedema Acquired angioedema Hereditary angioedema Contact urticaria Urticaria secondary to an ingested substance (food, medication or other) ♦♦ Pruritic and urticarial papules and plaques of pregnancy ♦♦ Urticarial vasculitis

Microscopic

Fig. 18.102. Porphyria. subepidermal. “Caterpillar bodies”.

♦♦ All of the subtypes of urticaria demonstrate similar histopathologic features ♦♦ Acute urticaria shows dermal interstitial edema, dilated venules with endothelial swelling and a minimal degree of inflammation, including intravascular neutrophils and perivascular lymphocytes and eosinophils ♦♦ In chronic urticaria, there is interstitial edema with a perivascular and interstitial polymorphous infiltrate of neutrophils, eosinophils, and lymphocytes, as well as intravascular neutrophils ♦♦ The deeper the clinical form of urticaria, the deeper the extension of the histopathologic findings ♦♦ Angioedema extends into the subcutaneous tissue ♦♦ Hereditary angioedema demonstrates deep dermal and subcutaneous edema with minimal accompanying inflammation

Immunopathology

Fig. 18.103. Porphyria. subepidermal. Strong deposition of IgG in and adjacent to papillary dermal blood vessels and weak thick linear deposition along the basement membrane zone. perturbations, inhaled allergens, various internal diseases and malignancies, contactants (via both immunologic and nonimmunologic mechanisms), primary skin diseases (immunobullous diseases for example), and genetic diseases

♦♦ DIF demonstrates deposition on eosinophils with IgA, and to a lesser degree with IgG, and IgM ♦♦ Fibrinogen shows diffuse deposition on the connective tissue throughout the dermis ♦♦ This pattern is nonspecific but consistent with the clinical diagnosis of urticaria

Deposition in Blood Vessels Vasculitis Immunopathology ♦♦ In general, vasculitis is characterized by intravascular deposition of immunoglobulins and complement

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♦♦ IgM is usually the predominant immunoglobulin deposited, but IgG and IgA are also seen ♦♦ Fibrinogen is often deposited in a perivascular pattern, with diffusion into the surrounding interstitial tissue ♦♦ The diagnosis of vasculitis should be reserved for specimens that show intravascular deposition with multiple immunoreactants ♦♦ Further, because vascular fluorescence can be seen nonspecifically in various inflammatory conditions, as well as in dependent locations (such as lower extremity), histopathology that is typical for vasculitis must also be present to justify the diagnosis

♦♦ Some of the clinical subtypes of vasculitis have more distinctive immunopathologic findings ♦♦ For example, Henoch–Schönlein purpura has a granular deposition of IgA in the superficial vessels that predominates over the deposition of other immunoglobulins ♦♦ Urticarial vasculitis has findings typical for urticaria in addition to immunoglobulin deposition in blood vessels ♦♦ Further, a subset of patients with urticarial vasculitis have systemic lupus erythematosus (either overt or in evolution) and demonstrate (in addition to features of urticarial vasculitis) granular deposition of IgM and other immune reactants along the basement membrane zone, typical for lupus erythematosus

TNM CLASSIFICATION OF MALIGNANT MELANOMA OF THE SKIN (2010 REVISION) ♦♦ T: Primary Tumor −− T0: No evidence of primary tumor −− Tis: Melanoma in situ (Clark Level I) −− T1: M  elanoma £1.0 mm in thickness −− T1a: M  elanoma £1.0 mm in thickness without ulceration and mitoses <1 per square mm −− T1b: Melanoma £1.0 mm in thickness with ulceration or mitoses greater than or equal (insert symbol) 1 per square mm −− T2: M  elanoma 1.01–2 mm in thickness with or without ulceration −− T2a: Melanoma 1.01–2  mm in thickness, no ulceration −− T2b: Melanoma 1.01–2  mm in thickness, with ulceration −− T3: M  elanoma 2.01–4 mm in thickness with or without ulceration −− T3a: 2.01–4 mm in thickness, no ulceration −− T3b: 2.01–4 mm in thickness, with ulceration −− T4: M  elanoma greater than 4.0 mm in thickness with or without ulceration −− T4a: Melanoma >4.0  mm in thickness, no ulceration −− T4b: Melanoma >4.0  mm in thickness, with ulceration

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♦♦ N: Regional Lymph Nodes −− NX: Regional nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Metastasis in one lymph node −− N1a: C  linically occult (microscopic) metastasis −− N1b: Clinically apparent (macroscopic) metastasis −− N2: Metastases in two to three regional nodes or intralymphatic regional metastasis without nodal metastasis −− N2a: Clinically occult (microscopic) metastasis −− N2b: Clinically apparent (macroscopic) metastasis −− N2c: S  atellite or in-transit metastasis without nodal metastasis −− N3: Metastasis in four or more regional nodes, or matted metastatic nodes, or in-transit metastasis or satellite(s) with metastasis in regional node(s) ♦♦ M: Distant Metastasis −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis −− M1a: Metastasis to skin, subcutaneous tissue or distant lymph nodes −− M1b: Metastasis to lung −− M1c: Metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehydrogenase (LDH)

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TNM Classification of cutaneous squamous cell carcinoma (cSCC) and other cutaneous carcinomas (2010 edition, AJCC) ♦♦ T: −− −− −−

Primary Tumor* T0: No evidence of primary tumor Tis: Carcinoma in situ T1:  Tumor 2 cm or less with less than two high risk features** −− T2:  Tumor greater than 2 cm or any size with two or more high risk features* −− T3: Tumor with invasion of maxilla, mandible, orbit or temporal bone −− T4:  Tumor with invasion of skeleton (axial or appendicular) or perineurial invasion of skull base

*Excludes cSCC of eyelid ** High risk features −− Depth invasion: >2 mm thickness, Clark level > or = IV, perineural invasion −− Anatomic location: Primary site ear; Primary site hairbearing lip −− Differentiation: Poorly differentiated or undifferen­tiated

♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0:  No regional lymph node metastases −− N1: Metastasis in a single ipsilateral lymph node, 3 cm or less −− N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm; or in multiple ipsilateral lymph nodes, none more than 6 cm; or in bilateral or contralateral lymph nodes, none more than 6 cm −− N2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm −−  N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm −−  N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm −− N3:  Metastasis in a lymph node more than 6 cm ♦♦ M: Distant Metastasis −− M0: No distant metastasis −− M1: Distant metastasis

TNM Classification of Merkel cell carcinoma (2010 edition, AJCC) ♦♦ T: Primary Tumor −− T0: No evidence of primary tumor (e.g. nodal/metastatic presentation without known primary) −− Tis: In situ primary tumor −− T1:  Less than or equal to 2 cm maximum tumor dimension −− T2: Greater than 2 cm but not more than 5 cm maximum tumor dimension −− T3: Greater than 5 cm maximum tumor dimension −− T4: Tumor invades bone, muscle, fascia or cartilage ♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastases −− cN0: Nodes negative by clinical exam (inspection, palpation and/or imaging)

−− pN0: Nodes negative by pathologic exam −− N1: Metastasis in regional lymph node(s) −− N1a: Micrometastasis (diagnosed after sentinel or elective lymphadenectomy) −− N1b: Macrometastasis (clinically detectable meta­stasis confirmed by lymphadenectomy or biopsy) −− N2: In transit metastasis (a tumor distinct from the primary lesion and located either between the primary lesion and draining regional lymph node, or distal to the primary lesion ♦♦ M: Distant Metastasis −− M0: No distant metastasis −− M1: Metastasis beyond regional lymph nodes −− M1a: Metastasis to skin, subcutis or distant lymph nodes −− M1b: Metastasis to lung −− M1c: Metastasis to all other visceral sites

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Suggested Reading Cutaneous Neoplasms and Developmental Anomalies Argenyi ZB. Newly recognized neural neoplasms relevant to the dermatopathologist. Dermatol Clin 1992;10:219–234. Argenyi ZB. Cutaneous neural heterotopias and related tumors relevant for the dermatopathologist. Semin Diagn Pathol 1996;13:60–71. Beltraminelli H, Leinweber B, Kerl H, Derroni L. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases. Am J Dermatopathol 2009;31:317–322. Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou C. Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol 2006;28:99–104. Cibull T, Thomas A, O’Malley D, Billings S. Myeloid leukemia cutis: a histologic and immunohistochemical review. J Cutan Pathol 2008;35:180–185.

Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilatation of preexisting vessels. J Am Acad Dermatol 1997;37:523–549. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997;37:887–919. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant ­vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol 1998;38:143–175. Singh R, Grayson W, Redston M, Diwan A, Warneke C, McKee P, Lev D, Lyle S, Calonje E, Laxar A. Site and tumor type predicts DNA ­mismatch repair status in cutaneous sebaceous neoplasia. Am J Surg Pathol 2008;32:936–942. Slater DN. The new World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol 2005;153:874–880.

Cruz DJ. Sweat gland carcinomas: a comprehensive review. Semin Diagn Pathol 1987;4:38–74.

Swanson PE, Cherwitz DL, Neumann MP, Wick MR. Eccrine sweat gland carcinoma: an histologic and immunohistochemical study of 32 cases. J Cutan Pathol 1987;14:65–86.

Fabrizi G, Pagliarello C, Prente P, Massi G. Atypical nevi of the scalp in adolescents. J Cutan Pathol 2007;34:365–369.

Tardio J. CD34-reactive tumors of the skin. An updated review of an ­ever-growing list of lesions. J Cutan Pathol 2008;35:1079–1092.

Fetsch J, Laskin W, Hallman J, Lupton G, Miettinen M. Neurothekeoma: an analysis of 178 tumors with detailed immunohistochemical data and longterm patient follow-up information. Am J Surg Pathol 2007;31:1103–1114.

Walsh N, Crotty K, Palmer A, McCarthy S. Spitz nevus versus spitzoid malignant melanoma: an evaluation of the current distinguishing ­histopathologic criteria. Hum Pathol 1998;29:1105–1112.

González SB. Histopathologic diagnosis of pigmented lesions of the skin. Pathol Res Pract 1991;187:387–431.

Wick MR, Goellner JR, Wolfe JT III, Su WPD. Adnexal carcinomas of the skin, I: eccrine carcinomas. Cancer 1985;56:1147–1162.

Groben P, Harvell J, White W. Epithelioid blue nevus: neoplasm or Sui generis or variation on a theme? Am J Dermatopathol 2000;22:473–488.

Wick MR, Goellner JR, Wolfe JT III, Su WPD. Adnexal carcinomas of the skin, II: extraocular sebaceous carcinomas. Cancer 1985;56:1163–1172.

Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, Zackheim H, Duvic M, Estrach T, Lamberg S, Wood G, Drummer R, Ranki A, Burg G, Heald P, Pittelkow M, Bernengo M, Sterrry W, Laroche L, Trautinger F, Whittaker S. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1713–1722.

Willemze R, Jaffe E, Burg G, Cerroni L, Berti E, Swerdlow S, Ralfkiaer E, Chimenti S, Diaz-Perez J, Duncan L, Grange F, Harris N, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpinelli N, Sander C, Santucci M, Sterry W, Vermeer M, Weschsler J, Whittaker S. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768–3785.

Massa M, Medenica M. Cutaneous adnexal tumors and cysts: a review. II. Tumors with apocrine and eccrine glandular differentiation and miscellaneous cutaneous cysts. Pathol Annu 1987;22:225–276. Massone C, El-Shabrawi-Caelen L, Kerl H, Cerroni L. The morphologic spectrum of primary cutaneous anaplastic large T-cell lymphoma: a ­histopathologic study on 66 biopsy specimens from 47 patients with report of rare variants. J Cutan Pathol 2008;35:46–53. Mentzel T, Kutzner H. Dermatomyofibroma: clinicopathologic and immunohistochemical analysis of 56 cases and reappraisal of a rare and distinct cutaneous neoplasm. Am J Dermatopathol 2009;31:44–49. Plaza J, Torres-Cabala C, Evans H, Diwan A, Prieto V. Immu­ nohistochemical expression of S100A6 in cellular neurothekeoma: clinicopathologic and immunohistochemical analysis of 31 cases. Am J Dermatopathol 2009;31:419–422. Reichard K, Burks E, Foucar K, Wilson C, Viswanatha D, Hozier J, Larson R. CD4(+) CD56(+) lineage-negative malignancies are rare tumors of plasmacytoid dendritic cells. Am J Surg Pathol 2005;29:1274–1283. Requena C, Requena L, Kutzner H, Yus E. Spitz nevus: a clinicopathologic study of 349 cases. Am J Dermatopathol 2009;31:107–116.

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Zelger BWH, Sidoroff A, Orchard G, Cerio R. Non-Langerhans cell ­histiocytoses. Am J Dermatopathol 1996;18:490–504.

Immunodermatology Abell E, Presbury DG, Marks R, et  al. The diagnostic significance of immunoglobulin and fibrin deposition in lichen planus. Br J Dermatol 1975;93:17–24. David-Bajar KM, Bennion SD, DeSpain JD, et al. Clinical, histologic and immunofluorescent distinctions between subacute cutaneous lupus ­erythemaatosus and discoid lupus erythematosus. J Invest Dermatol 1992;99:251–257. Gammon WR, Briggaman RA, Woodley DT, et al. Epidermolysis bullosa acquisita: a pemphigoid-like disease. J Am Acad Dermatol 1984;11: 820–832. Gately LE, Nesbitt LT. Update on immunofluorescent testing in bullous diseases and lupus erythematosus. Dermatol Clin 1994;1:133–142. Jones RR, Bhogal B, Dash A, et al. Urticaria and vasculitis: a ­continuum of histological and immunopathological changes. Br J Dermatol 1983;108:695–703. Korman NJ. Pemphigus. Immunodermatology 1990;8:689–700.

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Leonard JN, Tucker WFG, Fry JS, et  al. Increased incidence of ­malignancy in dermatitis herpetiformis. Br J Med 1983;286:16–18. Logan RA, Bhogal B, Das AK, et al. Localization of bullous pemphigoid antigen: an indirect immunofluorescence study of 228 cases using a ­split-skin technique. Br J Dermatol 1987;117:471–478. Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic pemphigus. Dermatol Clin 1993;11:473–481. Olansky AJ, Briggaman RA, Gammon WR, et al. Bullous systemic lupus erythematosus. J Am Acad Dermatol 1982;7:511–520. Person JR, Rogers RS III. Bullous and cicatricial pemphigoid: clinical, histologic, pathogenic and immunopathological correlations. Mayo Clin Proc 1977;52:54–66.

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Peters MS, Rogers RS III. Clinical correlations of IgA deposition at the cutaneous basement membrane zone. J Am Acad Dermatol 1989;20:761–770. Schroeter AL, Copeman PWM, Hordon RE, et al. Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol 1971;104:254–259. Shornick JK. Herpes gestationis. Dermatol Clin 1993;11:527–533. Zone JJ, Taylor TB, Meyer LJ. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990;85:812.

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19 Nonneoplastic Skin Diseases Steven D. Billings, md and Antoinette F. Hood, md

Contents

I. General Concepts..............................19-3 IV. Interface Dermatitis...........................19-9 Pattern Recognition..........................................19-3 Principle Patterns.............................................19-3 Epidermal Changes Predominant.........19-3 Dermal Changes Predominant..............19-3 Panniculitis..............................................19-3 Alopecia...................................................19-3

II. Spongiotic Dermatitis........................19-4 Eczematous Dermatitis....................................19-4 Contact Dermatitis.................................19-4 Atopic Dermatitis....................................19-5 Pompholyx (Dyshidrotic Eczema).........19-5 Nummular Dermatitis (Nummular Eczema)...............................................19-5 “Id” Reaction..........................................19-5 Eczematous Drug Reaction....................19-5 Vesicular Dermatophytosis..............................19-5 Pityriasis Rosea.................................................19-5 Seborrheic Dermatitis......................................19-6 Stasis Dermatitis...............................................19-6

III. Psoriasiform Dermatitis.....................19-6 Psoriasis Vulgaris.............................................19-6 Psoriasis Variants.............................................19-7 Pustular Psoriasis...................................19-7 Guttate Psoriasis.....................................19-7 Pityriasis Rubra Pilaris....................................19-8 Lichen Simplex Chronicus/Prurigo Nodularis......................................................19-8 Secondary Syphilis...........................................19-9 Dermatophytosis...............................................19-9

Interface Dermatitis with Associated Perivascular Infiltrate...............................19-10 Erythema Multiforme............................... 19-10 Toxic Epidermal Necrolysis.................19-10 Lupus Erythematosus..........................19-10 Dermatomyositis...................................19-11 Graft vs. Host Disease..........................19-12 Morbilliform Drug Eruption...............19-12 Viral Exanthem.....................................19-13 Interface Dermatitis with Lichenoid (Band-like) Infiltrate.................................19-13 Lichen Planus........................................19-13 Lichenoid Drug Eruption.....................19-13 Fixed Drug Eruption............................19-14

V. Superficial Perivascular Dermatitis........................................19-14 Morbilliform Drug Eruption.........................19-14 Postinflammatory Pigment Alteration.........19-14 Progressive Pigmented Purpuric Eruption (Schamberg Disease).................19-14 Urticaria..........................................................19-15 Urticaria Pigmentosa (Mastocytosis)............19-15

VI. Superficial and Deep Perivascular Dermatitis........................................19-16 Lupus Erythematosus ...................................19-16 Acute Neutrophilic Dermatosis (Sweet Syndrome)......................................19-16 Pityriasis Lichenoides et Varioliformis Acuta (PLEVA)..........................................19-16

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_19, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Lymphomatoid Papulosis..............................19-17 Arthropod Bite Reaction...............................19-17

VII. Interstitial Pattern............................19-18 Palisading Granulomatous Dermatitis.........19-18 Granuloma Annulare...........................19-18 Necrobiosis Lipoidica...........................19-18 Rheumatoid Nodule..............................19-18 Nodular or Diffuse Infiltrates........................19-19 Cutaneous Lymphoid Hyperplasia (Lymphocytoma Cutis)....................19-19 Eosinophilic Cellulitis (Wells Syndrome)........................................19-19 Mastocytosis..........................................19-20

VIII. Sclerosing Dermatoses.....................19-20 Scleroderma....................................................19-20 Morphea..........................................................19-20 Lichen Sclerosus.............................................19-20

IX. Panniculitis......................................19-21 Erythema Nodosum.......................................19-21 Lipodermatosclerosis (Lipomembranous Panniculitis, Sclerosing Panniculitis).............................19-21 Subcutaneous Morphea (Morphea Profundus)..................................................19-22

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Nodular Vasculitis (Erythema Induratum).................................................19-22 Lupus Panniculitis (Lupus Profundus)........19-22 Polyarteritis Nodosa.......................................19-23 Superficial Thrombophlebitis.......................19-23

X. Alopecia...........................................19-23 Nonscarring Alopecia.....................................19-23 Telogen Effluvium.................................19-23 Androgenetic Alopecia.........................19-24 Alopecia Areata....................................19-24 Trichotillomania...................................19-24 Scarring Alopecia...........................................19-24 Lupus Erythematosus .........................19-24 Lichen Planopilaris...............................19-25 Follicular Degeneration Syndrome (Central Centrifugal Scarring Alopecia)...........................................19-25 Dissecting Cellulitis..............................19-25 Acne Keloidalis Nuchae........................19-25 Folliculitis Decalvans............................19-26 End-stage Scarring Alopecia...............19-26

XI. Suggested Reading...........................19-26

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19-3

General Concepts Pattern Recognition

Superficial Perivascular

♦♦ The skin has limited ways to react to a variety of inflammatory conditions. The reactions have been defined by a variety of reproducible patterns ♦♦ The reaction pattern helps define diagnostic categories and differential diagnoses ♦♦ In a given biopsy, features of more than one reaction pattern may be present. The predominant pattern helps define which diagnostic category should be used ♦♦ As a caveat, inflammatory diseases are dynamic in their evolution. The reaction pattern can change over time. Therefore some diseases may be associated with more than one reaction pattern

♦♦ The inflammatory infiltrate is concentrated around blood vessels in the upper dermis; there is little to no epidermal change

Superficial and Deep Perivascular ♦♦ The inflammatory infiltrate is also seen around dermal blood vessels in the lower half of the dermis

Interstitial Infiltrate ♦♦ The infiltrate is not concentrated around blood vessels but intercalates between collagen fibers of the dermis. Some perivascular inflammation is almost invariably present, but it is less prominent ♦♦ Subtypes in this group include the nodular, diffuse and ­palisading granulomatous patterns

Principle Patterns

Sclerosing Dermatitis

♦♦ The reaction patterns discussed in this chapter can be broadly divided into four categories

♦♦ The patterns in this group are defined by changes in the epidermis

♦♦ Sclerotic changes in the dermal collagen are the most prominent finding ♦♦ The degree of an associated inflammatory infiltrate is variable. Usually the inflammatory infiltrate is most prominent in the early phases of the disease process before the sclerosing changes are fully manifest

Spongiotic Pattern

Panniculitis

♦♦ Characterized by intraepidermal edema (spongiosis)

♦♦ There is considerable overlap in spongiotic and psoriasiform dermatitis. Many cases of spongiotic dermatitis also have a component of acanthosis resulting in combination of spongiotic and psoriasiform reaction patterns

♦♦ Panniculitis often causes diagnostic difficulty and confusion. Almost all cases of panniculitis show overlapping features of both the septal and lobular patterns. The predominant pattern present helps define the reaction pattern category −− Septal panniculitis: The process predominantly involves the subcutaneous septae with associated inflammation and fibrosis. Involvement of the lobule tends to be at the periphery rather than the central zone of the subcutaneous lobule −− Lobular panniculitis: The process predominantly involves the central region of the subcutaneous lobules

Interface Pattern

Alopecia

♦♦ Epidermal damage caused by underlying inflammatory infiltrate in the dermis results in vacuolization of the basal layer and dyskeratotic (necrotic/apoptotic) keratinocytes. Interface dermatitis is further subdivided by the pattern of the inflammatory infiltrate, either lichenoid (band-like), or perivascular

♦♦ The patterns of alopecia are divided by the presence of inflammation and scarring −− Noninflammatory, nonscarring: Little to no inflammation or associated dermal fibrosis −− Noninflammatory, scarring: Dermal fibrosis but little inflammation −− Inflammatory, scarring: Significant scarring and inflam­ mation −− End-stage scarring alopecia: In end-stage scarring alopecia there is prominent fibrosis with few if any remaining follicles and a variable inflammatory infiltrate. Due to the paucity of residual follicles, it is often not possible to definitively categorize the process

Epidermal Changes Predominant

Psoriasiform Pattern ♦♦ Characterized by epidermal hyperplasia (acanthosis) with elongation of the rete ridges

Mixed Spongiotic and Psoriasiform

Dermal Changes Predominant ♦♦ The patterns in this group lack significant change in the overlying epidermis. They are subdivided by the distribution and pattern of the dermal inflammatory infiltrate. There is often considerable overlap in the patterns in this group, and one needs to look for the predominant pattern present in a given biopsy specimen

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Spongiotic Dermatitis ♦♦ Spongiotic dermatitis is one of the most common patterns encountered. It can be subdivided into three histologic subtypes, but it important to recognize that these subtypes exist along a continuous spectrum rather than as discrete entities. Overlap is to be expected. The patterns are largely subdivided based upon the epidermal changes ♦♦ Histologic subtypes −− Acute spongiotic dermatitis (Fig. 19.1) (a) In acute spongiotic dermatitis, the epidermis retains its normal “basket-weave” stratum corneum. The epidermis also has pale keratinocytes and spongiosis with or without spongiotic microvesicles (b) In the dermis, there is papillary dermal edema and a superficial perivascular inflammatory infiltrate that is predominantly lymphocytic but often has admixed eosinophils −− Subacute spongiotic dermatitis (Fig. 19.2) (a) In subacute spongiotic dermatitis, the epidermis has parakeratosis, acanthosis, a diminished granular layer, and spongiosis (b) The findings in the dermis are similar to acute spongiotic dermatitis but usually with less edema −− Chronic spongiotic dermatitis (Fig. 19.3) (a) In chronic spongiotic dermatitis, the epidermis has acanthosis, hyperkeratosis, parakeratosis, an irregular granular layer, and only minimal to mild spongiosis (b) In the dermis, the papillary dermis may become fibrotic and there is a variable perivascular inflammatory infiltrate

Eczematous Dermatitis ♦♦ Eczematous dermatitis is a clinical term that describes a papular to vesicular erythematous rash. Distinct etiologies are not always apparent, but some have an identifiable cause (e.g. contact dermatitis). All have essentially indistinguishable histologic features, and may have features of acute, subacute, or chronic spongiotic dermatitis. Correlation with the clinical presentation is necessary. The most common entities in the differential diagnosis of eczematous dermatitis are discussed below

Fig.  19.1. Acute spongiotic dermatitis with spongiotic microvesicles.

Fig. 19.2. Subacute spongiotic dermatitis.

Contact Dermatitis Allergic Contact Dermatitis Clinical ♦♦ Allergic contact dermatitis presents as pruritic erythematous papules and vesicles ♦♦ It is secondary to a type IV delayed hypersensitivity reaction ♦♦ Example: poison ivy

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Fig. 19.3. Chronic spongiotic dermatitis.

Nonneoplastic Skin Diseases

Microscopic ♦♦ The microscopic findings are those of typical spongiotic dermatitis ♦♦ Spongiotic microvesicles are a frequent finding, especially early in the course ♦♦ The presence of collections of Langerhans cells in the epidermis, also called Langerhans cell microabscesses, is suggestive of an allergic contact dermatitis ♦♦ In the dermis, there is a predominantly perivascular lymphocytic infiltrate with variable numbers of eosinophils

Irritant Contact Dermatitis Clinical ♦♦ Irritant contact dermatitis presents as erythematous papules and vesicles ♦♦ It is secondary to a direct irritant effect of an offending agent ♦♦ Example: diaper rash

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Nummular Dermatitis (Nummular Eczema) Clinical ♦♦ Nummular dermatitis presents as round to oval pruritic patches or plaques, usually involving the extremities

Microscopic ♦♦ Biopsies from early lesions show acute to subacute spongiotic dermatitis ♦♦ Biopsies from older lesions demonstrate chronic spongiotic dermatitis that may resemble psoriasis but with retention of granular layer, normal suprapapillary plate thickness and hyperkeratosis (see psoriasis below)

“Id” Reaction Clinical ♦♦ This is an acute dermatitis that develops distal to a primary inflammatory focus ♦♦ The primary inflammatory lesion is frequently tinea pedis or impetiginized stasis dermatitis

Microscopic

Microscopic

♦♦ There are subtle differences from allergic contact dermatitis ♦♦ There is ballooning degeneration of keratinocytes and focal necrotic keratinocytes ♦♦ In severe cases there may be necrosis of the upper portion of the epidermis ♦♦ The inflammatory infiltrate is typically mild in nature

♦♦ Biopsies demonstrate typical spongiotic dermatitis

Atopic Dermatitis Clinical ♦♦ Atopic dermatitis is characterized by a chronic, pruritic, relapsing papular dermatitis ♦♦ It is associated with history of asthma, and allergic rhinitis (atopy) ♦♦ There is a predilection for flexural areas, especially in children

Microscopic ♦♦ Biopsies typically demonstrate subacute to chronic spongiotic dermatitis

Pompholyx (Dyshidrotic Eczema) Clinical ♦♦ This is characterized by a symmetric vesicular eruption involving the hands and/or feet

Eczematous Drug Reaction Clinical ♦♦ Approximately 5-10% of drug reactions may be eczematous in nature

Microscopic ♦♦ Biopsies from eczematous drug eruptions demonstrate spongiotic dermatitis ♦♦ Eosinophils may be more prominent in eczematous drug eruptions, but this is not specific

Vesicular Dermatophytosis Clinical ♦♦ Vesicular dermatophytosis usually presents on the feet and resembles pompholyx (see above)

Microscopic ♦♦ The biopsy demonstrates spongiotic dermatitis and the presence of neutrophils in epidermis and/or stratum corneum ♦♦ In the dermis eosinophils are usually conspicuous ♦♦ PAS or GMS stains highlight the fungal hyphae in the stratum corneum

Microscopic

Pityriasis Rosea Clinical

♦♦ Biopsies typically demonstrate subacute to chronic spongiotic dermatitis ♦♦ Spongiotic microvesicles are common ♦♦ There may be features of either allergic contact or irritant contact dermatitis

♦♦ Pityriasis rosea usually presents in young adults as relatively asymptomatic patches and plaques ♦♦ It usually starts as a single round to oval salmon-colored ­herald patch that subsequently develops into a widespread, symmetric eruption on trunk that follows skin lines

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Fig. 19.4. Pityriasis rosea.

Fig. 19.5. Stasis dermatitis.

Microscopic (Fig. 19.4) ♦♦ Microscopically it resembles subacute spongiotic dermatitis with discrete mounds of parakeratosis and rare scattered dyskeratotic keratinocytes ♦♦ In the dermis there is a mild to moderate mononuclear cell infiltrate often with some extravasation of erythrocytes in papillary dermis

Seborrheic Dermatitis Clinical ♦♦ Seborrheic dermatitis affects the scalp (dandruff), ears, midface, upper chest ♦♦ Lesions present as erythematous patches with greasy, yellow scale ♦♦ In AIDS patients and patients with neurologic disorders, it can be severe

Microscopic ♦♦ It is rarely biopsied, but biopsies usually show features of subacute or chronic spongiotic dermatitis

♦♦ A clue to the diagnosis is the presence of parakeratotic mounds, often with neutrophils, around follicular ostia

Stasis Dermatitis Clinical ♦♦ Stasis dermatitis presents as an eczematous dermatitis of the lower extremities associated with underlying venous insufficiency ♦♦ The patient may also have associated venous stasis ulcers

Microscopic (Fig. 19.5) ♦♦ Biopsies demonstrate findings of subacute to chronic spongiotic dermatitis ♦♦ There is usually significant acanthosis of the epidermis ♦♦ The key histologic feature is the presence of lobular hyperplasia of superficial dermal blood vessels that is frequently accompanied by a mild perivascular lymphocytic infiltrate, extravasated erythrocytes, and siderophages ♦♦ Over time, the dermis becomes fibrotic

Psoriasiform Dermatitis ♦♦ Diseases associated with this pattern are characterized by epidermal acanthosis defined by elongation and widening of rete pegs

Psoriasis Vulgaris Clinical ♦♦ Psoriasis vulgaris usually presents in second to third decades as erythematous plaques with silvery scale on extensor surfaces, scalp, gluteal cleft, and glans penis

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♦♦ Nail findings including pitting and yellow discoloration are a frequent clinical finding ♦♦ Psoriatic arthritis is present in 1–5% of patients, generally in patients with severe cutaneous disease

Microscopic (Fig. 19.6) ♦♦ Psoriasis vulgaris is characterized by uniform acanthosis with elongated rete ridges and prominent parakeratosis ♦♦ The granular layer is absent or diminished

Nonneoplastic Skin Diseases

Fig. 19.6. Psoriasis vulgaris.

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Fig. 19.7. Pustular psoriasis.

♦♦ There are collections of neutrophils in stratum corneum (Munro microabcesses) and/or epidermis (pustules of Kogoj) ♦♦ Other findings include suprapapillary plate thinning and dilated, tortuous papillary dermal blood vessels ♦♦ Within the dermis there is a superficial perivascular lymphocytic infiltrate that may contain neutrophils ♦♦ Eosinophils are not present in the dermal infiltrate of psoriasis and their presence is against the diagnosis

Differential Diagnosis ♦♦ Includes nummular dermatitis, contact dermatitis, seborrheic dermatitis, and pityriasis rubra pilaris. In the first two considerations, the epidermis shows more irregular acanthosis, more spongiosis and often has eosinophils as part of the infiltrate. In seborrheic dermatitis, the clinical presentation differs and the parakeratosis with neutrophils is usually restricted to follicular ostia, but there are cases of so-called sebopsoriasis in which the clinical and histologic overlap precludes distinction. Pityriasis rubra pilaris may show a similar pattern of acanthosis but lacks neutrophils and has a granular layer

Psoriasis Variants Pustular Psoriasis Clinical ♦♦ Pustular psoriasis may be associated with pregnancy or discontinuation of systemic steroids in patients with known psoriasis ♦♦ The lesions are characterized by the acute onset of sterile pustules rather than large erythematous plaques

Microscopic (Fig. 19.7) ♦♦ Biopsy findings are characterized by large unilocular pustules in the stratum corneum/epidermis ♦♦ Because of the rapid nature of the onset, the epidermis has an intact or slightly diminished granular layer and has less prominent acanthosis

Fig. 19.8. Guttate psoriasis.

Differential Diagnosis ♦♦ Includes candidiasis, eczematous dermatitis with secondary impetiginization, and Reiter syndrome. In the first two considerations there is more spongiosis and usually eosinophils. Reiter syndrome is histologically indistinguishable and needs to be differentiated on clinical grounds

Guttate Psoriasis Clinical ♦♦ Guttate psoriasis is frequently associated with an antecedent streptococcal pharyngitis ♦♦ It is characterized by the rapid onset of widespread small scaly plaques

Microscopic (Fig. 19.8) ♦♦ Characterized by minimal acanthosis, a diminished granular layer, and focal mounds of parakeratosis with neutrophils

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Differential Diagnosis ♦♦ Includes pityriasis rosea and members of the eczematous dermatitis group of disorders. Pityriasis rosea lacks collections of neutrophils. Eczematous dermatitides have more spongiosis and frequently have some eosinophils as part of the inflammatory infiltrate

Pityriasis Rubra Pilaris Clinical ♦♦ Pityriasis rubra pilaris is characterized by hyperkeratotic perifollicular papules with surrounding yellow-orange erythema, islands of uninvolved skin and palmar, and/or plantar keratoderma

Microscopic (Fig. 19.9) ♦♦ The quintessential features are diffuse hyperkeratosis alternating with parakeratosis both vertically and horizontally in a so-called checkerboard pattern ♦♦ The epidermis also has acanthosis very similar to psoriasis vulgaris ♦♦ The granular layer is intact ♦♦ There is no suprapapillary thinning or collections of neutrophils in the epidermis ♦♦ In the dermis there is a mild lymphohistiocytic, superficial perivascular infiltrate

Differential Diagnosis ♦♦ Psoriasis: Psoriasis has neutrophils in the stratum corneum and a diminished granular layer ♦♦ Chronic spongiotic dermatitis: Chronic spongiotic dermatitis has less uniform acanthosis and lacks the checkerboard pattern of alternating parakeratosis and hyperkeratosis −− Subacute and chronic eczematous dermatitis −− Acanthosis is often a prominent feature in later-stage lesions of spongiotic dermatitis. Therefore, it could be

Fig.  19.9. Pityriasis rubra pilaris demonstrating the checkerboard pattern of parakeratosis.

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considered to also overlap with the psoriasiform dermatitis pattern (see Spongiotic Dermatitis above)

Lichen Simplex Chronicus/Prurigo Nodularis Clinical ♦♦ These two entities are considered a spectrum of the same disease with different clinical presentations ♦♦ Lichen simplex chronicus presents as pruritic, lichenified, indurated plaques ♦♦ Prurigo nodularis presents as pruritic nodules ♦♦ The lesions are related to repetitive rubbing/scratching ♦♦ Lesions occur only in areas that can be reached and scratched such as the posterior scalp, extremities, and genitalia ♦♦ Features of lichen simplex chronicus may be seen as a secondary superimposed process on a preexisting dermatitis such as an eczematous dermatitis

Microscopic (Fig. 19.10) ♦♦ There is prominent compact hyperkeratosis and a thickened granular layer that resembles acral skin ♦♦ The epidermal acanthosis may have a pseudoepitheliomatous pattern, the latter feature being more common in prurigo nodularis ♦♦ Vertical fibrosis of papillary dermis is a ­characteristic feature ♦♦ A mild superficial perivascular lymphocytic ­infiltrate is present

Differential Diagnosis ♦♦ Psoriasis: Psoriasis lacks a thickened granular layer and contains neutrophils in the stratum corneum/epidermis ♦♦ Lichen planus: Lichen planus has hyperkeratosis and a thickened granular layer but has a prominent lichenoid inflammatory infiltrate with interface change ♦♦ Verruca vulgaris: Verruca vulgaris has a papillomatous, koilocytic cells, and dilated blood vessels in the dermis without vertical fibrosis of the papillary dermis ♦♦ Chronic spongiotic dermatitis: Late-stage chronic spongiotic dermatitis may show similar epidermal features of

Fig. 19.10. Prurigo nodule.

Nonneoplastic Skin Diseases

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hyperkeratosis, a thickened granular layer and acanthosis, but usually has a more prominent inflammatory infiltrate and does not have vertical fibrosis of the papillary dermis. Chronic spongiotic dermatitis, however, can have superimposed features of lichen simplex chronicus in longstanding lesions ♦♦ Squamous cell carcinoma: The pseudoepitheliomatous hyperplasia seen in some cases of prurigo nodularis can be mistaken for a well-differentiated squamous cell carcinoma. The presence of nuclear atypia, atypical mitotic figures, adjacent actinic keratosis/squamous cell carcinoma in situ and true desmoplasia allows differentiation

Secondary Syphilis Clinical

Dermatophytosis Clinical ♦♦ Dermatophyte infections classically present as annular scaly plaques with central clearing, usually on the trunk ♦♦ On the feet, there may be confluent erythema with scale in a moccasin distribution, interdigital ­maceration, and nail alterations ♦♦ Lesions that are biopsied frequently do not have classic clinical presentations because they have been altered by topical therapy. The possibility of dermatophyte infection should always be considered in any “rash” that is not responsive to topical corticosteroids

Microscopic (Fig. 19.11)

♦♦ Lesions of secondary syphilis usually present as nonpruritic macules or papules involving trunk, extremities, palms, and soles

Microscopic ♦♦ The epidermis shows parakeratosis and psoriasiform hyperplasia ♦♦ Within the dermis there is a lichenoid or superficial and deep perivascular lymphocytic infiltrate that usually contains plasma cells ♦♦ Organisms can be visualized with a Warthin–Starry stain or immunohistochemical stains (the latter is superior)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Neutrophils in stratum corneum Parakeratosis Acanthosis +/− spongiosis Hyphae in stratum corneum (often only visualized with PAS or GMS stains)

Differential Diagnosis ♦♦ Psoriasis, spongiotic dermatitis

Differential Diagnosis ♦♦ Psoriasis: Cutaneous lesions of secondary syphilis lack neutrophils and have significant numbers of plasma cells ♦♦ Lichen planus: Secondary syphilis can rarely ­present as a lichenoid variant. Lichen planus ­typically does not contain plasma cells and has wedge-shaped hypergranulosis and interface d­ amage ♦♦ Chronic spongiotic dermatitis: There can be ­significant overlap. A deep perivascular component and plasma cells help distinguish secondary syphilis ♦♦ Pityriasis rosea: Secondary syphilis does not ­typically have the discrete parakeratotic mounds and has a denser infiltrate with plasma cells ♦♦ Mycosis fungoides: Mycosis fungoides has collections of atypical cerebriform lymphocytes in the epidermis and haloed lymphocytes. Plasma cells are not typically present in mycosis fungoides

Fig. 19.11. PAS stain demonstrating fungal hyphae in stratum corneum.

Interface Dermatitis ♦♦ Diseases associated with this pattern are characterized by epidermal basal vacuolization, dyskeratotic cells, and dermal

inflammation that is either perivascular or band-like in distribution

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Fig. 19.12. Erythema multiforme.

Interface Dermatitis with Associated Perivascular Infiltrate Erythema Multiforme Clinical ♦♦ Erythema multiforme is a self-limiting episodic eruption characterized by erythematous macules, papules and targetoid lesions ♦♦ It usually presents on extensor surfaces, palms, soles, and oral mucosa ♦♦ It can be clinically divided into minor ­(erythema multiforme) and major (Stevens–Johnson syndrome) forms based on extent of mucosal involvement ♦♦ It is associated with HSV and Mycoplasma infection and drugs (esp. sulfonamides)

Microscopic (Fig. 19.12) ♦♦ The epidermis has a normal basket-weave ­stratum corneum with variable spongiosis ♦♦ Within the epidermis there are scattered to confluent dyskeratotic cells at all levels of the epidermis ♦♦ There is interface change characterized by basal vacuolization ♦♦ Within the dermis there is a mild superficial perivascular lymphohistiocytic infiltrate with exocytosis of lymphocytes into epidermis. Eosinophils can sometimes be present ♦♦ In older and severe lesions epidermal necrosis can be seen

Differential Diagnosis ♦♦ Morbilliform drug eruption: There is significant histologic overlap, but the degree of epidermal damage is more pronounced in erythema ­multiforme ♦♦ Viral exanthem: Similar to drug eruptions, the degree of epidermal damage is more pronounced in erythema multiforme ♦♦ Dermatomyositis and lupus erythematosus: In these chronic diseases there is often hyperkeratosis, parakeratosis, and basement membrane thickening, unlike in erythema multiforme. Usually there are more dyskeratotic cells in erythema multiforme. Increased dermal mucin, a feature of

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Fig. 19.13. Toxic epidermal necrolysis. both dermatomyositis and lupus erythematosus, is not seen in erythema multiforme ♦♦ Toxic epidermal necrolysis: The distinction of toxic epidermal necrolysis from erythema multiforme is primarily based on clinical findings, though there is often more prominent epidermal damage, with full thickness necrosis, in toxic ­epidermal necrolysis

Toxic Epidermal Necrolysis Clinical ♦♦ Toxic epidermal necrolysis presents as a ­widespread tender macular erythematous e­ ruption with vesicles and bullae ♦♦ The lesions exhibit Nikolsky sign (epithelial detachment with mild pressure) ♦♦ It is often associated with medications ♦♦ It has a mortality of 25–50%

Microscopic (Fig. 19.13) ♦♦ The histologic features are similar to erythema multiforme (see above). Often the degree of epidermal damage is more pronounced than in erythema multiforme

Differential Diagnosis ♦♦ Erythema multiforme: As mentioned above the distinction is primarily clinical ♦♦ Fixed drug eruption: There is less epidermal damage, a denser inflammatory infiltrate with more eosinophils, and frequently melanophages. The clinical presentation as a solitary lesion or limited to a single geographic area is different ♦♦ Morbilliform drug eruption: There is less ­epidermal damage and clinically the disorders look different

Lupus Erythematosus Clinical ♦♦ Cutaneous lupus erythematosus presents in three different forms

Nonneoplastic Skin Diseases

−− Chronic (discoid): Well-demarcated scaly plaques, erythematous to hyperpigmented, ­usually on head; most patients have disease ­limited to skin −− Subacute: Scaly erythematous, often annular plaques on upper trunk, extensor surfaces of arms; positive ANA 75% (cytoplasmic Ro and La) −− Acute: Associated with systemic lupus erythematosus; erythematous lesions, malar rash; positive ANA and antiDNA antibodies

Microscopic (Figs. 19.14 and 19.15) ♦♦ There is significant histologic overlap between the different subtypes of lupus erythematosus −− Common features include basal vacuolization, a perivascular and variable periadnexal mononuclear cell infiltrate, and increased dermal mucin −− Epidermal changes can also include hyperkeratosis, parakeratosis, atrophy, follicular plugging, basement membrane thickening, and focal ­dyskeratotic keratinocytes

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−− Differentiating histologic subtypes is often dependent on the clinical presentation (see above), though the discoid subtype is more histologically distinct with a denser and deeper infiltrate and more prominent epidermal changes

Differential Diagnosis ♦♦ Dermatomyositis: Dermatomyositis tends to have a milder infiltrate, but otherwise closely resembles lupus erythematosus. Distinction requires clinical information ♦♦ Erythema multiforme: Erythema multiforme lacks many of the epidermal changes seen in lupus erythematosus (e.g., hyperkeratosis, basement membrane thickening), lacks dermal mucin and usually has more dyskeratotic keratinocytes ♦♦ Lichen planus: Lichen planus has characteristic thickening of the granular layer and a dense band-like infiltrate along the dermal–epidermal junction. It lacks dermal mucin and a deeper inflammatory component

Dermatomyositis Clinical ♦♦ This is classically a systemic disease with muscle weakness, heliotrope periorbital discoloration, violaceous rash on face and neck, periungual erythema, and Gottron papules on hands. Not infrequently patients may have cutaneous findings without reported muscle weakness

Microscopic (Fig. 19.16) ♦♦ There is interface change characterized by basal vacuolization ♦♦ There may be hyperkeratosis and/or parakeratosis and focal dyskeratotic keratinocytes ♦♦ Within the dermis there is a mild, superficial perivascular mononuclear cell infiltrate and increased dermal mucin

Differential Diagnosis

Fig. 19.14. Lupus erythematosus.

Fig. 19.15. Prominent interface change in lupus erythematosus.

♦♦ Lupus erythematosus: In dermatomyositis the infiltrate is milder than in most cases of lupus erythematosus, but knowledge of the clinical presentation is required to ­confidently distinguish dermatomyositis from lupus erythematosus ♦♦ Graft vs. host disease: The clinical setting is distinctly different. Graft vs. host disease lacks dermal mucin

Fig. 19.16. Dermatomyositis.

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Graft vs. Host Disease Clinical ♦♦ Acute: The acute form usually presents 2–4 weeks after bone marrow transplant. Late onset acute graft vs. host disease can occur with donor lymphocyte reinfusion ♦♦ It presents as macular erythema on trunk, neck, hands, and feet. Occasionally there may be b­ listers ♦♦ Chronic: This form usually presents months to years after bone marrow transplant. There are two forms: lichenoid and sclerodermoid −− Lichenoid chronic graft vs. host disease: this form presents as violaceous papules and plaques on extremities, palms, and soles; mucosal involvement is frequent −− Sclerodermoid chronic graft vs. host disease: this form presents as widespread dermal sclerosis

Microscopic ♦♦ Acute (Fig. 19.17) −− Acute graft vs. host disease is graded according to the following criteria −− Grade 1: Basal vacuolization, mild superficial perivascular lymphocytic infiltrate −− Grade 2: Basal vacuolization with dyskeratotic keratinocytes, excocytosis of lymphocytes, mild superficial perivascular lymphocytic infiltrate −− Grade 3: Same as grade 2 but with cleft formation between dermis and epidermis −− Grade 4: Same as grade 3 but with complete separation of epidermis and dermis ♦♦ Chronic −− Lichenoid: The epidermis is hyperkeratotic with a thickened granular layer. There is interface change with basal vacuolization and dyskeratotic keratinocytes. The dermal infiltrate is usually mild with a superficial perivascular to lichenoid pattern

Fig. 19.17. Acute graft vs. host disease.

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−− Sclerodermoid: The epidermis may be atrophic but there is no active interface change. The dermis is sclerotic with decreased space between the collagen bundles

Differential Diagnosis ♦♦ Acute −− Drug eruption: Distinction may not be ­possible on histologic grounds alone. Both drug eruptions and graft vs. host disease may have eosinophils. The degree of ­epidermal damage is usually more pronounced in graft vs. host disease, but this is not a consistent finding. From a practical perspective, bone marrow transplant patients often do not have a sufficiently robust immune system to mount a drug eruption −− Viral exanthem: There is significant ­histologic overlap, but there is less epidermal damage with most viral exanthems. Clinical correlation is necessary −− Lupus erythematosus/dermatomyositis: There are more epidermal changes in these connective tissue diseases (e.g., ­hyperkeratosis, basement membrane thickening). Graft vs. host disease does not have increased dermal mucin ♦♦ Chronic −− Lichenoid (a) Lichen planus: lichen planus is similar but has a denser infiltrate −− Sclerodermoid (b)  Scleroderma/morphea: histologically these are indistinguishable from sclerodermoid chronic graft vs. host disease. Clinical history is necessary for making the distinction

Morbilliform Drug Eruption Clinical ♦♦ Patients present with a blanchable symmetric, widespread macular or papular eruption

Microscopic (Fig. 19.18) ♦♦ There is a superficial perivascular infiltrate of lymphocytes and eosinophils, often with mild basal vacuolization. Sometimes the vacuolar change is absent

Fig. 19.18. Morbiliform drug eruption.

Nonneoplastic Skin Diseases

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♦♦ There may be rare dyskeratotic keratinocytes, but they are not a prominent feature and may be absent ♦♦ There is variable blood vessel ectasia

Differential Diagnosis ♦♦ Graft vs. host disease: Graft vs. host disease is only considered in a specific clinical context (see above). There is histologic overlap, but the degree of interface change/epidermal damage is often pronounced in graft vs. host disease ♦♦ Lupus erythematosus/dermatomyositis: These entities lack eosinophils. Drug eruptions lack dermal mucin ♦♦ Viral exanthem: There is significant overlap. Viral induced eruptions usually lack ­eosinophils

Viral Exanthem Clinical ♦♦ These are usually due to parvovirus, herpesvirus 6, HIV, enterovirus, EBV, hepatitis B, or coxsackievirus

Microscopic ♦♦ There is mild vacuolar change with variable dyskeratosis ♦♦ Within the dermis there is papillary dermal edema and a mild superficial perivascular lymphocytic infiltrate

Differential Diagnosis ♦♦ Graft vs. host disease: The clinical setting is important for distinguishing these entities (see above) ♦♦ Lupus erythematosus/dermatomyositis: There are more ­epidermal changes in these connective tissue diseases (e.g., hyperkeratosis, basement membrane thickening). Viral exanthems lack dermal mucin ♦♦ Morbilliform drug eruption: Viral exanthems usually do not have eosinophils (see above)

Interface Dermatitis with Lichenoid (Band-like) Infiltrate Lichen Planus Clinical ♦♦ Lichen planus presents as pruritic violaceous, polygonal papules usually on flexural surfaces of wrists and ankles but may be widespread ♦♦ Mucosal involvement, especially in the mouth, common. Oral lesions have a reticulated a­ ppearance

Microscopic (Fig. 19.19) ♦♦ There is hyperkeratosis without parakeratosis and acanthosis with wedge-shaped hypergranulosis ♦♦ There is interface change with “saw-tooth” rete pegs, scattered dyskeratotic cells, and a dense band-like lymphocytic infiltrate

Variants ♦♦ Atrophic lichen planus: Thinned epidermis with subtle interface change and subtle wedge-shaped hypergranulosis ♦♦ Hypertrophic lichen planus: Similar to classic lichen planus but with more prominent acanthosis

Fig. 19.19. Lichen planus. ♦♦ Bullous lichen planus: Subepidermal blister, wedge-shaped hypergranulosis, interface change at sides of blister

Differential Diagnosis ♦♦ Classic lichen planus −− Lichenoid benign keratosis: This is a solitary lesion. Histologically it can be identical to lichen planus. Adjacent areas of solar lentigo can be a clue to the diagnosis −− Lichenoid graft vs. host disease: Lichen planus has a denser infiltrate (see above) −− Fixed drug reaction: Fixed drug reactions lack the compact hyperkeratosis and ­hypergranulosis of lichen planus and typically have eosinophils in the infiltrate −− Lichenoid drug eruption: Lichenoid drug eruptions resemble lichen planus but have parakeratosis and eosinophils −− Lichenoid pigmented purpuric dermatosis: There is less epidermal change and more prominent dermal hemorrhage in this entity ♦♦ Atrophic lichen planus −− Resolving lichenoid benign keratosis: See above −− Lupus erythematosus/dermatomyositis: These entities usually do not have a lichenoid pattern. Lichen planus lacks dermal mucin ♦♦ Hypertrophic lichen planus −− Lichenoid benign keratosis: See above −− Squamous cell carcinoma: Cytologic atypia and a desmoplastic stromal response help distinguish this entity. Squamous cell carcinoma usually does not have a lichenoid inflammatory infiltrate

Lichenoid Drug Eruption Clinical ♦♦ It presents as widespread violaceous papules

Microscopic ♦♦ It is very similar to lichen planus with ­hypergranulosis, interface change and a lichenoid infiltrate

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♦♦ Important differences include the presence of occasional eosinophils and parakeratosis

Differential Diagnosis ♦♦ Lichen planus: The presence of eosinophils and parakeratosis help distinguish lichenoid drug reactions from lichen planus

Fixed Drug Eruption Clinical

Microscopic ♦♦ The epidermis has basket-weave stratum ­corneum or parakeratosis ♦♦ There is interface change with dyskeratotic ­keratinocytes ♦♦ In the dermis there is a lichenoid infiltrate of lymphocytes admixed with some eosinophils ♦♦ Melanophages are seen in older or recurrent lesions

Differential Diagnosis

♦♦ It presents as well-demarcated erythematous plaques secondary to a drug reaction. It frequently recurs in the same location on reexposure to the offending agent ♦♦ It most commonly involves hands, feet, genitalia, and face

♦♦ Erythema multiforme: The infiltrate is less dense in erythema multiforme, and the degree of ­epidermal damage is often more prominent ♦♦ Lupus erythematosus: Lupus erythematosus lacks eosinophils

Superficial Perivascular Dermatitis ♦♦ Inflammatory infiltrate confined to upper dermis ♦♦ Little epidermal change

Morbilliform Drug Eruption ♦♦ (See interface dermatitis section above)

Clinical ♦♦ Patients present with a blanchable symmetric, ­widespread macular or papular eruption ♦♦ Ampicillin in patients with mononucleosis is classic example

Microscopic ♦♦ There is a superficial perivascular infiltrate of lymphocytes and eosinophils, often with mild basal  vacuolization. Sometimes the vacuolar change is absent ♦♦ There may be rare dyskeratotic keratinocytes, but they are not a prominent feature and may be absent ♦♦ There is variable blood vessel ectasia

Differential Diagnosis ♦♦ Viral exanthem: See above ♦♦ Tinea versicolor: The presence of yeast and pseudohyphae in the stratum corneum allow distinction

Postinflammatory Pigment Alteration Clinical ♦♦ This may present as hyperpigmented or hypopigmented macules and patches ♦♦ It is the sequelae of a preexisting inflammatory disorder

Microscopic (Fig. 19.20) ♦♦ There is a mild superficial perivascular lymphohistiocytic infiltrate with scattered melanophages ♦♦ There is little or no epidermal change ♦♦ Melanocytes are still present in the epidermis

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Fig. 19.20. Postinflammatory pigment alteration.

Differential Diagnosis ♦♦ Vitiligo: On routine examination they can be ­histologically identical. Vitiligo shows an absence or marked decrease in melanocytes (usually requires special stains) ♦♦ Regressed melanocytic lesions: Regressed ­melanocytic lesions show more dermal fibrosis and may show focal evidence of a residual melanocytic proliferation ♦♦ Progressive pigmented purpuric eruption: There is hemorrhage and the pigment-containing cells in the dermis are siderophages not melanophages

Progressive Pigmented Purpuric Eruption (Schamberg Disease) Clinical ♦♦ This entity usually presents as red-brown macules most commonly on lower legs

Nonneoplastic Skin Diseases

Fig. 19.21. Progressive pigmented purpuric dermatosis.

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Fig. 19.22. Urticaria.

Microscopic (Fig. 19.21) ♦♦ There is little epidermal change; occasionally there may be some spongiosis ♦♦ Within the dermis there is a mild superficial ­lymphocytic infiltrate with extravasated erythrocytes and siderophages; occasionally cases may have a lichenoid infiltrate ♦♦ No fibrinoid necrosis of blood vessels present

Differential Diagnosis ♦♦ Stasis dermatitis: The clinical presentation helps distinguish these entities. In stasis dermatitis, there is often spongiosis and acanthosis. The lobular proliferation of superficial dermal blood vessels is characteristic of stasis dermatitis ♦♦ Postinflammatory pigment alteration: See above

Urticaria Clinical ♦♦ Classically, urticaria is characterized by transient edematous pruritic plaques (hives) that resolve within 24 hours ♦♦ Patients may have chronic forms with persistent lesions

Microscopic (Fig. 19.22) ♦♦ The epidermis appears normal ♦♦ The papillary dermis is edematous and there is a superficial perivascular infiltrate of lymphocytes and eosinophils and sometimes a few ­neutrophils ♦♦ The superficial dermal blood vessels often have neutrophils within the lumens

Differential Diagnosis ♦♦ Urticarial phase of bullous pemphigoid: The ­presence of eosinophils tagging the basal layer and eosinophilic spongiosis are features present not seen in urticaria. Direct immunofluorescence findings can also help ♦♦ Arthropod bite reaction: In arthropod bite reactions, the inflammatory infiltrate is denser ♦♦ Drug eruption: Histologically these are essentially indistinguishable. Interface change favors a drug eruption

Fig.  19.23. Giemsa stain highlighting mast cells in urticaria pigmentosa.

Urticaria Pigmentosa (Mastocytosis) Clinical ♦♦ This disease presents as persistent erythematous to tan macules and papules that can present in c­ hildren or adults ♦♦ Rarely, patients have associated systemic mast cell disease or mast cell leukemia ♦♦ The lesions urticate when stroked (Darier sign) ♦♦ Some patients, usually children, have solitary lesions; solitary lesions are diagnosed as m ­ astocytoma

Microscopic ♦♦ Normal epidermis ♦♦ Within the dermis there is a superficial perivascular infiltrate predominantly composed of mast cells admixed with some eosinophils ♦♦ The density of the mast cell infiltrate is variable ♦♦ A Giemsa stain (Fig. 19.23) or immunostains for tryptase or CD117 can confirm the infiltrate as mast cells

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Differential Diagnosis ♦♦ If the mast cells have a superficial perivascular pattern, the differential diagnosis includes −− Viral exanthem: Viral exanthems are not composed of mast cells −− Normal skin: In some cases the mast cell infiltrate is rather sparse. Special stains as outlined above can help with the diagnosis in this setting ♦♦ If the mast cell infiltrate has a dense superficial and deep pattern (usually in the setting of mastocytoma the differential diagnosis includes

−− Intradermal nevus: Nevi have a more nested growth pattern, often have evident melanin pigment and are positive for melanocytic markers −− Langerhans cell histiocytosis: Like mastocytoma, Langerhans cell histiocytosis frequently has accompanying eosinophils. Langerhans cell histiocytosis often has lesional cells within the epidermis. The tumor cells do not have granular cytoplasms and are immunoreactive for S100 protein and CD1a

Superficial and Deep Perivascular DERMATITIS Lupus Erythematosus

Differential Diagnosis

♦♦ May also exist without or with minimal interface change. This variant is called tumid lupus erythematosus ♦♦ See also Interface Dermatitis section

♦♦ Erythema elevatum diutinum: This is a form of chronic leukocytoclastic vasculitis that is associated with a fibroblastic proliferation late in its course. Recognition of the vasculitis differentiates this from Sweet syndrome ♦♦ Pyoderma gangrenosum: This is a chronic disease associated with epidermal ulceration. The dermal infiltrate can resemble Sweet syndrome, but ulceration is not a feature of Sweet ♦♦ Cellulitis: In most cases of cellulitis, the dermal infiltrate is not as dense as seen in Sweet syndrome

Acute Neutrophilic Dermatosis (Sweet Syndrome) Clinical ♦♦ It presents as violaceous tender nodules or plaques ♦♦ It may be associated with infections, myeloproliferative ­disorders, and treatment with granulocyte colony-stimulating factors. Some cases are idiopathic in nature

Microscopic (Fig. 19.24) ♦♦ There is no or minimal epidermal change ♦♦ Within the dermis there is a dense perivascular and/or diffuse infiltrate of neutrophils ♦♦ There may be leukocytoclasis but no true vasculitis is present

Pityriasis Lichenoides et Varioliformis Acuta (PLEVA) Clinical ♦♦ PLEVA presents as recurrent crops of flesh colored to ­erythematous papules ♦♦ The lesions evolve into vesicles, hemorrhagic lesions, and crusted ulcerations that leave varioliform scars

Microscopic (Fig. 19.25) ♦♦ The epidermal changes are variable depending on stage of lesion including minimal to no epidermal changes, parakeratosis, focal dyskeratosis, basilar vacuolar interface change to epidermal ulceration ♦♦ In the dermis, there is a wedge-shaped perivascular and interstitial dermal infiltrate of small lymphocytes with occasional neutrophils and some dermal hemorrhage

Differential Diagnosis

Fig. 19.24. Sweet syndrome.

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♦♦ Pityriasis rosea: Pityriasis rosea has discrete mounds of parakeratosis but no interface change. There may be hemorrhage but the infiltrate is restricted to the superficial dermis ♦♦ Lymphomatoid papulosis: The presence of large atypical CD30+ cells helps distinguish this entity from PLEVA ♦♦ Pityriasis lichenoides chronica: This is considered by many to be in the spectrum of PLEVA, but with a less dense milder infiltrate with less epidermal interface change

Nonneoplastic Skin Diseases

Fig. 19.25. Pityriasis lichenoides et varioliformis acuta (PLEVA).

19-17

Fig. 19.27. Arthropod bite reaction. ♦♦ The large atypical CD30+ cells are similar to those seen in anaplastic large cell lymphoma and comprise greater than 25% of the infiltrate

Differential Diagnosis ♦♦ Anaplastic large cell lymphoma: Histologically they may be indistinguishable. Clinical information as to the nature of the presentation (numerous papules vs. solitary mass) is required ♦♦ PLEVA: PLEVA lacks the atypical cells, but is otherwise very similar (see above) ♦♦ Arthropod bite reaction: Arthropod bite reactions usually lack significant numbers of atypical CD30+ cells, and are more eosinophil-rich

Fig. 19.26. Large atypical cells of lymphomatoid papulosis.

Lymphomatoid Papulosis Clinical ♦♦ Lymphomatoid papulosis presents as recurrent crops of papules that may vesiculate and become crusted ♦♦ Molecular studies have demonstrated T-cell clonality and some consider it a low grade T-cell dyscrasia/T-cell lymphoma ♦♦ Up to 20% of patients may develop a secondary lymphoid malignancy

Microscopic (Fig. 19.26) ♦♦ Epidermal changes −− Early: There is mild exocytosis of lymphocytes and parakeratosis −− Late: There is more pronounced exocytosis, dyskeratotic cells, and necrosis ♦♦ In the dermis, there is a wedge-shaped dermal infiltrate of small and large lymphocytes with occasional plasma cells, eosinophils, and neutrophils

Arthropod Bite Reaction Clinical ♦♦ The clinical presentation is variable, typically presenting as erythematous pruritic papule or papules

Microscopic (Fig. 19.27) ♦♦ The epidermal changes are variable and may show acute necrosis, epidermal hyperplasia, or appear normal ♦♦ In the dermis there is papillary dermal edema and a superficial and deep perivascular and interstitial infiltrate of eosinophils and mononuclear cells

Differential Diagnosis ♦♦ PLEVA: PLEVA is not eosinophil-rich ♦♦ Lymphomatoid papulosis: Lymphomatoid papulosis has more atypia (see above) ♦♦ Deep fungal infection: Fungal infections involving the dermis often have a prominent granulomatous component. Fungal stains can be helpful ♦♦ Eosinophilic cellulitis (Wells syndrome): Eosinophilic cellulitis is a morphologic pattern with a dense infiltrate of eosinophils in the dermis, often with flame figures (eosinophil granules encrusting collagen fibers). It is a diagnosis of exclusion

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Interstitial Pattern Palisading Granulomatous Dermatitis ♦♦ Characterized by interstitial histiocytic infiltrate surrounding altered collagen

Granuloma Annulare Clinical ♦♦ It presents as asymptomatic papules with annular configuration, usually on extremities

Microscopic (Fig. 19.28) ♦♦ It most commonly involves upper and mid reticular dermis ♦♦ There is a central zone of altered collagen fibers with associated dermal mucin surrounded by a palisade of histiocytes with some giant cells ♦♦ There is a perivascular lymphocytic infiltrate with variable numbers of eosinophils and neutrophils ♦♦ Rarely, the granulomas may resemble sarcoidal granulomas (sarcoidal granuloma annulare) ♦♦ Rarely, it may be confined to the subcutis

Fig. 19.28. Granuloma annulare.

Differential Diagnosis ♦♦ Necrobiosis lipoidica: The infiltrate in necro­biosis lipoidica has a tiered arrangement involving most of the dermis. The presence of plasma cells favors necrobiosis lipoidica ♦♦ Rheumatoid nodule: In rheumatoid nodule the degenerated collagen has a fibrinoid rather than mucinous appearance

Necrobiosis Lipoidica Clinical ♦♦ It usually presents as yellow, indurated plaques on the lower legs ♦♦ 15% of patients have underlying diabetes mellitus

Microscopic (Fig. 19.29) ♦♦ The epidermis is atrophic ♦♦ The inflammatory process affects the entire dermis ♦♦ There is a tiered arrangement of elongated zones of altered collagen (necrobiosis) separated by an interstitial infiltrate of histiocytes ♦♦ Multinucleated histiocytes are common ♦♦ Aggregates of lymphocytes and plasma cells are common

Differential Diagnosis ♦♦ Granuloma annulare: Granuloma annulare is more focal within the dermis and lacks the tiered pattern and plasma cells ♦♦ Sarcoidosis: Sarcoidosis has discrete epithelioid granulomas rather than the tiered histiocytic inflammatory pattern

Rheumatoid Nodule Clinical ♦♦ It occurs in 20% of patients with rheumatoid arthritis and presents as nodules, most commonly on the distal upper extremity

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Fig. 19.29. Necrobiosis lipoidica.

Microscopic (Fig. 19.30) ♦♦ Subcutis and deep dermis are the most common sites of involvement ♦♦ The lesions are characterized by a central zone of eosinophilic, degenerated collagen and nuclear debris surrounded by histiocytes

Differential Diagnosis ♦♦ Granuloma annulare: The granulomas of granuloma annulare are often less well formed and contain dermal mucin and less prominent eosinophilic degenerated collagen

Nonneoplastic Skin Diseases

Fig. 19.30. Rheumatoid nodule.

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Fig. 19.32. Flame figure in Wells syndrome.

Fig. 19.31. Cutaneous lymphoid hyperplasia.

Nodular or Diffuse Infiltrates Cutaneous Lymphoid Hyperplasia (Lymphocytoma Cutis) Clinical ♦♦ Usually presents as a solitary nodule or plaque, most commonly on head and neck

Microscopic (Fig. 19.31) ♦♦ It is a top-heavy nodular to diffuse lymphocytic infiltrate admixed with eosinophils and plasma cells ♦♦ Germinal center formation is common, and the germinal centers are polarized and contain tingible body macrophages

Differential Diagnosis ♦♦ Cutaneous marginal zone lymphoma: There is a proliferation of atypical monocytoid B-cells and frequently clonal plasma cells. Neoplastic B-cells are found outside the germinal centers in large numbers ♦♦ Cutaneous follicle center cell B-cell lymphoma: The germinal centers are not polarized and usually lack tingible body

Fig. 19.33. Mastocytosis. macrophages. Neoplastic B-cells are found outside the germinal centers in large numbers

Eosinophilic Cellulitis (Wells Syndrome) Clinical ♦♦ Erythematous painful or pruritic plaques resembling cellulitis or urticaria

Microscopic ♦♦ The dermis is edematous ♦♦ There are numerous interstitial eosinophils with flame ­figures (collagen fibers encrusted with eosinophilic granules) (Fig. 19.32)

Differential Diagnosis ♦♦ Fungal infection: This is a diagnosis of exclusion. Eosinophils are typically less numerous; however, a PAS or GMS stain should be performed before diagnosing eosinophilic cellulitis ♦♦ Arthropod bite reaction: Usually there is more of a mixture of eosinophils and lymphocytes

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Mastocytosis ♦♦ See also urticaria pigmentosa in superficial perivascular dermatitis section

♦♦ May be a dense interstitial infiltrate of mast cells (Fig. 19.33)

Sclerosing Dermatoses Scleroderma Clinical ♦♦ Scleroderma is a multisystem connective tissue disease that is subdivided into two major clinical groups −− Group 1: Disease is limited and involves the hands, forearms and face; patients often have CREST syndrome −− Group 2: Patients have diffuse cutaneous sclerosis and frequent visceral involvement ♦♦ The lesions present as indurated skin with hypopigmentation with perifollicular pigment retention and telangiectasias ♦♦ Sclerodactyly is common

Microscopic (Fig. 19.34) ♦♦ The epidermis is normal to atrophic ♦♦ In the dermis the collagen bundles are thickened, hyalinized and compacted ♦♦ There is decreased periadnexal fat ♦♦ There is a variable perivascular lymphoplasmacytic infiltrate that is more prominent early in the course

Differential Diagnosis ♦♦ Morphea, sclerodermoid graft vs. host disease: Histologically they are essentially identical; differentiation relies on clinical history/presentation

Morphea Clinical ♦♦ Also known as localized scleroderma ♦♦ Patients present with localized indurated plaques, frequently on trunk, that are identical to lesions of scleroderma (see above)

Microscopic ♦♦ Indistinguishable from scleroderma (see above)

Differential Diagnosis ♦♦ Scleroderma, sclerodermoid graft vs. host disease: Histologically they are essentially identical; differentiation relies on clinical history/presentation

Lichen Sclerosus Clinical ♦♦ Patients present with white papules and plaques, frequently with fine, crinkly scale ♦♦ There is predilection for the anogenital area, but other regions are also affected

Microscopic (Fig. 19.35) ♦♦ The epidermis is atrophic with loss of normal rete peg pattern ♦♦ Hyperkeratosis is common

Fig. 19.34. Scleroderma/morphea.

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Fig. 19.35. Lichen sclerosus.

Nonneoplastic Skin Diseases

19-21

♦♦ In early lesions there is evidence of interface change with basal vacuolization and a lichenoid lymphocytic infiltrate ♦♦ The diagnostic feature is the edematous and homogenized papillary dermal collagen ♦♦ Beneath the altered papillary dermal collagen, there is a variable lichenoid lymphocytic infiltrate

Differential Diagnosis ♦♦ Morphea: In morphea the collagen changes are centered in the reticular dermis and there is no lichenoid infiltrate beneath the zone of altered collagen ♦♦ Lupus erythematosus: Lupus erythematosus lacks the homogenized dermal collagen. Lupus erythematosus also presents on sun-exposed skin

Panniculitis ♦♦ General Comments −− Two primary patterns: Septal and lobular −− Most panniculitides usually have some septal as well as some lobular inflammation −− Categorization is based on the predominant pattern

Erythema Nodosum Clinical ♦♦ Erythema nodosum accounts for >85% of all cases of panniculitis ♦♦ It is present as acute onset of tender, erythematous nodules, most often involving the shins ♦♦ It is considered a subcutaneous hypersensitivity reaction that may be idiopathic or associated with infection (e.g., group A b-hemolytic streptococcus) or drugs (e.g., sulfa drugs, oral contraceptives)

Microscopic (Fig. 19.36) ♦♦ Biopsies demonstrate widened subcutaneous septae with edema, inflammation, and later fibrosis ♦♦ The inflammatory infiltrate is composed of lymphocytes, histiocytes, some neutrophils, and small granulomas within septae ♦♦ There is usually some lobular inflammation at periphery of subcutaneous fat lobule

Differential Diagnosis ♦♦ Infection: Infectious processes involving the subcutis do not usually have a septal pattern. Granulomas in infections have a suppurative appearance in most cases ♦♦ Trauma: Traumatic fat necrosis is less inflamed and less septal predominant ♦♦ Nodular vasculitis: This is a predominantly lobular panniculitis with medium vessel vasculitis ♦♦ Superficial migratory thrombophlebitis: The presence of intravascular thrombosis and vasculitis helps distinguish this entity from erythema nodosum ♦♦ Lipodermatosclerosis: This entity is less inflammatory and has characteristic membranocystic fat necrosis ♦♦ Lupus panniculitis: This rare form of lupus erythematosus is a lobular panniculitis with hyaline fat necrosis. It is more common on the upper body ♦♦ Subcutaneous morphea: Morphea may present as a septal process. The septae are sclerotic and resemble the dermal changes of morphea. There is less involvement of the periphery of fat lobules and granuloma formation is not a typical feature

Lipodermatosclerosis (Lipomembranous Panniculitis, Sclerosing Panniculitis) Clinical ♦♦ It usually presents as bilateral indurated plaques on medial aspects of lower legs ♦♦ Lipodermatosclerosis is associated with stasis changes secondary to venous insufficiency and/or obesity

Microscopic ♦♦ It is predominantly septal panniculitis but a lobular component is invariably present ♦♦ The septae are widened septae, and there is membranocystic fat necrosis characterized by cystic cavities lined by a crenulated, hyaline membrane (Fig. 19.37) ♦♦ There is a variable mild perivascular lymphocytic infiltrate ♦♦ The overlying epidermis and superficial dermis usually show features of stasis change

Differential Diagnosis Fig. 19.36. Erythema nodosum.

♦♦ Erythema nodosum: This entity is more inflammatory and lacks the membranocystic fat necrosis

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Fig. 19.37. Lipodermatosclerosis.

Fig. 19.38. Nodular vasculitis.

♦♦ Lupus panniculitis: The hyaline fat necrosis of lupus erythematosus has a different appearance than the membranocystic fat necrosis of lipodermatosclerosis. There is a more prominent inflammatory component ♦♦ Subcutaneous morphea: There is little change to the fat lobules and no membranocystic fat necrosis

Microscopic (Fig. 19.38)

Subcutaneous Morphea (Morphea Profundus) Clinical ♦♦ The subcutaneous form presents as multiple bound-down indurated plaques on extremities. The overlying skin has a dimpled appearance

Microscopic ♦♦ There is a septal panniculitis characterized by thickened, hyalinized, and compacted collagen fibers in subcutaneous septae and deep dermis ♦♦ There is a variable, usually mild, perivascular lymphoplasmacytic infiltrate; lymphoid aggregates without germinal centers may be present

Differential Diagnosis ♦♦ Late-stage erythema nodosum: Late-stage erythema nodosum may resemble subcutaneous morphea but the former shows more evidence of peripheral damage to the fat lobule ♦♦ Lupus panniculitis: This is predominantly a lobular panniculitis; the hyaline fat necrosis is a lobular, not septal process ♦♦ Lipodermatosclerosis: Subcutaneous morphea lacks the membranocystic fat necrosis

♦♦ This is a lobular panniculitis with fat necrosis associated with vasculitis (leukocytoclastic or lymphohistiocytic) of vessels in the subcutaneous septae ♦♦ Within the lobule there is a diffuse infiltrate of lymphocytes, histiocytes, and multinucleated histiocytes; irregular granulomas often present

Differential Diagnosis ♦♦ Erythema nodosum: Erythema nodosum does not diffusely involve the fat lobules and has septal thickening ♦♦ Infection: The presence of vasculitis can help distinguish nodular vasculitis. Demonstration of organisms on culture or special stains may be required in certain cases ♦♦ Polyarteritis nodosa: The vessels involved are medium to large vessels, and the inflammation of the subcutaneous lobule is less diffuse ♦♦ Thrombophlebitis: The presence of vascular thrombosis can help in recognition of this entity. There is less inflammation ♦♦ Lupus panniculitis: The hyaline fat necrosis of subcutaneous lupus erythematosus is not a feature of nodular vasculitis. The clinical presentation is usually different

Lupus Panniculitis (Lupus Profundus) Clinical ♦♦ Lesions present as deep subcutaneous nodules and plaques on upper arms, thighs, and trunk ♦♦ Patients may or may not have other manifestations of cutaneous lupus erythematosus; 10% of patients have associated systemic lupus erythematosus

Nodular Vasculitis (Erythema Induratum) Clinical

Microscopic (Fig. 19.39)

♦♦ Patients present with chronic, recurring tender nodules on lower legs, usually the calves ♦♦ In some patients, it is a subcutaneous hypersensitivity reaction to underlying infection with M. tuberculosis, though most cases in the USA are idiopathic

♦♦ This is a predominantly lobular panniculitis with hyaline fat necrosis characterized by dense eosinophilic sclerosis around remnants of adipocytes ♦♦ There are lymphoid nodules with germinal centers at periphery of fat lobules

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Nonneoplastic Skin Diseases

19-23

Fig. 19.39. Lupus profundus.

Fig. 19.40. Polyarteritis nodosa.

Differential Diagnosis

Differential Diagnosis

♦♦ Nodular vasculitis: The presence of hyaline fat necrosis and the clinical presentation help differentiate these entities ♦♦ Subcutaneous morphea: Subcutaneous morphea is a septal process and lacks the hyaline fat necrosis ♦♦ Lipodermatosclerosis: This entity is less inflammatory than lupus panniculitis and has membranocystic rather than hyaline fat necrosis. The clinical presentation is also different

♦♦ Superficial thrombophlebitis: This is secondary to thrombosis not vasculitis ♦♦ Nodular vasculitis: The inflammation affecting the fat lobule is more diffuse

Polyarteritis Nodosa Clinical ♦♦ This presents as tender, erythematous nodules on extremities, especially the legs ♦♦ There may be systemic disease (e.g., gastrointestinal, renal) with skin involvement or the disease may remain localized to skin only

Microscopic (Fig. 19.40) ♦♦ The key histologic feature is leukocytoclastic vasculitis involving small- to medium-sized arteries in subcutis. An elastic stain can highlight the internal elastic lamina confirming involvement of an artery ♦♦ There is a focal lobular panniculitis surrounding affected vessel

Superficial Thrombophlebitis Clinical ♦♦ This presents as a cord-like arrangement of tender nodules most commonly on legs ♦♦ It sometimes represents a paraneoplastic syndrome (Trousseau sign)

Microscopic ♦♦ In early lesions there is evident thrombosis of a vein in the subcutis or deep dermis. The vessel wall is inflamed; the infiltrate varies with time and is composed of neutrophils (early) or lymph ocytes and histiocytes (late)

Differential Diagnosis ♦♦ Polyarteritis nodosa: Thrombophlebitis affects veins not arteries; an elastic tissue stain can help in this distinction ♦♦ Erythema nodosum: Vasculitis is not a feature of erythema nodosum ♦♦ Nodular vasculitis: The inflammation involving the fat lobule is more diffuse

Alopecia Nonscarring Alopecia Telogen Effluvium Clinical ♦♦ This presents as diffuse alopecia with a rapid onset

♦♦ There is often a history of a preceding stressful event weeks to few months prior to onset (e.g., pregnancy, systemic illness)

Microscopic ♦♦ Acute phase: There are increased numbers of telogen phase follicles with a normal total numbers of follicles

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♦♦ Later stage: Biopsies in later stages often resemble normal scalp with primarily anagen-phase follicles ♦♦ Patients are more commonly biopsied in later stages of disease

Differential Diagnosis ♦♦ Normal scalp: Clinical history of alopecia helps distinguish late-stage lesions from normal scalp ♦♦ Alopecia areata: There is an increase in catagen follicles. The presence of a peribulbar lymphocytic infiltrate also helps differentiate these conditions

Androgenetic Alopecia Clinical ♦♦ This has also been termed male pattern baldness and female pattern baldness. In men, the hair loss is primarily bitemporal and occipital. In women, hair loss is concentrated on the scalp vertex

Microscopic (Fig. 19.41) ♦♦ There is a decreased number of total follicles with an increased percentage of miniaturized/vellus follicles ♦♦ Sebaceous glands appear relatively enlarged ♦♦ There is a variable patchy mild perivascular lymphocytic infiltrate

Differential Diagnosis ♦♦ Telogen effluvium: Acute phase telogen effluvium may be difficult to distinguish. In that setting clinical history is helpful. Miniaturization of follicles is not a feature of later-stage telogen effluvium ♦♦ Alopecia areata: Miniaturization is not a feature of alopecia areata. Increased catagen follicles and peribulbar lymphocytic infiltrate is more typical of alopecia areata

Fig. 19.41. Vellus hairs in androgenetic alopecia.

Alopecia Areata Clinical ♦♦ Patients typically present with a demarcated round area of hair loss typically localized to scalp. In some cases hair loss is widespread

Microscopic ♦♦ The most diagnostic feature is a peribulbar lymphocytic infiltrate (Fig. 19.42) ♦♦ There is an increased number of catagen and/or telogen follicles

Trichotillomania Clinical ♦♦ This is compulsive hair pulling and is more common in children and adolescents

Microscopic

Fig. 19.42. Lymphocytic infiltrate around hair bulb in alopecia areata.

♦♦ Biopsies demonstrate distorted or fractured hair shafts (trichodystrophy) and deposits of melanin within follicles (melanin casts) and fibrous root sheath tracks or stelae (Fig. 19.43)

Scarring Alopecia

Differential Diagnosis

Clinical

♦♦ Alopecia areata: Alopecia areata lacks the distorted hairs and melanin casts

♦♦ Lupus erythematosus causing alopecia is seen in setting of chronic discoid lupus erythematosus

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Lupus Erythematosus ♦♦ (See Also Interface Section)

Nonneoplastic Skin Diseases

19-25

Fig. 19.43. Distorted hair shaft in trichotilomania.

Fig. 19.44. Lichen planopilaris.

♦♦ There are variably hyperpigmented and hypopigmented plaques involving the scalp with follicular plugging and dilated follicles ♦♦ Women are more commonly affected

Microscopic

Microscopic ♦♦ See earlier description of lupus erythematosus ♦♦ There is interface change at follicular infundibulum and keratin plugs in follicles ♦♦ There is variable perifollicular and perivascular inflammation and fibrosis with increased dermal mucin

Differential Diagnosis ♦♦ Lichen planopilaris: This entity shows less interface change along the epidermis and does not have increased dermal mucin. Lichen planopilaris has less of a deep inflammatory infiltrate

Lichen Planopilaris Clinical ♦♦ Patients present with hyperkeratotic follicular papules ♦♦ There may be evidence of lichen planus elsewhere

Microscopic (Fig. 19.44.) ♦♦ The lichenoid interface change is concentrated at the follicular infundibulum usually with a lesser amount to no interface change at dermal–epidermal junction ♦♦ There is concentric perifollicular fibrosis around infundibulum

Follicular Degeneration Syndrome (Central Centrifugal Scarring Alopecia) Clinical ♦♦ This is most common in middle-aged African-American women ♦♦ It presents as irregular patches of alopecia on frontal vertex or crown ♦♦ Some consider this a form of chronic traction alopecia

♦♦ There is concentric perifollicular fibroplasia with surrounding mild lymphocytic infiltrate ♦♦ The follicles are atrophic with an eccentric follicular canal

Differential Diagnosis ♦♦ Lichen planopilaris: There is more inflammation and the follicular canal is usually not eccentric ♦♦ Lupus erythematosus: There is more inflammation and increased dermal mucin. The presence of interface change in the overlying epidermis also helps distinguish these entities

Dissecting Cellulitis Clinical ♦♦ This is most common in young African-American men and presents as fluctuant nodules with follicular pustules

Microscopic ♦♦ There are dilated follicles filled with neutrophils with ruptured follicles and naked hair shafts in dermis ♦♦ Dermal abscesses are common ♦♦ Some follicles have a keratotic plug in infundibulum

Differential Diagnosis ♦♦ Folliculitis decalvans: Distinction is primarily on clinical presentation ♦♦ Acne keloidalis nuchae: The keloid-like scars help distinguish this entity. Clinical history is also helpful

Acne Keloidalis Nuchae Clinical ♦♦ Most common in African-American men, it presents as follicular pustules and perifollicular keloidal scars on occipital scalp/upper neck

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Microscopic

Differential Diagnosis

♦♦ There is perifollicular fibroplasia, sometimes keloid-like with neutrophils and plasma cells within and around follicles

♦♦ Dissecting cellulitis, acne keloidalis nuchae: Distinction is predominantly based on the clinical presentation

Differential Diagnosis

End-stage Scarring Alopecia Clinical

♦♦ Folliculitis decalvans, dissecting cellulitis: The presence of keloid-like fibrosis and the clinical history helps distinguish acne keloidalis

Folliculitis Decalvans Clinical

♦♦ Patients with longstanding scarring alopecia may undergo biopsy. In this setting the underlying etiology may be any of the forms of inflammatory scarring alopecia

Microscopic

♦♦ Patients present with well-demarcated, jagged patches of scalp alopecia with perifollicular pustules

Microscopic ♦♦ There are perifollicular and intrafollicular neutrophilic infiltrates with some perifollicular fibroplasia and naked hair shafts surrounded by foreign body-type inflammatory response

♦♦ There is dermal fibrosis with a marked decrease in follicles with or without a residual inflammatory infiltrate and naked hair shafts

Differential Diagnosis ♦♦ Indistinguishable from end stage of other forms of scarring alopecia

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Krafchik BR. Localized cutaneous scleroderma. Semin Dermatol 1992;11:65–72.

Cooper PH, Innes DJ Jr, Greer KE. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) and myeloproliferative disorders. Cancer 1983;51: 1518–1526.

Leinweber B, Colli C, Chott A, Kerl H, Cerroni L. Differential diagnosis of B lymphocytes with follicular growth pattern. Am J Dermatopathol 2004;26:4–13.

Cox AJ, Watson W. Histologic variations in lesions of psoriasis. Arch Dermatol 1972;106:503–506.

Longley J, Duffy TP, Kohn S. The mast cell and mast cell disease. J Am Acad Dermatol 1995;32:545–561; quiz 562–564.

Crotty C, Pittelkow M, Muller SA. Eosinophilic spongiosis: A clinicopathological review of seventy-one cases. J Am Acad Dermatol 1983;8:337–343.

Lowitt MH, Dover S. Necrobiosis lipoidica. J Am Acad Dermatol 1991;25:735–748.

Doyle JA, Connolly SM, Hunziker, et al. Prurigo nodularis: A reappraisal of the clinical and histologic features. J Cutan Pathol 1979;6:392–403.

Mali JWH, Kuiper JP, Hamers AA. Acro-angiodermatitis of the foot. Arch Dermatol 1965;92:515–518.

Farmer ER. The histopathology of graft-versus-host disease. Adv Dermatol 1986;1:173–188.

McKee PH, Calonje E, Granter SR. Pathology of the Skin with Clinical Correlation, 3rd ed. Philadelphia, PA: Elsevier Mosby, 2005.

Farmer ER, Hood AF. Pathology of the Skin, 2nd ed. New York: McGrawHill, 2000.

Meffert JJ, Davis BM, Grimwood RE. Lichen sclerosus. J Am Acad Dermatol 1995;32:393–416; quiz 417–418.

Garcia de Silva L, Gardne PS. Pitryiasis rosea: A histologic and serologic study. Br J Dermatol 1968;80:514–515.

Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 1980;3: 217–230.

Hood AF, Mark EJ. Histopathologic diagnosis of pityriasis lichenoides et varioliformis acuta and its clinical correlation. Arch Dermatol 1982;118: 478–482.

Newton RC, Raimer SS. Pigmented pupuric eruption. Dermatol Clin 1985;3:165–169.

Huff JC, Weston WL, Tonnesen, MG. Erythema multiforme: A critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8:763–775. Hurwitz RM, DeTrana C. The cutaneous pathology of atopic dermatitis. Am J Dermpathol 1990;12:544–551. Jerdan MS, Hood AF, Moore W, et al. Histopathologic comparisons of the subsets of lupus erythematosus. Arch Dermatol 1990;126:52. Karp DL, Horn TD. Lymphomatoid papulosis. J Am Acad Dermatol 1994;30:379–395. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V. The clinical spectrum of lipodermatosclerosis. J Am Acad Dermatol 1993;28:623–627.

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Paquet P, Pierard GE. Erythema multiforme and toxic epidermal necrolysis: a comparative study. Am J Dermatopathol 1997;19:127–132. Ragaz A, Ackerman AB. Evolu tion, maturation, and regression of lesions of lichen planus: New observations and correlations of clinical and histologic findings. Am J Dermatopathol 1981;3:5–25. Sanz Vico MD, De Diego V, Sanchez Yus E. Erythema nodosum versus nodular vasculitis. Int J Dermatol 1993;32:108–112. Sellheyer K, Bergfeld WF. Histopathologic evaluation of alopecias. Am J Dermatopathol 2006;28:236–259. Review. Solomon AR. The transversely sectioned scalp biopsy specimen: The technique and an algorithm for its use in the diagnosis of alopecia. Adv Dermatol 1994;9:127–157.

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Soprano FF. Histologic criteria for the diagnosis of pityriasis rubra pilaris. Am J Dermatopathol 1986;8:277–283.

Wells GC, Smith NP. Eosinophilic cellulites. Br J Dermatol 1979;100: 101–109.

Weedon D. Skin Pathology, 2nd ed. New York: Churchill Livingstone; 2002.

Winkelmann RK. Panniculitis in connective tissue disease. Arch Dermatol 1983;119:336–344.

Weedon D, ed. Skin Pathology, 3rd ed. New York: Churchill Livingstone; 2010.

Immuodermatology is covered in Chapter 18

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20 Endocrine Pathology Lori A. Erickson, md

Contents

I. Thyroid Gland....................................20-3 II. Parathyroid Gland............................20-24 Introduction......................................................20-3 Pigment, Crystals, and Teflon.........................20-3 Aplasia and Hypoplasia of Thyroid.....................................................20-3 Heterotopic and Ectopic Thyroid...................20-3 Parasitic Nodule...............................................20-4 Thyroglossal Duct Cyst....................................20-4 Acute Thyroiditis..............................................20-5 Granulomatous Thyroiditis.............................20-5 Reidel Fibrous Thyroiditis...............................20-6 Lymphocytic Thyroiditis..................................20-7 Hashimoto Thyroiditis.....................................20-7 Postpartum Thyroiditis....................................20-8 Focal Lymphocytic Thyroiditis.......................20-8 Graves Disease..................................................20-8 Nontoxic Simple and Multinodular Goiters........................................................20-10 Dyshormonogenetic Goiter............................20-11 Toxic Multinodular Goiter............................20-11 Papillary Thyroid Carcinoma.......................20-11 Hyalinizing Trabecular Tumor.....................20-15 Follicular Adenoma........................................20-15 Follicular Thyroid Carcinoma......................20-16 Hürthle Cell Adenoma...................................20-17 Hürthle Cell Carcinoma................................20-18 Poorly Differentiated Carcinoma..................................................20-19 Anaplastic Thyroid Carcinoma.....................20-20 C-Cell Hyperplasia.........................................20-21 Medullary Thyroid Carcinoma.....................20-22

Introduction....................................................20-24 Parathyroid Cyst............................................20-24 Amyloid...........................................................20-25 Parathyroiditis................................................20-25 Glycogen Storage Diseases............................20-25 Parathyroid Hyperplasia...............................20-25 Parathyroid Adenoma....................................20-27 Parathyroid Carcinoma.................................20-30 Parathyromatosis...........................................20-33

III. Adrenal Gland.................................20-33 Adrenal Heterotopia......................................20-33 Focal Adrenalitis............................................20-33 Adrenal Cysts..................................................20-34 Adrenal Cytomegaly......................................20-34 Beckwith–Wiedemann Syndrome.................20-34 Adrenal Leukodystrophy...............................20-35 Congenital Adrenal Hyperplasia (Adrenogenital Syndrome).......................20-35 Primary Adrenal Insufficiency (Idiopathic Addison Disease)....................20-36 Secondary Adrenal Insufficiency..................20-36 Adrenal Cortical Hyperplasia.......................20-37 Adrenal Cortical Hyperplasia Associated with Hyperaldosteronism......20-37 Adrenal Cortical Macronodular Hyperplasia................................................20-37 Microadenomatous Hyperplasia (Primary Pigmented Nodular Adrenocortical Disease, PPNAD).............20-38

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_20, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Ovarian Thecal Metaplasia...........................20-39 Adrenal Medullary Hyperplasia...................20-39 Adrenal Cortical Adenoma...........................20-40 Adrenal Cortical Carcinoma.........................20-43 Pheochromocytoma........................................20-45 Myelolipoma...................................................20-46 Ganglioneuroma.............................................20-46

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Ganglioneuroblastoma...................................20-47 Neuroblastoma................................................20-47

IV. TNM Classification of Thyroid Carcinomas (2010 Revision)............20-48 V. Suggested Reading...........................20-49

Endocrine Pathology

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THYROID GLAND Introduction ♦♦ The thyroid anlage arises in the foramen cecum of the tongue and descends as part of the thyroglossal duct to the neck. The C-cells migrate to the ultimobranchial bodies from the neural crest and are incorporated into the thyroid gland. The adult thyroid gland weight is between 15 and 25 g ♦♦ The thyroid gland is made up of lobules, which are composed of 20–40 follicles, which are in turn composed of follicular cells. Follicular cells are positive for thyroglobulin, keratin, and TTF-1. The calcitonin-producing C-cells have pale to clear cytoplasm and oval nuclei, and are difficult to be identified with hematoxylin and eosin stain. C-cells are positive for calcitonin, chromogranin, and synaptophysin ♦♦ The thyroid follicular cells utilize exogenous iodine for the synthesis of thyroxine (T4) and triiodothyronine (T3). Thyroglobulin is synthesized and stored as colloid. Hydrolysis of thyroglobulin leads to the release of T3 and T4 as colloid from the follicular lumen is endocytosed. This process is regulated by thyroid stimulating hormone (TSH). T4 is resorbed within the thyroid cells and then transferred to the plasma, which is also regulated by TSH. The breakdown of thyroglobulin and release of T3 and T4 are inhibited by various chemicals including iodine, which inhibits the stimulation of thyroid adenylate cyclase by thyroid stimulating hormone. C-cells produce calcitonin, which lowers serum calcium by acting on bone, kidney, and the gastrointestinal tract

Pigment, Crystals, and Teflon ♦♦ Iron pigment can be seen in the thyroid when there has been traumatic hemorrhage and in disorders of iron metabolism. Minocycline chronically ingested can result in the classic “black thyroid.” Minocycline pigment is dark brown/black and located in the apical portion of the follicular cells and in the colloid. Birefringent calcium oxylate crystals are seen in benign and malignant thyroid parenchyma, a helpful feature in distinguishing thyroid from parathyroid gland. Teflon paste injected for vocal cord paralysis can be found in thyroid tissue associated with granulomatous inflammation

coid cartilage). Rarely, thyroid tissue may be identified in ectopic sites such as the mediastinum, pericardium, chest wall, vagina, and porta hepatis. Up to 10% of population may have heterotopic thyroid tissue, although it is usually subclinical due to small size. Clinically, it can present as a nodule in the midline neck or base of tongue (most common location). Patients with heterotopic thyroid (especially those with lingual thyroid) may lack a normal thyroid gland. Heterotopic tissue can give rise to thyroid malignancies such as papillary carcinoma. Additionally, the presence of normal-appearing thyroid tissue in lymph nodes most likely represents metastatic papillary thyroid carcinoma to lymph nodes, especially if the lymph nodes are located lateral to the jugular vein rather than heterotopic or ectopic thyroid tissue

Macroscopic (Fig. 20.1) ♦♦ Heterotopic and ectopic thyroid tissue may be encapsulated and resemble normal thyroid tissue

Microscopic (Fig. 20.2) ♦♦ Heterotopic and ectopic thyroid tissue is a histologically normal thyroid tissue, but can manifest pathologic processes that affect the thyroid gland (hyperplasia, neoplasia, inflammation, etc.). Individual follicles may proliferate between adjacent structures (such as muscle) simulating invasion

Differential Diagnosis ♦♦ Metastatic thyroid carcinoma −− Follicular carcinoma or follicular variant of papillary carcinoma may resemble normal thyroid tissue; thus, careful examination for solid areas, necrosis, mitoses, anaplasia, true invasion, or cytologic features of papillary thyroid carcinoma is needed to rule out a metastasis

Aplasia and Hypoplasia of Thyroid ♦♦ Thyroid aplasia and hypoplasia are the most common causes of congenital hypothyroidism. Patients with Di George syndrome, which is associated with arrested development of the parathyroid and thymus glands associated with the third and fourth bronchial pouches, also have arrested C-cell development

Heterotopic and Ectopic Thyroid Clinical ♦♦ Heterotopic thyroid tissue is a normal thyroid tissue found along the course of thyroglossal duct (from foramen cecum in posterior tongue down along anterior midline to below cri-

Fig. 20.1. Lingual thyroid: Depression at the site of excision of lingual thyroid.

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Fig. 20.2. Lingual thyroid: Variable-sized hyperplastic follicles, some lined by cubical cells and featuring occasional papillary infoldings.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  20.3. Thyroglossal duct: Duct lined by columnar epithelium with lymphocytic infiltrate. Mucous glands and striated muscle separate the duct from the hyoid bone.

Parasitic Nodule Clinical ♦♦ A parasitic nodule is a thyroid nodule in the neck that is anatomically separate from the main thyroid gland. The background thyroid gland is often a multinodular goiter. The parasitic nodule probably results from a colloid or hyperplastic nodule located outside of the thyroid gland, which becomes enlarged and migrates laterally in the neck

Macroscopic ♦♦ Parasitic nodules range in size from 1 to 4 cm and may be connected to the thyroid gland by a thin strand of fibrovascular tissue or it may be completely separate and blood supply from the surrounding tissues

Microscopic

Fig. 20.4. Thyroglossal duct: Pseudostratified ciliated columnar epithelium line duct.

♦♦ The histologic appearance is similar to normal thyroid tissue with hyperplastic or colloid-filled follicles

Differential Diagnosis ♦♦ Metastatic thyroid carcinoma −− The presence of many lymphoid cells in a patient with Hashimoto thyroiditis and a parasitic or sequestered nodule may lead to a mistaken diagnosis of metastatic carcinoma to a lymph node. Thus, careful determination of the exact location of the tissue is important as well as the histologic features

Thyroglossal Duct Cyst Clinical ♦♦ Thyroglossal duct cyst is a cystic dilation of remnant of thyroglossal duct, found along course of thyroglossal duct (from posterior tongue down along the anterior midline to below cricoid cartilage). The duct may run anterior to, within, or posterior to the hyoid bone ♦♦ Thyroglossal duct cysts are usually present in childhood with a midline nodule that may be tender and can be associated

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with the sinus tract. Fistulas may develop secondary to infection and may open into the pharynx or skin ♦♦ Heterotopic thyroid tissue associated with the cyst may give rise to thyroid malignancies (papillary carcinoma)

Macroscopic ♦♦ Thyroglossal duct cyst is filled with mucin and measures up to 3 cm in diameter. Normal thyroid tissue may be seen in the wall of the cyst

Microscopic (Figs. 20.3 and 20.4) ♦♦ Thyroglossal ducts cysts are usually lined by pseudostratified ciliated or squamous epithelium. The epithelial lining may not be identified if inflammation is prominent. The surrounding stroma shows thyroid follicles and inflammation

Differential Diagnosis ♦♦ Heterotopic thyroid −− Heterotopic thyroid shows only thyroid tissue, with no cyst or duct lining

Endocrine Pathology

♦♦ Branchial cleft cyst −− Located in the anterolateral neck, branchial cleft cysts lack the classic midline location of thyroglossal duct cysts. Branchial cleft cysts are lined by mixed squamous and respiratory epithelium and are associated with lymphoid follicles, but no thyroid tissue is seen ♦♦ Thyroid neoplasm with cystic degeneration −− Follicular adenoma, adenomatous goiter, or carcinoma may show cystic change. Thus, careful examination of the cyst wall and surrounding tissue is important

Acute Thyroiditis Clinical ♦♦ Acute thyroiditis is usually caused by bacteria, although fungi and viruses have also been implicated. Usually, the thyroid is secondarily involved by a systemic infection or local infection in the neck ♦♦ Patients often present with chills, fever, and malaise and an enlarged and painful thyroid. Gram-positive organisms such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus epidermidis, and Streptococcus pneumoniae are most common, but Gram-negative bacilli can also be isolated

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♦♦ Granulomatous thyroiditis is usually associated with pain and systemic symptoms such as fever, malaise, and weakness. The clinical course of granulomatous thyroiditis has been divided into hyperthyroid phase, hypothyroid phase, and recovery phase ♦♦ The etiology is unknown, but some cases of granulomatous thyroiditis are thought to be caused by a viral infection, either systemic or an infection of the thyroid itself. Many patients have recently had an upper respiratory infection, and epidemiology studies have shown association with numerous viruses (mumps, Coxsackie, adenovirus, influenza, Epstein Barr, measles, mononucleosis, among others) ♦♦ The overwhelming majority of patients recover in a few months. Mild cases are treated with aspirin, while prednisone is used in severe cases

Macroscopic (Fig. 20.5) ♦♦ The thyroid is enlarged (usually asymmetrical) up to twice normal size. The cut surface shows areas of irregular firm tan tissue among more normal-appearing thyroid tissue

Microscopic (Fig. 20.6)

♦♦ The thyroid may be enlarged, with areas of necrosis and abscesses

♦♦ Granulomatous thyroiditis is characterized by patchy uneven involvement of the thyroid by neutrophils and microabscesses early to mixed lymphohistiocytic inflammation and vague, noncaseating granulomata with foreign body-type giant cells centered on and destroying follicles and engulfing free colloid. Patchy areas of fibrosis and regenerating follicles may be seen later in the disease

Microscopic

Differential Diagnosis

♦♦ Acute thyroiditis is characterized by acute inflammation of the thyroid gland with neutrophils and microabscess formation as well as foci of necrosis. Special stains for bacteria and fungal organisms can help identify the organism

♦♦ Autoimmune thyroiditis −− Autoimmune thyroiditis shows significantly less ­inflammation, which is predominantly lymphocytic with

Macroscopic

Differential Diagnosis ♦♦ Other types of thyroiditis (granulomatous or lymphocytic) −− In other types of thyroiditis, predominant inflammatory cells are either histiocytes or lymphocytes (neutrophils, if present, usually represent minority) and are not associated with other acute infections or trauma ♦♦ Trauma and ischemic necrosis −− Although trauma and ischemic necrosis may present with pain, histologically these entities lack the marked acute inflammation and abscess formation seen in acute infectious thyroiditis

Granulomatous Thyroiditis Clinical ♦♦ Granulomatous inflammation occurs in the thyroid in a variety of conditions including infection, sarcoidosis, foreign body reaction, reaction to hemorrhage, among others ♦♦ Granulomatous thyroiditis includes nonsuppurative thyroiditis, subacute thyroiditis, and De Quervian thyroiditis ♦♦ Women are more commonly affected than men

Fig. 20.5. Granulomatous thyroiditis: Localized involvement of the right upper lobe by a demarcated tan-yellow inflammatory mass.

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Fig.  20.6. Granulomatous thyroiditis: Normal thyroid parenchyma has largely been replaced by fibrosis and an inflammatory mass, including multinucleated giant cells. Thyroid follicles are in various stages of destruction.

♦♦

♦♦

♦♦

♦♦

g­ erminal centers. There is no gland destruction; rather, follicles show atrophy with Hürthle cell change Acute thyroiditis −− Acute thyroiditis is usually associated with infections (bacterial or fungal) or local trauma. Inflammation is predominantly neutrophilic rather than granulomatous Tuberculosis or mycosis −− Tuberculosis or fungal infections of the thyroid are extremely rare, generally occurring in patients with disseminated systemic involvement. Histologically, the thyroid shows necrotizing granulomas Sarcoidosis −− Sarcoidosis involving the thyroid occurs in patients with systemic sarcoidosis. The granulomas are interstitial and do not result in follicular destruction Palpation thyroiditis −− Palpation thyroiditis is an incidental finding as a result of vigorous palpation of or minor trauma to the thyroid. Histologically, patchy, multifocal mixed lymphocytic and histiocytic foci of inflammation are identified involving isolated and widely distant follicles, in an otherwise histologically normal gland

Reidel Fibrous Thyroiditis Clinical ♦♦ Riedel fibrous thyroiditis is a rare, idiopathic inflammatory process manifested by extensive fibrosis of the thyroid gland, extending beyond the gland into the surrounding tissue and usually involving the cervical musculature ♦♦ Fibrous thyroiditis may be related to fibrosing mediastinitis and retroperitoneal fibrosis (idiopathic fibrosclerosis) ♦♦ Patients tend to be adult or elderly (average age = 50 years), with slight female predilection. Patients present with pain-

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 20.7. Reidel fibrous thyroiditis: Ragged external aspect of 230 g thyroid gland. Portion of the strap muscles are inextricably attached to the left lobe.

Fig. 20.8. Reidel fibrous thyroiditis: Hyalinized fibrous proliferation has penetrated through the thyroid capsule and surrounds nerves. There is a lymphocytic infiltrate focally.

less, poorly defined, thyroid enlargement that is often firm to rock hard

Macroscopic (Fig. 20.7) ♦♦ The thyroid gland is enlarged and hard with white fibrous tissue replacing parenchyma and extending into surrounding tissue, obliterating normal anatomic boundaries and extending into adjacent muscles, nerves, and vessels, making excision difficult or impossible

Microscopic (Fig. 20.8) ♦♦ The thyroid shows extensive fibrosis, infiltrating beyond the thyroid into the muscle and other tissue, with keloid-like hyalinized collagen. Areas of more normal uninvolved thyroid are seen. There is a patchy lymphoid and plasmacytic infiltrate ♦♦ Involved vessels may show mural inflammation and occlusive phlebitis

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♦♦ Giant cells are not prominent, which helps to differentiate Reidel thyroiditis from granulomatous thyroiditis, although granulomatous thyroiditis lacks that extensive fibrosis seen in Reidel thyroiditis

Differential Diagnosis ♦♦ Fibrosing Hashimoto thyroiditis −− Patients with the fibrous variant of Hashimoto thyroiditis are hypothyroid (although Riedel thyroiditis can also be associated with hypothyroidism), have high antibody titers, and lack pressure symptoms. The thyroid gland in fibrosing Hashimoto thyroiditis is also involved by fibrosis, but the capsule remains intact and may be separated from adjacent structures. Microscopically, fibrosis appears more typical in fibrosing Hashimoto thyroiditis, rather than the keloid-like collagen seen in Reidel fibrous thyroiditis. Occlusive phlebitis and vasculitis may be seen in Riedel thyroiditis, but not in the fibrous variant of Hashimoto thyroiditis ♦♦ Granulomatous thyroiditis −− Giant cells are not prominent in Riedel thyroiditis, which helps to differentiate Riedel thyroiditis from granulomatous thyroiditis. Granulomatous thyroiditis also lacks the extensive fibrosis seen in Riedel thyroiditis

Fig. 20.9. Lymphocytic thyroiditis (painless thyroiditis): VimSilvermann needle biopsy of a patient with transient hyperthyroidism. There is a moderately heavy lymphocytic infiltrate involving variable-sized thyroid follicles.

Lymphocytic Thyroiditis Clinical ♦♦ Lymphocytic thyroiditis is an autoimmune thyroiditis caused by autoantibodies directed against thyroglobulin and other follicular cell antigens ♦♦ Lymphocytic thyroiditis is usually seen in children and adults and is more common in women (F:M = 2:1). Patients present with asymptomatic goiter and may have transient hyperthyroidism. The process usually resolves within 1 year

Macroscopic ♦♦ The thyroid shows mild to moderate enlargement and has a slightly nodular appearance

Microscopic (Figs. 20.9 and 20.10) ♦♦ The thyroid shows scattered interstitial lymphoid follicles with germinal centers. The follicles typically show minimal reaction to inflammation, but there may be some mild atrophy or Hürthle cell change

Differential Diagnosis ♦♦ Hashimoto thyroiditis −− Hashimoto thyroiditis has larger, more numerous lymphoid follicles and scattered plasma cells and histiocytes than lymphocytic thyroiditis. Hürthle cell change is present in Hashimoto thyroiditis ♦♦ Graves disease −− Graves disease is associated with hyperthyroidism. The thyroid shows diffuse follicular hyperplasia often with a prominent papillary architecture

Fig. 20.10. Lymphocytic thyroiditis (painless thyroiditis): Focal heavy lymphocytic infiltrate with follicles showing degenerative changes characterized by swelling of lining follicular cells and inflammatory infiltration.

Hashimoto Thyroiditis Clinical ♦♦ Hashimoto thyroiditis is an autoimmune thyroiditis characterized by a goiter and circulating antithyroglobulin and antithyroid peroxidase (antimicrosomal) antibodies ♦♦ Classically, Hashaimoto thyroiditis occurs in young to middleaged females (30–50 years old; F:M = 10:1). Hashimoto ­thyroiditis is the most common thyroid disease in children and adolescents. Different HLA haplotypes have been associated with Hashimoto disease. Hashimoto thyroiditis is associated with other autoimmune diseases. Hashimoto thyroiditis may be associated with autoimmune disease of adrenals (Addison disease), pancreas (diabetes), or stomach (pernicious anemia). Individuals with Down syndrome

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have an increased susceptibility to autoimmune thyroid diseases, including Hashimoto thyroiditis ♦♦ Patients present with diffuse firm goiter, tenderness, and hyperthyroidism. As the disease progresses, thyroid function decreases, eventually resulting in hypothyroidism ♦♦ There is an increased risk of lymphoma, leukemia, and thyroid carcinoma

Macroscopic ♦♦ The thyroid gland shows diffuse, firm enlargement. The cut surface may show areas of fibrosis and pale tan color due to the chronic inflammatory infiltrate, unlike the beefy red diffuse appearance of the thyroid in Graves disease. Increasing fibrosis is noted with increasing age

Microscopic (Figs. 20.11 and 20.12) ♦♦ The thyroid shows marked interstitial lymphocytic inflammation with prominent lymphoid follicles with germinal centers. The thyroid follicles are small and atrophic lined by oxyphilic epithelium (Hürthle cells). Interstitial fibrosis may accentuate lobular architecture. Regenerative hyperplasia and squamous metaplasia may be seen

Essentials of Anatomic Pathology, 3rd Ed.

Variants ♦♦ Fibrosing Hashimoto thyroiditis −− Approximately 10% of Hashimoto thyroiditis shows prominent fibrosis, which is usually seen in elderly patients. The thyroid shows marked enlargement with some adhesion of gland to surrounding tissue (although surgical planes are readily identifiable). Histologically extensive fibrosis, follicular atrophy with Hürthle cell change, squamous metaplasia and lymphocytes and plasma cells are seen −− This variant may be confused with Riedel thyroiditis as well as carcinoma due to its adherence to adjacent structures. The parenchyma of Hashamoto thyroiditis retains its normal lobular architecture and lacks cytologic features of malignancy −− The prominent lymphoplasmacytic infiltrate in Hashimoto thyroiditis can be mistaken for malignant lymphoma. Because thyroid lymphomas usually arise in the setting of Hashimoto thyroiditis, a high index of suspicion is needed when examining thyroid tissues with prominent lymphoid infiltrates

Differential Diagnosis ♦♦ Lymphocytic thyroiditis −− Lymphocytic thyroiditis shows milder inflammation, with scattered lymphoid follicles and little or no reactive changes in thyroid follicles ♦♦ Graves disease −− The follicles in Graves disease appear hyperplastic, rather than atrophic

Postpartum Thyroiditis

Fig. 20.11. Hashimoto thyroiditis: The follicles are smaller than normal and lined by oxyphilic epithelium. There is a patchy lymphocytic infiltrate with germinal centers.

♦♦ Postpartum thyroiditis is an autoimmune disorder, associated with microsomal antibodies, which affects women in the first postpartum year. Postpartum thyroiditis has an early thyrotoxic phase and a longer hypothyroid phase. Histologically, postpartum thyroiditis is shown by focal or diffuse chronic thyroiditis and resembles spontaneous silent thyroiditis. The hypothyroid phase is characterized by follicular disruption and hyperplasia while focal lymphocytic thyroiditis is seen in the recovery phase

Focal Lymphocytic Thyroiditis ♦♦ Focal lymphocytic thyroiditis (nonspecific thyroiditis, focal autoimmune thyroiditis) is thought to be an incidental finding, which usually affects elderly, is more common in women than in men, and is relatively common with autopsy studies showing 20% of thyroids are involved. The thyroid shows dense lymphoid aggregates with or without germinal centers

Graves Disease Clinical Fig. 20.12. Hashimoto thyroiditis: Oxyphilic cells with granular cytoplasm together with a lymphocytic infiltrate.

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♦♦ Graves disease (diffuse hyperplasia) is an autoimmune thyroiditis caused by autoantibodies directed against thyroid stimulating hormone receptors, resulting in chronic follicular stimulation and hyperthyroidism (diffuse toxic goiter)

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♦♦ Graves disease is most commonly seen in young females (20–40 years old; F:M =  4:1) and may occur in children. In the United States, Graves disease affects about one of every 2,000 people ♦♦ Patients present with diffuse goiter and hyperthyroidism. Patients often have a family history of autoimmune diseases. Graves disease is diagnosed clinically by physical examination and laboratory testing including elevated serum thyroxine with low TSH, and high radioactive iodine uptake ♦♦ Untreated, Graves disease can cause severe thyrotoxicosis, osteoporosis, catabolism of muscle and bone with myopathy, among others complications

Macroscopic (Fig. 20.13) ♦♦ The thyroid shows mild to moderate diffuse enlargement, has soft consistency and pink tan color

Microscopic (Figs. 20.14–20.16) ♦♦ The thyroid shows markedly hyperplastic follicles lined by active tall columnar cells showing clear, sometimes vacuolated, cytoplasm. Colloid appears pale and depleted, with scalloped edges at the epithelial border. Epithelial hyperplasia resulting in papillae with fibrovascular cores, resembling papillary carcinoma is characteristically seen ♦♦ Interstitial lymphoid aggregates with germinal centers may be present ♦♦ The classic appearance is usually altered by preoperative medication. Iodine therapy can greatly diminish hyperplasia, resulting in an almost normal-appearing gland with involution of the epithelium with cuboidal rather than columnar cells, increased colloid, and decreased vascularity while propylthiouracil and methimazole therapy are associated with hyperplastic changes

Differential Diagnosis ♦♦ Papillary thyroid carcinoma −− Papillary thyroid carcinoma generally presents as a mass, rather than a diffuse process. Histologically, classic cytologic features of papillary thyroid carcinoma (ground glass nuclei, nuclear grooves, and nuclear pseudo inclusions) are identified.

Fig. 20.13. Graves disease: Enlarged thyroid (94 g) with a glistening, finely nodular cut surface.

Fig.  20.14. Graves disease: Irregularly shaped follicles are partially filled with pale colloid.

Fig.  20.15. Graves disease: Follicles show multiple papillary infoldings and some scalloping of the colloid.

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Fig. 20.17. Multiple degenerating and hemorrhagic nodules.

Nontoxic Simple and Multinodular Goiters Clinical

Fig. 20.16. Graves disease: Cubical and low columnar eosinophilic epithelium lines follicles, one of which has a papillary infolding. −− In difficult cases of Graves disease with papillary hyperplasia, p27 protein and HBME-1 may be used to separate these two lesions. p27 shows higher expression in Graves disease compared with papillary thyroid carcinoma ♦♦ Lymphocytic thyroiditis −− Lymphocytic thyroiditis usually affects young patients who are euthyroid. Thyroid follicles appear normal or show only mild atrophy when compared with the hyperplastic follicles classic of Graves disease ♦♦ Hashimoto thyroiditis −− Hashimoto thyroiditis show atrophy and Hürthle cell change, not hyperplasia ♦♦ Toxic nodular goiters −− Toxic nodular goiters can also be associated with hyperthyroidism, but appear more multinodular than the diffuse appearance of the thyroid in Graves disease. Additionally, histologic involvement of the thyroid is focal in toxic nodular goiters while it is diffuse in Graves disease

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♦♦ Goiter means enlarged thyroid gland. Simple nontoxic goiters can be sporadic or endemic. Sporadic nontoxic goiter is the most common nontoxic goiter. Sporadic goiters are identified in approximately 5% of the population, are more common in women, and are uncommon in children. The cause of sporadic goiters is generally unknown, but they can be associated with some medications and may have a hereditary component. When the thyroid cannot produce sufficient thyroid hormone, the gland enlarges to overcome this deficiency. Endemic goiters are seen in areas of iodine deficiency and have become relatively uncommon due to iodized table salt ♦♦ Most patients are euthyroid, presenting with symptoms of simple or multinodular thyroid enlargement, which may be generalized or have dominant nodule. Goiters may cause obstructive symptoms due to tracheal or esophageal compression and voice change due to laryngeal nerve compression. Goiters are usually slow-growing and painless. A sudden increase in growth, a new nodule, or a dominant nodule in a multinodular goiter are concerning for malignancy. Goiters are treated with thyroxine, radioactive iodine, and surgery and can recur

Macroscopic (Fig. 20.17) ♦♦ The thyroid gland is enlarged in both simple and multinodular goiters. Simple goiters are diffusely enlarged, while multinodular goiters show multiple nodules grossly. The normal thyroid gland weighs 15–25 g, while goiterous thyroid glands can weigh over a hundred grams

Microscopic (Fig. 20.18) ♦♦ The histologic features of goiters can be varied. Goiters are generally composed of a mixture of small follicles with cuboid lining cells and large follicles with flattened lining cells. Large cystic structures showing hyperplastic areas of follicles or papillary structures (foci of secondary proliferation) are often seen ♦♦ Endemic and sporadic multinodular goiters show similar histologic features

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Toxic Multinodular Goiter Clinical ♦♦ Toxic multinodular goiters are multinodular goiters associated with thyrotoxicosis, although these patients lack the ophthalmic changes seen in Graves disease. Multinodular goiters may be present for years, and may insidiously become toxic goiters

Macroscopic ♦♦ Grossly toxic multinodular goiters appear similar to nontoxic multinodular goiters. Both are enlarged thyroids composed of multiple nodules with fibrosis

Microscopic Fig. 20.18. Macrofollicular nodule and colloid cyst. ♦♦ Multinodular goiters show many nodules of different sizes, some encapsulated, compress the adjacent thyroid parenchyma. An individual nodule, particularly a dominant nodule, in a multinodular goiter can be difficult to be distinguished from a follicular adenoma ♦♦ Degenerative changes with hemorrhage, fibrosis, and calcification are common

Differential Diagnosis

♦♦ Toxic multinodular goiters are composed of a mixture of hypercellular nodules with tall columnar cells, papillary hyperplasia, and inactive appearing nodules with flat epithelium ♦♦ The pattern of hypercellular nodules of toxic multinodular goiter differs from that of dyshormonogenetic goiters, which show more diffuse hyperplasia throughout the gland

Papillary Thyroid Carcinoma Clinical

♦♦ Dyshormonogenetic goiters are large and multinodular

♦♦ Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma, accounting for approximately 80% of thyroid carcinomas. They occur in adults and children, with females being affected more commonly than males. Rare familial PTC can occur ♦♦ A variety of thyroid disorders including Graves, Hashimoto thyroiditis, and hyperplastic nodules have been identified with PTC. PTCs are associated with a history of radiation exposure, and radiation associated tumors have been associated with aggressive behavior and solid growth pattern ♦♦ Papillary thyroid carcinomas are often irregular or well demarcated masses on ultrasound and cold nodules on radioactive iodine scan ♦♦ The prognosis of PTC is generally excellent, with overall survival greater than 90%. Poor prognostic factors include increased age (>40 years), male sex, large tumor size, multicentricity, vascular invasion, extrathyroid extension, distant metastases, and dedifferentiation to poorly differentiated and anaplastic thyroid carcinoma. Variants of PTC with more aggressive behavior include tall cell, columnar cell, and solid variant ♦♦ Papillary thyroid carcinomas are often treated by complete thyroidectomy, ipsilateral lymph node dissection, and radioactive iodine can be used to ablate any remaining tumor

Microscopic

Macroscopic

♦♦ The nodules are diffusely hypercellular and show an irregular growth pattern. The follicular cells show nuclear atypia and mitotic activity and can be confused with malignancy. Thyroid carcinomas, particularly follicular, can occur in these goiters

♦♦ Papillary thyroid carcinomas are variably sized, from microscopic to >10 cm, usually 2–3 cm, solid, white, infiltrating masses, often with a granular cut surface and calcifications. These tumors may be single or multiple and may undergo cystic change

♦♦ Follicular neoplasms −− Follicular adenomas are difficult to be separated from a nodule of a multinodular goiter, particularly a dominant nodule. Multinodular goiters have multiple nodules, while follicular adenomas are more often single. However, clonality has been shown in adenomatous nodules. Follicular carcinoma arising in the setting of a multinodular goiter must show a clearly invasive growth pattern

Dyshormonogenetic Goiter Clinical ♦♦ Dyshormonogenetic goiters are usually due to an autosomal recessive genetic defect in the synthesis of thyroid hormone. Although most dyshormonogenetic goiters develop in childhood, they can be identified over a wide age range. Patients present with hypothyroidism, goiter, or growth deficiencies. Patients with congenital goiter and congenital sensorineural deafness have a defect in the Pendred syndrome gene, 7q22-31.1, which encodes pendrin, an iodide/ chloride transporter

Macroscopic

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Microscopic (Figs. 20.19 and 20.20) ♦♦ Papillary thyroid carcinomas are composed of complex papillae with single layer or stratified epithelial cells supported by branching fibrovascular cores lined by follicular cells with characteristic cytologic features. Classic cases usually show a predominance of papillary structures, although this feature can be extremely variable. Foci of more

♦♦

♦♦

♦♦ ♦♦

follicular areas and solid areas as well as squamous metaplasia can be seen Diagnostic nuclear features include nuclear enlargement, nuclear irregularity, ground glass nuclei (large optically clear “Orphan Annie” nuclei that tend to overlap), nuclear grooves (due to folded nuclear membrane), and nuclear pseudoinclusions (due to intranuclear cytoplasmic invagination) Psammoma bodies (laminated basophilic bodies) occur in 50% of cases and are more common in tumors with prominent papillary growth The colloid in PTC is often darker than that of the surrounding normal thyroid The stroma is often abundant, fibrous, and sclerotic. A lymphocytic infiltrate can be seen at the periphery of the tumor lobules. Cystic change is common. Mitotic figures and necrosis are uncommon. A significant number of cases (25–75% depending on sampling) show multiple tumor foci

Immunohistochemistry

Fig.  20.19. Papillary carcinoma: The tumor has papillary and follicular components separated by a fibrous bands.

♦♦ Papillary thyroid carcinomas are positive for thyroglobulin, thyroid transcription factor (TTF-1), and keratin (see Table  20.1). Papillary thyroid carcinomas are negative for chromogranin, synaptophysin, and calcitonin. Immuno­ histochemical markers that may be helpful confirming a diagnosis of PTC include HMBE-1, galectin-3, cytokeratin 19, and CITED-1

Molecular Genetics ♦♦ BRAF mutations and RET/PTC rearrangements are alternative events in the pathogenesis of PTC ♦♦ BRAF mutations, especially BRAF(V600E), is detected in 36–69% of PTC. BRAF mutations are frequent in PTC with papillary or mixed papillary-follicular growth pattern, Warthin-like PTC, micropapillary PTC, and oncocytic/ oxyphilic (Hürthle cell) variant of PTC. BRAF mutations are rarely detected in pediatric or radiation associated PTC. BRAF mutations are also present in poorly differentiated and anaplastic carcinomas arising from PTC ♦♦ RET/PTC rearrangement is identified in approximately 20–30% of PTC, although the prevalence varies among geographical sites and tumor subtypes. This rearrangement is particularly common in radiation associated PTC. RET/ PTC1 and RET/PTC3 account for greater than 90% of the rearrangements. RET/PTC1 is more common in papillary microcarcinomas, tumors with classic papillary growth, and a more benign clinical course, while RET/PTC3 is more common in the solid variant of PTC and aggressive behavior

Variants

Fig. 20.20. Papillary carcinoma: Papillary processes with capillary cores mantled by medium-sized cells with eosinophilic cytoplasm and slightly irregular open nuclei with occasional grooves.

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♦♦ Papillary microcarcinoma −− Papillary microcarcinoma is defined as a PTC measuring 1 cm or less. These tumors are usually indolent, incidental findings in thyroids removed for benign clinical nodules or thyroditis. Autopsy and surgical studies show that approximately 8% of thyroids when serially sectioned will have a papillary microcarcinoma

Endocrine Pathology

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Table 20.1. Immunohistochemical Profile of Thyroid Tumors Tumor

Thyroglobulin

TTF

Keratin

Calcitonin

Chromogranin

Synaptophysin

Papillary thyroid carcinoma

+

+

+

−

−

−

Follicular and Hürthle cell thyroid tumors

+

+

+

−

−

−

Poorly differentiated thyroid carcinoma

+

+

+

−

−

−

Anaplastic thyroid carcinoma

Focal

Focal

Focal

−

−

−

Medullary thyroid carcinoma

−

+

+ (CAM 5.2)

+

+

+

TTF thyroid transcription factor

−− The treatment for papillary microcarcinoma has been controversial. Papillary microcarcinomas presenting as a clinical mass or a lymph node metastasis are treated as a clinical cancer. In up to 15–20% of papillary microcarcinomas, another focus is the contralateral lobe, and that long-term recurrent disease may reach 20% in the absence of complete resection. Despite their small size, 5% of these microcarcinomas may be associated with invasion of the capsule or distant metastases. When papillary microcarcinomas present as a clinically occult incidental finding, the behavior appears more indolent than those presenting clinically, and some suggest a conservative approach to management ♦♦ Follicular variant of PTC −− Follicular variant of PTC (FVPTC) is the most common variant of PTC and is also the most difficult type to diagnose. Encapsulated tumors can be particularly problematic if the tumor shows only borderline features for PTC. These tumors can show a microfollicular, macrofollicular, or diffuse growth pattern. Differentiating FVPTC from the follicular neoplasms can be extremely difficult. Cytologic features classic of PTC may only be focally noted in FVPTC. Important diagnostic features of FVPTC are nuclear pseudoinclusions (cytoplasmic invaginations into the nucleus), abundant nuclear grooves, and ground glass nuclei. Immunohistochemical studies such as HBME-1, CK19, galectin, and CITED are helpful in separating some cases of FVPTC from follicular adenoma. FVPTC behaves similarly to conventional PTC ♦♦ Tall cell variant of PTC −− The tall cell variant of PTC is more common in the elderly and in males. These tumors are usually large at diagnosis. Histologically, prominent papillary structures are lined by cells that are least twice as tall as they are wide. The tall cells have basally located nuclei and abundant eosino-

♦♦

♦♦

♦♦

♦♦

philic cytoplasm. The tall cell variant of PTC is associated with extrathyroidal disease, vascular invasion, recurrence, and metastases. These are aggressive tumors with shorter disease-free survival than conventional PTC, and have a fatality rate of up to 25% Columnar variant of PTC −− The columnar variant of PTC is an uncommon, aggressive variant of PTC that occurs over a wide age range, can metastasize widely, and usually does not respond to radioactive iodine or chemotherapy. The columnar variant has a prominent papillary architecture and elongated cells with nuclear stratification and scant cytoplasm Solid variant of PTC −− The solid variant of PTC is uncommon, comprising only 2–3% of PTC, is more common in children, and may be associated with radiation exposure. This variant has a less favorable prognosis than classic PTC Diffuse sclerosing variant of PTC −− The diffuse sclerosing variant of PTC is more common in women and younger patients. This variant is characterized by diffuse thyroid involvement, intrathyroid ­lymphatic spread, squamous metaplasia, prominent psammoma bodies, fibrosis, and a lymphocytic infiltrate. This variant shows frequent cervical lymph node as well as lung metastases. Some studies have found decreased ­survival while others have shown similar to survival to classic PTC Oxyphilic (oncocytic/Hürthle cell variant of PTC) −− The oxyphilic (oncocytic/Hürthle cell) variant of PTC is uncommon. These tumors often show a papillary architecture, have oxyphilic cytoplasm, and nuclear features classic of PTC. This variant may behave similarly to or more aggressively than classic PTC, depending on the study

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♦♦ Warthin-like variant of PTC −− The Warthin-like variant of PTC resembles a Warthin tumor of the salivary gland with oxyphilic cells and lymphocytic stroma. However, the cytologic features are classic of PTC, and these tumors behave similarly to classic PTC ♦♦ Cribriform-morular variant of PTC −− The cribriform-morular variant of PTC can occur sporadically, but often occurs in the setting of familial adenomatous polyposis with germ line APC gene mutations. These tumors are often multicentric and are more common in women. These tumors show cribriform, solid/trabecular, and morular growth and cytologic features classic of PTC. These tumors behave similarly to conventional PTC ♦♦ Clear cell variant of PTC −− The clear cell variant of PTC is uncommon and behaves similar to conventional PTC. This variant must be differentiated from other clear cell tumors such as metastatic renal cell carcinoma ♦♦ Papillary thyroid carcinoma with nodular fasciitis-like stroma −− Rarely, PTC shows prominent nodular fasciitis-like stroma that can be mistaken for a mesenchymal tumor or an anaplastic thyroid carcinoma. Small tubules and nests of epithelioid cells with cytologic features characteristic of PTC are noted in a nodular-fasciitis-like stroma ♦♦ Papillary thyroid carcinoma with lipomatous stroma −− Papillary thyroid carcinoma can show a lipomatous stroma. Lipomatous stroma is not specific for PTC as it can also be seen in adenomatous nodules, follicular neoplasms, goiters, and lymphocytic thyroiditis

Differential Diagnosis ♦♦ Graves disease −− Graves disease can show papillary architectural features, but it lacks typical nuclear features such as nuclear clearing, large nuclei with irregular nuclear membranes, nuclear clearing (“Orphan Annie” nuclei), nuclear grooves, and intranuclear holes are helpful in separating PTC from Graves ♦♦ Hyalinizing trabecular tumor (Figs. 20.21 and 20.22) −− The nuclei in hyalinizing trabecular tumors are similar to those of PTC, and occasional psamomma bodies can be seen in hyalinizing trabecular tumors. However, hyalinizing trabecular tumors often resemble neuroendocrine neoplasm (paraganglioma or medullary thyroid carcinoma). Hyalinizing trabecular tumors are characterized by trabecular growth pattern with prominent intratrabecular hyaline material. Hyalinizing trabecular tumors show a characteristic cytoplasmic staining pattern for MIB1 (Ki-67), which can also be helpful in their diagnosis ♦♦ Follicular carcinoma −− Follicular thyroid carcinomas may resemble PTC, particularly FVPTC. Follicular thyroid carcinomas do not

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Fig. 20.21. Hyalinizing trabecular adenoma: Well circumscribed, solid, tan tumor.

Fig. 20.22. Hyalinizing trabecular adenoma: Abundant hyaline material. Nuclei are polymorphic, many are oval. Intranuclear and cytoplasmic inclusions are present.

show papillary architecture or classic cytologic features (nuclear grooves, intranuclear cytoplasmic inclusions) of PTC ♦♦ Follicular adenoma − − Follicular adenomas may resemble PTC, particularly FVPTC. Follicular adenomas do not show papillary architecture, invasive growth, or classic cytologic features (nuclear grooves, intranuclear cytoplasmic inclusions) of PTC. Cytologic features classic of PTC may only be focally noted in follicular variant of PTC often at the peripheral aspect of the tumor. Important features to diagnose follicular variant of PTC are nuclear pseudoinclusions (cytoplasmic invaginations into the nucleus), abundant nuclear grooves, and ground glass nuclei. Immunoperoxidase studies, including HBME-1, galectin-3, and cytokerain 19 can also be helpful in difficult cases as PTC are usually positive

Endocrine Pathology

♦♦ Hürthle cell tumors −− The Warthin-like variant and oxyphilic variant of PTC can be mistaken for benign Hürthle cell tumors. Cytologic features classic of PTC are helpful in separating the Warthinlike variant of PTC from Hürthle cell tumors. The prominent lymphoplasmacytic infiltrate seen in Warthinlike variant of PTC is a low power clue to the diagnosis

Hyalinizing Trabecular Tumor Clinical ♦♦ Hyalinizing trabecular tumors are unique can mimic PTC and medullary thyroid carcinoma. The biologic potential has been controversial, but the overwhelming majority of these tumors behave in an indolent fashion. They should probably only be treated as a malignancy when there is obvious capsular or vascular invasion or metastasis

Macroscopic ♦♦ Hyalinizing trabecular tumors are circumscribed, yellow-tan, encapsulated nodules that measuring 0.3–4 cm in diameter

Microscopic (Figs. 20.21 and 20.22) ♦♦ Hyalinizing trabecular tumors are circumscribed or encapsulated solid tumors that show a trabecular growth pattern with prominent extracellular eosinophilic hyaline fibrosis that is reminiscent of amyloid but negative for Congo red ♦♦ The trabeculae and nests of cells are composed of polygonal and elongated cells with oval nuclei with perinuclolar vacuoles, nuclear inclusions, nuclear grooves, and fine granular cytoplasm. The prominent intranuclear cytoplasmic inclusions can cause confusion with PTC ♦♦ Cytoplasmic yellow bodies are frequently noted in hyalinizing trabecular tumors, but these are not specific as they can be seen in other tumors

Immunohistochemistry ♦♦ Hyalinizing trabecular tumors are positive for thyroglobulin and TTF-1 and negative for calcitonin, chromogranin, and CEA. These tumors also show characteristic cytoplasmic and cell membrane staining for MIB-1 (Ki-67) ♦♦ Galectin-3 shows variable staining. HBME-1, a marker that is usually positive in PTC is negative in hyalinizing trabecular tumors

Molecular Genetics ♦♦ Ret protooncogene rearrangements are a common finding in PTC, and have been detected by RT-PCR and immunohistochemistry in some cases. However, some of the cases also harbored PTC, thus this finding is difficult to interpret ♦♦ BRAF mutations are generally not detected in hyalinizing trabecular tumors

Differential Diagnosis ♦♦ Medullary thyroid carcinoma −− The trabecular growth pattern, elongated cells, and hyalinization, which are reminiscent of amyloid, are features of

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hyalinizing trabecular tumor that can be confused with medullary thyroid carcinoma. However, the hyaline material, unlike amyloid, is negative for Congo red. Cytologically, the nuclear features of hyalinizing trabecular tumors are more similar to PTC rather than the neuroendocrine nuclear features seen in medullary thyroid carcinoma. The immunophenotype is also helpful in differentiating these tumors as hyalinizing trabecular tumors are positive for thyroglobulin and negative for chromogranin, synaptophysin, and calcitonin ♦♦ Papillary thyroid carcinoma −− Hyalinizing trabecular tumors show prominent nuclear inclusions, a feature often seen in PTC. However, the nuclear inclusions are much more prominent and numerous in hyalinizing trabecular tumors. Additionally, PTC generally lacks the trabecular growth pattern and prominent stromal hyalinization characteristic of hyalinizing trabecular tumors. HBME-1 is generally positive in PTC and negative in hyalinizing trabecular tumors. Hyalinizing trabecular tumors also show characteristic cytoplasmic membrane staining with MIB1 (Ki-67)

Follicular Adenoma Clinical ♦♦ Follicular adenomas are benign, encapsulated tumors showing follicular differentiation ♦♦ Follicular adenomas occur in 5–10% of the population, predominantly in adults, and are more common in women. Patients present with a palpable nodule showing little to no I131 uptake or as asymmetrical thyroid enlargement

Macroscopic ♦♦ Follicular adenoma is a single encapsulated nodule, 1–3 cm in size. The cut surface varies from gray-tan to pink and fleshy, depending on cellularity and colloid. Larger adenomas may show hemorrhage, cyst formation, fibrosis, and calcification

Microscopic ♦♦ Follicular adenomas have a complete, usually thin, capsule with compression of surrounding thyroid tissue. No invasion of the capsule or vessels is present ♦♦ A variety of growth patterns may be seen within the nodule including microfollicular, macrofollicular, trabecular, solid, and focal pseudopapillary architecture can be seen occasionally (Figs.  20.23 and 20.24). The growth pattern of cells within nodule classically stands in sharp contrast to appearance of normal thyroid parenchyma outside capsule ♦♦ Many histologic variants of follicular adenoma have been described as follicular adenoma with bizarre nuclei, adenolipomas, adenochondromas, mucinous follicular adenomas toxic adenomas, follicular adenomas with clear cell change, follicular adenoma with papillary hyperplasia, and signet ring cell adenomas ♦♦ Atypical follicular adenomas are cellular tumors, which may show nuclear atypia or irregular growth, but lack definitive vascular or capsular invasion. Atypical adenomas usually behave in an indolent fashion

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Immunohistochemistry ♦♦ Follicular adenomas are immunoreactive for thyroglobulin, keratin, and TTF-1 ♦♦ Follicular adenomas generally do not show prominent staining for HBME-1, CK19, galectin 3, and CITED as is often seen in PTC

Molecular Genetics ♦♦ Specific genetic markers diagnostic of follicular adenoma have not been identified. Follicular adenomas frequently show RAS mutations and a small percentage of tumors may show PAX8 to PPAR gamma (peroxisome proliferator-activated receptor gamma) rearrangements

Differential Diagnosis

Fig.  20.23. Cystic adenoma surrounded by a thick fibrous capsule.

♦♦ Follicular thyroid carcinoma −− By definition follicular thyroid carcinomas show capsular or vascular invasion, features not seen in follicular adenomas. The capsule in follicular adenomas is usually not as thick as in follicular carcinoma ♦♦ Follicular variant of PTC −− Differentiating follicular adenoma from FVPTC can be extremely difficult as the tumors show architectural similarities. In most cases, FVPTC shows cytologic features classic of PTC, but classic cytologic features of PTC may only be focally noted often near the capsule in FVPTC. Thus careful histologic evaluation is critical to differentiate these entities. Immunohistochemical markers somewhat helpful in this distinction include HBME-1, CK19, and galectin 3 ♦♦ Adenomatous nodule −− Adenomatous nodules are usually multiple, but may present as a dominant nodule. Adenomatous nodules are often not completely encapsulated. Prominent secondary hyperplastic papillary changes can be seen ♦♦ Hyalinizing trabecular tumor (Figs. 20.21 and 20.22) − − Hyalinizing trabecular tumors with trabecular growth and prominent hyaline material are very helpful in identification of these tumors. The nuclei are similar to PTC, and numerous intranuclear holes can be seen. Hyalinizing trabecular tumor shows a characteristic cytoplasmic membrane staining pattern for MIB1 (Ki-67)

Follicular Thyroid Carcinoma Clinical

Fig.  20.24. Adenoma: Papillations are lined by a uniform ­epithelium with basal hyperchromatic nuclei.

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♦♦ Follicular carcinoma is a malignant epithelial tumor showing follicular differentiation and lacking the diagnostic nuclear features of PTC ♦♦ Follicular carcinomas account for 10–15% of thyroid carcinomas, present as a single palpable neck mass, affect females more commonly than males, and occur at an average age of 50 years. A higher incidence of follicular carcinomas is identified in iodine deficient regions. These tumors show little or no I131 uptake

Endocrine Pathology

♦♦ Unlike PTC, follicular carcinomas show infrequent regional lymph node metastases ♦♦ Patients with follicular thyroid carcinomas usually undergo total thyroidectomy. Minimally, invasive follicular carcinomas have an excellent prognosis with a mortality of 5%, while widely invasive carcinomas have a mortality of 50%

Macroscopic

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♦♦ Vascular invasion or capsular invasion is required for the diagnosis of follicular carcinoma. Capsular invasion often shows a mushroom-type of growth through the capsule. This pattern is different from the linear pattern of tumor associated with hemorrhage, inflammation, and young collagen that is seen in fine-needle aspiration sites ♦♦ Follicular carcinomas have been classified as minimally and widely invasive based on the amount and type of invasion. Minimally, invasive tumors show focal capsular and/or vascular invasion, while widely invasive carcinomas show many areas of invasion

♦♦ Follicular carcinomas are solid, round to oval tumors, tan to brown in color. These tumors may grossly appear encapsulated or may form a poorly circumscribed mass. The capsule is often thicker and more irregular than in follicular adenoma ♦♦ Widely invasive tumors may show gross capsular or vascular invasion. The cut surface usually appears similar to follicular adenoma (gray-tan to pink and fleshy)

Immunohistochemistry

Microscopic (Figs. 20.25 and 20.26)

Molecular Genetics

♦♦ Histologically, follicular carcinoma can be difficult to distinguish from follicular adenoma. Follicular carcinomas are cellular, show a follicular or solid growth pattern, and lack cytologic features of PTC

♦♦ PAX8-PPARgamma translocation t(2;3)(q13;p25) resulting in a fusion oncoprotein has been identified in a proportion of follicular carcinomas and occasionally in follicular adenomas. Follicular carcinomas with PAX8-PPAR gamma occur in younger patients with smaller, but overtly invasive, tumors, which are usually positive for galectin-3 and negative for HBME-1 ♦♦ RAS mutations appear separate from PAX8-PPAR gamma translocations. Follicular carcinomas with RAS mutations are often positive for HBME-1 and negative for galectin-3

♦♦ Follicular carcinomas are positive for thyroglobulin, TTF-1, and low molecular weight cytokeratin (CAM 5.2) (Table 20.1)

Differential Diagnosis

Fig. 20.25. Follicular carcinoma: The tumor shows invasion of a capsular blood vessel.

♦♦ Follicular adenoma −− Follicular carcinomas shows similar encapsulation and growth patterns as follicular adenomas, but follicular carcinomas by definition show capsular and/or vascular invasion. The capsules of adenomas tend to be thinner than carcinomas ♦♦ Papillary carcinoma, follicular variant −− Follicular variant of PTC may show invasive growth; however, cytologic features of PTC are present. Often, focal papillary differentiation is noted

Hürthle Cell Adenoma Clinical ♦♦ Hürthle cell adenomas are benign thyroid neoplasms composed exclusively or predominantly of Hürthle cells (oxyphil cells, oncocytes). Women are affected more commonly than men. The mean age at diagnosis is 55 years. These tumors are solitary nodules on ultrasound and show little or no I131 uptake

Macroscopic (Fig. 20.27)

Fig.  20.26. Follicular carcinoma: The tumor has mushroomed through the wall of its fibrous capsule.

♦♦ Hürthle cell adenomas are solid tumors, round to oval in shape, encapsulated, and have a brown cut surface typical of oncocytic tumors. Areas of hemorrhage, cyst formation, or calcification may be seen in larger tumors. Infarction can be seen in tumors that have undergone fine-needle aspiration biopsy

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Fig.  20.27. Oxyphilic adenoma: Circumscribed slightly lobulated tan-colored tumor.

Microscopic (Figs. 20.28 and 20.29) ♦♦ Hürthle cell adenomas are encapsulated and lack capsular or vascular invasion ♦♦ The tumors can show a variety of growth patterns including follicles, solid areas, trabecular growth, and papillary growth. They are composed of at least 75% Hürthle cells, which are polygonal cells with abundant granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Areas of nuclear pleomorphism (“endocrine atypia”) may be identified

Immunohistochemistry ♦♦ Hürthle cell adenomas are positive for thyroglobulin and TTF-1 and are negative for chromogranin, synaptophysin, and calcitonin

Differential Diagnosis

Fig. 20.28. Oxyphilic adenoma: Solid tumor composed of cells with eosinophilic cytoplasm that shows some follicle formation.

♦♦ Hürthle cell carcinoma −− Hürthle cell adenomas lack capsular and vascular invasion of carcinomas ♦♦ Hyperplastic Hürthle cell adenomatous nodule in Hashimoto thyroiditis −− Adenomatous Hürthle cell nodules are multiple, lack a well-defined capsule, and are associated with a prominent lymphoplasmacytic infiltrate ♦♦ Hürthle cell/oxyphil/oncocytic variant of PTC −− Hürthle cell adenomas lack cytologic features classic of PTC

Hürthle Cell Carcinoma Clinical ♦♦ Hürthle cell carcinomas malignant neoplasms composed predominantly or exclusively of Hürthle (oncocytic/oxyphilic) cells ♦♦ Hürthle cell carcinoma accounts for 2–3% of thyroid carcinomas. Women are more commonly affected than men. The mean age at diagnosis is 55 years. Hürthle cell carcinoma is

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Fig. 20.29. Oxyphilic adenoma: Large, poorly demarcated cells with granular eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. a well-demarcated nodule on ultrasound and shows little or no I131 uptake ♦♦ Hürthle cell carcinomas are slightly more aggressive than follicular carcinomas and have an overall 5-year survival

Endocrine Pathology

of 50–60%. Hürthle cell carcinomas show extrathyroidal invasion more frequently than follicular carcinomas, and show lymph node metastases more often than follicular carcinomas. However, the most common sites of metastases are lung and bone, followed by regional lymph nodes. Poor prognostic factors include large tumor size and vascular invasion

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♦♦ Oxyphilic variant of medullary thyroid carcinoma −− Hürthle cell carcinomas lack the neuroendocrine nuclear features of medullary thyroid carcinoma. In difficult cases, immunohistochemical studies can be helpful as Hürthle cell carcinomas lack staining for chromogranin, synaptophysin, and calcitonin

Macroscopic ♦♦ Hürthle cell carcinomas are solid, encapsulated, round to oval tumors, with a brown cut surface. They are generally larger than adenomas and have a thicker more irregular capsule. Widely invasive tumors may show gross invasion of the capsule or vessels

Microscopic ♦♦ Hürthle cell carcinomas are cellular tumors, composed of at least 75% Hürthle cells, and show a follicular, solid, or trabecular growth pattern. Hürthle cells are large polygonal cells with round nuclei and nucleoli, abundant granular eosinophilic cytoplasm, and lack cytologic features of papillary thyroid carcinoma ♦♦ Vascular or capsular invasion is required for the diagnosis of Hürthle cell carcinoma. Capsular invasion often shows a mushroom-type of growth through the capsule. This pattern is different from the linear pattern of tumor associated with hemorrhage, inflammation, and young collagen that is seen in fine-needle aspiration sites. Hürthle cell carcinomas have been classified as minimally or widely invasive based on the amount and type of invasion. Minimally invasive tumors show focal capsular and/or vascular invasion, while widely invasive follicular carcinomas show many areas of invasion

Immunohistochemistry ♦♦ Hürthle cell carcinomas are immunoreactive for thyroglobulin, although staining is not as strong as other thyroid follicular neoplasms (Table 20.1). Hürthle cell carcinomas are also positive for TTF-1 and are negative for chromogranin, synaptophysin, and calcitonin

Molecular Genetics ♦♦ Numeric chromosomal abnormalities including changes in p53 and cyclin D1 and chromosomal gains and have been identified in Hürthle cell carcinomas. These tumors tend to show more chromosomal losses than adenomas. PAX8PPAR gamma rearrangements and RAS mutations are not frequent in Hürthle cell carcinomas. GRIM-19 point mutations were the first mutation relatively specific to Hürthle cell tumors

Differential Diagnosis ♦♦ Hürthle cell adenoma −− Hürthle cell adenomas are usually smaller, have a thinner more regular capsule, and lack diagnostic capsular and vascular invasion of Hürthle cell carcinomas ♦♦ Hürthle cell/oxyphilic variant of PTC −− Hürthle cell carcinomas lack the classic cytologic features of PTC

Poorly Differentiated Carcinoma Clinical ♦♦ Poorly differentiated carcinomas are follicular cell neoplasms that are in between well-differentiated follicular and papillary carcinomas and undifferentiated or anaplastic carcinomas ♦♦ Patients usually present with a large solitary thyroid mass. They often have a history of recent thyroid enlargement or enlargement of a tumor that has been present for a number of years. Patients are usually >50 years of age, and women are affected more commonly than men. Poorly differentiated thyroid carcinomas appear to be more common in Italy and Latin America ♦♦ Treatment is total thyroidectomy with resection of any involved lymph nodes and radioactive iodine therapy. The prognosis is relatively poor with lymph node and distant metastases being relatively common. The 5-year survival rate is approximately 50%

Macroscopic ♦♦ Poorly differentiated tumors are large, have a pale, gray-white cut surface with areas of necrosis, and may have a pushing border, extrathyroid extension, and satellite nodules

Microscopic ♦♦ These tumors can show a variety of growth patterns including insular, trabecular, and solid. Some authors refer to tumors showing an insular or trabecular growth pattern growth as “insular carcinomas.” Tumors may also show a characteristic “peritheliomatous” pattern of growth with extensive necrosis with preservation of viable cells around vessels. The tumor cells may show nesting or sheet-like growth with necrosis and vascular invasion frequently identified. The tumor cells are small and uniform with vesicular or hyperchromatic nuclei, small nucleoli, and prominent mitotic activity. Areas resembling papillary or follicular carcinomas are identified in some tumors, raising the possibility that these tumors may have dedifferentiated

Immunohistochemical ♦♦ These tumors are positive for thyroglobulin, low molecular weight kininogen, and TTF (see Table 11.1). If present TP53 nuclear staining is usually focal, and high Ki-67 index is common

Molecular Genetics ♦♦ Mutations of H-, K-, and N-RAS are identified in 50% of poorly differentiated carcinomas. Mutations of TP53 mutations are present in 20–30%, and p53 overexpression is

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present in 40–50%. A small percentage of tumors may show BRAF mutation, RET/PTC, or NTRK1 rearrangements

Differential Diagnosis ♦♦ Medullary thyroid carcinoma −− Medullary thyroid carcinomas show neuroendocrine differentiation with stippled chromatin and are positive for chromogranin, synaptophysin, and calcitonin ♦♦ Follicular carcinoma −− Follicular carcinomas lack the nuclear atypia, prominent mitotic figures, and necrosis seen in poorly differentiated thyroid carcinoma ♦♦ Solid variant of PTC −− Poorly differentiated carcinomas often show prominent mitotic activity and areas of necrosis and lack the cytologic features classic of PTC ♦♦ Metastatic carcinomas to the thyroid −− Poorly differentiated thyroid carcinomas are positive for TTF-1, a marker helpful in differentiating primary thyroid carcinomas from metastases, except those from the lung which also show positivity for TTF-1

Fig. 20.30. Anaplastic carcinoma: The tumor occupies most of the right lobe of thyroid.

Anaplastic Thyroid Carcinoma Clinical ♦♦ Anaplastic (undifferentiated) thyroid carcinoma is a highly malignant tumor composed in part or entirely of undifferentiated cells with immunohistochemical and ultrastructural features supporting epithelial differentiation ♦♦ These tumors usually present as a rapidly expanding mass with symptoms of regional invasion (dysphagia, dyspnea, or dysphonia) in elderly patients. Females are affected more commonly than males (1.5:1) ♦♦ At surgery, invasion of adjacent structures including the neck muscles, trachea, esophagus, laryngeal nerve, and larynx are common. Almost half of all patients have distant metastases at diagnosis. The most common metastatic sites include lung, bone, and brain. These are highly aggressive tumors with a mortality rate of greater than 90% and a mean survival of 6 months

Macroscopic (Fig. 20.30) ♦♦ The tumors are grossly invasive, replace the thyroid, and extensively involve regional neck structures. The tumors have a white to tan cut surface and are firm to hard. Hemorrhage and necrosis are common

Microscopic (Fig. 20.31) ♦♦ The tumors can be composed of different cell types, sometimes in combination, including spindle cells, pleomorphic multinucleated and epithelioid cells. Mitotic activity, necrosis, and angiolymphatic invasion are often prominent. Areas of typical papillary or follicular carcinoma may be seen, suggesting dedifferentiation from a more differentiated thyroid carcinoma. In cases where anaplastic pattern represents minority of tumor, the prognosis is slightly better

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Fig.  20.31. Anaplastic carcinoma: Solid sheet of pleomorphic malignant cells with focal necrosis.

Immunohistochemistry ♦♦ Anaplastic thyroid carcinomas show positivity for keratin, often low molecular weight keratin, although the staining is usually not strong and diffuse. These tumors are positive for vimentin and TP53. TTF-1 immunopositivity is focally seen. Strong diffuse staining for TTF-1 would favor a pulmonary metastasis over an anaplastic thyroid carcinoma

Molecular Genetics ♦♦ Anaplastic thyroid carcinomas may show overexpression of cyclin D1, inactivation of PTEN and p16, decreased expression of p27, TP53 mutation, b-catenin gene (CTNNB1) mutation, and chromosomal alterations

Differential Diagnosis ♦♦ Sarcoma −− Anaplastic thyroid carcinomas can show prominent spindling and can be mistaken for sarcomas. Cytokeratin and

Endocrine Pathology

focal TTF-1 immunostaining are helpful in confirming a diagnosis of anaplastic thyroid carcinoma ♦♦ B-cell lymphoma −− Lymphomas can present as a rapidly growing thyroid mass. Primary thyroid lymphomas are often B-cell lymphomas and frequently arise in the setting of Hashimoto thyroiditis. Immunohistochemical studies can be useful in these cases ♦♦ Metastatic carcinomas to the thyroid −− Metastases to the thyroid can be differentiated from anaplastic thyroid carcinoma with immunohistochemical studies. One caveat is that TTF-1 positivity in anaplastic thyroid carcinomas is usually quite focal, thus the presence of strong diffuse TTF-1 positivity would favor a pulmonary metastases to the thyroid over a primary anaplastic thyroid carcinoma

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Fig. 20.32. C-cell hyperplasia: Two follicles each exhibit a collar of sharply demarcated C-cells.

C-Cell Hyperplasia Clinical ♦♦ Hyperplasia of C-cells is seen in association with (and thought to be precursor of) medullary thyroid carcinoma, although this may be seen in association with other tumors and conditions and as physiologic C-cell hyperplasia with over-stimulation by TSH. C-cell hyperplasia is commonly associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma. Patients with neoplastic C-cell hyperplasia usually undergo total thyroidectomy as it may progress to medullary thyroid carcinoma if untreated

Macroscopic ♦♦ C-cell hyperplasia may not be evident grossly, although a few small 1- to 2-mm foci in the middle to upper portions of the thyroid lobes may be identified in familial disease ♦♦ When a thyroidectomy has been performed in the setting of MEN2A, MEN2B, or familial medullary thyroid carcinoma, the gland should be serially sectioned with particular attention to the junction of the upper and middle one-third of the lobes as this is the area of highest concentration of C-cells and immunoperoxidase studies performed with chromogranin, synaptophysin, and calcitonin

Fig. 20.33. C-cell hyperplasia: C-cells with ample slightly basophilic cytoplasm surrounding and between thyroid follicles.

Microscopic (Figs. 20.32 and 20.33) ♦♦ C-cell hyperplasia is defined by an increase in the total mass of C-cells in the thyroid gland. C-cells can be increased in a diffuse or a nodular form. Nodular C-cell hyperplasia is described as clusters of more than 6 cells in several foci from both lobes. Diffuse C-cell hyperplasia describes an increase in C-cells measured as greater than 50 C-cells per low power field in both lobes

Immunohistochemistry ♦♦ C-cells are positive for calcitonin, low molecular weight keratin (CAM 5.2), synaptophysin, chromogranin, and CEA. Hyperplastic C-cells tend to show greater CEA immunoreactivity than normal C-cells

Differential Diagnosis ♦♦ Reactive and physiologic C-cell hyperplasia −− Reactive C-cell hyperplasia can be seen in lymphocytic thyroiditis, hyperparathyroidism, and adjacent to thyroid neoplasms. The significance of C-cell hyperplasia in patients without a family history of MEN or medullary thyroid carcinoma is unknown ♦♦ Medullary thyroid microcarcinoma −− If C-cells are tumifactive, infiltrative, or there is a desmoplastic response, then they are best classified as a medullary thyroid carcinoma

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Medullary Thyroid Carcinoma Clinical ♦♦ Medullary thyroid carcinoma (MTC) is a neuroendocrine carcinoma composed of C-cells. MTC accounts for 5–10% of thyroid malignancies ♦♦ Patients usually present with a thyroid nodule, while some may present with metastatic disease. Approximately 50% of patients have metastases while diagnosis. Serum calcitonin levels are elevated and these tumors may be associated with ectopic hormone secretion (adrenocorticotrophic hormone, histamine, insulin, serotonin, etc.) ♦♦ Although the majority of MTC occur sporadically, approximately 25% are familial and associated with MEN2A, MEN2B, or familial MTC (FMTC). Patients with sporadic tumors present at an average age of 50 years, while those with familial tumors can present much earlier. Familial tumors are more often bilateral and multicentric. RET mutational analysis is recommended in patients diagnosed with MTC. If a patient has a RET mutation, then genetic testing is offered to the patient’s relatives. Syndrome associated MTC generally presents at an earlier age than sporadic cases. Patients with MEN 2A often present with MTC in early adulthood, while with patients with MEN 2B are often diagnosed as infants or children. FMTC usually presents at an older age than the other syndrome associated MTC patients ♦♦ Patients with MTC are treated with total thyroidectomy and lymph node dissection for metastatic disease. These tumors are radioresistant and chemotherapy resistant and they do not take up reactive iodine. Five- and 10-year survival rates are 83.2% and 73.7%, respectively. Patients with familial tumors diagnosed by biochemical or molecular methods have a better prognosis than patients who are not screened. Poor prognostic factors include older age, male sex, clinical presentation (versus biochemical or molecular), metastatic disease, and high TNM stage. Widespread metastases may be associated with diarrhea, bone pain or flushing, and the five-year survival of about 10%

Macroscopic (Fig. 20.34) ♦♦ MTC are usually nonencapsulated, firm, gray-white tumors that are gritty on cut section. Sporadic tumors are usually single and unilateral, while familial tumors are often multicentric and bilateral

Microscopic (Figs. 20.35–20.38) ♦♦ Medullary thyroid carcinomas usually show infiltrative growth but may appear circumscribed. They are composed of round cells with granular amphophilic cytoplasm and round regular nuclei with coarse chromatin, growing in nests separated by vascular septa and hyalinized collagen ♦♦ The tumor cells can be quite variable and show spindling, giant cells, mucin production, cytologic clearing, pigmentation, plasmacytoid cytomorphology, oncocytic features or can appear almost squamoid. These tumors may show a variety of growth patterns (trabecular, glandular, pseudopapillary) ♦♦ Amyloid (amorphous eosinophilic hyaline material) is classically seen in stroma, although some tumors do not have any

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Fig.  20.34. Medullary carcinoma: Poorly demarcated tumor located at the upper pole of lateral lobe of thyroid.

Fig.  20.35. Medullary carcinoma: Much solid, structureless eosinophilic material (amyloid) in a background of tumor cells without pattern. visible amyloid. Calcification, sometimes coarsely laminated, may be present ♦♦ The surrounding thyroid parenchyma may show C-cell hyperplasia

Immunohistochemistry ♦♦ The tumor cells are positive for calcitonin, chromogranin, synaptophysin, calcitonin gene-related peptides, keratin (cytokeratin 7, CAM 5.2), and TTF-1 and are negative for thyroglobulin. Other neuroendocrine peptides such as somatostatin, bombesin, and pro-opiomelanocortin may also be expressed. The immunostains may also highlight areas of C-cell hyperplasia in the surrounding thyroid parenchyma ♦♦ Amyloid stains appropriately with various reagents (cresyl violet, sulfated alcian blue) demonstrate typical apple green birefringence with congo red under polarized light

Molecular Genetics ♦♦ The heritable forms of medullary thyroid carcinoma, MEN 2A, MEN 2B, and FMTC, are autosomal dominant diseases caused by germline mutations in RET protooncogene. Thus, RET mutation testing is recommended for patients diagnosed

Endocrine Pathology

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Fig.  20.36. Medullary carcinoma: Large aggregates of tumor cells create a carcinoid-like picture. Fig. 20.38. Medullary carcinoma: Oval and spindling cells with vesicular nuclei.

Variants

Fig.  20.37. Medullary carcinoma: Solid sheet of cells with eosinophilic cytoplasm and eccentric nuclei. with MTC. If the patient is found to be positive then their relatives are also offered testing. The vast majority of cases of MEN 2B are associated with germline mutation in RET protooncogene at codon 918 (>95%) or 883 (2–3%). MEN 2A and FMTC are associated with RET mutations involving codons 609, 611, 618, 620, and 634. FMTC can also be associated with mutations of 768, 790, 791, 804, 844, and 891, which are associated with later onset and less aggressive disease

♦♦ Medullary thyroid microcarcinoma −− Medullary thyroid microcarcinomas are defined as tumors less than 1 cm in diameter. They may be associated with elevated serum calcitonin, but are often discovered as incidental findings during surgery for thyroid nodules. Microcarcinomas have a much better prognosis than larger MTC, and lymph node metastases are rarely present at the time of surgery in patients with medullary microcarcinomas ♦♦ Oncocytic/oxyphilic variant of MTC −− MTC may show prominent Hürthle/oxyphilic cytologic changes, but the nuclear changes are of a neuroendocrine tumor. The finding of amyloid is also a helpful clue to the diagnosis of MTC

Differential Diagnosis ♦♦ Papillary thyroid carcinoma −− MTC may show papillary architectural features, but lack the classic cytologic features of PTC. Immunoperoxidase studies can be helpful as both are positive for TTF-1, but MTC are negative for thyroglobulin and are positive for chromogranin, synaptophysin, and calcitonin

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Hürthle cell carcinoma −− The oxyphilic/oncocytic variant of MTC can be confused with Hürthle cell neoplasms. Immunoperoxidase studies can be helpful as both are positive for TTF-1, but MTC are negative for thyroglobulin and are positive for chromogranin, synaptophysin, and calcitonin ♦♦ Atypical laryngeal carcinoid −− Both atypical laryngeal carcinoid and MTC are neuroendocrine tumors and both show positivity for chromogra-

nin, synaptophysin, and calcitonin; thus TTF-1 is essential to differentiate these entities as atypical laryngeal carcinoid is negative and MTC is positive for TTF-1 ♦♦ Neuroendocrine lung tumors −− Both MTC and neuroendocrine lung tumors are positive for TTF-1, cytokeratin 7, CAM 5.2, chromogranin, and synaptophysin, but neuroendocrine lung tumors are generally negative for calcitonin, a marker positive in MTC

PARATHYROID GLAND Introduction ♦♦ Parathyroid glands produce parathyroid hormone (PTH), which is encoded by the PTH gene on 11p15. PTH promotes calcium entry into blood from bone, kidney, and gastrointestinal tract. PTH stimulates renal calcitrol synthesis, which promotes calcium and phosphorus absorption in the GI tract and stimulates osteoclasts to mobilize calcium from bone. PTH stimulates reabsorption of calcium in the kidney and phosphate clearance. Elevated calcium inhibits conversion of pre-pro-PTH to PTH. Low serum calcium is sensed by a calcium-sensing receptor (CASR) on the surface of parathyroid cells and results in PTH secretion, and high serum calcium inhibits PTH secretion ♦♦ The parathyroid glands are derived from the 3rd (inferior parathyroid glands and thymus) and 4th (superior ­parathyroid glands) branchial pouches. Most people have 4 parathyroid glands, but around 10% of people have >4 parathyroid glands, and a few have <3 parathyroid glands. Parathyroid glands can be identified ectopically in the thyroid, mediastinum, thymus, soft tissue behind esophagus and pharynx. Normal parathyroid glands are 4–6 mm in length and weigh 20–40 mg each. A parathyroid gland greater than 50–60 mg is considered abnormal. There is significant variation in cellu­ larity even among glands in a single individual. Generally, parathyroid glands contain about 10–30% stromal fat. Stromal fat and connective tissue increase with age and vary with constitutional factors. Within a parathyroid gland, the polar regions have more stromal fat than the central aspect of the gland ♦♦ Parathyroid parenchymal cells include chief cells, oncocytic/oxyphilic cells, transitional cell, and clear cells. Chief cells are10  mm, polyhedral, round central nuclei, eosinophilic to amphophilic cytoplasm, fat droplets (adults), and have well-defined cytoplasmic membranes. Oncocytic/ oxyphilic cells are 10–20 mm, abundant eosinophilic cytoplasmic granules (mitochondria). Oncocytic cells appear at puberty, increase with age, and may form nodules. Clear cells are variably seen in normal and diseased parathyroid tissues

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♦♦ Intraoperative PTH monitoring is a useful adjunct in confirming the removal of the diseased parathyroid gland or glands and decrease the risk of missing multiglandular disease. Intraoperative pathology assessment of parathyroid biopsies is done to confirm the specimen is parathyroid parenchyma (versus thyroid). Parathyroid cells are smaller and more vacuolated than thyroid and have round nuclei with dense chromatin and cytoplasmic lipid/fat droplets and welldefined cytoplasmic membranes

Parathyroid Cyst Clinical ♦♦ Parathyroid cysts are relatively uncommon, may be nonfunctioning, and can present as a palpable nodule if large or local tenderness. Small microcysts are not uncommon incidental findings at autopsy. Functioning parathyroid cysts can be associated with hyperparathyroidism and may represent cystic degeneration of a parathyroid adenoma. Although parathyroid cysts are usually benign, parathyroid carcinoma has been reported in association with a parathyroid cyst

Macroscopic (Fig. 20.39) ♦♦ Parathyroid cyst is a solitary, thin walled, fluid-filled cyst, 1–6 cm in diameter, usually identified in the inferior glands, but may occur in the thyroid or mediastinum

Microscopic (Fig. 20.40) ♦♦ Parathyroid cysts have a thin wall lined by cuboidal epithelium with clear cytoplasm. The cyst wall often is associated with adjacent normal parathyroid tissue, but can contain lymphoid, muscular, thymic, adipose, and mesenchymal tissues

Differential Diagnosis ♦♦ Parathyroid adenoma −− Large parathyroid adenomas can undergo cystic degeneration. Parathyroid adenomas are usually associated with laboratory evidence of hyperparathyroidism. Cystic parathyroid adenomas usually show residual adenoma in the tissue surrounding the cyst

Endocrine Pathology

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follicular and shows apple-green birefringence with Congo red stain

Parathyroiditis ♦♦ Parathyroiditis can be autoimmune associated and may result in hypoparathyroidism or hyperparathyroidism

Glycogen Storage Diseases ♦♦ Generalized glycogen storage diseases, such as Pompe disease (type II glycogenosis), affect many organ systems and can affect the parathyroid glands Fig. 20.39. Parathyroid cyst: Roughly spherical cyst with areas of ballooning of the cyst wall.

Fig.  20.40. Parathyroid cyst: The cavity is lined by cubical e­ pithelium with clear cytoplasm.

♦♦ Thyroglossal duct cyst −− Thyroglossal duct cysts are midline, at or above level of the thyroid, with thyroid tissue identifiable in the wall ♦♦ Branchial cleft cyst −− Branchial cleft cysts are in the anterolateral neck. These cysts are lined by mixed squamous and respiratory epithelium and lack thyroid or parathyroid tissue

Amyloid ♦♦ Amyloid can be identified in parathyroids in patients with and without systemic amyloidosis. Amyloid can involve normal and diseased parathyroid glands. Amyloid is often intra-

Parathyroid Hyperplasia Clinical ♦♦ Hyperparathyroidism is an increase in PTH, which results in increased serum calcium levels. Hyperparathyroidism is caused by parathyroid hyperplasia, parathyroid adenoma, and parathyroid carcinoma. Parathyroid hyperplasia is an enlargement of multiple parathyroid glands due to autonomous hyperplasia (primary chief cell hyperplasia) or in response to chronically low serum calcium (secondary chief cell hyperplasia). Hyperplasia accounts for 15% of primary hyperparathyroidism, is twice as common in women as it is in men, and is most common in the fifth decade. The incidence of parathyroid hyperplasia has increased with the utilization of screening calcium levels in asymptomatic patients. Historically, patients presented with clinical signs and symptoms such as osteopenia and nephrocalcinosis ♦♦ Parathyroid hyperplasia can be hereditary in multiple endocrine neoplasia (MEN) type 1, MEN2A, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism ♦♦ Parathyroid hyperplasia is the most common manifestation of MEN1. Parathyroid hyperplasia associated with MEN1 occurs around 20 years of age, which is much earlier than sporadic hyperplasia. In addition to parathyroid hyperplasia, MEN1 is also associated with pituitary adenomas, neuroendocrine tumors of the pancreas, duodenum, thymus and lung, gastrinomas, adrenal cortical adenomas and hyperplasia, cutaneous angiofibromas, collagenomas, and café au lait macules, lipomas, gingival papules, meningiomas, ependymonas, and leiomyomas ♦♦ Approximately 20–30% of cases of MEN2A are associated with parathyroid hyperplasia and or adenomas. Other features of MEN2A include medullary thyroid carcinoma and pheochromocytoma ♦♦ Other causes of familial hyperparathyroidism are familial hypocalciuric hypercalcemia and neonatal primary hyperparathyroidism, which are caused by a mutation in the CASR gene. Hyperparathyroidism jaw tumor syndrome is an autosomal dominant disorder associated with parathyroid hyperplasia or adenoma, fibroosseus jaw tumors, renal cysts, hamartomas, Wilms tumors, and an increased incidence of parathyroid carcinoma. Familial isolated hyperparathyroidism

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Fig. 20.41. Chief-cell hyperplasia: Four parathyroid glands are enlarged and together weigh 920 mg.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  20.42. Chief-cell hyperplasia: Hyperplastic parathyroid gland features multiple nodules and cyst.

Immunohistochemistry accounts for 1% of primary hyperparathyroidism and has an increased risk of parathyroid carcinoma ♦♦ Secondary parathyroid hyperplasia has increased PTH due to low serum calcium caused by disorders of phosphate metabolism, vitamin D deficiency, tissue resistance to vitamin D, and malabsorption. The most common cause of secondary hyperparathyroidism is chronic renal failure. Patients with secondary hyperparathyroidism can develop an autonomously functioning parathyroid gland (tertiary hyperparathyroidism)

Macroscopic (Fig. 20.41) ♦♦ Parathyroid hyperplasia shows enlargement of multiple parathyroid glands (up to 10g each). Sporadic and hereditary forms of primary parathyroid hyperplasia are histologically indistinguishable, but primary hyperplasia may show more nodular enlargement of parathyroid glands, while secondary hyperplasia may show a more diffuse pattern of enlargement. Depending on degree of hypocalcemia, secondary chief cell hyperplasia is more variable in appearance, with glands ranging from normal size to moderately enlarged size (up to 6 g each) ♦♦ One must be cautious in evaluating parathyroid glands in relation to size and cellularity as these parameters can vary greatly even within a single patient. An asymmetrically enlarged gland can be misinterpreted as a parathyroid adenoma. Communication between the pathologist and surgeon is critical for the appropriate interpretation

Microscopic (Fig. 20.42) ♦♦ Parathyroid hyperplasia principally involves chief cells, although other cells types (oxyphil, water-clear, and transitional) may be involved. Cells grow in large hyperplastic nodules scattered throughout gland (nodular hyperplasia), giving it an irregular, asymmetrical appearance. Diffuse growth may also be seen, especially in young patients. The cells can show sheet-like growth, palisading, glandular formations, cribriform growth, papillary areas, fibrosis, and cystic change

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♦♦ Hyperplastic parathyroid tissues are positive for the same immunohistochemical markers as normal parathyroid tissue: chromogranin A, synaptophysin, low molecular weight keratins, and PTH. Parathyroid tissue is negative for TTF-1, which is helpful in separating it from thyroid tissue

Molecular Genetics ♦♦ Parathyroid hyperplasia is usually polyclonal, although areas of monoclonality can be identified in nodular areas. Genetic abnormalities have not been well-defined in sporadic hyperparathyroidism, although more is known about the genes associated with in hereditary hyperparathyroidism such as MEN1, RET, CASR, among others ♦♦ Germline MEN1 mutations are identified in 80–94% of patients with familial MEN1 and 65–88% with sporadic MEN1. MEN1 is a tumor suppressor gene on chromosome 11q13 that encodes menin, a protein that is truncated or absent when MEN1 is mutated. MEN1 is an autosomal dominant disorder with high penetrance, but it can occur sporadically from new mutations. Over 1,000 different MEN1 mutations have been identified. The detection rate of MEN1 mutation increases with the number of MEN1 related tumors and family history of MEN1, as sporadic cases can be due to somatic mosaicism ♦♦ Approximately 95% of MEN2A families have a RET mutation in exon 10 or 11. RET protooncogene (10q21) encodes a plasma membrane tyrosine kinase involved in cell growth and differentiation. The majority of mutations involve codon 634, which is associated with high penetrance ♦♦ The CASR is present in parathyroid, kidney, thyroid C-cells, intestine, and bone. Calcium sensing receptors sense extracellular calcium levels, which inversely regulates the release of PTH. An inactivating mutation in the CASR gene (3q13.321) results in decreased calcium sensitivity and excess PTH secretion. Heterozygous inactivating CASR mutations occur in familial hypocalciuric hypercalcemia, and homozygous inactivating mutations occur in neonatal severe hyperparathyroidism. Hypocalciuric hypercalcemia is due autoantibodies

Endocrine Pathology

against CASR and can simulate familial hypocalciuric hypercalcemia ♦♦ The HRPT2 gene mapped to 1q25-q32 encodes parafibromin. HRPT2 is a putative tumor-suppressor gene, the inactivation of which is involved in HPT-JT syndrome and some sporadic parathyroid tumors

Variants ♦♦ Clear cell hyperplasia (Figs. 20.43 and 20.44) −− Clear cell hyperplasia is a rare sporadic variant of parathyroid hyperplasia with marked parathyroid enlargement (combined weights may be >100 g) and associated primary hyperparathyroidism. The enlargement is usually asymmetric, with upper glands larger than lower glands. The cells have a diffuse or alveolar growth pattern. The cells are large and ballooned, with finely vacuolated water-clear showing marked size variation

Fig. 20.43. Wasserhelle hyperplasia: Three glands are enlarged (the right superior and right inferior glands were fused). The cut surfaces are brown. Total parathyroid weight = 2.5 g.

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♦♦ Lipohyperplasia −− Lipohyperplasia is another rare variant of parathyroid hyperplasia that can occur sporadically or with familial benign hypocalciuric hypercalcemia

Differential Diagnosis ♦♦ Parathyroid adenoma −− Parathyroid adenoma generally involves only a single gland, with other glands usually appearing atrophic. Parathyroid adenoma is an encapsulated cellular nodule compressing normal, sometimes atrophic, rim of parathyroid tissue

Parathyroid Adenoma Clinical ♦♦ Parathyroid adenoma is a benign parathyroid neoplasm, affecting a single gland, composed of chief, oncocytic, transitional, water clear, or mixtures of cells ♦♦ Parathyroid adenoma is the most common cause of hyperparathyroidism (80% of cases) ♦♦ Parathyroid adenomas are more common in women (3:1) than in men and are usually too small and soft to be identified on physical examination. Parathyroid adenomas can be seen at any age, but are commonly identified in the 4th decade ♦♦ Parathyroid adenomas occur in ectopic locations 10% of the time ♦♦ The majority of parathyroid adenomas are hormonally active. Most cases are identified by elevated serum calcium levels. Historically patients were identified because of clinical symptoms. Serum calcium levels are elevated in parathyroid adenoma, but not as markedly elevated as is seen in parathyroid carcinoma

Macroscopic (Fig. 20.45) ♦♦ Grossly, parathyroid adenoma is a small, slightly lobulated nodule, weighing 0.5–5 g, with a delicate capsule. Parathyroid adenomas have a smooth, shining exterior, without adjacent tissues attached. They are gray-brown in color, with soft consistency. Other parathyroid glands should appear normal or atrophic

Microscopic (Figs. 20.46–20.50)

Fig.  20.44. Wasserhelle hyperplasia: Very large parathyroid cells with clear cytoplasm are sharply outlined and have generally central nuclei.

♦♦ Microscopically, parathyroid adenoma is an encapsulated nodule of highly cellular parathyroid tissue. The growth pattern is usually solid, but follicles or papillary structures can be seen. Parathyroid adenomas are composed predominantly of chief cells, but other cell types can be seen ♦♦ A rim of compressed normal tissue is identified in 50–60% of parathyroid adenomas, but the chance of identifying a rim of normal decreases as the size of the tumor increases ♦♦ Areas of nuclear pleomorphism (endocrine atypia) may be noted as well as rare mitotic figures. Prominent mitotic activity would be worrisome for parathyroid carcinoma (Table 20.2)

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 20.45. Parathyroid adenoma: Cut surface of oval enlarged parathyroid gland is tan. Weight = 2.07 g. Fig. 20.47. Parathyroid adenoma: Tumor composed of chief cells features oxyphil cell nodules with eosinophilic cytoplasm.

Fig. 20.46. Parathyroid adenoma: A mantle of normal parathyroid surrounds a sheet of adenoma cells.

Immunohistochemistry ♦♦ Parathyroid adenomas have an identical immunohistochemical staining pattern to that of normal parathyroid chief cells with positivity for chromogranin, synaptophysin, and parathyroid hormone, and negative for TTF-1

Molecular Genetics ♦♦ A number of genes thought to be important in parathyroid tumorigenesis are located on chromosome 11. Cyclin D1 is a regulator of cell cycle progression from G1 to S phase. Encoded by the cyclin D1/PRAD1 (parathyroid adenoma) gene on chromosome 11q13, cyclin D1 overexpression has been observed in neoplastic parathyroid glands. Genetic alterations in cyclin D1/PRAD1 gene have been found in approximately 5% of parathyroid adenomas

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Fig. 20.48. Parathyroid adenoma: Adenoma features trabeculae of cells with clear cytoplasm and basal nuclei, supported by a delicate capillary network.

♦♦ The MEN1 tumor suppressor gene is located in the region of 11q13. Loss of heterozygosity (allelic losses) in this region is known to be frequent in parathyroid adenomas, but not carcinomas. Also, patients with MEN1 associated familial parathyroid disease rarely develop parathyroid carcinoma. Deletion of 11q23 has also been reported to be frequently lost in parathyroid adenomas and occasionally in parathyroid hyperplasias suggesting the possibility of a tumor suppressor gene at this site

Endocrine Pathology

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Fig. 20.50. Parathyroid adenoma: Oxyphil tumor with sharply outlined cells and clear granular eosinophilic cytoplasm.

Fig.  20.49. Parathyroid adenoma: The adenoma features scattered multinucleated cells set in a background of cells with oxyphilic cytoplasm.

Variants ♦♦ Ectopic parathyroid adenoma −− Parathyroid adenomas are located in ectopic locations in approximately 10% of cases. Locations include intrathy-

roidal, mediastinum, thymus, and soft tissue behind esophagus and pharynx. Intrathyroidal parathyroid adenomas are usually derived from the superior parathyroid glands. Intrathyroidal adenomas are often partly in the thyroid capsule or in a cleft in the thyroid surface rather than being truly intrathyroidal. Thymus or mediastinal parathyroid adenomas usually derive from the inferior parathyroid glands ♦♦ “Double” parathyroid adenomas −− Double parathyroid adenomas are exceptionally rare. Most cases are later found to be asymmetric parathyroid hyperplasia. Occasionally, glands involved by parathyroid hyperplasia may show rims of normal parathyroid tissue. A diagnosis of “double” or “triple” parathyroid adenomas would require resolution of hypercalcemia and hyperparathyroidism and long-term followup to be certain that no other glands involved

Table 20.2. Parathyroid Carcinoma vs. Adenoma Parathyroid adenoma

Parathyroid carcinoma

Symptomatic

Unusual

Yes

Serum calcium

Elevated

Markedly elevated (>13 mg/dL)

Tumor size

Can overlap in size

Larger

Vascular invasion

No

Yes

Invasion into adjacent structures

No

Yes

Metastases

No

Yes

Growth pattern

Patterns (acinar, follicular)

Monotonous

Cellular features

Often mixed cell types, “endocrine atypia”

Often monotonous, prominent nucleoli

Mitoses

Can have mitoses, but infrequent

Fibrous bands

Can be seen due to degenerative changes

Yes (higher mitotic rate than adenomas) Yes

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♦♦ Oxyphil adenoma −− Oxyphil adenoma is a benign encapsulated neoplasm composed exclusively or predominantly (more than 90%) of mitochondrion-rich oncocytes (Fig.  20.50). Oxyphil adenomas comprise 3–6% of parathyroid adenomas, and are usually functional −− Oxyphilic parathyroid adenomas and carcinomas must be distinguished from Hürthle cell thyroid neoplasms. Parathyroid tissues have very well-defined cytoplasmic membranes, lack colloid, and are positive for PTH, chromogranin, and synaptophysin and negative for TTF-1 and thyroglobulin ♦♦ Clear cell adenoma −− Clear cell adenoma is a benign encapsulated neoplasm composed exclusively or predominantly of large ­polyhedral cells with distinct plasma membranes and extensively vacuolated (water-clear) cytoplasm. Clear cell parathyroid adenomas are an exceeding rare cause hyperparathyroidism −− Clear cell adenoma must be differentiated from hyperplasia with clear cell change, which is more common than clear cell adenomas. Multiple glands are involved in hyperplasia with clear cell change. The absence of normalization of PTH suggests that a putative clear cell parathyroid adenoma may be a normal parathyroid or hyperplasia with clear cell change ♦♦ Lipoadenoma (Figs. 20.51 and 20.52) −− Lipoadenoma is an encapsulated nodular growth composed of islands or cords of chief cells separated by abundant adipose tissue. Parachymal chief or oxyphil cells are arranged in anastomosing trabeculae or acinar formations

Differential Diagnosis ♦♦ Parathyroid hyperplasia −− Parathyroid hyperplasia involves multiple parathyroid glands. Distinguishing parathyroid adenoma from hyperplasia usually necessitates examination of at least one additional gland, which should be normal in cases of

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 20.52. Parathyroid lipoadenoma: Tumor is composed of an intimate mixture of mature fat and groups of parathyroid cells.

parathyroid adenoma. Microscopically, the parathyroids in hyperplasia appear diffusely enlarged, with an even distribution of cellularity and adipose tissue ♦♦ Atypical parathyroid adenoma −− Atypical parathyroid adenomas show some worrisome features including mitotic activity and fibrous bands, but lack unequivocal invasion. Atypical parathyroid adenomas usually behave in an indolent manner ♦♦ Parathyroid carcinoma −− Parathyroid carcinomas may be palpable, are often symptomatic, large, and are associated with higher serum calcium (13–15.5  mg/dL) than parathyroid adenomas. Parathyroid adenomas, particularly atypical parathyroid adenomas, can be very difficult to distinguish from carcinomas. Parathyroid carcinomas usually show monotonous growth rather than acinar and follicular growth patterns of adenomas. Mitotic figures can be seen in both, but are more numerous in carcinomas. Fibrous bands are concerning, but can be seen in both adenomas and carcinomas (Table 20.2) −− The diagnosis of parathyroid carcinoma requires invasive growth or metastases, features not seen in parathyroid adenoma or atypical parathyroid adenoma

Parathyroid Carcinoma Clinical

Fig.  20.51. Parathyroid lipoadenoma: Irregularly lobulated tumor with a yellow cut surface.

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♦♦ Parathyroid carcinoma is a malignant epithelial tumor composed of parathyroid cells. Parathyroid carcinoma accounts for less than 1% of cases of hyperparathyroidism. These tumors usually occur in middle aged and older adults, but can occur over a wide age range. Females and males are equally affected. The majority of parathyroid carcinomas are sporadic, but there is an increased incidence of parathyroid carcinoma in patients with hyperparathyroidism jaw tumor syndrome ♦♦ Patients with parathyroid carcinoma are usually symptomatic with fatigue, weakness, weight loss, nausea, polyuria, or polydypsia and may have a palpable mass

Endocrine Pathology

♦♦ Most parathyroid carcinomas are functional, and patients have a markedly elevated serum calcium (13–15.5 mg/dL), PTH, and alkaline phosphatase. Because of the markedly elevated serum calcium, patients can present with nephrolithiasis, nephrocalcinosis, renal insufficiency, and may have bone disease ♦♦ Parathyroid carcinoma is treated by en bloc resection of the parathyroid tumor and the surrounding structures, including the ipsilateral thyroid lobe. Tumors often recur before they metastasize to the cervical and mediastinal lymph nodes, lungs, bone, and liver. Death is usually due to uncontrollable hypercalcemia. Survival at 5 years and 10 years is 85% and 49%, respectively ♦♦ Patients treated with surgery and postoperative radiation have decreased risk of locoregional disease progression and improved cause-specific survival

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malignancy include vascular invasion, perineural invasion, invasion into adjacent structures and metastases ♦♦ Local recurrence of a previously diagnosed “parathyroid adenoma” is also a worrisome feature, but other explanations must be taken into account including parathyromatosis

Macroscopic (Fig. 20.53) ♦♦ Parathyroid carcinoma is usually a firm mass adherent to regional structures. The tumor ranges from 1 to 6 cm (mean 3 cm) in size and weighs 1.5–30 g (mean 6.7 g). Parathyroid carcinomas are larger than parathyroid adenomas, but the tumors can overlap in size

Microscopic (Figs. 20.54–20.56 and Table 20.2)

Fig.  20.54. Parathyroid carcinoma: Tumor composed of ­variable-sized masses of subtly invasive parathyroid cells.

♦♦ The histologic diagnosis of parathyroid carcinoma can be difficult. Parathyroid carcinomas usually have a monotonous, solid growth with sheets of cells. Prominent patterns, follicular and acinar, are not often seen. The cellular constituency is usually chief cells, but tumor can be composed of oncocytes or mixtures of cell types. Prominent nucleoli are often seen in parathyroid carcinoma, but cellular and nuclear pleomorphism is not diagnostic of parathyroid carcinoma. Parathyroid carcinomas show prominent mitotic activity, thick fibrous bands, and may show necrosis. Mitotic activity can be seen in parathyroid adenomas, although carcinomas generally have higher mitotic rates than adenomas and higher proliferative indices (Ki-67). Parathyroid adenomas can show degenerative changes with cells trapped within the capsule and fibrous bands. Features diagnostic of

Fig. 20.55. Parathyroid carcinoma: Nodules of invasive tumor are present in the cervical fat.

Fig. 20.53. Parathyroid carcinoma: Very ragged coarsely lobulated tumor.

Fig.  20.56. Parathyroid carcinoma: Well-differentiated tumor with sharply outlined regular cells. Mitosis is present.

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Immunohistochemistry ♦♦ Parathyroid carcinomas are positive for chromogranin, synaptophysin, parathyroid hormone, and keratin (CAM 5.2) and are negative for TTF-1 and thyroglobulin (Table 20.3) ♦♦ The cyclin-dependent kinase inhibitor protein p27 shows decreased expression in parathyroid carcinomas compared with parathyroid adenomas. An immunophenotype of positive staining for p27, bcl-2, mdm2, and negative staining for Ki-67 is more common in typical and atypical adenomas than in parathyroid carcinomas. Parafibromin is discussed under molecular genetics

Molecular Genetics ♦♦ Inactivating mutations of the tumor suppressor HRPT2 gene (1q21-q32), which is responsible for the HPT-JT syndrome, have been implicated in a high proportion of parathyroid carcinomas. Germline mutations of the HRPT2 gene can be seen in a subset of patients with mutation-positive carcinomas. The HRPT2 gene is involved in both the hyperparathyroidism-jaw tumor syndrome and a subset of cases of familial isolated hyperparathyroidism. Sporadic parathyroid carcinomas have been found to have acquired inactivation of HRPT2, a finding very uncommon in parathyroid adenomas. This finding suggests that some patients with apparent sporadic parathyroid carcinomas may have the HPT-JT syndrome or a variant of this syndrome ♦♦ The HRPT2 gene encodes parafibromin. Loss of nuclear parafibromin immunoreactivity has been identified in parathyroid carcinomas as well as adenomas associated with HRPT2 mutation. Several studies have examined whether loss of nuclear parafibromen expression can be helpful in the diagnosis of parathyroid carcinoma. This marker shows some promise; however, the reproducibility and variability in the interpretation of this immunostain needs to be confirmed. Additionally, distinguishing parathyroid adenoma from carcinoma is less problematic than distinguishing atypical parathyroid adenoma from parathyroid carcinoma, but this marker has not yet been evaluated in this situation

♦♦ Cyclin D1 is a regulator of cell cycle progression from G1 to S phase. Encoded by the cyclin D1/PRAD1 (parathyroid adenoma) gene on chromosome 11q13, cyclin D1 overexpression has been observed in neoplastic parathyroid glands. Genetic alterations in cyclin D1/PRAD1 gene have been found in approximately 5% of parathyroid adenomas ♦♦ p53 gene on chromosome 17p13.1 is the most common genetic alteration in human cancers, but differentiated endocrine malignancies usually have a low frequency of p53 mutation. Allelic loss of the p53 gene has been noted parathyroid carcinomas, but without great frequency ♦♦ The MEN1 tumor suppressor gene is located in the region of 11q13. Loss of heterozygosity (allelic losses) in this region is known to be frequent in parathyroid adenomas, but not carcinomas. Also, patients with MEN1 associated familial parathyroid disease rarely develop parathyroid carcinoma. Deletion of 11q23 has also been reported to be frequently lost in parathyroid adenomas and occasionally in parathyroid hyperplasias suggesting the possibility of a tumor suppressor gene at this site

Differential Diagnosis ♦♦ Parathyroid adenoma −− Parathyroid adenomas generally are asymptomatic, while parathyroid carcinomas are more often associated with clinical symptoms. Parathyroid carcinoma may be associated with a palpable mass, a feature highly unusual for a parathyroid adenoma. Serum calcium levels in parathyroid adenomas usually are not as markedly elevated as those in patients with parathyroid carcinomas, who may have serum calcium levels 13–15.5 mg/dL. Parathyroid adenomas are usually smaller than carcinomas, but there can be overlap in size. Parathyroid adenomas lack the invasive growth that is diagnostic of parathyroid carcinoma (Table 20.2) ♦♦ Atypical parathyroid adenoma −− Atypical parathyroid adenomas are noninvasive parathyroid neoplasms composed of chief cells with variable numbers of oncocytes and transitional oncocytes, with

Table 20.3. Parathyroid Carcinoma Differential Diagnosis Chromogranin

Synaptophysin

Parathyroid hormone

Thyroglobulin

TTF

Calcitonin

Parathyroid carcinoma

+

+

+

−

−

−

Follicular, Hürthle, or papillary thyroid carcinoma

−

−

−

+

+

−

Medullary thyroid carcinoma

+

+

+

−

+

+

Metastatic carcinoma

−

−

−

−

a

−

Tumor

Metastatic carcinomas from particular sites, such as lung, can show positivity for thyroid transcription factor (TTF)

a

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Endocrine Pathology

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some of the features of parathyroid carcinoma but lacking unequivocal capsular, vascular, or perineural space invasion or metastases. These tumors may show adherence to adjacent structures, mitotic activity, fibrosis, trabecular growth pattern, and tumor cells within the capsule, but they lack invasive growth ♦♦ Parathyroid hyperplasia −− Parathyroid hyperplasia involves multiple glands. The glands in hyperplasia lack the infiltrative growth diagnostic of parathyroid carcinoma ♦♦ Parathyromatosis −− Parathyromatosis is generally not associated with a palpable neck mass or the degree of hypercalcemia seen in parathyroid carcinoma. Unlike parathyroid carcinoma, parathyromatosis lacks vascular invasion, infiltrative growth, and significant mitotic activity ♦♦ Thyroid neoplasms −− Parathyroid cells show well-defined cytoplasmic membranes and lack the colloid seen in thyroid tissues. In difficult cases, immunoperoxidase studies can be very helpful in separating these entities as parathyroid tissue is positive for synaptophysin, chromogranin, and PTH and negative for TTF-1 and thyroglobulin. Thyroid follicular tumors are positive for TTF-1 and thyroglobulin and negative for chromogranin, synaptophysin, and parathyroid hormone. Similar to parathyroid carcinoma, medullary thyroid carcinoma is positive for synaptophysin and chromogranin, but medullary thyroid carcinomas are also positive for TTF and calcitonin and negative for PTH

Parathyromatosis Clinical ♦♦ Parathyromatosis is a rare cause of hyperparathyroidism. It is caused by inadvertent autotransplantation of tissue from previous operations or hyperfunction of tissue left behind during organogenesis

Macroscopic ♦♦ Nodules of parathyroid tissue are present in fibrofatty tissue

Microscopic ♦♦ Nodules of hyperfunctioning chief cells with well-defined cytoplasmic membranes and lacking prominent mitotic activity are identified in fibrous tissue or fibrofatty tissue. The nests of cells lack highly infiltrative growth pattern

Immunophenotype ♦♦ Parathyromatosis shows positivity for neuroendocrine markers chromogranin and synaptophysin and is positive for PTH and cytokeratin (CAM 5.2) and negative for TTF

Differential Diagnosis ♦♦ Parathyroid carcinoma −− Unlike parathyromatosis, parathyroid carcinoma may present as a palpable neck mass and significant hypercalcemia. Parathyromatosis lacks the vascular invasion, infiltrative growth, and mitotic activity seen in parathyroid carcinoma

ADRENAL GLAND Adrenal Heterotopia Clinical

Focal Adrenalitis Clinical

♦♦ Adrenal heterotopia is a benign congenital anomaly with normal adrenal tissue appearing in abnormal locations. This condition is relatively common, as it has been seen in up to 30% of autopsies. The ectopic tissue is usually located in retroperitoneal space near the adrenals and kidneys, in the pelvis, or in the inguinal area. The ectopic tissue may undergo hyperplasia in response to increased ACTH levels and rarely may give rise to cortical neoplasms

♦♦ Focal adrenalitis is identified in up to 50% of autopsy patients, and is particularly common in the elderly

Macroscopic ♦♦ Grossly, adrenal heterotopias are small (<1 cm) nodules of yellow tissue resembling normal adrenal cortex

Microscopic ♦♦ Most adrenal heterotopias consist of adrenal cortical tissue only, but some may also contain medulla

Immunohistochemistry ♦♦ Adrenal heterotopias have identical staining pattern to normal adrenal tissues

Microscopic (Fig. 20.57) ♦♦ Perivascular aggregates of lymphocytes and plasma cells are identified in the cortical and medullary tissue

Differential Diagnosis ♦♦ Autoimmune adrenalitis −− Inflammatory response is more diffuse in autoimmune adrenalitis than the foci of lymphocytes and plasma cells seen in focal adrenalitis. Autoimmune adrenalitis is associated with marked cortical atrophy, a feature not seen in focal adrenalitis ♦♦ Adrenal aplasia −− Adrenal aplasia is unilateral or bilateral absence of adrenal gland, usually in setting of multiple congenital anomalies such as acardia, anencephaly, and renal agenesis

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Fig.  20.58. Adrenal cyst. Fibrous-walled cyst partially filled with an amphophilic coagulum. Fig.  20.57. Focal “adrenalitis”: Foci of lymphocytes in the medulla have no known significance.

Adrenal Cysts Clinical ♦♦ Adrenal cysts are uncommon, usually incidental findings on CT or MRI, but can be symptomatic. The majority of adrenal cysts are benign, but adrenal cysts can be identified with adrenal neoplasms, both benign and malignant. Adrenal cysts are generally seen in adults in the fourth to sixth decades ♦♦ In a recent study from Mayo Clinic, 41 macroscopically cystic lesions were identified over a 25-year period. Of these 41 cases, 32 were pseudocysts, 8 were endothelial cysts, and 1 was an epithelial cyst. Of the 32 pseudocysts, 6 were associated with adrenal neoplasms (2 adrenal cortical carcinomas, 2 adrenal cortical adenomas, and 2 pheochromocytomas). One pheochromocytoma case was identified with an endothelial cyst. Both patients with cystic adrenal cortical carcinomas died of disease

Macroscopic ♦♦ Fluid-filled cysts range in size from 2 to 10 cm. The cyst wall may be focally calcified. The wall should be extensively sampled to search for an associated adrenal neoplasm

Microscopic (Figs. 20.58 and 20.59) ♦♦ Adrenal cysts are classified as pseudocysts, endothelial cysts, epithelial cysts, and infectious cysts ♦♦ The cyst walls are composed of fibrous tissue or have a lining of endothelial or epithelial cells. The wall often contains hemosiderin and elastic tissue. The wall needs to be carefully evaluated to be certain that the cyst is not associated with an adrenal neoplasm

Differential Diagnosis ♦♦ Adrenal cortical neoplasm or pheochromocytoma with cystic degeneration −− Adrenal adenoma, adrenal carcinoma, and pheochromocytoma may undergo cystic degenerative changes that grossly mimic an adrenal cyst

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Fig. 20.59. Adrenal cyst: The cyst in Fig. 20.58 was partially lined by epithelioid cells, interpreted as plum endothelial cells.

Adrenal Cytomegaly Clinical ♦♦ Adrenal cytomegaly is an incidental histologic finding in up to 3% of newborns and in 6.5% of stillborn fetuses. Adrenal cytomegaly is particularly prominent in the adrenal glands infants with Beckwith–Wiedemann syndrome

Microscopic (Fig. 20.60) ♦♦ The adrenal cortical cells are markedly enlarged cells (up to 120  mm) with prominent nuclear enlargement, hyperchromasia, and pleomorphism. Nuclear cytoplasmic inclusions can be seen

Beckwith–Wiedemann Syndrome Clinical ♦♦ Beckwith–Widemann syndrome is a congenital disorder, sometimes familial, manifested by craniofacial abnormalities, abdominal wall defects, gigantism, macroglossia, and adrenal hyperplasia. The estimated incidence is 1 in 13,000 births. About 7.5% of affected children develop a malignant neoplasm (nephroblastoma or adrenal cortical carcinoma)

Endocrine Pathology

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Fig.  20.61. Adrenal leukodystrophy: Slices of adrenal gland biopsy in adrenoleukodystrophy shows much replacement of the yellow cortex by black and brown nodules. Fig.  20.60. Adrenal cytomegaly: enlarged cells with enlarged nuclei in provisional cortex of 7 month fetus.

Macroscopic ♦♦ The adrenal glands are enlarged (up to 16 g) and have a cerebriform appearance

Microscopic ♦♦ Microscopically, the cells show marked cytomegaly affecting nearly all the cells of cortex. Cortical microcysts may be seen. The medullary tissue may be hyperplastic

Adrenal Leukodystrophy Clinical ♦♦ Adrenal leukodystrophy is an X-linked metabolic disorder characterized by spastic paraplegia and adrenal insufficiency culminating in Addison disease

Macroscopic (Fig. 20.61) ♦♦ Grossly, the adrenal cortex is atrophic

Microscopic (Fig. 20.62)

Fig.  20.62. Adrenal leukodystrophy: Ballooned cortical cells with somewhat clear cytoplasm and intracytoplasmic striations.

ciency (seen in >90% of cases). Patients affected with longstanding disease may develop steroid neoplasms (adrenal cortical and testicular) because of stimulatory effects of chronically increased adrenocorticotrophic hormone (ACTH) levels

♦♦ The cortex is attenuated and consists of ballooned cells with abundant granular or hyaline eosinophilic cytoplasm. Cells may have clear cytoplasm with intracytoplasmic striations

Macroscopic

Congenital Adrenal Hyperplasia (Adrenogenital Syndrome) Clinical

Microscopic (Fig. 20.63)

♦♦ Congenital adrenal hyperplasia is a pathologic ­manifestation of group of autosomal recessive disorders characterized by enzymatic defects in cortisol synthesis. Insufficient cortisol results in increased ACTH secretion and subsequent bilateral adrenal hyperplasia. Biosynthesis pathway blockages result in shunting of steroids into other pathways, usually those for sex steroids. This disorder usually presents in first few years of life with abnormal hormone levels (sexual development abnormalities, hypertension, adrenal insufficiency, sodium imbalances). The most common enzymatic defect is 21-hydroxylase defi-

♦♦ The adrenal glands show marked diffuse enlargement, each weighing 10–15 g, with a cerebriform appearance and tanbrown color ♦♦ The zona fasciculata shows marked hyperplasia. Compact cells with eosinophilic cytoplasm (lipid-depleted) replace normal vacuolated (lipid-laden) fasciculata cells

Differential Diagnosis ♦♦ Adrenal cortical hyperplasia −− Usually older patients are affected by adrenal cortical hyperplasia ♦♦ Hormonal syndromes usually associated with glucocorticoid or mineralocorticoid excess, rather than sex steroid excess −− Commonly, nodular or mixed diffuse and nodular hyperplasia are seen

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Fig.  20.63. Congenital adrenal hyperplasia: Normal cortex replaced by clear-cell nodules.

♦♦ Beckwith–Wiedemann syndrome −− Beckwith–Wiedemann syndrome is associated with multiple anatomic anomalies. The adrenal glands show marked cortical cytomegaly

Fig.  20.64. Primary adrenal insufficiency: Small normally shaped adrenal glands in primary adrenal atrophy. The two glands weighed 6 g.

Primary Adrenal Insufficiency (Idiopathic Addison Disease) Clinical ♦♦ Primary adrenal insufficiency is an autoimmune disease where antibodies directed against adrenal antigens result in cortical cell destruction and subsequent adrenal insufficiency. Adults are usually affected. The disorder is more common in females (F:M = 2:1) than in males. Patients manifest signs and symptoms of deficiencies in glucocorticoids and mineralocorticoids, including fatigue, weight loss, hypotension, poor stress tolerance, and increased pigmentation (due to increased ACTH). Primary adrenal insufficiency can be associated with autoimmune disease of thyroid (Hashimoto thyroiditis resulting in hypothyroidism), stomach (chronic atrophic gastritis resulting in pernicious anemia), or pancreas (inflammation of islets causing diabetes mellitus)

Macroscopic (Fig. 20.64) ♦♦ Grossly the adrenal glands show marked cortical atrophy

Fig.  20.65. Primary adrenal insufficiency: A thinned cortex shows loss of normal zona fasciculata with clear cells. The cortical cells are smaller than normal.

Secondary Adrenal Insufficiency Clinical

♦♦ Microscopically, the cortex is atrophic and has a lymphocytic infiltrate, while the medulla is uninvolved. The residual cortical cells are hypertrophied and have compact eosinophilic cytoplasm and enlarged nuclei (ACTH stimulation effect)

♦♦ Secondary adrenal insufficiency is usually due to pituitary disease such as pituitary neoplasm or post-partum necrosis (Sheehan syndrome), which results in adrenal cortical atrophy due to lack of ACTH stimulation ♦♦ Patients present with features of hypocortisolism such as anorexia, weight loss, hypotension, poor stress tolerance, and hyperpigmentation (due to increased ACTH)

Differential Diagnosis

Macroscopic

Microscopic (Fig. 20.65)

♦♦ Other causes of adrenal cortical insufficiency −− Infectious agents such as mycobacteria, fungi, or viruses −− Amyloid deposition −− Adrenal hemorrhage (Waterhouse–Friderichsen syndrome) −− Metastatic tumor −− Pituitary lesions (tumor, necrosis, hemorrhage)

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♦♦ Grossly, the cortex is atrophic, but appears bright yellow due to accumulation of lipid. The brown zona reticularis (normally seen internal to yellow zona fasciculata) is not present. The medulla appears normal

Microscopic ♦♦ The zona fasciculata and reticularis are atrophic, and there is relative sparing of zona glomerulosa

Endocrine Pathology

Differential Diagnosis ♦♦ Primary adrenal insufficiency ♦♦ Exogenous steroid administration

Adrenal Cortical Hyperplasia Clinical ♦♦ Adrenal cortical hyperplasia is characterized by enlargement of adrenal cortex with increased serum cortisol, usually due to increased stimulation by ACTH, either from pituitary or ectopic sources. Patients may present with extra-adrenal tumor (ectopic ACTH secretion) or with symptoms of hypercortisolism ♦♦ The most common sources of ACTH include pituitary adenoma (Cushing disease), small cell lung carcinoma, carcinoid tumor (lung, gastrointestinal tract, thymus, or pancreas), islet cell carcinoma, and medullary thyroid carcinoma

Macroscopic (Fig. 20.66)

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Adrenal Cortical Hyperplasia Associated with Hyperaldosteronism Clinical ♦♦ Approximately 40% of cases of primary hyperaldosteronism are due to adrenal cortical hyperplasia. Manifestations of hyperaldosteronism include hypertension, weakness, hypo­ kalemia, and hypernatremia

Macroscopic ♦♦ The cortex may be diffusely widened or have nodular appearance

Microscopic ♦♦ Microscopically, the cortex is expanded by hyperplasia of zona glomerulosa, and tongues of glomerulosa cells often extend down into adjacent zona fasciculata. Patients treated with diuretic spironolactone (Aldactone) may have laminated eosinophilic inclusions (“spironolactone bodies”) in the cells

♦♦ The adrenal cortex is enlarged either diffusely or in a nodular pattern. Diffuse hyperplasia results in moderate enlargement (12–24  g each) with uniform widening of cortex, which appears tan-brown. Nodular hyperplasia shows nodules in the cortex, which measures up to 3  cm, and adrenals may weigh up to 50 g. Diffuse and nodular hyperplasia may coexist in the same patient

Differential Diagnosis

Microscopic (Fig. 20.67)

Adrenal Cortical Macronodular Hyperplasia Clinical

♦♦ Diffuse hyperplasia microscopically is characterized by expanded zona fasciculata with compact, lipid-depleted cells, and the zona glomerulosa cells appear vacuolated ♦♦ Nodular hyperplasia (Figs.  20.68 and 20.69) shows nodules of clear cells, compact cells, or a mixture of both

Differential Diagnosis

♦♦ Typical adrenal cortical hyperplasia −− Adrenal cortical hyperplasia is associated with increased glucocorticoid levels. The hyperplastic cortex is made up mostly of fasciculata cells, rather than glomerulosa cells

♦♦ Macronodular hyperplasia is a rare type of primary adrenal hyperplasia with tumor-like enlargement of both glands. Patients usually present around 50 years of age with symptoms of hypercortisolism

♦♦ Adrenal cortical adenoma −− Adrenal adenomas are usually a single dominant nodule, rather than multiple nodules

Fig.  20.66. Adrenal cortical hyperplasia: Generally thickened yellow-brown cortex in cortical hyperplasia. The glands together weighed 25.2 g.

Fig.  20.67. Adrenal cortical hyperplasia: Irregular thickening with beginning nodularity of the cortex in diffuse cortical hyperplasia (Cushing syndrome).

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Macroscopic (Fig. 20.68) ♦♦ The adrenal glands are markedly enlarged (combined weight of 60–180 g), and grossly distorted by multiple nodules up to 3.5 cm in size. On cut section, the nodules are nonencapsulated and bright yellow in color

Microscopic (Fig. 20.69) ♦♦ The cortical cells are varied in appearance, predominantly large and vacuolated (lipid-laden) with some scattered, eosinophilic, compact (lipid-depleted) cells, and rare balloon cells. Pseudoglandular formations and focal lipomatous or myelolipomatous metaplasia can be seen

Differential Diagnosis ♦♦ Adrenal cortical carcinoma −− Adrenal cortical carcinomas are unilateral, typically weigh >100 g, show cellular atypia, mitoses, necrosis, and invasion ♦♦ Typical adrenal hyperplasia −− In typical adrenal hyperplasia, the combined weight of adrenals is usually <50 g. The glands may appear nodular, but individual nodules are small (<0.5 cm)

Essentials of Anatomic Pathology, 3rd Ed.

Microadenomatous Hyperplasia (Primary Pigmented Nodular Adrenocortical Disease, PPNAD) Clinical ♦♦ PPNAD is a type of primary adrenal hyperplasia with characteristic macroscopic findings. Patients are often young women with typical signs and symptoms of hypercortisolism (truncal obesity, muscle weakness, hypertension, abdominal striae, menstrual abnormalities/impotence). Osteoporosis is often a prominent feature ♦♦ PPNAD can occur in a familial setting with Carney syndrome with myxomas (cardiac, cutaneous, and mammary), spotty cutaneous pigmentation (ephelides, lentigines, and blue nevi), endocrine overactivity (acromegaly due to pituitary adenoma and sexual precocity due to large-cell calcifying Sertoli cell tumor of testes), and schwannomas (psammomatous melanotic type)

Macroscopic (Fig. 20.70) ♦♦ Multiple pigmented cortical nodules (1–3 mm in size) are situated in an atrophic cortex, often at the corticomedullary junction. The adrenal glands are of usually normal size

Microscopic (Fig. 20.71) ♦♦ The small nodules are composed of large granular eosinophilic cells, some with large hyperchromatic nuclei and prominent nucleoli. The cells contain lipofuscin pigment

Differential Diagnosis

Fig.  20.68. Cortical macronodular hyperplasia: Bilateral macronodular cortical hyperplasia featuring massive nodular enlargement of both adrenal glands. Total weight equals 218 g.

♦♦ Pigmented cortical adenoma −− Pigmented adrenal adenomas are larger (3–6 cm) than the nodules of PPNAD and are single ♦♦ Adrenal cortical carcinoma −− Adrenal cortical carcinomas are single, dominant masses, rather than multiple nodules. Carcinomas show cellular atypia, mitoses, necrosis, fibrous bands, and invasion

Fig.  20.69. Cortical macronodular hyperplasia: Low power micrograph showing adjacent large cortical nodules, which blend with a thickened cortex.

Fig. 20.70. Primary pigmented nodular adrenocortical disease. Slices of formalin-fixed right and left adrenal glands show multiple small brown and black nodules.

940

Endocrine Pathology

Fig. 20.71. Primary pigmented nodular adrenocortical disease. A nodule composed of cells with eosinophilic and clear cytoplasm straddles the corticomedullary function. The extranodular cortex is atrophic.

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Fig. 20.72. Ovarian thecal metaplasia. A dense fibrous proliferation emanating from the adrenal capsule penetrates into the cortex.

Ovarian Thecal Metaplasia Clinical ♦♦ Ovarian thecal metaplasia occurs in <5% of females, usually postmenopausal, and can rarely occur in males. It is of no known clinical significance

Macroscopic ♦♦ Ovarian thecal metaplasia appears as a small (<2 mm) firm fibrous nodule, usually wedge-shaped, attached to adrenal capsule. Occasionally, multiple foci may be present

Microscopic (Figs. 20.72 and 20.73) ♦♦ Histologically, ovarian thecal metaplasia is a subcapsular proliferation of spindle cells that resemble normal ovarian stroma. Scattered cortical cells may be entrapped in the spindle cell proliferation. Fibrosis is common, and calcifications may be present

Fig. 20.73. Ovarian thecal metaplasia: Clusters of cortical cells with clear cytoplasm are surrounded by a cellular spindle cell proliferation.

Adrenal Medullary Hyperplasia Clinical ♦♦ Adrenal medullary hyperplasia is an uncommon hyperplastic expansion of the medulla. It is usually identified incidentally in associated with MEN types 2A and 2B, but can occur sporadically on rare occasion. Adrenal medullary hyperplasia is thought to be precursor lesion to pheochromocytoma, especially in patients with MEN

Macroscopic (Fig. 20.74) ♦♦ Grossly, adrenal medullary hyperplasia shows an increase in adrenal medullary volume, which may be uniform or nodular and have a pearly gray color. Medullary tissue may extend beyond its normal location (restricted to head and body of adrenal) and be found within alar and tail regions of the adrenal gland

Fig. 20.74. Adrenal medullary hyperplasia: Slices of both adrenal glands show that the medulla of both glands is massively expanded and dwarfs the cortex.

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Microscopic (Fig. 20.75)

Microscopic

♦♦ Microscopically, increased numbers of medullary cells are identified, either in sheets or nodules, expanding the medulla. The cells may show significant pleomorphism

♦♦ Adrenal adenomas are well-circumscribed, usually encapsulated, tumors composed of nests and cords of cells resembling those normally found in glomerulosa, fasciculata, or reticularis. Adenomas may be composed of a mixture of cell types. Some adenomas may show significant nuclear pleomorphism, which is thought to be degenerative

Differential Diagnosis ♦♦ Adrenal cortical atrophy −− Adrenal cortical atrophy can mimic medullary hyperplasia grossly by making medulla appear relatively large compared with thin, attenuated cortex ♦♦ Pheochromocytoma −− Nodular adrenal medullary hyperplasia may look similar to early pheochromocytoma and is thought to be a possible precursor of pheochromocytoma

Adrenal Cortical Adenoma Clinical ♦♦ Adrenal cortical adenomas are benign cortical neoplasms, often associated with hormonal secretion. The signs and symptoms related to specific hormones elaborated by adenoma: hypercortisolism (Cushing syndrome), hyperaldosteronism (Conn syndrome), or increased androgenic or estrogenic steroids (adrenogenital syndrome). Some adenomas secrete multiple hormones and others are nonfunctional ♦♦ Adrenal cortical adenomas are often identified incidentally on MRI or CT (“incidentalomas”), and autopsy series show 10–20% incidence

Immunohistochemistry ♦♦ Adrenal cortical adenomas are positive for keratin (weak), Melan-A/Mart-1, inhibin, and synaptophysin and are negative for chromogranin and S-100

Variants ♦♦ Adenomas associated with Cushing syndrome (Figs. 20.76– 20.79) −− Adrenal adenomas associated with Cushing syndrome usually measure 3–4 cm in diameter and weigh 10–50 g. They usually appear as mixture of colors (yellow to brown) and may occasionally be darkly pigmented (“black

Macroscopic ♦♦ Grossly, adrenal cortical adenomas are well-­circumscribed, encapsulated masses, which are well-demarcated from surrounding cortex. The size varies from several grams up to 500 g in rare cases. Adrenal cortical tumors >100 g should be carefully evaluated for the presence of diagnostic features of malignancy. Although adrenal adenomas may show cystic degeneration, the presence of necrosis would be a worrisome feature for adrenal cortical carcinoma ♦♦ In cortisol-secreting tumors, the adjacent cortex and contralateral adrenal gland are often atrophic due to suppression of pituitary ACTH secretion by the tumor’s hormone secretion

Fig. 20.75. Adrenal medullary hyperplasia: Diffuse enlargement of the medulla without nodules.

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Fig. 20.76. Cortisol-secreting adrenal adenoma: The cut surface of the adenoma is marbled yellow and brown. The cortex protruding on both sides of the tumor is very thin (atrophic).

Fig. 20.77. Cortisol-secreting adenoma: Adenoma is composed of populations of cells with eosinophilic and clear cytoplasm.

Endocrine Pathology

Fig. 20.78. Cortisol-secreting adenoma showing cells with clear and dark cytoplasm and foci of myeloid metaplasia.

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Fig.  20.80. Aldosterone-secreting adenoma: Yellow-orange tumor and associated cortex (showing outer zona fasciculata and inner zona reticularis) and medulla. The adrenal gland weighed 5.5 g.

Fig. 20.81. Aldosterone-secreting adenoma: The tumor is almost entirely composed of cells with clear cytoplasm. The attached cortex and medulla are normal.

Fig. 20.79. Cortical atrophy in association with cortisol-secreting adenoma. The thin extratumoral cortex has lost normal zonation and is largely composed of large cells with clear cytoplasm. adenoma”). The constituent cells resemble zona reticularis and fasciculata with lipid-depleted (dark) and lipidrich (pale) cytoplasm. Fatty or myeloid metaplasia is common. The cells of “black adenoma” contain abundant

lipofuscin. The adjacent cortex (and that of contralateral adrenal) typically appears atrophic, with absence of normal zona reticularis ♦♦ Adenomas associated with Conn syndrome (Figs.  20.80– 20.83) −− Adrenal adenomas associated with Conn syndrome are usually small (<2 cm), bright yellow, and often poorly demarcated from the surrounding cortex. The tumor cells resemble those of glomerulosa or fasciculata (clear cells) or a combination. In patients treated with diuretic spironolactone (Aldactone), tumor cells (and sometimes extratumoral zona glomerulosa cells) may contain eosinophilic inclusions (“spironolactone bodies”) ♦♦ Adenomas associated with adrenogenital syndromes −− Adenomas associated with adrenogenital syndromes tend to be larger, may have red-brown appearance, and are not associated with atrophy of the normal cortical tissue.

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Fig. 20.82. Aldosterone-secreting adenoma: The tumor features large clear cells arranged in trabeculae supported by a minimal fibrovascular stroma. There is focal nucleomegaly.

Fig.  20.83. Spironolactone bodies: There are scattered laminated eosinophilic structures in a group of cells with eosinophilic cytoplasm (the latter unusual in an aldosterone-secreting adenoma).

These tumors are relatively uncommon and must be carefully distinguished from cortical carcinoma ♦♦ Nonfunctional adenomas and cortical nodules −− Nonfunctional adenomas are small (>3  cm), yellow to brown in color, and may be multicentric. They are not associated with atrophy of normal cortical tissue ♦♦ Oncocytic adenoma (oncocytoma) −− Oncocytic adenoma is an epithelial adrenal cortical neoplasm composed of oncocytic cells, which is often asymptomatic, but may be associated with hormonal syndrome. Oncocytomas are usually benign, but the behavior is difficult to predict with certainty −− Grossly (Fig. 20.84), oncocytic adenomas can be variable in size (60–850  g), but are usually well-circumscribed and often encapsulated. They are typically tan-brown in

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Fig. 20.84. Oncocytoma: Brown cut surface with some gaping vessels.

Fig.  20.85. Oncocytoma: Moderately large cells with eosinophilic cytoplasm and nuclei are central and eccentric. Multi­ nucleation is present. color, often have a central scar, and may show hemorrhage or cystic change −− Microscopically (Fig. 20.85), these tumors are composed of sheets of large regular polygonal cells with abundant granular eosinophilic cytoplasm, and often show some nuclear pleomorphism

Differential Diagnosis ♦♦ Nodular or macronodular hyperplasia −− Nodular hyperplasia is characterized by multiple nodules rather than single dominant nodule. The adjacent cortex and contralateral adrenal gland appears hypertrophic, not atrophic ♦♦ Adrenal cortical carcinoma −− Adrenal cortical carcinomas are typically large tumors (>100  g) and show nuclear atypia, mitoses, necrosis, and invasion

Endocrine Pathology

♦♦ Pheochromocytoma −− Arising from adrenal medulla with normal adrenal cortex stretched out over its surface, pheochromocytomas are redbrown in color with areas of hemorrhage or cystic degeneration if large. Organoid growth pattern with nests of cells (“zellballen”) and delicate vascular septa are characteristic −− Pheochromocytomas are immunoreactive for neurofilament, chromogranin, and synaptophysin, and negative for keratins, Melan-A/Mart-1, and inhibin. S-100 marks the sustentacular cells

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philic cytoplasm (lipid-depleted) to large and vacuolated (lipid-laden) cells. The growth pattern may be alveolar, trabecular, or diffuse

Adrenal Cortical Carcinoma Clinical ♦♦ Adrenal cortical carcinomas (ACC) are rare, accounting for about 3% of endocrine tumors. All ages can be affected, although some studies have found a higher incidence in the 40- to 50-year old population. Females are affected more commonly than males ♦♦ Approximately 45–49% of tumors are functional with production of glucocorticoids resulting in Cushing syndrome or androgens with virilization. Hormonal hypersecretion is more common in women ♦♦ Adrenal cortical carcinomas are aggressive tumors with 5-year survival of 25%. They are treated surgically with improved survival with localized disease that is completely removed surgically. Adjuvant therapies (op'-DDD) have limited, if any, benefit

Fig. 20.87. Adrenal cortical carcinoma: A sheet of relatively ­uniform cells with clear to dark cytoplasm and dilated blood vessels.

Macroscopic (Fig. 20.86) ♦♦ Adrenal cortical carcinomas vary in size, but are usually large cortical masses, usually >6 cm in size (usually >100 g in adults and >500 g in children). On cut section, ACCs are pink to tan to yellow, depending on lipid content of tumor cells, and often lobulated with areas of fibrosis, necrosis, hemorrhage, and invasion of adjacent structures

Microscopic (Figs. 20.87–20.89) ♦♦ Adrenal cortical carcinomas have a varied cellular appearance depending on lipid content: small cells with eosino-

Fig. 20.88. Adrenal cortical carcinoma: Zone of necrosis in a background of relatively uniform cells with mostly clear cytoplasm.

Fig. 20.86. Adrenal cortical carcinoma: The tumor (870 g) shows variable sized lobules and a zone of necrosis.

Fig.  20.89. Adrenal cortical carcinoma: Atypical nuclei are present.

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Histologic features of malignancy include invasive growth, angiolymphatic invasion, necrosis, broad fibrous bands, capsular invasion, increased mitotic rate (>5 per 50 high power fields), atypical mitotic figures, prominent clear cells, and nuclear pleomorphism

Immunohistochemistry (Table 20.4) ♦♦ Adrenal cortical carcinomas are positive for low molecular weight keratin (CAM 5.2), and may show focal staining for other keratins and vimentin. They are also positive for Melan A/MART1 (A103), but are negative for S-100. Functioning tumors show positivity for inhibin. Adrenal cortical carcinomas are positive for synaptophysin, but they are negative for chromogranin, which is helpful in differentiating them from pheochromocytomas

Variants ♦♦ Oncocytic adrenal carcinoma −− In a series of ACC from Mayo Clinic, 6 of 67 (11.2%) ACC were composed predominantly of oncocytic cells. These tumors ranged in size from 8 to 20 cm, and three of these patients died of disease. Only one of the oncocytic carcinomas (20 cm) was functional (feminizing) ♦♦ Myxoid adrenal cortical carcinoma −− Adrenal cortical carcinomas and adenomas can show prominent myxoid change and must be distinguished from metastases to the adrenal glands ♦♦ Pediatric adrenal cortical carcinoma −− Differentiating ACC from adenoma in children is very difficult. Pediatric ACC can occur in Beckwith– Wiedemann syndrome, but most occur sporadically. Patients often present with hormone-related symptoms. Features associated with malignant clinical behavior are tumor weight >400 g, size >10.5 cm, vena cava invasion,

capsular and/or vascular invasion, extension into periadrenal soft tissue, confluent necrosis, severe nuclear atypia, >15 mitotic figures/20 hpf, and atypical mitotic figures

Differential Diagnosis (Table 20.4) ♦♦ Adrenal cortical adenoma −− Adrenal cortical adenomas are usually smaller (usually 3–6 cm) than ACC and well-circumscribed, often encapsulated. Adrenal adenomas may show some nuclear pleomorphism, but generally lack necrosis, increased mitotic activity, and invasion of capsule or vessels ♦♦ Metastatic tumors to the adrenal gland −− Adrenal cortical carcinomas must be differentiated from metastatic carcinomas such as from lung, breast, gastrointestinal tract, thyroid, and kidney. The growth pattern of metastases is usually solid rather than alveolar or trabecular. Immunohistochemical studies are very helpful in difficult cases. Metastatic lung adenocarcinomas show strong diffuse immunopositivity for cytokeratin 7 and TTF-1. Metastatic breast cancer is positive for cytokeratin 7, GCDFP-15 (BRST2), mammoglobin, estrogen, and progesterone receptors, and is negative for TTF-1 and Melan A/Mart-1. Metastases from colon adenocarcinomas are positive for cytokeratin 20 and CDX2, markers generally negative in ACC ♦♦ Melanoma −− Although exceptionally rare cases of primary adrenal melanomas have been described, the overwhelming majority of melanomas involving the adrenal gland are metastatic. Malignant melanomas often show melanin pigment and are positive for MelanA/Mart-1, similar to adrenal cortical tumors, but melanomas are usually positive for other markers of melanocytic differentiation such as S-100, tyrosinase, and HMB45, which are negative in adrenal cortical tumors

Table 20.4. Immunophenotype of Differential Diagnosis of Adrenal Cortical Carcinoma Tumor

Keratin

Chromogranin Synaptophysin

TTF S-100 MelanA/Mart1

Inhibin

Adrenal cortical carcinoma

+ (CAM 5.2)

−

+

−

−

+

+

Pheochromocytoma

−

+

+

−

a

−

−

Metastatic breast carcinoma

+ (keratin 7)

−

−

−

−/+

−

−

Metastatic lung

+ (keratin 7)

−

−

+

−

−

−

Metastatic melanoma

−

−

−

−

+

+

Renal cell carcinoma

+

−

−

−

−

−

− −

a

S-100 protein marks sustentacular cells

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Pheochromocytoma ♦♦ Pheochromocytomas are red-brown in color with areas of hemorrhage or cystic degeneration when large. These tumors have an organoid growth pattern with nests of cells (“zellballen”) and delicate vascular septa. Immunohistochemically, pheochromocytomas are positive for chromogranin, synaptophysin, and S-100 (in sustentacular cell staining pattern), and negative for CAM 5.2, inhibin, and Melan A/MART1. One caveat to keep in mind is that adrenal cortical tumors can show positivity for synaptophysin, similar to pheochromocytomas. However, adrenal cortical tumors are negative for chromogranin

Pheochromocytoma Clinical ♦♦ Pheochromocytomas are composed of adrenal medullary chromaffin cells. The highest incidence of pheochromocytoma is in fourth and fifth decades, although 10% occur in children. Patients present with signs and symptoms of catecholamine secretion (hypertension, cardiac dysrhythmias, and diaphoresis). Ectopic hormones may be produced as well (ACTH, somatostatin, or calcitonin). Extraadrenal pheochromocytomas (paragangliomas) account for approximately 10–20% of cases and occur elsewhere in retroperitoneum, mediastinum, neck, or bladder. Ten to twenty percent of pheochromocytomas are associated with familial syndromes: MEN Type 2A and 2B, von Hippel-Lindau disease, von Recklinghausen disease, and Sturge–Weber syndrome ♦♦ Approximately 5–10% of pheochromocytomas are malignant. There are no reliable gross or histologic criteria exist for malignancy other than invasion of adjacent structures or metastases

Fig.  20.90. Pheochromocytoma: The soft fleshy-pink tumor shows an area of hemorrhage.

Macroscopic (Fig. 20.90) ♦♦ Pheochromocytoma usually presents as an encapsulated mass, 3–5  cm, weighing <100, gray-pink to tan-brown in color. The tumors usually have a soft consistency and may have areas of hemorrhage and cyst formation in larger tumors

Microscopic (Fig. 20.91) ♦♦ Pheochromocytomas grow in cords or nests (zellballen = “cell balls”), with delicate fibrovascular septa. The cells are variable in size with generally basophilic granular cytoplasm that may be vacuolated in some cases. Occasional spindled cells can be seen as well as PAS + cytoplasmic hyaline globules. Cytologically, the cells are round to oval with slightly irregular nuclei, coarsely clumped chromatin (salt and pepper chromatin) and single, ordinarily inconspicuous nucleoli. Moderate nuclear pleomorphism may be present. Mitoses can be seen, but are not prominent

Immunohistochemistry ♦♦ Tumor cells are immunoreactive for chromogranin and synaptophysin with S-100 staining thin, spindled sustentacular cells (Table 20.4). They are negative for cytokeratins

Fig. 20.91. Pheochromocytoma: Clusters of cells with granular slightly basophilic cytoplasm are surrounded by a fibrovascular stroma.

Differential Diagnosis ♦♦ Adrenal cortical adenoma −− Adrenal cortical adenomas are small (3–6 cm) with bright yellow to tan-brown color and uninvolved adrenal cortical tissue usually appears atrophic. Adrenal cortical adenomas are positive for synaptophysin, but negative for chromogranin. Adrenal cortical tumors also show weak immunopositivity for keratin while pheochromocytomas are negative ♦♦ Adrenal cortical carcinoma −− Adrenal cortical carcinomas often show marked nuclear pleomorphism, necrosis, invasion, and prominent mitotic

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activity. Adrenal cortical carcinomas are positive for synaptophysin, but negative for chromogranin. Adrenal cortical tumors also show weak immunopositivity for keratin while pheochromocytomas are negative ♦♦ Metastatic carcinoma −− Common primary sites of metastases to the adrenal include lung, breast, gastrointestinal tract, thyroid, and kidney. The growth pattern of metastases to the adrenal is usually solid rather than nested or zell-ballen. Metastatic carcinomas are positive for keratin, and may be positive for other markers characteristic of the location of the primary such as TTF-1 in  pulmonary adenocarcinoma, etc ♦♦ Melanoma −− Although exceptionally rare cases of melanoma may be primary in the adrenal gland, the absolute overwhelming majority of melanoma in the adrenal gland is metastatic. Melanomas often show melanin pigment, and immunohistochemically mark for S-100, Melan A/MART1, and HMB-45

Myelolipoma Clinical ♦♦ Myelolipoma is a benign mixed stromal tumor composed of mature adipose and myeloid elements. Myelolipoma is usually an incidental finding at autopsy or adrenalectomy. Small foci of myelolipomatous change are commonly seen in adenomas or hyperplasia

Macroscopic (Fig. 20.92) ♦♦ Myelolipomas are small, nonencapsulated spongy lesions, often bright yellow with scattered small red-brown foci

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic (Fig. 20.93) ♦♦ These tumors are composed of mature adipose tissue with scattered normal-appearing hematopoietic elements

Ganglioneuroma Clinical ♦♦ Ganglioneuroma is a benign neurogenic tumor arising in adrenal medulla and sympathetic ganglia, which occur most often in older children (>7 years) and young adults. These tumors may present as a mass or be seen as an incidental finding on CT or MRI or at autopsy. Ganglioneuromas may be associated with clinical syndromes such as hypertension, diarrhea, and/or hypokalemia (95% of patients have detectable elevations in catecholamine metabolites in urine). These tumors may be solitary or associated with other neurogenic tumors. Less than 30% of cases located in adrenal glands as most found in posterior mediastinum or in retroperitoneum, particularly presacral region

Macroscopic ♦♦ Myelolipomas are large (average size = 8 cm), sharply circumscribed firm masses, homogenous gray-white in appearance

Microscopic (Figs. 20.94 and 20.95) ♦♦ The stroma closely resembles neurofibroma, with thin wavy spindled cells (Schwann cells) in collagenous matrix. Scattered mildly atypical to normal ganglion cells with abundant cytoplasm and multiple nuclei are seen. These tumors may contain lymphocytic infiltrates that may be confused with neuroblasts

Immunohistochemistry ♦♦ Stroma is immunoreactive with S-100 protein (Table  20.4). Ganglion cells are immunoreactive with neurofilament, chromogranin, and neuron-specific enolase

Differential Diagnosis ♦♦ Neurofibroma −− The stroma in neurofibroma may appear identical to that of ganglioneuroma; however, no ganglion cells are seen in neurofibroma

Fig.  20.92. Myelolipoma: Bulging juxtaposed myelolipomas with a dark red appearance.

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Fig. 20.93. Myelolipoma: Panoramic view of tumor with a large fatty core surrounded by a cellular collar (bone marrow cells).

Endocrine Pathology

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(or differentiating) elements. Differentiated variants tend to resemble typical ganglioneuromas (circumscribed firm white-gray masses). Undifferentiated variants show large nodular areas grossly resembling neuroblastoma (soft whitegray with areas of necrosis and hemorrhage)

Microscopic ♦♦ Differentiated and undifferentiated areas with morphologic features of ganglioneuroma and neuroblastoma are seen, respectively. Differentiated areas have collagenous stroma with scattered atypical ganglion cells, while undifferentiated areas show sheets or nodules of small regular cells with hyperchromatic nuclei

Immunohistochemistry Fig.  20.94. Ganglioneuroma: Ganglion cells, their processes, and ensheathing Schwann cells.

♦♦ Immunohistochemical features are characteristic for respective elements (see neuroblastoma and ganglioneuroma)

Neuroblastoma Clinical

Fig.  20.95. Ganglioneuroma: Appearance is reminiscent of a neurofibroma except for the presence of abnormal and mature ganglion cells. ♦♦ Ganglioneuroblastoma −− Ganglioneuroblastoma contains less differentiated foci of neuroblasts (with typical microscopic and immunohistochemical features)

♦♦ Neuroblastoma is a malignant neurogenic tumor composed of immature neuroblasts occurring in 1 in 7,000–10,000 live births. Fifty percent of patients are <2-years old, 90% <8-years old; median age = 21 months. Patients usually present with intraabdominal mass, and these tumors may rarely be associated with hormonal (catecholamines, vasoactive intestinal peptide) or other para-neoplastic syndromes. Seven percent occur in retroperitoneum, usually adrenal gland. Other sites include mediastinum, head and neck region, and pelvic region ♦♦ Prognosis related to number of factors including stage, age, favorable or unfavorable histology, ploidy, N-myc, adrenal or extra-adrenal location, among others ♦♦ Common cytogenetic abnormalities include 1p deletions and amplification of N-myc oncogene. There is an association with Beckwith–Wiedemann syndrome and neurofibromatosis

Macroscopic (Fig. 20.96) ♦♦ Neuroblastomas are usually solitary, soft gray, wellcircumscribed masses, which may contain areas of hemorrhage, necrosis, calcification, or cystic degeneration

Microscopic (Fig. 20.97)

♦♦ Ganglioneuroblastoma is a combination tumor representing maturational intermediate between neuroblastoma and ganglioneuroma, which is usually seen in children <10 years, can occur in adults. This tumor usually presents as intraabdominal or intrathoracic mass, rarely seen with hormonal syndromes similar to neuroblastoma. These tumors may occur in the adrenal gland, but are more in extra-adrenal retroperitoneum and mediastinum

♦♦ The individual cells are separated by a fine fibrillar eosinophilic matrix. The cells are small and uniform, with little cytoplasm and round, hyperchromatic nuclei with small nucleoli. The cells are arranged in sheets, which form vague lobules divided by thin fibrovascular septa, and Homer– Wright pseudorosettes (rings of neuroblasts, 1–2 layers thick, surrounding central area filled with eosinophilic fibrillary material) are seen in 30% of cases. Necrosis, hemorrhage, and calcifications are common findings ♦♦ Tumors may show varying degrees of differentiation toward ganglioneuroma, with cellular and nuclear enlargement, prominent nucleoli, and stroma resembling neurofibroma

Macroscopic

Immunohistochemistry

Ganglioneuroblastoma Clinical

♦♦ The histologic features are varied, depending on relative proportion of fully differentiated and undifferentiated

♦♦ The tumor cells are immunoreactive for neuron-specific enolase, chromogranin, synaptophysin, microtubule-­associated

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 20.97. Neuroblastoma: Population of small cells interspersed with pseudorosettes.

Fig.  20.96. Neuroblastoma: Circumscribed tumor with coarse red and yellow nodules. proteins, neurofilaments, alpha-internexin, secretogranin II, and vasoactive intestinal peptide. Stromal cells immunoreactive for S-100 protein, glial fibrillary acidic protein, and myelin basic protein

Differential Diagnosis ♦♦ Ewings sarcoma (extraskeletal) −− Ewing sarcoma/PNET usually affects older patients (>5 years). The histology is very similar to neuroblastoma

(may even have pseudorosettes rarely). Cytogenetic studies show a characteristic t(11;22) translocation ♦♦ Nephroblastoma (Wilm tumor) − − Microscopically, Wilm tumors are composed of undifferentiated blastema, mesenchyme, and epithelium. Tumors composed largely of blastema may resemble neuroblastoma; thus, one needs to look carefully for other elements ♦♦ Lymphoma −− Lymphomas are composed of sheets of poorly cohesive cells with lymphocytic to epithelioid appearance and irregular nuclear borders. Immunohistochemical studies can be very helpful to separate these entities

TNM Classification of Thyroid Carcinomas (2010 Revision) ♦♦ Primary Tumor (T)* ♦♦ All category may be subdivided into (a) solitary tumor and (b) multifocal tumor (the largest determines the classification) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1:  Tumor 2 cm in greatest dimension limited to thyroid −− T1a: Tumor 1 cm or less, limited to the thyroid −− T1b: Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid

−− T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to thyroid −− T3: Tumor more than 4 cm in greatest dimension limited to thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissue) −− T4a: Moderately advanced disease; tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve −− T4b: Very advanced disease; tumor invades prevertebral fascia or encase carotid artery or mediastinal vessels

*All anaplastic carcinomas are considered T4, which is subdivided into T4a (intrathyroid anaplastic carcinoma) and T4b (extrathyroidal anaplastic carcinoma)

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♦♦ Regional Lymph Nodes (N) ♦♦ Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastases −− N1: Regional lymph node metastases −− N1a: Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)

−− N1b: Metastasis to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII) ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis

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Parathryoid

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Edited by RA DeLellis, Lloyd, R.V., Heitz. P.U., Eng, C. Lyon, IARC Press, 2004, pp 124–132. Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 2002;32:676–680. Castleman B, Schwantz A, Roth SI. Parathyroid hyperplasia in primary hyperparathyroidism: review of 85 cases. Cancer 1976;38:1668–1675. Chandur-Mnaymneh L, Kimura N. Parathyroid adenoma histopathologic definition with study of 172 cases of primary hyperparathyroidism. Am J Pathol 1984;115:70–83. Chow LS, Erickson LA, Abu-Lebdeh HS, Wermers RA. Parathyroid lipoadenomas: a rare cause of primary hyperparathyroidism. Endocr Pract 2006;12:131–136. Cetani F, Pardi E, Borsari S, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 2004;89: 5583–5591. Erickson LA, Lloyd RV. Familial disorders of the pathology of the parathyroid gland. Diagn Histopathol 2009. Erickson LA, Jalal SM, Harwood A, Shearer B, Jin L, Lloyd RV. Analysis of parathyroid neoplasms by interphase fluorescence in situ hybridization. Am J Surg Pathol 2004;28:578–584. Erickson LA, Jin L, Papotti M, Lloyd RV. Oxyphil parathyroid carcinomas: a clinicopathologic and immunohistochemical study of 10 cases. Am J Surg Pathol 2002;26:344–399. Erickson LA, Jin L, Wollan P, Thompson GB, van Heerden JA, Lloyd RV. Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27Kip1 protein. Am J Surg Pathol 1999;23:288–295. Erickson LA, Jin L, Wollan P, et al. Parathyroid hyperplasia, adenomas, and carcinomas differential expression of p27(Kip1) protein. Am J Surg Pathol 1999;23:288–295. Haven CJ, van Puijenbroek M, Tan MH, et al. Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas. Clin Endocrinol (Oxf) 2007;67:370–376. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995;80:3107–3110. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 1996;81:1736–1739. Janicic N, Soliman E, Pausova Z, et al. Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16. Mamm Genome 1995;6:798–801. Juhlin C, Larsson C, Yakoleva T, et al. Loss of parafibromin expression in a subset of parathyroid adenomas. Endocr Relat Cancer 2006;13: 509–523. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008;29:22–32. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863–1875. Marx SJ, Agarwal SK, Kester MB, et al. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog Horm Res 1999;54:397–438; discussion 438–439.

Black WC III, Haff RC. Surgical pathology of parathyroid chief cell hyperplasia. Am J Clin Pathol 1970;53:565–579.

Oishi S, Sato T, Takiguchi-Shirahama S, Nakamura Y. Mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A (Sipple’s syndrome). Endocr J 1995;42:527–536.

Bondeson L, Grimelius L, DeLellis RA, Lloyd R, Akerstrom G, Larsson C, Arnold A, Eng C, Shane E, Bilezekian JP. Parathyroid carcinoma. In Pathology and Genetics of Tumours of Endocrine Organs.

Shattuck TM, Valimaki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003;349:1722–1729.

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Szabo J, Heath B, Hill VM, Jackson CE, Zarbo RJ, Mallette LE, Chew SL, Besser GM, Thakker RV, Huff V, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet 1995;56:944–950.

Lack EE, Mulvihill JJ, Travis WD, et al. Adrenal cortical neoplasms in pediatric and adolescent age group: clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors. Pathol Annu 1992;27:1–53.

Adrenal

Lloyd RV, Blaivas M, Wilson BS. Distribution of chromogranin and S-100 protein in normal and abnormal adrenal medullary tissues. Arch Pathol Lab Med 1985;109:633–635.

Beckwith JB, Martin RF. Observations on histopathology of neuroblastoma. J Pediatr Surg 1968;3:106–110. Bodie B, Novick AC, Pontes JE, Straffon RA, Montie JE, Babiak T, Sheeler L, Schumacher P. The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 1989;141:257–260. Brown FM, Gaffey TA, Wold LE, Lloyd RV. Myxoid neoplasms of the adrenal cortex: a rare histologic variant. Am J Surg Pathol 2000;24: 396–401. Carney JA, Sizemore GW, Sheps SG. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Pathol 1976;66:279–290. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996;119:161–170. Erickson LA, Jin L, Sebo TJ, Lohse C, Pankratz VS, Kendrick ML, van Heerden JA, Thompson GB, Grant CS, Lloyd RV. Pathologic features and expression of insulin-like growth factor-2 in adrenocortical neoplasms. Endocr Pathol 2001;12:429–435. Erickson LA, Lloyd RV, Hartman R, Thompson G. Cystic adrenal neoplasms. Cancer 2004;101:1537–1544. Hough AJ, Hollifield HW, Page DL, et al. Prognostic factors in adrenal cortical tumors. Am J Clin Pathol 1979;72:390–399. Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS, Thompson GB, Rowland C, Young WF Jr, van Heerden JA. Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 2001;136: 543–549. Lack EE. Pathology of Adrenal and Extra-Adrenal Paraganglia. Philadelphia, PA, WB Saunders Co, 1994.

Lloyd RV, Shapiro B, Sisson JC, et al. An immunohistochemical study of pheochromocytomas. Arch Pathol Lab Med 1984;108:541–544. Loy TS, Phillips RW, Linder CL. A103 immunostaining in the diagnosis of adrenal cortical tumors: an immunohistochemical study of 316 cases. Arch Pathol Lab Med 2002;126:170–172. Macadam RF. Black adenoma of human adrenal cortex. Cancer 1971;27:116–119. Medeiros LJ, Wolf BC, Balogh K, et  al. Adrenal pheochromocytoma: clinicopathologic review of 60 cases. Hum Pathol 1985;16:580–589. Sasano H, Suzuki T, Moriya T. Adrenal cortex. In Endocrine Pathology: Differential Diagnosis and Molecular Advances. Edited by RV Lloyd. Totowa, NJ, Humana Press, 2004, pp 211–226. Shenoy BV, Carpenter PC, Carney JA. Bilateral primary pigmented nodular adrenocortical disease: rare cause of Cushing syndrome. Am J Surg Pathol 1984;8:335–344. van Slooten H, Schaberg A, Smeenk D, Moolenaar AJ. Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 1985;55:766–773. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8: 163–169. Weiss LM, Medeiros LJ, Vickery AL, Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13: 202–206. Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003;27:867–881.

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21 Bone and Joints Jasvir S. Khurana, md and Guldeep Uppal, md

contents

IV. Metabolic Bone Diseases.................21-10 I. Skeletal Trauma and Other Common Osteoporosis....................................................21-10 Conditions.........................................21-3 Fracture.............................................................21-3 Heterotopic Ossification..................................21-3 Myositis Ossificans (“Traumatica”)................21-3 Reflex Sympathetic Dystrophy (Algodystrophy or Sudeck Osteodystrophy)...........................................21-4 Osteonecrosis (Avascular, Aseptic, Ischemic Necrosis)........................................21-4 Osteochondritis “Juvenilis”............................21-5

II. Bone Infections..................................21-6 Pyogenic Osteomyelitis....................................21-6 Acute Osteomyelitis...............................21-6 Chronic Osteomyelitis...........................21-6 Sclerosing Osteitis (Garre Osteomyelitis)..................................21-7 Chronic Multifocal Recurrent Osteomyelitis................................................21-7 Tubercular Osteomyelitis................................21-7 Fungal Osteomyelitis.......................................21-7

III. Arthritides..........................................21-8 Osteoarthritis (OA)..........................................21-8 Neuropathic Arthropathy (Charcot Joints)............................................21-9 Crystal Arthropathies......................................21-9 Gout and Gouty Arthritis......................21-9 Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout, Chondrocalcinosis).............................21-9 Rheumatoid Arthritis....................................21-10

Rickets and Osteomalacia.............................21-11 Primary Hyperparathyroidism.....................21-11 Paget Disease (Osteitis Deformans)..............21-12 Osteopetrosis (Albers-Schönberg Marble Bone Disease)................................21-13 Osteogenesis Imperfecta................................21-13 Mucopolysaccharidoses.................................21-14 Gaucher Disease.............................................21-14

V. Musculoskeletal Neoplasms.............21-14 Bone Cysts.......................................................21-14 Simple (Unicameral) Bone Cyst (UBC)..............................21-14 Intraosseous Ganglion.........................21-14 Aneurysmal Bone Cyst........................21-15 Bone-Forming Lesions...................................21-16 Osteoid Osteoma..................................21-16 Osteoblastoma......................................21-17 Osteosarcoma and Its Variants.............................................21-18 Cartilaginous Lesions....................................21-23 Osteochondroma (Osteocartilaginous Exostosis)...........................................21-23 Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion).............21-23 Chondroma...........................................21-24 Chondroblastoma.................................21-25 Chondromyxoid Fibroma....................21-26 Chondrosarcoma and Its Variants.............................................21-27 Vascular Lesions.............................................21-29

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_21, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Solitary Lymphangioma, Hemangioma, and Skeletal Angiomatosis.....................................21-29 Gorham Disease (Massive Osteolysis).........................21-29 Hemophilic Pseudotumor....................21-29 Epithelioid (Histiocytoid) Hemangioendothelioma...................21-29 Angiosarcoma.......................................21-30 Hemangiopericytoma/Solitary Fibrous Tumor..................................21-30 Glomus Tumor.....................................21-30 Vascular Tumors in Immunocompromised Patients.......21-30 Giant Cell Lesions..........................................21-30 Giant Cell Tumor (Osteoclastoma).................................21-30 Giant Cell Reparative Granuloma.....21-32 Fibrous Lesions..............................................21-33 Desmoplastic Fibroma.........................21-33 Fibrosarcoma........................................21-33 Fibrohistiocytic Lesions.................................21-33 Benign and Atypical Fibrous Histiocytoma.....................................21-33 Malignant Fibrous Histiocytoma........21-33 Other Mesenchymal Lesions.........................21-34

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Fibrous Dysplasia (FD, JaffeLichtenstein Syndrome)...................21-34 Campanacci Disease (Osteofibrous Dysplasia)..........................................21-34 Fibrocartilaginous Mesenchymoma................................21-35 Adamantinoma.....................................21-35 Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET)..................................21-35 Conventional Chordoma.....................21-36 Chondroid Chordoma.........................21-37 Plasma Cell Dyscrasias (Plasmacytoma/Multiple Myeloma)..........................................21-37 Non-Hodgkin Lymphoma....................21-37 Langerhans Cell Histiocytosis.............21-37 Erdheim-Chester Disease....................21-38 Metastatic Bone Disease................................21-38

VI. Staging of Musculoskeletal Neoplasms.......................................21-38 VII. Tnm Classification of Bone Tumors (2010 Version).................................21-39 VIII. Suggested Reading...........................21-39

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SKELETAL TRAUMA AND OTHER COMMON CONDITIONS Fracture Definition ♦♦ The term fracture refers to a break in the bone, generally, but not necessarily, as a consequence of trauma. Fractures can be partial or complete. They can be closed (no breach of skin) or open (fragments of bone exposed)

Clinical ♦♦ Fractures can go on to heal (union), which can sometimes be delayed or complicated by a variety of clinical problems (angular or rotational deformities or malunions), or they may go on to nonunion Angular, but not rotational deformities, can often be resolved (especially in children) through remodeling ♦♦ The pathologist is involved only rarely in cases that are complicated – for example pathological fracture resulting from infection, metabolic disease or tumor. In some children, a pseudarthrosis of the tibia can result from neurofibromatosis, fibroma, or Campanacci disease (osteofibrous dysplasia) and may require input from a pathologist

Microscopy ♦♦ Fracture healing is often described as having three phases (inflammatory, reparative, and remodeling). Essentially, the fracture hematoma gets invaded by fibroblasts that eventually change into bone via a metaplastic reaction in a fashion similar to the developing skeleton. There is sometimes a cartilage phase in between, especially if there is micromotion of the involved fragments (similar to endochondral ossification)

Heterotopic Ossification Definition ♦♦ The term “heterotopic ossification” refers to bone formation within soft tissues ♦♦ By definition, the underlying tissue is normal, and there is no history of trauma and no known underlying metabolic condition. If the underlying tissue is abnormal (for example, burnt, damaged, or injured), then the term dystrophic ossification is used. If there is an underlying metabolic condition, for example, hyperparathyroidism, then the term metastatic ossification is sometimes employed

Clinical ♦♦ The most common clinical situation is postoperative ossification in the hip following arthroplasty (although, strictly speaking, this is following surgical trauma) ♦♦ Prevalence: 2–90%, depending on the population studied and the criteria used ♦♦ There are two types

−− Central type seen around the neck of the femur in certain individuals with a genetic predisposition −− Lateral type seen around the greater trochanter, following the lateral (McFarland) surgical approach to bone. The lateral type is actually a misnomer as it represents a form of traumatic ossification (myositis ossificans)

Differential Diagnosis ♦♦ Metastatic calcification in hyperparathyroidism ♦♦ Traumatic ossification (myositis ossificans)

Myositis Ossificans (“Traumatica”) Definition ♦♦ Myositis ossificans is a reaction to trauma. It is most often seen within the deep soft tissues but may also be seen in a subperiosteal location (subperiosteal hematoma) ♦♦ Myositis ossificans is a time-honored term and is considered acceptable despite the reaction being neither a muscle nor an inflammatory disorder ♦♦ There is some emerging evidence that myositis ossificans might be related to a group of lesions that include aneurysmal bone cyst (ABC) and giant cell reparative granuloma of bone; all the three lesions show translocations involving the USP6 gene

Clinical ♦♦ Most cases present as a painful mass arising after significant trauma. The radiological studies are often able to demonstrate a peripheral rim of ossification around a central area

Microscopic ♦♦ Ossification commences from the outside and progresses within; in late stages, the entire mass may become ossified (Fig. 21.1A). In most cases, an orderly pattern of maturation or zonation is present with maturation at periphery, and immature fibroblasts located more centrally ♦♦ The central fibroblastic repair reaction can be alarming and sometimes mistaken for a malignant sarcoma if taken out of context without any attention being paid to the low power impression of zonation (Fig. 21.1B)

Differential Diagnosis ♦♦ Fibrodysplasia progressiva (previously called myositis ossificans progressiva): this is an entirely different and progressive condition that is genetic ♦♦ Bone-forming tumors (such as osteosarcoma): can be differentiated since there is no peripheral maturation (zonation) in tumors. Additionally, osteosarcoma has a hypercellular ­spindle cell proliferation with considerable cytological ­atypia and sometimes sheets of atypical osteoblasts

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Fig.  21.1. Myositis ossificans (gross) forming a circumscribed mass with a bony shell and a hemorrhagic fibrous center (A). Myositis ossificans (micro) at frozen section a

well developed “zonation” is identified (B). Mature new bone formation in a patient with myositis ossificans of the softtissues of the thigh (c–d).

Reflex Sympathetic Dystrophy (Algodystrophy or Sudeck Osteodystrophy) Definition

Microscopic

♦♦ A condition of severe regional, patchy osteopenia following trauma that is almost always accompanied by pain, redness, and swelling of the affected portion of body (generally the limbs)

Clinical ♦♦ It is associated with trophic skin changes, edema of the extremity, and psychological disturbances ♦♦ The radiological differential diagnosis includes other forms of osteopenia such as bone marrow edema, transient osteoporosis, migratory osteolysis, and idiopathic regional osteoporosis. The clinical findings of pain and sympathetic nervous system involvement can help differentiate these conditions

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♦♦ The changes are not very specific. There is a proliferation of fibroblasts within the marrow space ♦♦ In some cases, bone necrosis and new bone formation may be seen

Osteonecrosis (Avascular, Aseptic, Ischemic Necrosis) Definition ♦♦ The in situ death of bone, presumably from one or more vascular insults. By definition, necrosis of bone occurring as a result of infection is excluded (Fig. 21.2A). The term osteonecrosis includes instances resulting from insults such as radiation and is a more encompassing term than avascular necrosis although the morphological features are almost identical

Clinical ♦♦ There are two main forms

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−− −− −− −− −− −− −− −− −− −−

Connective tissue disorders Vasculitis Hemoglobinopathies and coagulopathies Radiation injury Corticosteroid therapy Pregnancy Aging Gout Pancreatitis Childhood osteochondritides such as Perthe, Keinbock, Sever, Kohler, Larsen, Blount, or Panner diseases (the pathogenesis of these is uncertain, probably avascularity, but the morphological features are those of osteonecrosis) ♦♦ Osteonecrosis is suspected on the basis of clinical history, physical findings, x-ray, and other scanning techniques. Magnetic resonance imaging (MRI) is especially sensitive and helpful in the diagnosis ♦♦ Diagnosis is confirmed by biopsy

Microscopic

Fig. 21.2. Avascular necrosis of the femoral head (gross) (A). The photograph shows the infarcted bone beginning to separate from the adjacent bone and the overlying cartilage (A). The trabeculae are anucleate and the adjacent marrow shows necrosis and fibrosis (B).

−− Medullary infarction (marrow cavity and trabecular bone). This form is often silent −− Corticomedullary infarction (cortex also involved). This form is often painful ♦♦ Conditions predisposing to osteonecrosis −− Trauma, infection, and fatigue fractures −− Alcohol abuse −− Dysbarism −− Gaucher disease

♦♦ The hallmark of osteonecrosis is the finding of anucleate bone (with empty lacunae) (Fig. 21.2B). Surrounding this is reactive hyperemia in the early course. This is followed by a fibrovascular proliferation adjacent to the necrotic bone. The necrotic bone is then walled off, in a fashion similar to sequestrum formation in osteomyelitis ♦♦ Revascularization of dead bone occurs in a few weeks ♦♦ In a few days, cutting cones of osteoclasts arrive, carrying blood vessels. They enter the dead bone and remove it gradually by osteoclastic resorption ♦♦ At the same time, osteoblasts lay down new bone on top of the necrotic fragment. The laying down of new (woven) bone on top of necrotic trabeculae is quite characteristic ♦♦ The next stage is unpredictable, depending on the site and extent of damage −− May culminate in restitution (complete healing) −− May lead to the relentless continuation of the repair process that damages the integrity of bone. This then leads to fatigue fractures, collapse of the subchondral bone, cartilage disintegration, and joint deformity (secondary osteoarthritis)

Osteochondritis “Juvenilis” ♦♦ Refers to the earlier set of eponymic names for avascular necrosis occurring in certain bones ♦♦ Includes conditions such as Perthe, Keinbock, Sever, Kohler, Larsen, Blount, or Panner diseases ♦♦ With the exception of Perthe disease (which may be associated with constitutional skeletal abnormalities), these conditions are similar to the osteonecrosis occurring in the noneponymic locations

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BONE INFECTIONS Pyogenic Osteomyelitis Acute Osteomyelitis Clinical ♦♦ Infections can reach the bone by −− Hematogenous route (a) From an antecedent focus of infection elsewhere. This is the most common form of osteomyelitis, ­especially in children (b) Most cases of hematogenous osteomyelitis occur in the metaphyses of long tubular bones in children −− Direct extension (a) Infection can also reach bone by direct extension, for example, from an infected wound or a deep chronic ulcer overlying the bone. Often, this form of ostemyelitis is seen in association with trauma (compound fractures) ♦♦ Commonly encountered organisms −− Staphylococcus aureus (most common) −− Escherichia coli, Klebsiella, and Pseudomonas species −− Salmonella (seen in patients with sickle cell anemia in the form of a cortically based osteomyelitis) −− Treponema, gram negative rods, Streptococci, Hemophilus influenzae, and Listeria species (occur in neonates) −− Pseudomonas infections (seen in addicts abusing intravenous street drugs)

Macroscopic ♦♦ The infected region of bone is often like an abscess filled with necropurulent exudate and surrounded by intensely hyperemic fibrovascular tissue. The pus is in a rigid confined space (bone) and so exerts pressure on the surrounding small vessels. This may result in additional ischemic damage to the bone ♦♦ The exudate follows the path of least resistance and exits through the Volkmann canals into the subperiosteal space ♦♦ In the neonatal age group, the Sharpey fibers are less well developed; thus, considerable subperiosteal spread may occur ♦♦ The pus may also track along the medullary cavity. This can become quite extensive in some cases ♦♦ In severe cases, the combination of subperiosteal and intramedullary spread can cause the entire diaphysis to become necrotic, forming a “ring sequestrum”

Microscopic ♦♦ There is bone destruction surrounded by polymorphonuclear leukocytes and cell debris. The necrotic bone is called a sequestrum

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Chronic Osteomyelitis Clinical ♦♦ Although de  novo cases also occur, the vast majority of chronic infection result from unresolved acute osteomyelitis ♦♦ Chronic osteomyelitis follows a protracted course, interspersed with acute exacerbations ♦♦ Because of the low levels of causative organisms, cultures may be negative ♦♦ Common organisms include −− Staphylococcus aureus −− Streptococci (group A is more frequent) −− Klebsiella (may cause extensive bone damage) −− Aerobacter, Proteus, Brucella, Staphylococcus epidermidis, and Bacteroides

Microscopic ♦♦ Necrotic bone in a chronic inflammatory background ♦♦ When the necrotic fragment separates from the adjacent tissue, it is known as a sequestrum −− Separation of the sequestrum generally takes months to complete −− The sequestrated bone is often of cortical origin ♦♦ The bone surrounding a focus of chronic osteomyelitis is often dense and is referred to as the “involucrum” −− The involucrum is often of periosteal origin −− The involucrum frequently has several openings of “cloacae” through which exudate, bone debris, and sequestra exit and pass through sinus tracts to the surface (Fig. 21.3A) −− Constant destruction of the neighboring soft tissues leads to scarring and squamous metaplasia of the sinus tract ♦♦ The microscopic diagnosis of chronic osteomyelitis can be difficult since in some cases, the inflammatory infiltrate may be sparse and may mimic the normal elements of the marrow space. Alternatively, in other cases it may be mistaken for a hematological malignancy (Fig. 21.3B) ♦♦ Microscopic recognition of the sequestrum is helpful for the diagnosis of infection −− The sequestrum is recognized by virtue of its anucleate nature; often the edges are jagged (because of the action of proteolytic enzymes and osteoclastic action) −− Overdecalcification of bone during processing can cause the bone to become artificially “anucleate,” making the recognition of dead bone difficult

Differential Diagnosis ♦♦ Normal marrow −− Preservation of normal fat pattern of marrow −− Lack of a fibrous background

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Chronic Multifocal Recurrent Osteomyelitis Clinical ♦♦ Patients present with recurrent episodes of bone pain, erythema, and swelling ♦♦ X-rays and bone scans are consistent with osteomyelitis ♦♦ The signs and symptoms usually resolve with time. Antimicrobial therapy is not helpful

Microscopic ♦♦ Bone biopsies confirm the suspicion of osteomyelitis ♦♦ Organisms are usually not isolated ♦♦ May be related to the seronegative spondyloarthropathies

Tubercular Osteomyelitis Clinical ♦♦ Tubercular osteomyelitis is generally more frequent in children although there is a wide age range, especially for tubercular spondylitis (Pott spine), which often afflicts adults ♦♦ In the long tubular bones, the disease usually has a metaphyseal location; in adults, the vertebrae (or rarely epiphysis of long bones) can be involved

Pathology

Fig. 21.3. Chronic osteomyelitis showing bone thickening and colaca/sinus formation (A). Chronic osteomyelitis may show several plasma cells and have to be differentiated from a plasma cell dyscrasia or myeloma (B).

Sclerosing Osteitis (Garre Osteomyelitis) Definition ♦♦ Sclerosing osteitis is gradual, usually unilateral (occasionally bilateral and symmetrical) bony sclerosis, often associated with pain. It is speculated to be a form of chronic osteomyelitis

Clinical ♦♦ Constitutional symptoms are infrequent ♦♦ Usually affects children ♦♦ Most frequent sites include the tibia, jaw, and clavicle (and pubis in adults)

Microscopic ♦♦ The biopsy findings are nonspecific and often there is no significant inflammation ♦♦ Culture results are often negative

♦♦ May affect the bone, the joints, or (frequently) both (Fig. 21.4A) ♦♦ Often occurs by hematogenous spread ♦♦ Is usually associated with a reactivation of a preexisting primary focus in the lung ♦♦ The emergence of multidrug-resistant tuberculosis and the AIDS epidemic have reemphasized the importance of mycobacterial infections

Microscopic ♦♦ The disease has traditionally been divided into the “dry or granular” and the “exudative” types (Fig. 21.4B) ♦♦ The hallmark of the infection is the finding of granulomas. Quite often, these are of the necrotizing type (Fig. 21.4C) ♦♦ Special stains for acid-fast organisms may be positive (but in many cases, negative also). Cultures are more frequently positive than histological stains

Fungal Osteomyelitis ♦♦ Fungal infection of bone is uncommon ♦♦ More common infections include −− Blastomycosis −− Coccidiodomycosis −− Actinomycosis −− Maduramycosis −− Sporotrichosis ♦♦ These infections often involve the hands, feet, or craniofacial skeleton

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Fig. 21.4. Tuberculosis of the knee showing multiple lucencies and an erosion of the femoral condyle (A) Caries sicca – a “dry or nonexudative” form of tuberculosis involving the shoulder joint (B). Granulomatous inflammation in the intertrabecular spaces (C).

ARTHRITIDES Osteoarthritis (OA) ♦♦ Also termed degenerative joint disease ♦♦ Generally refers to a failure of diarthrodial (movable, synovium-lined) joint ♦♦ There are two forms −− Idiopathic (primary) OA (a) Most common (b) No known predisposing factor −− Secondary OA (a) Attributed to an underlying cause (developmental disorders, metabolic or endocrine conditions, crystal deposition, trauma, infection, avascular necrosis, neuropathic disease, etc.) (b) Pathologically indistinguishable from idiopathic form

Microscopic ♦♦ The most striking changes are seen in load-bearing areas of the articular cartilage

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♦♦ In the very early stage, the cartilage is thicker than normal. This stage is not often seen in surgical pathology material ♦♦ The joint surface eventually becomes thinner, and the cartilage softens with progression of the disease ♦♦ The integrity of the surface is breached, and vertical clefts develop with fibrillation (Fig. 21.5) ♦♦ Areas of fibrocartilaginous repair may develop ♦♦ The articular cartilage is metabolically active, and the chondrocytes replicate, forming clusters (termed “cloning”). Later, the cartilage becomes hypocellular ♦♦ Fractures of the subchondral plate can occur, or there can be osteoarthritic cyst formation in the subchondral region ♦♦ Remodeling and hypertrophy of bone are also major features −− Appositional bone growth occurs in the subchondral region −− The abraded bone under a cartilage ulcer may resemble ivory wood (termed “eburnation”)

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Crystal Arthropathies Pathogenesis ♦♦ Crystal arthropathy can be caused by endogenous (monosodium urate [MSU], calcium pyrophosphate) and exogenous (corticosteroid ester crystals, talc, polyethylene, methylmethacrylate) crystal deposition, producing disease by triggering a cascade that results in cytokine-mediated cartilage destruction

Gout and Gouty Arthritis Clinical

Fig. 21.5. Osteoarthritis with clefting of the articular cartilage. ♦♦ Growth of cartilage and bone at the joint margin leads to osteophytes (spurs) ♦♦ Osteophytes alter the contour of the joint, restricting movement ♦♦ Thickening of the joint capsule along with chronic synovitis further restricts joint movement

♦♦ Gout is the common end point of a group of disorders that produces hyperuricemia ♦♦ Marked by transient attacks of acute arthritis initiated by the crystallization of urates within and around joints ♦♦ Deposition of masses of urates in joints and other sites, creating tophi ♦♦ Factors that may result in the conversion of hyperuricemia into primary gout −− Age (gout rarely appears before age 20–30 years) −− Duration of the hyperuricemia −− Genetic predisposition (a) X-linked abnormalities of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) (b) Multifactorial inheritance −− Heavy alcohol consumption −− Obesity −− Thiazide diuretics ♦♦ Gout can result in −− Acute arthritis −− Chronic tophaceous arthritis −− Gouty nephropathy −− Tophi in various sites

Microscopic

Neuropathic Arthropathy (Charcot Joints) Clinical

♦♦ Characteristic needle-like crystals that are negatively birefringent under polarized light

♦♦ An extremely destructive joint disorder in patients with neurosyphilis, diabetes, or other causes of damaged sensory innervation to the joint ♦♦ With the decline of tertiary syphilis, other causes of neuropathic joints have now become more important, such as −− Diabetes −− Syringomyelia −− Amyloidosis −− Alcoholic neuropathy −− Leprosy

Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout, Chondrocalcinosis)

Microscopic ♦♦ There is marked fragmentation of the joint surface with extensive detritic synovitis resulting from particles of bone and cartilage embedded in the synovium

♦♦ Three types −− Sporadic −− Hereditary −− Secondary types linked to (a) Hyperparathyroidism (b) Hemochromatosis (c) Hypomagnesemia (d) Hypothyroidism (e) Ochronosis (f) Diabetes ♦♦ More common at age 50 or above

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♦♦ Joint involvement may mimic OA or rheumatoid arthritis (RA) ♦♦ Pathogenesis is uncertain −− Altered activity of the cartilage matrix enzyme produces and degrades pyrophosphate, resulting in its accumulation and eventual crystallization −− The crystals first develop in the articular matrix, menisci, and intervertebral discs

Rheumatoid Arthritis Clinical ♦♦ A systemic disease that manifests in the joints as a synovial lesion

♦♦ Autoimmune inflammatory process that primarily targets the synovial tissue −− Humoral and cellular immune response is involved

Microscopic ♦♦ Nonsuppurative chronic inflammation in the capsule of the joint −− Hypertrophy and hyperplasia of the synovial cells resulting grossly in a papillary pattern on the surface of the synovium −− Later, a pannus forms (a) A combination of proliferating mesenchymal cells and granulation tissue starts at the periphery of a joint, subsequently destroying articular cartilage

METABOLIC BONE DISEASES Osteoporosis Definition ♦♦ A condition characterized by a reduced amount of normally mineralized bone

Classification ♦♦ Postmenopausal (type I) ♦♦ Age related (type II) ♦♦ Secondary (accounts for ~5% of cases) −− Can be seen in a variety of conditions (a) Osteogenesis imperfecta (OI) (b) Turner syndrome (c) RA (d) Systemic mastocytosis (e) Hyperthyroidism (f) Adrenal disease (g) Steroid or heparin therapy (h) Chronic alcoholism (i) Space travel

Clinical ♦♦ Higher incidence associated with −− Race (Caucasians > African Americans) −− Sex (F > M) −− Physical inactivity −− Slender body builds −− Smoking −− Nulliparity −− Early menopause ♦♦ The major clinical symptoms are those of fractures ♦♦ Common sites of fractures are −− Spinal vertebral crush fractures −− Hip fractures

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−− Colle fracture or other fractures of the distal radius ♦♦ Laboratory investigations include the exclusion of other metabolic diseases by assessing −− Serum calcium −− Serum phosphate −− Alkaline phosphatase −− 25-hydroxy and 1,25-dihydroxy-vitamin D −− Urinary calcium ♦♦ Biologic markers that may be useful for assessing bone turnover −− Bone-specific alkaline phosphatase −− Serum/urinary osteocalcin −− Serum Type I collagen extension peptides −− Plasma tartrate resistant acid phosphatase −− Urinary levels of hydroxyproline −− Urinary pyridinoline crosslinks of type I collagen ♦♦ Pathogenesis −− Postmenopausal osteoporosis (a) Associated with increased osteoclastic activity (b) May be initiated or maintained by a variety of bone cytokines, perhaps initiated by RANK and RANKligand interaction (c) May be genetically predetermined by the polymorphisms of the Vitamin D receptor gene −− Age-related osteoporosis (a) Inefficiency of bone formation in a normal remodeling cycle (b) Less bone is formed than is resorbed with each remodeling cycle throughout life

Microscopic ♦♦ Cortex −− Enlarged Haversian and Volkmann canals tunneled by osteoclasts

Bone and Joints

−− The cortex is thinned (a) Caused by resorption of the subperiosteal and endosteal surfaces (b) Endosteal resorption results in a blurring of the cortical-cancellous border, referred to as “trabeculization” of the cortex ♦♦ Trabecular bone −− Thinning and perforation of the trabeculae (a) Perforation is an irreversible process, which occurs when an osteoclast resorbs bone all the way through a trabeculum or when two osteoclasts fortuitously located at opposite ends of the trabeculum meet midway −− These thin trabeculae seem to “float” in the marrow space −− Increased osteoclastic activity may be seen in “high turnover” (postmenopausal) osteoporosis

Rickets and Osteomalacia Definition ♦♦ Syndromes (rather than specific disease entities) characterized by a failure of normal mineralization of bone and epiphyseal cartilage ♦♦ Clinically characterized by bone deformities ♦♦ In Rickets (which occurs in children), bone and epiphyseal cartilage is involved

Causes of Rickets and Osteomalacia ♦♦ Deficiency states −− Diet −− Lack of sunlight ♦♦ Gastrointestinal causes −− Gastric resections −− Biliary and enteric causes ♦♦ Renal tubular causes −− Hypophosphatemic states −− Fanconi syndromes −− End organ defect −− Renal tubular acidosis ♦♦ Unusual causes −− Phosphaturic tumors (Fig. 21.6) −− Anticonvulsant therapy ♦♦ Renal osteodystrophy −− Renal failure

Pathology ♦♦ Rickets −− A disease of the growing skeleton −− Affects the physeal plate and epiphysis of bones of children ♦♦ Osteomalacia −− Occurs in adults, after the growth cartilage has fused and the physis is obliterated

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Fig. 21.6. Mesenchymal phosphaturic tumor (initially called a cartilaginous neoplasm) that caused oncogenic osteomalacia.

♦ ♦ In both instances, there is insufficient ionized calcium or inorganic phosphate (or both) to mineralize the skeleton, leading to less mineralized bone per unit volume of bone ♦♦ There may in some cases be less bone overall, but more strikingly, the bone that is present fails to mineralize properly ♦♦ Trabeculae are surrounded by unmineralized osteoid, called “osteoid seams” −− Osteoid seams >12.5 µm are virtually diagnostic −− Bone histomorphometry has shown that the mineralization lag time is >100 days in rickets/osteomalacia (normal = 80–90 days) ♦♦ All rachitic syndromes have similar histology and the individual diagnosis cannot be made on the basis of a bone biopsy ♦♦ Stains for aluminum may be considered in renal osteodystrophy ♦♦ In rickets, pressure effects cause deformity at the epiphysis– metaphysis junction, resulting in metaphyseal flaring and a disordered physis

Primary Hyperparathyroidism ♦♦ This entity was defined in part by von Recklinghausen under the term osteitis fibrosa cystica generalisata ♦♦ Most often results from a hyperplasia or adenoma (and rarely a carcinoma) of the parathyroid glands −− The diseased gland does not recognize the signal of high serum calcium concentration −− There is increased production of 1,25-dihydroxy-vitamin D and parathyroid hormone, increasing absorption of calcium from the gut and bone and preventing its excretion in the kidney −− Simultaneously, there is hyperphosphaturia −− Serum levels of alkaline phosphatase are frequently high

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Microscopic ♦♦ The bones are characterized by −− Fibrosis of the marrow −− Osteoclastic resorption −− Osteoblastic rimming on new and often incompletely mineralized lamellar bone trabeculae (narrow osteoid seams) −− “Brown tumors” (Fig. 21.7) (a) These represent granulation tissue, inflammatory cells, and macrophages containing hemosiderin and giant cell formation (b) There is virtually no bone present in these areas ♦♦ Occasionally, cystic change may supervene ♦♦ Increased osteoclastic activity is seen in subperiosteal, intracortical, endosteal, subchondral, and trabecular surfaces −− Intracortical resorption is characterized by groups of osteoclasts (known as cutting cones) that tunnel through the cortex, enlarging the Haversian and Volkmann canals (a) These channels are often expanded to 1 mm or more in some cases, and may be seen radiographically as lucent lines within the cortex −− Endosteal resorption is also visible radiographically as “scalloping” of the cortex at its marrow interface −− Subchondral resorption is best seen histologically (and radiographically) at the sacroiliac joint

Paget Disease (Osteitis Deformans) Clinical ♦♦ The disease is generally seen in older individuals (unusual before the 4th decade) ♦♦ There is a slight male predominance ♦♦ Common among the white population of England, France, Austria, Germany, Australia, New Zealand, and the United States ♦♦ Rare in Scandinavia, China, Japan, and Africa

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ May be uni- or multifocal ♦♦ Most frequent involvement in the axial and the proximal appendicular skeleton ♦♦ Less frequent involvement in the ribs, fibulae, and bones of the hands and feet ♦♦ Presenting symptoms −− Pain −− Increased width of bone −− Weight bearing bones may be bowed or deformed −− May be asymptomatic and discovered incidentally ♦♦ Complications of disease −− Hyperdynamic circulation may lead to a high output cardiac failure −− The most common secondary malignancy is osteosarcoma ♦♦ Radiographically, three phases can be discerned: lytic, mixed, and blastic −− Eventually, the disease “burns itself out” in that particular site ♦♦ Laboratory investigations reflect this increased bone turnover through increased levels of serum alkaline phosphatase and urinary hydroxyproline

Etiology ♦♦ There is a debate about the role of genetics and infectious viral agents. Current thought appears to be leaning towards the latter. The virus is thought to be a paramyxovirus, similar to measles or respiratory syncitial virus −− In situ hybridization studies have localized canine distemper virus (a paramyxovirus) in Pagetic osteoblasts, osteoclasts, and osteocytes −− The target of the virus is probably the osteoblast; however, the cell-associated virus particles have only been found in the osteoclasts −− Retroviruses can induce the secretion of IL-6 from fibroblasts and macrophages −− IL-6 is thought to be important in the pathogenesis of Paget disease and is implicated in the recruitment and activation of osteoclasts

Microscopic

Fig.  21.7. Brown tumor. There is fibrosis, hemorrhage and a cluster of osteoclast giant cells.

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♦♦ Paget disease is a focal process ♦♦ The histologic hallmark is mosaic lamellar bone −− Characterized by haphazard cement lines (jigsaw-like pattern) (Fig. 21.8) ♦♦ Lytic phase −− Waves of osteoclastic activity −− Numerous resorptive pits ♦♦ Mixed phase −− The osteoclasts are admixed with osteoblasts, which line the bone surfaces −− The marrow adjacent to the bone becomes replaced by loose, vascularized, connective tissue

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♦♦ Extramedullary hematopoiesis results in hepatosplenomegaly

Microscopic

Fig. 21.8. Mosaic bone of Paget disease. −− The newly formed bone is initially woven bone, and is later remodeled into lamellar bone −− As the mosaic pattern becomes prominent, cell activity ceases −− The fibrovascular tissue is replaced by normal marrow (burnt out phase) −− Eventually, the bone becomes larger, with thick, irregular trabeculae and porous cortices ♦♦ Blastic phase −− Characterized by reactive and lamellar bone

Osteopetrosis (Albers-Schönberg Marble Bone Disease) Definition ♦♦ A group of hereditary diseases characterized by osteoclast dysfunction resulting in diffuse, symmetric, stone-like, skeletal sclerosis and abnormally brittle bone ♦♦ Bisphosphonate–induced osteopetrosis has been reported

Clinical ♦♦ Several clinical variants have been distinguished −− Autosomal recessive form (“malignant”) (ARO) (a) 50% of patients harbor mutations of the ATP 6i gene (TCIRG 1) encoding the osteoclast-specific a3 subunit of the vacuolar H+-ATPase −− Autosomal dominant form types 1 and 2 (a) ClCN7 gene mutations underlie type 2 ADO. This gene encodes for the type 7 chloride channel located in the osteoclast border membrane ♦♦ Other genetic abnormalities have been described (a) Deficiency of osteoclast carbonic anhydrase II, deletions of c-src gene, macrophage colony stimulating factor, etc ♦♦ Patients have a high postnatal mortality ♦♦ Survivors have anemia, fractures, and hydrocephalus ♦♦ Later in life, patients are prone to cranial nerve problems and recurrent infections

♦♦ Bones lack a medullary cavity ♦♦ The ends of the bones are bulbous (Erlenmeyer flask deformity) ♦♦ Neural foramina are small, compressing the exiting nerves ♦♦ There is persistence of the primary spongiosa consisting of ossifying cartilage ♦♦ Medullary cavity contains little or no hematopoietic elements due to overgrowth and accumulation of the primary spongiosa ♦♦ Bones are mainly woven and lack remodeling ♦♦ The numbers of osteoclasts may be normal, increased, or decreased

Osteogenesis Imperfecta Definition ♦♦ A heterogeneous group of conditions characterized by bone fragility and mutations in the loci coding for the pro-a1 and pro-a2 collagen chains (COL1A1 on 17q21 and COL1A2 on 7q22.1) ♦♦ Classification ♦♦ Type 1 (a) Autosomal dominant (b) The less severe form (c) Loose joints and low muscle tone (d) Bone predisposed to fractures (e) Blue/purple tint of the sclera ♦♦ Type 2 (a) Autosomal dominant with new mutation (b) The most severe form (c) Lethal at or shortly after birth due to respiratory ­failure (d) Numerous fractures and severe bone deformity ♦♦ Type 3 (a) Autosomal dominant with new mutation. Rarely, autosomal recessive forms are observed (b) Bone fractures easily with fractures often present at birth (c) Bone deformity frequent and severe (d) Associated respiratory problems ♦♦ Type 4 (a) Autosomal dominant (b) Severity between types 1 and 3

Microscopic ♦♦ Amount of osseous tissue is decreased ♦♦ There may be fibromembranous tissue with foci of bone, especially in the severe forms (this finding is more common in the skull) ♦♦ In the long bones, the cortices are thin, except at the site of a fracture ♦♦ Sparse trabeculae in the medullary cavity

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♦♦ The inner (cambium) layer of the periosteum may be prominent ♦♦ Osteoblasts lining the bone trabeculae tend to be less plump and more spindled than is normal ♦♦ Osteoclasts are sparse ♦♦ The growth plates are normal, and ossification is not delayed ♦♦ The ossification centers may be smaller than normal ♦♦ The chondrocytes and cartilage matrix appear normal by light microscopy ♦♦ The teeth are abnormal −− The mesodermal component is severely affected and may be deficient −− The ectodermal component is usually normal

Classification (Several Types, Common Ones Are) ♦♦ Type 1 (Hurler syndrome) −− Associated with defects in a-l-iduronidase −− Results in accumulation of dermatan sulfate ♦♦ Type 2 (Hunter syndrome) −− Associated with defects in l-iduronosulfate sulfatase −− Results in accumulation of heparan sulfate

Gaucher Disease Definition ♦♦ A group of conditions resulting from different allelic mutations in the structural gene of the enzyme glucocerebrosidase

Biochemical Basis

Mucopolysaccharidoses Definition

♦♦ The gene of glucocerebrosidase is located on chromosome 1q21 ♦♦ The enzyme cleaves glucose from ceramide

♦♦ A heterogeneous group of lysosomal storage disorders, associated with glycosaminoglycan excretion in the urine and accumulation in the tissues ♦♦ Deficiencies in enzymes (acid hydrolases) that degrade the glycosaminoglycans ♦♦ Cartilage tends to be severely affected

Clinical ♦♦ Glucocerebroside accumulates in phagocytic cells and in cells of the central nervous system ♦♦ Skeletal manifestations include the Erlenmeyer flask deformity of the femur, osteonecrosis of the femoral head, bone infarcts, and pathologic fractures

MUSCULOSKELETAL NEOPLASMS Bone Cysts

Macroscopic

Simple (Unicameral) Bone Cyst (UBC) Definition ♦♦ A benign usually unilocular, intramedullary cyst filled with serous or serosanguineous fluid

♦♦ The lesion is typically a unilocular intramedullary cyst filled with a clear or straw-colored fluid. In cases that have had a superimposed fracture, the fluid may be bloody or bloodtinged. In cases that are healing, there may be a few septae or loculations within the cyst

Clinical

Microscopic

♦♦ Most patients are within the first two decades of life. There is a slight male predominance ♦♦ Patients might be asymptomatic or present with sudden onset of pain from a pathologic fracture ♦♦ About 80% of cases are seen in either the humerus or the femur. Other relatively common sites include the ilium and the calcaneus (especially in somewhat older patients)

♦♦ Cyst lined by a thin, fibrovascular membrane ♦♦ Irregular fragments of membranous, fibrovascular tissue ♦♦ Hemosiderin, granulation tissue, or mild focal chronic inflammatory cells ♦♦ Pink, cementum-like, rounded material may be seen −− These may be examples of the Liesegang phenomenon, forming from diffusion and precipitation of supersaturated solutions

X-rays and Imaging Findings ♦♦ Geographic, lytic, and cystic lesions (often metaphyseal) ♦♦ May encroach the epiphysis in skeletally immature individuals ♦♦ As the bone lengthens at the physeal end, the cyst may appear to “move” into a diaphyseal location

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Intraosseous Ganglion Definition ♦♦ An intramedullary, mucin-filled, fibrous-lined lesion

Bone and Joints

Clinical ♦♦ Wide age range, often with pain, and incidental finding ♦♦ The distal and proximal tibia, femur, ulna, and the hands and feet are commonly involved

X-rays and Imaging Findings ♦♦ Geographic lesions that are epiphyseally located and show sclerotic margins ♦♦ The joint articular surface is usually normal (as opposed to subchondral osteoarthritic cysts)

Microscopic ♦♦ Mainly myxoid tissue mixed with fibroblasts ♦♦ Fibrous tissue may be haphazardly interspersed or arranged in the form of septa ♦♦ The outer layer is often heavily collagenized

Differential Diagnosis ♦♦ Extragnathic fibromyxoma ♦♦ Chondromyxoid fibroma ♦♦ Subchondral cysts of degenerative joint disease

Aneurysmal Bone Cyst Definition ♦♦ A benign cyst composed of blood-filled spaces separated by connective tissue septae containing fibroblasts, osteoclasts, and woven bone. The lesion may be primary (contain no underlying bone tumor) or secondary (arise in the setting of a prior benign or malignant bone tumor) ♦♦ A solid (noncystic) variant of this lesion has been described (solid aneurysmal bone cyst or giant cell reparative granuloma)

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−− Hemangioma −− Osteosarcoma ♦♦ The diagnosis of ABC is essentially that of exclusion ♦♦ Some of these lesions spontaneously regress ♦♦ There appears to be molecular evidence that primary ABC (including the solid ABC) are true neoplasms since they have a consistent translocation involving the USP6 gene. This translocation is lacking in secondary ABC

X-rays and Imaging Findings ♦♦ A benign lesion that is often multicystic, rapidly expansile, and locally destructive ♦♦ The ABCs of long bones may be central, eccentric or less commonly parosteal ♦♦ In the initial (or incipient) phase, there is a small lytic lesion that does not expand the bone ♦♦ In the stable phase, the x-rays have a characteristic picture, with expanded bone and a “shell” around the lesion, along with trabeculations coursing within it ♦♦ In the healing phase, progressive ossification results in a coarsely trabeculated bony mass ♦♦ Fluid/fluid levels on CT scan or MRI are characteristic (Fig. 21.9A)

Macroscopic ♦♦ Grossly (if intact), the lesions have a thin osseous bony shell surrounding a honeycombed mass with cavernous vascular spaces that “ooze” blood like a sponge ♦♦ Older cysts may contain serosanguinous fluid rather than blood ♦♦ A careful search should be made for solid areas that may represent the precursor lesion

Clinical

Microscopic

♦♦ There is a wide age range but it mostly occurs between ages 5–25 years ♦♦ Pain of a few weeks duration is the most common presenting symptom ♦♦ Most primary ABCs of long bones are metaphyseal in location ♦♦ Secondary ABCs follow the site of predilection of their primary lesions ♦♦ Secondary ABC may represent a change secondary to a variety of different bone neoplasms, including −− Giant cell tumor −− Nonossifying fibroma −− Giant cell reparative granuloma −− Fibrous dysplasia −− Chondromyxoid fibroma −− Chondroblastoma −− Osteoblastoma −− Unicameral (simple) bone cyst

♦♦ Fibrous walls that contain varying proportions of osteoid, chondroid, giant cells, and inflammation (Fig. 21.9B) ♦♦ Cavernous spaces that are filled with blood ♦♦ Lack the smooth muscle wall and endothelial cells of blood vessels ♦♦ The mineralizing component may have a chondroid aura, unusual in any other lesion ♦♦ The chondroid usually has a fibrillary or chondromyxoid quality and may be focally calcified ♦♦ Mitotic figures may be numerous, particularly in the areas of osteoid formation ♦♦ The stromal cells lack anaplasia ♦♦ The solid variant of ABC (reparative giant cell granuloma) lacks the blood-filled spaces but is otherwise similar to the usual ABC

Differential Diagnosis ♦♦ Telangiectatic osteosarcoma −− Occasionally misleading radiographic appearance

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Fig. 21.10. Osteoid osteoma. There is fibrovascular tissue rich in osteoblasts that is part of the nidus (in the lower part of the picture). It is sharply demarcated from the surrounding dense lamellar bone.

Clinical ♦♦ Majority found within the first three decades ♦♦ Presentation −− Severe, unremitting pain −− Relief of pain by aspirin is seen in many patients

X-rays and Imaging Findings

Fig.  21.9. Aneurysmal bone cyst - MRI showing fluid levels within a well-delineated lesion limited to the cuboid (a). Microscopic examination showed hypocellular fibrous septae with some reactive osteoid and hemosiderin (b). −− Presence of cellular anaplasia and atypical mitotic figures −− Irregular lace-like deposition of osteoid ♦♦ Ossifying hematoma and pseudotumor of hemophilia −− Subperiosteal hematomas −− Radiographically, may mimic a parosteal ABC −− Hemosiderin, zonation, and organized appearance of bone ♦♦ Giant cell tumor with ABC component −− Older patients −− Sheets of giant cells −− No marked osteoblastic change

Bone-Forming Lesions Osteoid Osteoma Definition ♦♦ A benign bone-forming tumor characterized by small size, limited growth potential, and often severe pain

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♦♦ Classic location: long bones ♦♦ The lesion has sclerotic borders on x-rays. It is characterized by a central radiolucent nidus and surrounding dense bone, in most cases ♦♦ The nidus is lucent, but it may have a small central radiodense spot of calcification ♦♦ Demonstration of the nidus may require tomograms or CT scans ♦♦ Osteoid osteomas of the joints can be difficult to detect by plain films ♦♦ Osteoid osteomas are characteristically hot on Technetium pyrophosphate bone scans

Macroscopic ♦♦ The nidus is red, spherical, and gritty ♦♦ Usually can be “shelled” out from the surrounding bone

Microscopic ♦♦ A benign neoplasm consisting of a nidus and surrounding reactive, sclerotic bone. There is a sharp demarcation between the nidus and the surrounding bone (Fig. 21.10) ♦♦ The nidus is a highly vascular, sharply defined osteoblastic proliferation, usually <1.5 cm ♦♦ The nidus is variably ossified. In some cases, it is poorly ossified with a richly vascularized stroma. In others, it can be heavily ossified, with calcific or lacy osteoid composed of osteoid rimmed with plump osteoblasts ♦♦ Although mitotic activity can be seen within the nidus, there are no atypical mitotic figures

Bone and Joints

♦♦ The woven bone shows prominent osteoblastic rimming ♦♦ 0.1–0.2  cm zone of less trabeculated fibrovascular tissue around the nidus ♦♦ Sclerotic compact or spongy lamellar bone surrounds the fibrovascular tissue

Differential Diagnosis ♦♦ Clinical and radiologic mimics −− Intracortical abscess (such as Salmonella infection) −− Sclerosing osteomyelitis (of Garre) −− Enostosis −− Aseptic necrosis −− Stress fracture −− Langerhans cell histiocytosis −− Metastasis ♦♦ Histologic mimics −− Osteoblastoma (a) Osteoid osteomas are always <2 cm (most cases are less than 1.5 cm) (b) The previously termed “giant” osteoid osteomas (>2 cm) were probably examples of osteoblastomas −− Osteosarcoma (a) Osteosarcomas are usually large and most have broken through the cortex by the time of presentation (b) Osteosarcomas show bone formation that lacks osteoblastic rimming (c) Osteosarcomas have an infiltrative permeative ­margin with entrapped cortical bones (d) Cytologic atypia or atypical mitotic figures are seen in osteosarcoma (e) Cartilage may be present in chondroblastic osteosarcoma, but not in osteoid osteoma

Osteoblastoma Definition ♦♦ A benign bone forming tumor, larger in size, but histologically similar to osteoid osteoma. When located in the jaw, they are sometimes referred to as cementoblastoma (but are thought to be the same tumor)

Clinical ♦♦ Most seen in patients <30 years old, with a slight male predilection ♦♦ Pain may be present, but often it is less intense than that of osteoid osteoma, and is not relieved by aspirin ♦♦ There is a predilection for the axial skeleton, with the majority of spinous cases affecting the posterior elements of the spine ♦♦ Metaphyseal or diaphyseal location

X-rays and Imaging Findings ♦♦ Most lesions measure 4–6 cm ♦♦ They are uniform, geographic, expansile lucent lesions ♦♦ Most lesions are cortical or coticomedullary. About 1/3 may be intramedullary ♦♦ There may be a stippled calcification in the matrix of the lesion

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Macroscopic ♦♦ Circumscribed, 2–10 cm ♦♦ A secondary cystic change (aneurysmal bone cyst) may supervene

Microscopic ♦♦ There is a microscopic similarity to the osteoid osteomas ♦♦ The lesions are well-circumscribed, with anastomosing bony trabeculae in a fibrovascular stroma ♦♦ The edges of the lesion merge into the adjacent bone, imparting an appearance of maturation ♦♦ The bony trabeculae are variably calcified −− Some lesions are heavily mineralized, whereas others may be made of just osteoid −− Considerable intralesional variations in trabeculum size exist (a) In the majority of cases, the trabeculae are thick (b) Plump, mitotically active osteoblasts line these trabeculae ♦♦ Early lesions may be rich in giant cells ♦♦ Chondroid differentiation can occur, but is unusual in the absence of fracture ♦♦ Bizarre pleomorphic nuclei (thought to represent a secondary degenerative change) may be present ♦♦ Secondary aneurysmal bone cyst-like change occurs in 10% of cases

Variant ♦♦ “Aggressive” osteoblastomas −− Larger lesions occur in a wider age range −− A subgroup also termed “malignant” osteoblastomas or “low grade osteosarcomas” by some authors −− Tend to recur −− Histologically, aggressive osteoblastomas tend to have wider and more irregular forms of trabecular patterns of osteoid (a) They may have occasional areas of nontrabecular (lace-like) osteoid (b) The osteoblasts are large (almost twice the size of normal osteoblasts) with an epithelioid quality (c) The nuclei may have a vesicular “histiocyte-like” appearance

Differential Diagnosis ♦♦ Low grade osteosarcoma (osteoblastoma-like osteosarcoma) −− The relationship between these two lesions is still unclear −− The distinction between osteoblastoma and osteosarcoma may be impossible in limited material −− Essentially, osteosarcoma lacks sharp circumscription and osteoblastic rimming of the trabeculae and shows areas of permeation (infiltrative growth). If this feature is seen, however focally, the diagnosis should be osteoblastomalike osteosarcoma rather than aggressive osteoblastoma −− Cellular anaplasia and atypical mitotic figures may be seen in osteosarcoma

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Fig. 21.11. Osteosarcoma and its variants.

Osteosarcoma and Its Variants (Fig. 21.11) Definition ♦♦ A malignant tumor in which the neoplastic cells produce osteoid, even if only in small amounts

Clinical ♦♦ Osteosarcomas may arise −− De novo (see below) −− Secondarily on other lesions (a) Paget disease (b) Osteogenesis imperfecta (c) Bone infarct (d) Chronic osteomyelitis (e) Fibrous dysplasia (f) Giant cell tumor (g) Osteoblastoma (h) Rare cases in association with orthopedic implants −− Traditionally, osteosarcomas that arise on an underlying low grade chondrosarcoma have been termed dedifferentiated chondrosarcoma and are not included in the discussion of osteosarcoma −− Secondary osteosarcoma has a much higher incidence of flat bone and diaphyseal involvement

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♦♦ Some cases of osteosarcoma may be familial −− Children with bilateral retinoblastomas −− Li Fraumeni Syndrome (see Chapter 13)

De Novo Conventional Osteosarcoma Clinical ♦♦ >85% of patients are <30 years of age ♦♦ Osteosarcoma is most commonly seen in the long tubular bones, in the active growth phase (2nd decade) (~3/4 of all tumors) ♦♦ The metaphyseal region is the site of >85% of these tumors; the diaphysis is the primary site in about 10% of patients. Epiphyseal location is very rare ♦♦ Very low incidence of osteosarcoma (in fact of all malignant bone tumors) in the distal appendicular skeleton, such as the hands and feet ♦♦ Clinical presentations −− Pain is the most frequent presenting symptom, followed by swelling −− The duration of the symptoms is a few weeks to months −− Pathologic fractures (5% of cases)

Bone and Joints

Laboratory ♦♦ The serum alkaline phosphatase may be raised in the heavily osteoblastic tumors, but is often normal in the lytic cases ♦♦ A rise in alkaline phosphatase following excision may herald a recurrence

X-rays and Imaging Findings ♦♦ Radiographic appearances are diagnostic in about 2/3 of all cases ♦♦ Classical cases are intramedullary lytic and sclerotic lesion with cortical breakthrough and associated bone formation (Fig. 21.12A–B) ♦♦ Some lesions may be purely lytic or sclerotic ♦♦ The margins vary from focally circumscribed to permeative ♦♦ The periosteum is often lifted to form a Codman angle, “Codman triangle”

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♦♦ Rapid growth may result in an “onion skinning” appearance of periosteum. Other cases may show spicules of bone extending into the soft tissues (“sun-burst” pattern)

Macroscopic ♦♦ The tumor is generally centered in the metaphysis (Intramedullary). There is often penetration of the cortex with an extraosseous soft tissue extension. The physis generally acts as a barrier, and there is often no extension into the epiphysis (Fig. 21.12C) ♦♦ The intramedullary extension can be extensive and may be underestimated by conventional radiologic studies (x-rays). MRI scans are better at delineating tumor size ♦♦ Distant foci within the marrow cavity of the same bone (“skip” lesions or skip-metastases) are important potential causes of recurrent disease ♦♦ Foci of hemorrhage and necrosis are common

Fig. 21.12. Osteosarcoma. (a) X-ray showing a characteristic lifting of the periosteum by the tumor producing Codman angles. The tumor can be seen to be producing osseous matrix. (b) CT scan of a patient with osteosarcoma showing typical findings of bone production with extension into the soft tissues. (c) Gross specimen showing extensive necrosis as a result of preoperative chemotherapy. Note the relatively good barrier the physeal plate forms, preventing extension of the tumor into the epiphysis. The tumor extends through the cortex and lifts up the periosteum. (d) Osteosarcoma showing delicate lacy osteoid and a high grade sarcomatous stroma.

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♦♦ Large blood-filled areas may represent a telangiectatic component ♦♦ The periosteal reaction is frequently visible as spicules or lamellae of bone ♦♦ Joint extension may occur along the intraarticular ligaments (ligamentum teres in the femoral head, or the cruciate ligaments in the knee)

Microscopic ♦♦ Malignant, high grade neoplasms of bone composed of proliferating cells that produce osteoid, at least focally (Fig. 21.12D) ♦♦ Osteoblastic, chondroblastic, and fibroblastic differentiation is common ♦♦ The amount of osteoid production can be minimal or absent in otherwise typical osteosarcomas − − Such lesions may be arbitrarily designated as osteosarcomas as opposed to malignant fibrous histiocytomas −− Such lesions may produce heavily ossified metastases ♦♦ The tumor may be composed of spindle or oval anaplastic cells with atypical mitotic figures ♦♦ “Normalization” is the tendency of the osteoblasts to become smaller and less pleomorphic as they get incorporated into the osteoid ♦♦ Osteoid may have variable thickness and degrees of mineralization ♦♦ A thin, highly mineralized pattern (filigreed pattern) without osteoblastic rimming is suggestive of neoplastic osteoid ♦♦ Some osteosarcomas are composed of epithelioid-appearing cells −− Rosette formation may give the appearance of gland formation −− Immunohistochemical stains may be positive for markers of epithelial differentiation ♦♦ Chemonecrosis of the tumor (following neoadjuvant therapy) −− It is important to recognize and quantitate the amount of chemonecrosis. Necrosis less than 90% is thought to have a poorer outcome and often the chemotherapy regime is changed in the postoperative period (adjuvant therapy) −− The appearance of the tumor after chemotherapy depends on its original morphology (a) Chondroblastic foci appear as acellular chondroid, often with ghost cells in the lacunae (b) Telangiectatic foci appear as acellular blood-filled cysts (c) Osteoblastic foci appear as acellular osteoid matrix (d) Atypical stromal cells may be scattered in all of these foci

Variants ♦♦ Osteosarcoma with prominent giant cells (giant cell-rich osteosarcoma)

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−− There is a proliferation of uniform giant cells amidst a sarcomatous stroma −− Osteoid production is usually sparse, encircling mononuclear pleomorphic stromal cells −− The tumor is generally metaphyseal (similar to other osteosarcomas) rather than epiphyseal (like other giant-cell tumors) ♦♦ Osteosarcomas of the jaw bones (gnathic osteosarcomas) −− Frequently chondroblastic −− Thought to have a somewhat better outcome −− The average age of patients is usually higher −− The tumors tend to have less anaplasia and are often of a lower grade −− The differentiation from benign lesions may be difficult in many cases

Differential Diagnosis ♦♦ Osteoblastoma −− About 10% of osteosarcomas may appear radiologically benign −− Conversely, ~1/4 of osteoblastomas may be worrisome on x-rays −− Osteoblastic rimming favors osteoblastomas −− Lacks infiltration; cellular anaplasia; atypical mitotic figures −− Lacks cartilage ♦♦ Fracture callus −− Callus can be extremely hypercellular, forming compact masses of osteoid in a mitotically active stroma −− Zonation (a pattern of peripheral ossification with a fibrous or less ossified center) −− Osteoblastic rimming −− Lacks atypical mitotic figures or significant atypia −− Lacks atypical or frankly malignant cartilage

Multifocal Osteosarcoma ♦♦ A small but distinct subgroup of osteosarcomas ♦♦ Divided traditionally into synchronous and metachronous types −− Synchronous lesions (a) Arise (or are discovered) simultaneously (within 6 months) (b) May represent multifocal primary osteosarcomas (c) Subdivided into the “juvenile” and “adult” types *  Juvenile (or childhood-adolescent) form (1) Typically found in the age group 5–17 years (2) Lesions are osteoblastic and of high grade *  Adult form (1)  Mean age 37 years (2) The tumors are better differentiated (resemble the low grade intraosseous osteosarcoma) −− Metachronous (asynchronous) lesions (a) More common than the synchronous variant (b) Several long-term survivors are known

Bone and Joints

Telangiectatic Osteosarcoma ♦♦ Diagnostic criteria for this entity have been varied, but the term should generally be reserved for lesions where the vast majority (or the entire portion) of the tumor is made up of blood-filled cysts and has a purely lytic x-ray appearance ♦♦ The incidence is low (<10%) ♦♦ Radiologically −− Purely lytic with features of rapid growth −− Permeative margins, cortical destruction, and soft tissue extension −− ABC-like appearance may be seen on radiological studies with fluid-fluid levels on MRI

Macroscopic ♦♦ Hemorrhagic-necrotic mass ♦♦ Multicystic with blood-filled spaces

Microscopic ♦♦ Two variants are described, corresponding to the gross appearances −− Hemorrhagic-necrotic variant (Fig. 21.13) −− ABC-like variant

Small Cell Osteosarcoma ♦♦ A microscopically distinct variant of a high grade intramedullary osteosarcoma composed of small round cells (but by definition having at least some foci that show osteoid production) ♦♦ May contain hemangiopericytotoma-like pattern ♦♦ Hypocellular uniform round or slightly spindled cells ♦♦ Islands of long parallel arranged trabecular bone without osteoblastic rimming ♦♦ Small round cells with delicate lace-like osteoid deposition ♦♦ Glycogen may be demonstrated in some cases. But the t(11;22) chromosomal translocation (or EWS-FLI1 or EWSERG fusion) is not seen

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Intraosseous Well-Differentiated Osteosarcoma (Low Grade Central Osteosarcoma) ♦♦ An intramedullary variant of osteosarcoma with better prognosis ♦♦ Low grade fibrous and osseous tissue with only minimal cytologic atypia

Differential Diagnosis ♦♦ Desmoplastic fibroma: lacks osteoid production ♦♦ Fibrous dysplasia −− Chinese-letter trabeculae are seen in FD. They are less often seen in low grade central osteosarcoma which often has longer trabeculae (like parosteal osteosarcoma) −− Permeative growth is the hallmark of low grade central osteosarcoma and is absent in fibrous dysplasia

Intracortical Osteosarcoma ♦♦ This is an extremely rare variant of conventional osteosarcoma arising in and limited to the cortex of a long bone ♦♦ Only rare cases have been reported in the diaphysis of tibia and femur

Periosteal Osteosarcoma ♦♦ This is an intermediate grade chondroblastic osteosarcoma arising on the surface of bone. Some cases were formerly called juxtacortical chondrosarcoma ♦♦ There is a predilection for the diaphysis of long bones in young patients (20–30 s) ♦♦ Radiographic −− Located on the external surface of the cortex and extends into the surrounding soft tissues −− Predominantly lucent lesions −− Mineralization, if any, is confined to the base of the tumor adjacent to the cortex −− Characteristic spiculated (radiating) pattern of calcification (oriented perpendicular to the cortex) −− Intramedullary extension is absent by definition ♦♦ Macroscopic −− Sharply demarcated, lobulated, and cartilaginous tumor ♦♦ Microscopic −− Dominant chondrosarcomatous areas (Grade 2–3) with at least focal osteoid formation

High Grade Surface Osteosarcoma

Fig. 21.13. Telangiactetic osteosarcoma with several blood filled spaces lined by a high grade sarcoma.

♦♦ A rare variant of high grade osteosarcoma arising from the outer cortex of the bone ♦♦ Intramedullary extension is absent or minimal ♦♦ The lesions are often diaphyseal ♦♦ Presentation is similar to the high grade, conventional intramedullary osteosarcoma ♦♦ Microscopically similar to conventional high grade osteosarcoma

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Parosteal Osteosarcoma Clinical ♦♦ A well-differentiated, low grade, fibroosseous variant of juxtacortical osteosarcoma ♦♦ The prognosis is often much better compared to the conventional type ♦♦ Presentation −− Painless mass, often seen in individuals in the third decade, with a female predominance −− Most commonly situated in the posterior metaphysis of the distal femur (>2/3 of cases) −− Other common sites include the tibia and humerus

X-rays and Imaging Findings ♦♦ A dense mass of bone attached to the outer metaphyseal cortex by a broad base (Fig. 21.14A) ♦♦ Plain x-ray has sometimes misdiagnosed these lesions as osteochondromas ♦♦ There is dense mineralization, which is often less prominent peripherally ♦♦ The tumor tends to encircle the parent bone, a feature demonstrable by CT scanning ♦♦ A lucent line may be seen between the mass and the bone (string sign) ♦♦ Periosteal new bone is usually absent ♦♦ Intralesional lucencies are uncommon, but if seen, suggest the possibility of dedifferentiation ♦♦ In dedifferentiated tumors, CT scan may demonstrate satellite lesions and intramedullary extension

Macroscopic ♦♦ Large, ossified exophytic mass with a broad base ♦♦ Less often, the tumor encircles the bone ♦♦ Resemblance to an osteochondroma may be considerable, including the presence of a cartilaginous cap ♦♦ The lesions are heavily ossified and may be lobulated

Microscopic ♦♦ Long, narrow trabeculae, or ill-defined areas of osteoid and woven bone separated by a fibrous stroma ♦♦ The trabeculae may show maturation (normalization), which may result in lamellar bone (Fig. 21.14B) ♦♦ The spaces between the trabeculae are often filled with spindled fibroblastic tissue showing only minimal cytologic atypia ♦♦ Most lesions are histologically equivalent to grade 1 (of 3), and high grade areas resembling conventional osteosarcomas should be interpreted as evidence of dedifferentiation

Differential Diagnosis ♦♦ High grade surface osteosarcomas ♦♦ Conventional osteosarcomas with a prominent extraosseous component ♦♦ Periosteal osteosarcoma ♦♦ Osteochondromas

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Fig.  21.14. Parosteal osteosarcoma is seen as a distal femoral exophytic mass mimicking an osteochondroma (a). Microscopic examination showed a well differentiated tumor with well developed bone and cellular stroma (b). −− Extension of the medullary cavity into the extracortical portion is seen in osteochondromas −− Osteochondromas lack an atypical fibrous stroma −− Osteochondromas have fat or hematopoietic marrow between trabeculae ♦♦ Reactive soft tissue and periosteal processes (including Nora lesion or bizarre parosteal osteochondromatous proliferation) −− May be difficult to differentiate on radiologic grounds −− Such conditions include myositis ossificans and reactive periostitis (Nora lesion) −− Evidence of zonation is helpful in diagnosing these conditions as benign

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Cartilaginous Lesions Osteochondroma (Osteocartilaginous Exostosis) Definition ♦♦ A benign cartilage capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone

Clinical ♦♦ An outgrowth of bone with the combination of medullary and cortical bone ♦♦ Often asymptomatic and incidentally found ♦♦ Projects from the cortical surface and is covered with a cartilage cap ♦♦ Most often seen in the first 2 decades of life with no gender predilection ♦♦ Mostly occurs on long bones formed by endochondral ossification ♦♦ Earlier thought to result from a displaced epiphyseal cartilage that herniated through a periosteal defect, but currently thought to be a true neoplasm because of defects involving the EXT genes in the lesional tissue ♦♦ Multiple osteochondromas −− Sporadic −− Familial (a) Termed (multiple) hereditary exostoses or diaphyseal (or metaphyseal) aclasis (b) Autosomal dominant inheritance (c) Associated with a generalized osseous modeling ­defect (d) Associated with limb growth asymmetry ♦♦ Malignant transformation −− Long-standing osteochondromas rarely show an aggressive (invasive or malignant) change −− The incidence is probably <1% for solitary osteochondromas and slightly more for multiple osteochondromas

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♦♦ The finding of a cartilage cap >2.0 cm especially in an adult is suspicious for a chondrosarcoma having supervened on an osteochondroma (secondary chondrosarcoma)

Microscopic ♦♦ Presence of periosteum over the cartilage cap ♦♦ The cartilage is organized similar to a growth plate with enchondral calcification occurring in a zonal fashion and extending for a short distance into the stalk of the lesion ♦♦ The chondrocytes −− The cells occur in clusters and in lacunae in the superficial portion of the cap −− Toward the base, the chondrocytes line up, simulating a growth plate −− Below this, enchondral ossification is often seen ♦♦ A spindle cell proliferation occurring within an osteochondroma may be the result of a repair reaction from trauma

Differential Diagnosis ♦♦ Chondrosarcoma developing in an osteochondroma ♦♦ Parosteal osteosarcoma

Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion) Clinical ♦♦ An exophytic outgrowth from the cortex, consisting of a mixture of cartilage, fibrous tissue, and bone ♦♦ Occurs in patients 20–35 years of age, without gender predilection ♦♦ Predilection for the bones of the hands and feet, especially proximal phalanges of the hand ♦♦ Long bone involvement is less common

Macroscopic ♦♦ The lesions have a stalk and may have a well-defined cartilage cap ♦♦ The mass may sometimes show lobulations

X-rays and Imaging Findings

Microscopic

♦♦ Located in the metadiaphyseal region. The lesions may be sessile or pedunculated ♦♦ MRI scan is useful for measuring the thickness of the cartilage cap and locating the presence of wide fibrous septae within the osteochondroma ♦♦ MRI or CT scan can be used for establishing the continuation of the native medullary cavity into the marrow cavity of the osteochondroma

♦♦ An admixture of cartilage, bone, and a spindle cell element (fibrous tissue) is seen (Fig. 21.15) ♦♦ The cartilage may form a cap and is often very cellular, with enlarged, bizarre nuclei at the periphery of the lesion ♦♦ The chondrocytes often show bi- or multinucleation ♦♦ The interface with the underlying bone is irregular, with admixtures of bone and cartilage ♦♦ Occasionally, no cap is seen and the cartilage is admixed with bone and spindle cells ♦♦ The bone may show considerable osteoblastic prominence and is more irregular than is typically seen in osteochondromas ♦♦ A helpful clue is the blue tinctorial quality of the bone in routine hematoxylin and eosin-stained sections ♦♦ Fibrous tissue and osteoclast-type giant cells may be intermixed within the lesion

Macroscopic ♦♦ Entirely (extraperiosteally) resected lesions are covered by periosteum ♦♦ Osteochondromas show a well-defined bony stalk especially in the pedunculated lesions. The bone is capped by cartilage ♦♦ The marrow cavity of the parent bone continues into the osteochondroma

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−− Increased risk of angiosarcoma, astrocytoma, hepatobilary tumors, and ovarian cancer (juvenile granulosa cell tumor of ovary)

X-rays and Imaging Findings ♦♦ Small lesions with well-defined margins, sometimes with lobulated edges ♦♦ Mineralization in the form of semicircles and circles (“Cs” and “Os”) ♦♦ Often “hot” on Technetium bone scans

Macroscopic

Fig. 21.15. Bizarre parosteal osteochondromatous proliferation (Nora lesion). The lesion shows an admixture of blue bone, cartilage and spindle cell (fibrous type tissue). These lesions can be quite cellular.

Chondroma Definition ♦♦ Chondroma is a benign hyaline cartilaginous neoplasm of bone. If present in the medullary cavity, it is termed an enchondroma and if on the surface of bone, it is termed a periosteal chondroma. Some cases of enchondroma push out to the surface of bone and are sometimes termed enchondroma protuberans

Clinical ♦♦ Enchondroma of the long tubular bone is usually painless. Enchondromas of the hands and feet may be associated with pain or even occasionally pathological fracture; however, the latter two features (pain and fracture) occurring in lesions of the long tubular bone are concerning for chondrosarcoma ♦♦ The most frequent locations for enchondroma are the metaphysis or diaphysis of the hand and foot bones ♦♦ Periosteal chondromas are more frequent in the appendicular skeleton ♦♦ Flat bones are less often involved ♦♦ Multiple enchondromas may occur in the setting of Ollier disease −− Multiple enchondromas confined to one limb (unilateral) −− 5–30% of patients may have malignant transformation −− Associated with ovarian sex-cord stromal tumor −− May be associated with mutations of the PTHR1 gene encoding a receptor for parathyroid hormone (PTH) and PTH related protein (PTHrP) ♦♦ Maffuci syndrome −− Multiple unilateral enchondromas associated with soft tissue hemangiomas

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♦♦ Enchondromas are well-circumscribed, small (3–5 cm) cartilaginous lesions ♦♦ Periosteal chondromas are on the surface of bones with the underlying bone often showing some thickening and buttressing especially on the sides

Microscopic ♦♦ Lobules and islands of hyaline cartilage intermixed with normal bone trabeculae and marrow ♦♦ The lobular configuration of cartilage is characteristic −− The lobules are separated by fibrous or lamellar bony septae −− These may be rimmed by reactive woven bone or calcification ♦♦ Enchondromas in the tubular long bones (excluding the hands and feet) −− Small chondrocytes lying in lacunae −− Round, regular nuclei, which are barely visible at low magnification ♦♦ Enchondromas of the hands and feet −− Can be alarmingly cellular −− Chondrocytes may be present in clusters or even in sheets −− Nucleomegaly, binucleation, and slight myxoid change of cartilage −− Permeation of the cortex of the phalanges, however, is diagnostic of a chondrosarcoma −− Extreme hypercellularity, nuclear pleomorphism, and extensive myxoid change are suggestive of malignancy ♦♦ Periosteal chondromas −− Well-demarcated lesions with no tendency to permeation −− May also show cytologic atypia −− Myxoid change is unusual −− Lobules of hyaline cartilage in a fibrous stroma ♦♦ Multiple enchondromas −− Histologically, the lesions of patients with multiple enchondroma are more cellular, and show more atypia and myxoid change −− However, marked atypia, myxoid change, and mitotic activity are worrisome for chondrosarcoma. Permeative growth pattern should be sought to establish the diagnosis of chondrosarcoma

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Differential Diagnosis ♦♦ Juxtacortical chondrosarcoma and periosteal osteosarcoma are in the differential diagnosis for periosteal chondroma ♦♦ Conventional low grade chondrosarcoma is in the differential diagnosis for enchondroma

Chondroblastoma Definition ♦♦ A benign neoplasm of fetal type cartilage often arising in the epiphysis of skeletally immature individuals

Clinical ♦♦ A benign cartilaginous neoplasm with predilection for the epiphysis (giant cell tumor, clear cell chondrosarcoma, and eosinophilic granuloma also share the predilection for epiphysis) ♦♦ The majority occur in patients <25 years of age ♦♦ Chondroblastomas in unusual locations may occur in older patients ♦♦ 20–30% of chondroblastomas occur in flat bones or the short tubular bones ♦♦ The most common benign tumor of the foot (in the talus or the calcaneus) ♦♦ Occasionally, lesions occur in the craniofacial skeleton, especially the temporal bone ♦♦ Rare examples of “benign” metastases have been reported. These are typically nonprogressive and can be treated by resection or observation

X-Rays and Imaging Findings ♦♦ Lytic geographic lesions, with sclerotic or well-defined margins ♦♦ Centered in the epiphysis but may grow into the metaphysis (Fig. 21.16A) ♦♦ No matrix production in the majority of cases −− Fine matrix calcifications or trabeculations may be seen in ~1/3 of cases −− Some cases are associated with a secondary aneurysmal bone cyst

Macroscopic ♦♦ Circumscribed, variegated lesions ♦♦ A secondary ABC component may be seen

Microscopic (Fig. 21.16B–C) ♦♦ A spectrum of histologic appearances due to the inconstant amounts of matrix secondary changes like mineralization and cyst formation (secondary ABC) ♦♦ The characteristic cell of the neoplasm is a chondroblast −− Typically, a polygonal to oval cell with a sharp cytoplasmic border and lightly staining or clear cytoplasm −− Some chondroblastomas lack this feature and may be referred to as the syncytial variant −− The nucleus is round to oval, often with prominent grooves

Fig. 21.16. Chondroblastoma. (A) X-rays showing a well-delineated radiolucency with sclerotic margins involving the epiphyseal end of the humerus. (b) Tumor cells have abundant eosinophilic cytoplasm and oval nuclei with grooves. (c) It shows an area with pericellular “chicken-wire” calcification. −− Reticulin fibers surround individual chondroblasts −− Mitotic figures may be seen, but are not frequent −− Epithelioid variants of chondroblastomas are comprised of cells with abundant pink cytoplasm −− Focal aggregates of spindle cells may be seen −− Scattered osteoclast-type giant cells may be seen −− ~1/4 of chondroblastomas show a small number of cells with enlarged, hyperchromatic nuclei, but this change is not related to an adverse outcome

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♦♦

♦♦ ♦♦ ♦♦ ♦♦

−− Pigment is often prominent in lesions occurring in the craniofacial and skull bones The matrix −− Has an eosinophilic quality in most cases −− Calcification may be found focally or more typically surrounding the chondroblast, especially in foci of necrotic chondroblasts −− A characteristic “chicken wire” pattern of calcium deposition (Fig. 21.16C) Mature chondrocytes are unusual Features suggestive of a chondromyxoid fibroma may be seen admixed with other more typical areas Focal cellular atypia or necrosis can be seen in up to 10% of cases Vascular invasion may be present, especially in lesions of the skull bones

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 21.17. Chondromyxoid fibroma showing the typical hypocellular and hypocellular areas.

Differential Diagnosis ♦♦ Giant cell tumor −− Generally occurs after the epiphyseal plate closes −− Mononuclear stromal cells with folded nuclei ♦♦ Clear cell chondrosarcomas −− Broad sheets of cells with a voluminous clear cytoplasm, also often in older individuals

Chondromyxoid Fibroma Definition ♦♦ A benign tumor characterized by lobules of spindle or stellate shaped cells with abundant myxoid or chondroid intercellular matrix

Clinical ♦♦ The majority of the patients are <30 years of age ♦♦ Mild pain is the most common presenting symptom ♦♦ Most cases occur in the long bones of the appendicular skeleton, especially the tibia ♦♦ 1/4 of cases are seen in the flat bones, especially the ilium ♦♦ Involvement of the short tubular bones of the hands and feet is not infrequent

X-rays and Imaging Findings ♦♦ ♦♦ ♦♦ ♦♦

Geographic and well-demarcated lesions Often eccentric and centered around the metaphysis Epiphyseal extension may be seen Chondromyxoid fibromas of the hands and feet are often central and cause expansion of the short tubular bones ♦♦ Tumors of the flat bones are often irregularly lobulated ♦♦ Matrix calcification in any site should raise suspicion of a chondrosarcoma ♦♦ Surface lesions may be heavily mineralized

Macroscopic ♦♦ Small, circumscribed, and lobulated lesion with a semitranslucent quality

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Microscopic ♦♦ The microscopic appearance is variable and may show ­several different components in varying proportions ♦♦ The chondroid lobules have hypercellular septae surrounding a hypocellular myxoid matrix (Fig. 21.17) ♦♦ The fibrous component is usually small and often confined to the septae separating the lobules ♦♦ The septae occasionally contain blood vessels, osteoclast type giant cells, and osteoid ♦♦ The cells in the septae may be spindle or stellate ♦♦ Features suggestive of chondroblastomas may be seen (some lesions show considerable overlap) ♦♦ The myxoid component within and between the lobules is variably cellular ♦♦ Pleomorphic cells are frequent and should not be considered a sign of malignancy. Mitoses can be seen, but atypical mitotic figures are not seen ♦♦ Either chunky or fine, lace-like calcification, and necrotic foci may be seen

Differential Diagnosis ♦♦ Chondrosarcoma; −− Differentiation may be difficult on cytological grounds alone; the overall growth pattern is important. A permeative growth pattern is seen in chondrosarcoma −− Both tumors can have a lobular growth pattern, peripheral cellularity, atypical cells, and a myxoid stroma −− Reactive osteoid can be seen along the edges of the lobules in both lesions −− Radiographic and clinical features are of utmost importance in differentiating the lesions −− Features indicative of malignancy (a) Infiltrative margin or radiologic appearance with permeation of the cortex (b) Entrapment of (necrotic) bone (c) Infiltration of the Haversian system

Bone and Joints

−− Atypical mitotic figures and marked cytologic atypia −− Invasion into soft tissue

Osteochondromyxoma −− Associated with Carney complex (pigmented skin spots, myxomas, endocrine overactivity, and schwannomas); −− Clinically – painless masses in distal long bones and small flat bones;

Macroscopic −− Circumscribed but not encapsulated tumors −− Cause erosion of bone and extend into soft tissue

Microscopic ♦♦ Solid sheets with a macrolobular and microlobular pattern ♦♦ Myxomatous mesenchyme, cartilage, bone (formed de novo and from cartilage), and myxomatous tissue ♦♦ Hypodense to moderately dense polymorphic cell population with uniformly bland nuclei and few mitotic figures

Chondrosarcoma and Its Variants Conventional Chondrosarcoma Definition ♦♦ A malignant tumor in which the neoplastic cells differentiate to form chondroid but not osteoid

Classification ♦♦ Primary chondrosarcoma −− Arising in a previously normal bone (may be central or peripheral in location) ♦♦ Secondary chondrosarcoma −− Arising in an underlying benign, usually cartilaginous neoplasm, such as osteochondroma or enchondroma

Clinical ♦♦ Occurs in age groups older than de novo osteosarcomas ♦♦ Primary chondrosarcomas have a peak incidence in the 5th to 7th decades ♦♦ <2% chondrosarcomas occur in patients <20 years of age ♦♦ Presentation −− Central chondrosarcomas (a) Pain with or without a mass −− Peripheral chondrosarcomas (a) Mass with or without pain ♦♦ Most frequent involvement seen in the bones of the pelvis and long tubular bones of the appendicular skeleton ♦♦ Involvement of the bones of the hands and feet is rare ♦♦ Chondrosarcomas are often centered around the trunk and proximal limbs ♦♦ ~2/3 of chondrosarcomas occur in the limb-girdles, femora, and humeri ♦♦ A minority of chondrosarcomas give rise to highly malignant tumors, such as osteosarcomas, malignant fibrous histiocytomas, fibrosarcomas, etc. (dedifferentiation)

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♦♦ Cartilaginous tumors of the sternum are almost always malignant, regardless of the histologic appearance ♦♦ Chondromas of the hands and feet, perosteal chondromas, enchondromas of Ollier disease and Maffuci syndrome, synovial chondromatosis, and soft tissue chondromas of the hands and feet are most often benign, in spite of sometimes alarming cellularity

X-rays and Imaging Findings ♦♦ Central chondrosarcomas arise in either the diaphysis or the metaphysis ♦♦ Epiphyseal origin and joint involvement is rare, except in the clear cell variant of chondrosarcoma ♦♦ Intramedullary spread is common and can be extensive ♦♦ Peripheral chondrosarcomas appear as masses protruding from the bone ♦♦ Matrix calcifications in the form of “Cs” and “Os” are common in tumors of cartilage origin ♦♦ The margins of the lesion can vary from irregular ­geographic to permeative ♦♦ Areas of increased lucency or inhomogeneity within the lesion should raise suspicion of dedifferentiation

Macroscopic ♦♦ A lobular large lesion with a hyaline quality ♦♦ Foci of hemorrhage, necrosis, and cystic or myxoid change may be present ♦♦ The matrix can vary in consistency from firm hyaline cartilage in very low grade lesions to thin mucus-like cartilage. The myxoid almost liquid feel of matrix is very characteristic, and it has a tendency to run when held

Microscopic ♦♦ The most important feature is a low power view showing infiltration or entrapment of preexisting bone (Fig.  21.18). The entrapped bone can also appear as islands of (usually necrotic) bone

Fig. 21.18. Grade 2 (of 3) chondrosarcoma showing a permeative growth pattern.

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♦♦ The tumor may be diffuse or lobular. It is variably cellular. Hypercellular tumors that are mitotically more active are considered higher grade ♦♦ Myxoid cystic change and areas of necrosis are commonly seen ♦♦ Necrotic foci can later calcify ♦♦ Peripheral/secondary chondrosarcomas often lack an infiltrative quality and frequently demonstrate a “pushing” border ♦♦ Soft tissue involvement (in the absence of fracture or previous surgery) is a sign of malignancy ♦♦ Calcification can be present, often around the lobules of cartilage ♦♦ Reactive woven bone may be present; however, malignant osteoid is a feature of an osteosarcoma and by definition should not be present in chondrosarcoma ♦♦ When chondrosarcomas supervene on a previous osteochondroma −− The thickness of the cartilage cap increases (Fig. 21.19)

Fig. 21.19. Chondrosarcoma arising in an osteochondroma. The cartilage cap was 2 cm thick. The lesion had grown over the past 3 months (as demonstrated by repeated MR scans).

−− The normal columnar arrangement of chondrocyte columns is lost −− Nodules of cartilage can sometimes be found in the adjacent soft tissues

Differential Diagnosis ♦♦ Chondroblastic osteosarcoma −− Identification of malignant osteoid is required for this distinction −− The woven bone that surrounds chondrosarcoma lobules should not be overinterpreted −− Osseous metaplasia is not diagnostic of an osteosarcoma ♦♦ Tophaceous pseudogout −− Finding of polarizable crystals and the presence of a granulomatous response −− Tissue processing for regular histology may dissolve the crystals

Variants of Chondrosarcoma ♦♦ Dedifferentiated chondrosarcoma (Table 21.1) −− Refers to chondrosarcomas with a component of high grade, noncartilaginous sarcoma adjacent to (and presumably arising from) a low grade cartilaginous neoplasm −− The nonchondromatous component may be (a) Osteosarcoma (b) Malignant fibrous histiocytoma (MFH) (c) Rhabdomyosarcoma ♦♦ Clear cell chondrosarcoma −− Malignant, but slow-growing tumors composed of neoplastic chondrocytes with abundant clear cytoplasm and a sparse intercellular matrix (Fig. 21.20) −− Foci of conventional chondrosarcoma may also be present −− Often mistaken clinically as well as histologically for chondroblastomas and osteoblastomas ♦♦ Mesenchymal chondrosarcoma −− Often occurs in young adults, affecting the jaw bone and ribs

Table 21.1. Tumors containing components of sarcoma and cartilage Dedifferentiated chondrosarcoma

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Mesenchymal chondrosarcoma

Chondroblastic osteosarcoma

Cartilage Junction between cartilage and sarcoma Sarcoma

Low grade Sharp

Low grade Sharp

Intermediate-high grade Fuzzy

High grade spindle cell

High grade spindle cell

Outcome

Poor

Intermediate grade round or short spindle Variable

Relatively good

Bone and Joints

Fig. 21.20. Clear cell chondrosarcoma showing sheets of chondrocytes with clear cytoplasm.

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Fig. 21.22. Hemangioma of the vertebra – the “dot-like” pattern on CT scan is characteristic. ♦♦ There may be associated extraosseous vascular malformations or combined “skeletal-extraskeletal” angiomatosis in continuity ♦♦ Epitheloid hemangioma (similar to the soft tissue or skin counterpart) has been reported in bone. The lesion has a tendency for multifocality

Gorham Disease (Massive Osteolysis)

Fig. 21.21. Mesenchymal chondrosarcoma showing a very sharp junction between the small cell component and the cartilage. −− Prognosis is good −− Malignant, cartilage-forming tumors that are primarily composed of small, round to oval cells arranged in a hemangiopericytoma-like pattern −− Small areas of osteoid may be present −− Abrupt transition to low grade cartilage from these small round cell areas (Fig. 21.21)

Vascular Lesions Solitary Lymphangioma, Hemangioma, and Skeletal Angiomatosis ♦♦ Lymphangiomas and hemangiomas are benign proliferations of lymphatic or vascular channels that occur in and replace bone (Fig. 21.22) ♦♦ Angiomatosis is a multifocal or diffuse intraosseous proliferation of benign hemangiomatous or lymphangiomatous channels

♦♦ Predilection for mandible and rib ♦♦ A vanishing or disappearing bone disease resulting in massive osseous resorption ♦♦ Characterized by resorption of most or almost all of the bone associated with a proliferation of benign vascular channels ♦♦ The difference with skeletal angiomatosis is the extent of involvement ♦♦ Involves one or more contiguous bones in contrast to the multifocal nature of skeletal angiomatosis

Hemophilic Pseudotumor ♦♦ A tumor-like lesion that may mimic several aggressive bone neoplasms ♦♦ May cause massive bone destruction ♦♦ Not strictly a vascular proliferation; arises secondary to the large amounts of hemorrhage that occurs in bleeding disorders ♦♦ The hemorrhage is often intraarticular and associated with reactive synovitis and degenerative joint disease

Epithelioid (Histiocytoid) Hemangioendothelioma ♦♦ A low grade malignant neoplasm composed of endothelial cells with conspicuous cytoplasm ♦♦ The cells are present in the form of cords set in a myxoid background

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♦♦ Vasoformative features are often limited to vacuolization of cells with some vacuoles showing red cells ♦♦ Patients often have concomitant cutaneous, systemic, or soft tissue disease ♦♦ Multifocal disease is common ♦♦ Soft tissue or lung “metastases” should raise the question of possible multifocal primary tumors

Angiosarcoma ♦♦ A high grade (sometimes surface) sarcoma of bone composed of cytological malignant endothelial cells ♦♦ Multifocality is common ♦♦ Lytic, destructive, permeated lesions with frequent soft tissue extension ♦♦ Areas of poorly or well-formed anastamosing vascular channels lined by atypical endothelial cells, with large vesicular or hyperchromatic nuclei ♦♦ The vasoformative nature may not be easily evident in solid, poorly differentiated areas

Hemangiopericytoma/Solitary Fibrous Tumor ♦♦ A potentially low grade malignant vascular tumor consisting of pericyte-like cells with a prominent vascular pattern similar to the soft tissue counterpart ♦♦ Occasionally, a paraneoplastic syndrome of hypophosphatemic osteomalacia may be present ♦♦ A variety of tumors can exhibit hemangiopericytoma-like areas −− Synovial sarcoma −− Mesenchymal chondrosarcomas −− MFH −− Small cell osteosarcoma −− Solitary fibrous tumor

Glomus Tumor ♦♦ A benign, highly vascular tumor composed of small, uniform, specialized smooth muscle cells resembling those of the glomus body ♦♦ Osseous glomus tumors are less frequent than their soft tissue counterparts ♦♦ Most commonly occur in the distal phalanges

Vascular Tumors in Immunocompromised Patients ♦♦ Both Kaposi sarcoma and bacillary angiomatosis have been described in bone

Giant Cell Lesions Giant Cell Tumor (Osteoclastoma) Definition ♦♦ A benign, but locally aggressive neoplasm composed of sheets of neoplastic ovoid mononuclear cells interspersed with uniformly distributed osteoclast like multinucleated giant cells (Table 21.2)

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Clinical ♦♦ Giant cell tumors are more common in the skeletally mature adult population ♦♦ Peak incidence in the 3rd decade; occur in the region of the epiphysis ♦♦ Complaints are usually nonspecific; there may be pain or a mass ♦♦ ~10% of patients present with a pathologic fracture

Laboratory ♦♦ Serum chemistries are generally normal ♦♦ Elevated serum calcium should raise the possibility of hyperparathyroidism ♦♦ Elevated serum alkaline phosphatase should raise the possibility of Paget disease in older individuals

Location ♦♦ ~1/2 of all giant cell tumors arise around the knee; −− Other common sites include the distal radius, proximal femur, proximal humerus, and distal tibia −− The flat bones most commonly involved are the sacrum and pelvic bones ♦♦ Most giant cell lesions of the gnathic skeleton are thought to be giant cell reparative granulomas rather than true giant cell tumors

X-rays and Imaging Findings ♦♦ Most lesions are epiphyseal, with frequent metaphyseal extensions (Fig. 21.23A) ♦♦ 15% of patients are <20 years of age ♦♦ The tumors occur (for this age group) in a metaphysical or epimetaphysical location ♦♦ Lytic usually geographic lesions with well-defined (but not always sclerotic) margins ♦♦ May show lesional trabeculations ♦♦ Aggressive periosteal reactions and calcifications (sunburst, onion-skinning or Codman angles) are not features of the giant cell tumor ♦♦ Lesions extending into the soft tissue often have a thin rim of bone (“egg-shell”) ♦♦ A radiological system (Enneking system) to try and predict behavior has been used. In this system, there are three stages −− Benign latent tumors (a) Devoid of features of local aggressiveness −− Benign active tumors (a) Symptomatic (b) Show bone expansion on imaging studies −− Aggressive tumors (a) Correspond to the hypervascular lesions that erode into the soft tissues (b) May have an associated pathologic fracture

Macroscopic ♦♦ Hemorrhagic with focal aneurysmal bone cyst-like areas

Histology

Very few cases reported. Often aggressive. Similar to primary lesion.

Clinical features of hypercalcemia in primary or renal failure in secondary hyperparathyroidism (including anorexia, muscle weakness, neurocognitive problems, renal insufficiency, renal stones, peptic ulcer, pancreatitis etc.).

Very few cases reported. Often metaphyseal.

Similar to primary lesion.

Hyperparathyroidism

Giant cell rich osteosarcoma

Other lesions that may be rich in giant cells including fibrous dysplasia, osteoblastoma, non-ossifying fibroma, Paget disease etc.

Similar to primary lesion.

Very few cases reported. Often a sarcomatous background.

Undermineralized bones with prominent osteoclastic activity along with fibrosis (at Haversian canals and trabecular surfaces). Porous cortices, fractures. Brownish foci (Brown tumors) with collections of multinucleate giant cells in a fibrotic background. Cysts (sometimes multiloculated) filled with thin albuminous material and cholesterol crystals (possibly a residue of old hemorrhage).

Blood-filled spaces and septae in the usual ABC (absent in solid ABC). Osteoclast type giant cells with some amount of clustering around hemorrhage or hemosiderin. Fibrotic background with reactive woven bone. Translocations involving USP 6 by molecular methods (often in situ hybridization).

Common in first two decades, but wide age range. Lytic, expansile lesion with well-defined margins, often lined by a thin shell of subperiosteal bone. Any bone, but more often the metaphysis of Fluid-fluid levels are often seen by MRI. long bones and posterior elements of spine.

Aneurysmal bone cyst, solid aneurysmal bone cyst (giant cell reparative granuloma)

Bone resorption (cortical more than trabecular). Late stages – subperiosteal resorption of phalanges and proximal/medial tibia, “salt and pepper” skull, subchondral bone resorption in acromioclavicular joints, periodontal resorption, brown tumors. May have superimposed osteomalacia. Soft tissue calcifications and osteosclerosis of skull, ribs, vertebrae (rugger jersey) and pelvis in secondary hyperparathyroidism. Nephrolithiasis/nephrocalcinosis.

Uniform round or polygonal cell with eosinophilic cytoplasm and well-defined cytoplasmic borders. The nuclei are elongated and generally show longitudinal grooves. The matrix is eosinophilic or may sometimes be blue chondroid. May show pericellular chicken-wire calcification.

Most cases between the ages of 10 and 20 years. Lytic, central or eccentric, small, sharply demar75% cases involve the epiphyses of long bones. cated (geographic), often with sclerotic margins.

Chondroblastoma

Mononuclear stromal cells with uniformly Expansile, eccentric, lytic, epiphyseal lesion with geographic margins that may range from sclerotic to dispersed giant cells. The nuclei of the stromal cells and giant cells ill-defined with some cortical destruction. show similarity. The background is not fibrotic and shows no atypia.

Radiology

70% of cases are in the age group 20-45. 90% of cases involve the ends of long bones (epiphysis).

Clinical

Giant cell tumor

Lesion

Table 21.2. Giant cell rich lesions

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♦♦ Occasional cases may have broad bands of collagen coursing throughout, especially in recurrent tumors

“Malignant Giant Cell Tumor” ♦♦ The term has been used −− To designate true bone sarcomas rich in giant cells (for example, giant cell rich osteosarcoma); however, the term should not be used in this fashion −− To describe a “dedifferentiated” giant cell tumor (high grade sarcoma arising in association with an otherwise characteristic giant cell tumor (primary malignancy) −− To describe well-documented giant cell tumors that subsequently (often after radiation) become a sarcoma (secondary malignancy) ♦♦ The term is confusing and it is best to avoid its use

Differential Diagnosis

Fig. 21.23. Giant cell tumor. (a) X-ray showing tumor involving the distal radius. The epiphyseal location is usual in this tumor. (b) The tumor is characterized by a mononuclear stromal cells and multinucleate osteoclast type giant cells. The giant cells are evenly dispersed and there is no clustering. The nuclei of the giant cells resemble the nuclei of the mononuclear stromal cells. The mononuclear stromal cells are mitotically active, but lack atypia and the mitoses are also not atypical.

Microscopic ♦♦ The diagnosis is made on the background population of stromal cells −− Stromal cells are round to oval, occasionally spindled, with storiform pattern −− Nuclei resembling those of the giant cells −− Mitotic figures may be abundant (2–3 per high power field) −− No cytologic features of malignancy ♦♦ Giant cells are numerous and diffusely distributed with a few to hundreds of nuclei (Fig. 21.23B)

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♦♦ Giant cell reparative granulomas −− Giant cells tend to be aggregated around areas of hemorrhage. The giant cells tend to have fewer nuclei. In a true giant cell tumor, the giant cells are uniformly dispersed −− The stroma of giant cell reparative granuloma is fibrotic, with hemorrhage and hemosiderin deposition −− Foci of reactive bone are more common ♦♦ Nonossifying fibroma −− Spindled stromal cells, stromal fibrosis, and xanthomatous foamy macrophages are more prominent −− Occur in metaphysis of pediatric patients (rather than epiphysis) ♦♦ Aneurysmal bone cysts −− Nonepiphyseal tumor −− Differentiation from a true ABC may be difficult in the spine ♦♦ Osteosarcoma with prominent giant cells −− Osteoid production may be minimal, limited to thin strands encircling mononuclear pleomorphic stromal cells −− The stromal cells usually have hyperchromatic nuclei, often with numerous atypical mitotic figures −− The radiographic pattern suggests a permeative growth, not extending into the epiphyses ♦♦ Metastatic carcinoma −− Cytokeratin positive

Giant Cell Reparative Granuloma ♦♦ A benign, reactive intraosseous proliferation characterized by granuloma-like aggregates of giant cells in a fibrovascular stroma ♦♦ The lesion is commonly seen in the gnathic skeleton ♦♦ Cherubism occurring bilaterally in the jaws of children, as well as the “solid” aneurysmal bone cyst may be other entities that are related to the giant cell reparative granuloma

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Differential Diagnosis

Microscopic

♦♦ Giant cell tumor −− More uniform distribution of giant cells with more nuclei −− Characteristic stromal mononuclear cells −− Less stromal fibrosis and hemorrhage

♦♦ The lesion is intracortical and composed of cytologically bland spindle cells in a storiform pattern, histiocyte-like giant cells, foam cells (xanthoma cells), and a polymorphic infiltrate ♦♦ These lesions are unrelated to histiocytes ♦♦ Reactive woven bone may be present in the presence of fracture or in the healing phase

Fibrous Lesions

Malignant Fibrous Histiocytoma Definition

Desmoplastic Fibroma ♦♦ Considered to be the bone counterpart of the soft tissue aggressive fibromatosis ♦♦ A nonmetastasizing, but locally aggressive lesion ♦♦ Composed of cytologically typical fibroblasts in an abundantly collagenized stroma

Liposclerosing Myxofibrous Tumor ♦♦ Benign myxofibrous tumor with predilection for the proximal femur ♦♦ Complex mixture of histologic elements which may include lipoma, fibroxanthoma, myxoma, myxofibroma, fibrous dysplasia-like features, cyst formation, fat necrosis, ischemic ossification, and rarely cartilage ♦♦ Radiologic – well-defined, geographic lytic lesion with sclerotic margin ♦♦ Potential risk for malignant transformation – osteosarcoma, MFH

Fibrosarcoma ♦♦ A malignant spindle cell lesion that exclusively exhibits fibrous differentiation ♦♦ Lacks osteoid and chondroid matrices ♦♦ The skeletal site distribution is similar to osteosarcoma ♦♦ The age of the patients is more evenly distributed from the 2nd to the 7th decades

Fibrohistiocytic Lesions Benign and Atypical Fibrous Histiocytoma ♦♦ Also called metaphyseal fibrous defect, cortical fibrous defect, nonossifying fibroma, or fibroxanthoma

Clinical ♦♦ Up to 35% of all children (if screened) are thought to have these lesions; most common between the ages of 4–8 years ♦♦ The majority of the lesions in this group are <0.5 cm in size ♦♦ The vast majority of lesions occur in the distal femur, distal and proximal tibia, and fibula

X-rays and Imaging Findings ♦♦ Most lesions are geographic, lytic lesions with sclerotic margins ♦♦ Varying amounts of sclerosis within the lesion in the healing phase

♦♦ A malignant high grade sarcoma composed of fibroblasts and pleomorphic cells with a prominent storiform pattern. It corresponds to the undifferentiated high grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma of soft tissues

Clinical ♦♦ Wide age range with no predilection for gender ♦♦ Presentation: pain or a mass ♦♦ Some lesions arise in the setting of orthopedic implants, Paget disease, fibrous dysplasia, and bone infarcts ♦♦ Associated with a pathologic fracture in up to 25% of cases

X-rays and Imaging Findings ♦♦ The metaphyseal regions of long bones are the most frequently involved ♦♦ Ill-defined, lytic lesions ♦♦ Cortical expansion and breakthrough with minimal periosteal reaction

Macroscopic ♦♦ A variegated tumor with hemorrhage and necrosis ♦♦ Margins are frequently permeative

Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

May exhibit a variety of patterns similar to soft tissue MFH Multinucleated malignant giant cells are present in most cases Histiocytic cells with grooved nuclei are frequent Fibrosis is variable Spindle cell areas with a storiform arrangement are common Chronic inflammatory cells are often seen Lack malignant osteoid or low grade areas

Immunohistochemistry ♦♦ S-100 protein ±, cytokeratin – (or focal +)

Differential Diagnosis ♦♦ Fibrosarcomas −− The fasicular arrangement or herringbone pattern ♦♦ Osteosarcoma −− Areas of malignant osteoid ♦♦ Metastatic spindle cell carcinoma and melanoma −− Immunohistochemistry is useful

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Other Mesenchymal Lesions Fibrous Dysplasia (FD, Jaffe-Lichtenstein Syndrome) Clinical ♦♦ Monoostotic FD (80%) −− May be seen at any age (usually <30 years old) ♦♦ Polyostotic FD (20%) −− Generally presents before the age of puberty ♦♦ Presentation −− Pain, pathologic fracture, deformity (especially gnathic or upper femoral FD) −− May be asymptomatic −− Secondary sarcomas rarely develop ♦♦ Associated syndromes −− McCune-Albright syndrome (a) Polyostotic FD with macular skin lesions, precocious puberty, with or without fibromyxomatous soft tissue tumors (b) Hypophosphatemic rickets or osteomalacia has been associated −− Mazabraud syndrome (a) Associated with a soft tissue or intramuscular myxoma ♦♦ Location −− Monoostotic (a) 33% involve the craniofacial bones (b) 33% involve the tibia and femur (c) 20% involve the ribs −− Polyostotic (a) Femur, tibia, and pelvis are commonly involved (b) Small bones of the hands and feet, the ribs, and the skull may also be involved ♦♦ Pathogenesis −− Somatic mutation in the gene that encodes the a subunit of the GTP binding protein leading to the substitution of  His or Cys for Arg at amino acid 201 of the alphasubunit of Gs

X-rays and Imaging Findings ♦♦ Intramedullary, geographic lesions with sclerotic or welldefined margins and a “ground-glass” matrix ♦♦ The lesions are intensely hot on bone scans

Microscopic ♦♦ Trabeculae of woven bone in a background of moderately cellular fibrous tissue (Fig. 21.24) ♦♦ The trabeculae often obtain a variety of shapes (Cs, circles, etc.) (“Chinese-letters”) ♦♦ Osteoid tends to merge into the background (“metaplastic”) ♦♦ Osteoblasts are interspersed in the woven bone, but are not conspicuous around the trabeculae

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Fig.  21.24. Fibrous dysplasia – emerging trabeculae of metaplastic bone within a fibrous stroma. ♦♦ Small foci of lamellar bone may be seen ♦♦ The fibroosseous proliferation may show a slight or minimal infiltrative pattern at the junction with nonlesional bone – a more extensive infiltrative pattern should raise the possibility of well-differentiated osteosarcoma ♦♦ The fibrous stroma may be highly or sparsely cellular, myxomatous, or show considerable collagenization ♦♦ The fibroblasts usually have plump, ovoid nuclei ♦♦ Multinucleated osteoclast type giant cells may be present ♦♦ Cartilage with peripheral enchondral ossification may be present ♦♦ Collections of foam cells are common

Differential Diagnosis −− Osteofibrous dysplasia (Fig. 21.25): A cortically based lesion −− Most often affects the tibia or fibula in children (often <5 years) −− Reactive woven bone −− Osteoblastic rimming is more prominent ♦♦ Well-differentiated intraosseous osteosarcoma −− The stromal cells have larger nuclei with cytologic atypia and atypical mitotic figures −− The edges of the lesion show permeation into the preexisting bone and into the medullary canal with entrapment of trabeculae ♦♦ Desmoplastic fibroma −− Usually heavily collagenized with little or no trabecular bone

Campanacci Disease (Osteofibrous Dysplasia) ♦♦ Osteofibrous dysplasia is a cortically based fibroosseous proliferation (Fig. 21.26A) ♦♦ Predilection for the tibia (and less frequently fibula) in children and infants

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Fig.  21.26. Adamantinoma (gross) involving the tibia causing a prominent bowing deformity (a). Microscopic examination showed groups of epithelial cells within a fibrous background (b). ♦♦ Controversial relationship with Campanacci disease or osteofibrous dysplasia Fig. 21.25. Osteofibrous dysplasia. (a) The CT scan shows a cortically based lesion in the Tibia of a 6-year-old. Histologically, the lesions are similar to fibrous dysplasia of the usual intramedullary type except that osteoblastic rimming of trabeculae is more prominent. (b) There are emerging bone trabeculae in a fibrous background in a case of osteofibrous dysplasia. The trabeculae are surrounded by a prominent rim of osteoblasts. (Picture courtesy Dr. Edward McCarthy, Johns Hopkins University).

Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET) Definition ♦♦ A round cell sarcoma that shows varying degrees of neuroectodermal differentiation. The term Ewing sarcoma is used when there is no neuroectodermal differentiation whereas the term PNET is preferred when this is more prominent

Clinical ♦♦ Histologically, it is similar to fibrous dysplasia except that osteoblastic rimming around trabeculae might be more prominent (Fig. 21.26B) ♦♦ Occasional cytokeratin positive cells can be seen

Fibrocartilaginous Mesenchymoma ♦♦ Consists of a combination of bone, spindle cells, and cartilage, predominantly in the chest wall ♦♦ The cartilage has a characteristic appearance of epiphyseal plate formation ♦♦ A dense, spindle cell proliferation is seen between wellformed bony trabeculae ♦♦ No or little collagen

Adamantinoma ♦♦ Shows marked predilection for the tibia (Fig. 21.26A) ♦♦ A low grade malignant neoplasm with epithelial differentiation (Fig. 21.26B)

♦♦ Affects patients in the first two decades of life. Although it is the second most common bone and soft tissue malignancy in children, its incidence is less than myeloma, osteosarcoma, and chondrosarcoma ♦♦ Localized pain and a mass with fever, leukocytosis, and a raised sedimentation rate ♦♦ Up to 10% of patients may have skeletal metastases at the time of presentation ♦♦ Most often involves the diaphysis of long tubular bones (femur) as well as some flat bones (pelvis and ribs) ♦♦ Characteristic chromosomal translocation: t(11;22) (also seen in primitive neuroectodermal tumor [PNET] and Askin tumor of chest) −− Occurs in 85% of patients −− The EWS gene (located on chromosome 22q12) is translocated to the FL1 (a gene of the ETS family located on chromosome 11), resulting in the formation of a chimeric protein product

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♦♦ Scant cytoplasmic organelles and glycogen lake

Differential Diagnosis

Fig. 21.27. Ewing sarcoma – sheets of small blue cells are identified with no matrix production. ♦♦ A second, t(21;22), translocation has been identified in 15% of patients −− Fusion of the EWS gene with a different member of the ETS family, the ERG gene located at chromosome 21q22, resulting in a chimeric EWS/ERG protein product

X-rays and Imaging Findings ♦♦ Ill-defined, lytic lesions with permeative margins ♦♦ A periosteal reaction of the onion-skin or sunburst type ♦♦ A soft tissue component is detected by CT or MR scans

Microscopic ♦♦ Classic form −− Sheets and large nests of uniform, small, round to polygonal cells with scanty cytoplasm (Fig. 21.27) −− The chromatin is finely dispersed, usually with no nucleoli −− Variable number of mitotic figures −− Perivascular cuffing may be evident in areas of necrosis −− Cytoplasmic glycogen, demonstrated by the PAS stain, is evident

Variants ♦♦ Large-cell type pattern −− Cells may be larger and may have nucleoli ♦♦ Filigree pattern −− Bicellular architecture, separated by stroma ♦♦ A rare “adamantinoma-like” variant with epithelial cells has also been reported

Immunohistochemistry ♦♦ MIC2 (CD99) + in a membranous pattern (also + in PNETs, some rhabdomyosarcomas, acute lymphoblastic leukemia, pancreatic islets, and ependymoma) ♦♦ Vimentin +, CK ±, neurofilament +, synaptophysin ±, NSE ±

Electron Microscopy ♦♦ Nuclei with euchromatic pattern

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♦♦ Small cell osteosarcoma and mesenchymal chondrosarcoma −− Production of malignant osteoid or cartilage matrices ♦♦ Lymphoma −− LCA + ♦♦ Metastatic neuroblastoma −− More common than Ewing sarcoma −− Patients are usually <5 years of age −− Homer–Wright pseudorosettes, pink fibrillary background, ganglion cell differentiation −− Neuritic cell processes containing neurofilaments, neural tubules, and dense core granules by electron microscopy −− Increased catecholamine metabolite levels in neuroblastoma −− Demonstration of an adrenal mass on CT scan ♦♦ Primitive neuroectodermal tumor (PNET) −− An entity closely related to Ewing sarcoma, with neuroectodermal differentiation −− Homer–Wright rosettes −− Immunohistochemistry (a) NSE +, synaptophysin +, neurofilament +, MIC2 + −− Ultrastructural evidence of dense core granules −− Age/sex distribution and radiologic features are similar to Ewing sarcoma

Conventional Chordoma Definition ♦♦ A low intermediate grade malignant tumor that recapitulates the notochord

Clinical ♦♦ A low grade malignant tumor occurring predominantly in the axial skeleton in the region of the embryonic notochord ♦♦ Particular predilection to the caudal and cranial extremes ♦♦ The clivus and the sacrum are the most common sites ♦♦ Vestigial rests of notochord-like tissue located in the sphenooccipital region are sometimes found and termed ecchordosis physaliphora

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Lobulated lesions with a myxoid background Cords, sheets, or occasionally haphazardly arranged cells Vacuolated cytoplasm (physaliphorous cells) Some cells may have abundant eosinophilic cytoplasm or may mimic signet ring cells ♦♦ Nuclear pleomorphism is mild and mitotic activity low to absent

Immunohistochemistry ♦♦ S-100+, Cytokeratins +, EMA +, Brachyury +, D2-40 negative

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♦♦ Multinucleated nuclei and prominent nucleoli may be present ♦♦ Amyloid deposits may be seen

♦♦ Mucinous carcinoma ♦♦ Chondrosarcoma ♦♦ Giant notochordal rest or Benign notochordal cell tumor

Immunohistochemistry

Chondroid Chordoma

♦♦ Plasma cells usually CD38+, CD 56+, CD 79a+, CD 138+ and show clonality with either k or l

♦♦ A variant of conventional chordoma with foci of cartilaginous differentiation often seen in the base of the skull where it can be misdiagnosed as chondrosarcoma

Benign Notochordal Cell Tumor

Differential Diagnosis ♦♦ Osteomyelitis ♦♦ Malignant lymphoma

♦♦ These lesions are usually small, well defined by imaging studies (sclerotic margins) ♦♦ Histologically, they are composed of solid sheets of physaliphorous cells along with eosinophilic cells showing only slight vacuolation ♦♦ No myxoid matrix is seen ♦♦ The lesions are benign and nonprogressive

Non-Hodgkin Lymphoma

Plasma Cell Dyscrasias (Plasmacytoma/ Multiple Myeloma) Clinical

♦♦ Terms such as histiocytosis X, eosinophilic granuloma, Letterer–Siewe disease, Hand–Schuller–Christian disease, etc. have been used ♦♦ The cells bear ultrastructural resemblance to Langerhans cells of the skin, with the characteristic “Birbeck” granules ♦♦ A clonal, (possibly neoplastic rather than a reactive) process ♦♦ More common in the first three decades of life, although no age is completely exempt ♦♦ Pain and swelling are the most frequent presentations ♦♦ Systemic symptoms include diabetes insipidus, exophthalmos, skin lesions, and mastoiditis

♦♦ Most common tumor of the bone. It is a tumor of a clone of immunoglobulin-secreting plasma cells ♦♦ Pathogenesis involves osteoclastic activation by IL-6 ♦♦ Multiple myeloma −− There may be bone lesions, marrow plasmacytosis, or foci of collections of plasma cells −− Secretion of monoclonal immunoglobulin chains into the blood −− Anemia, bone pain, pathologic fracture, neurologic abnormalities, renal failure, and amyloid deposits are some other features ♦♦ Plasmacytoma −− Frequently, only a single deposit of clonally proliferating plasma cells −− With or without secretion of immunoglobulins into the blood ♦♦ POEMS syndrome −− A variant consisting of sclerotic bone lesions along with polyneuropathies, endocrine abnormalities, and skin changes

X-rays and Imaging Findings ♦♦ Lytic (punched out) lesions in the diaphysis or metaphysis ♦♦ The radiological differential diagnosis −− Metastatic carcinoma −− Malignant lymphoma −− Hyperparathyroidism

Microscopic ♦♦ Sheets or aggregates of atypical plasma cells with a pink cytoplasm

♦♦ Bone lymphomas are very uncommon before the second decade ♦♦ Osseous lymphoma lesions are far more common as a secondary rather than a primary form of involvement

Langerhans Cell Histiocytosis Clinical

X-rays and Imaging Findings ♦♦ Lytic, geographic lesions occasionally showing bony expansion ♦♦ Multiple punch out lesions

Microscopic ♦♦ Proliferation of histiocytoid cells with variable amounts of cytoplasm ♦♦ The cell borders may be well defined or syncytium-like ♦♦ The nuclei have characteristic “grooves” and may be reniform or coffee bean like ♦♦ Multinucleated giant cells may be present ♦♦ A variable number of mitotic figures may be seen ♦♦ Associated inflammatory response, often rich in eosinophils ♦♦ Lipid-laden histiocytes are sometimes seen

Immunohistochemistry ♦♦ S-100 protein +, CD1a+

Differential Diagnosis ♦♦ Granulomatous inflammation ♦♦ Osteomyelitis −− May be particularly difficult to distinguish on x-rays

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−− Necrotic bone trabeculae −− Predominantly neutrophils with a fewer number eosinophils in most cases −− Rarely involves the skull −− S-100 protein negative, CD1a negative ♦♦ Hodgkin lymphoma −− The diagnostic Reed–Sternberg cells −− Distinct immunohistochemical profile

Erdheim-Chester Disease −− A condition of unknown cause that may be related to Langerhans cell histiocytosis (LCH) −− Most patients are male −− Presentation: weight loss and bone pain; may be asymptomatic −− Bilateral, symmetric sclerosis of the metadiaphyseal regions of the long bones

Metastatic Bone Disease Clinical ♦♦ Young children −− Neuroblastoma is most common ♦♦ Older adults −− Metastatic carcinoma predominates ♦♦ Most frequent primary sites −− Lytic lesions (majority of lesions) (a) Kidney (b) Thyroid (c) Gastrointestinal tract −− Blastic lesions (a) Prostate

(b) Carcinoid tumors (c) Medulloblastoma −− Blastic and/or lytic (a) Breast ♦♦ Adult patients commonly present with pain, swelling, tenderness, or pathologic fracture ♦♦ The bones of the axial skeleton and proximal appendicular skeleton are more frequently affected ♦♦ IL-1, IL-6, TGF-b, PDGF, plasminogen activator, and bone morphogenetic proteins (BMPs) may be involved

X-rays and Imaging Findings ♦♦ Blastic, lytic, or mixed lesions ♦♦ Periosteal reactions are infrequent ♦♦ Lesions are often geographic and occasionally expansile

Macroscopic ♦♦ Metastatic lytic tumors tend to be more sharply demarcated ♦♦ Other metastatic tumors tend to be exquisitely vascular (kidney and thyroid tumors) ♦♦ Tumors can vary from hard, bony tumors to soft, fleshy, or friable

Microscopic ♦♦ Well-differentiated metastatic tumors do not pose a problem ♦♦ Renal cell or thyroid carcinomas can often be diagnosed without immunohistochemical stains ♦♦ Mucicarmine or immunostains for epithelial markers are helpful ♦♦ Reactive bone formation may mimic osteosarcoma ♦♦ Some sarcomas can be ± for epithelial markers such as cytokeratin (leiomyosarcomas, MFH, epithelioid osteosarcomas, epithelioid hemangioendotheliomas, etc)

STAGING OF MUSCULOSKELETAL NEOPLASMS ♦♦ The system uses the GTM approach (Grade, SiTe, Metastasis or the Enneking system) −− Grade (a) G0: Benign (b) G1: Low grade (c) G2: High grade −− Tumor site (a) T1: Intracompartmental locations, including *  Intraosseous *  Intraarticular * Intrafascial (ray of hand, volar compartment of forearm, etc.)

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(b) T2: Extracompartmental locations *  Evidence of soft tissue or fascial extension * Certain anatomic locations are always considered to be T2 locations (1) Popliteal and antecubital fossa (2) Femoral triangle (3) Mid and hind foot (4) Mid hand (5) Intrapelvic locations (6) Axilla −− Metastasis (a) M0: Absent (b) M1: Present

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The Surgical Staging System of the Musculoskeletal Tumor Society (MSTS) Stage

Grade

Site

Metastasis

IA IB IIA IIB IIIA IIIB

Low (G1) Low (G1) High (G2) High (G2) G1 or G2 G1 or G2

Intracompartmental (T1) Extracompartmental (T2) Intracompartmental (T1) Extracompartmental (T2) Intracompartmental (T1) Extracompartmental (T2)

None (M0) None (M0) None (M0) None (M0) Yes (M1) Yes (M1)

TNM CLASSIFICATION oF BONE TUMORS (2010 Version) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor 8 cm or less in greatest dimension −− T2: Tumor more than 8 cm in greatest dimension −− T3: Discontinuous tumors in the primary bone site ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed

−− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis −− M1a: Lung metastasis −− M1b: Other distant site

Suggested Reading Carney JA. Psammomatous melanotic schwannoma: a distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing’s syndrome. Am J Surg Pathol 1990;14:206–222.

Jambhekar NA, Desai PB, Chitale DA, Patil P, Arya S. Benign metastasizing chondroblastoma: a case report. Cancer 1998;82: 675–678.

Czerniak B, Rojas-Corona RR, Dorfman H. Morphologic diversity of long bone adamantinoma: the concept of differentiated (regressing) adamantinoma and its relationship to osteofibrous dysplasia. Cancer 1989;64:2319–2334.

Manolagas SC, Jilka RL. Bone marrow, cytokines and bone remodeling: emerging insights into the pathphysiology of osteoporosis. New Engl J Med 1995;332:305–311.

Enneking WF. A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res 1986;204:9–24.

Morrison NA, Qi JC, Tokita A, et  al. Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284–287.

Enneking WF, Spannier SS, Goodman MA. A system of surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980;153:106–120.

Nascimento AG, Unni KK, Pritchard DJ, et al. A clinico-pathologic study of 20 cases of large-cell (atypical) Ewing’s sarcoma of bone. Am J Surg Path 1980;4:29–36.

Goorin AM, Abelson HT, Frei E. Osteosarcoma: fifteen years later. N Engl J Med 1985;313:1637–1643. Hipp JA, Springfield DS, Hayes WC. Predicting pathologic fracture risk in the management of metastatic bone disease. Clin Orthop Relat Res 1995;312:120–135.

Oliveira AM, Perez-A A, Inwards CY, et al. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol 2004;165:1773–1780.

Ishida T, Dorfman HD, Bullough PG. Tophaceous pseudogout (tumoral calcium pyrophosphate dihydrate crystal deposition disease). Hum Pathol 1995;26:587–593.

Raymond KA, Chawla SP, Carrasco CH, et  al. Osteosarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol 1987;4: 212–236.

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Sukov WR, Franco MF, Erickson-Johnson M, et al. Frequency of USP6 rearrangements in ­myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of “myositis ossificans-like lesions” are the early phases in the formation of soft-tissue aneurysmal bone cyst. Skeletal Radiol 2008;37:321–327 Turcotte RE, Kurt A, Sim FH, et  al. Chondroblastoma. Hum Pathol 1993;24:944–999. Unni KK. Adamantinoma of long bones: the mystery endures. Adv Anat Pathol 1996;3:16–21. Unni KK, ed. Practical approach to rapid histologic diagnosis in Dahlin’s bone tumors. Philadelphia, PA: Lippincott-Raven; 1996.

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Willman CL, Busque L, Griffith BB, et al. Langerhans’ cell histiocytosis (histiocytosis X): a clonal proliferative disease. N Engl J Med 1994; 331:154–160. Wold LE, Dobyns JH, Swee RG, et al. Giant cell reaction (giant cell reparative granuloma) of the small bones of the hands and feet. Am J Surg Path 1986;10:491–496. Wold LE, Swee RG. Giant cell tumors of the hands and feet. Semin Diag Path 1984;1:173–184. Yamaguchi TJI, Sugihara S, McCarthy EF, Karita M, et al. Distinguishing benign notochordal cell tumors from vertebral chordoma. Skeletal Radiol 2008;37:291–299.

22 Soft Tissue Tumors Leona A. Doyle, md and Alessandra F. Nascimento, md

contents

I. Introduction.......................................22-4

II. Fibroblastic/Myofibroblastic Tumors...............................................22-4 Classification of Fibroblastic/ Myofibroblastic Tumors..............................22-4 Benign................................................................22-4 Keloid Scar..............................................22-4 Nodular Fasciitis.....................................22-4 Proliferative Fasciitis..............................22-7 Proliferative Myositis.............................22-8 Ischemic Fasciitis (Atypical Decubital Fibroplasia)........................................22-8 Elastofibroma..........................................22-8 Fibroma of Tendon Sheath....................22-9 Desmoplastic Fibroblastoma.................22-9 Mammary-Type Myofibroblastoma......22-9 Angiomyofibroblastoma.........................22-9 Cellular Angiofibroma.........................22-10 Nuchal-Type Fibroma..........................22-10 Solitary Fibrous Tumor........................22-10 Pediatric Fibrous Tumors..............................22-11 Fibrous Hamartoma of Infancy..........22-11 Myofibroma/Myofibromatosis.............22-11 Fibromatosis Colli................................22-11 Juvenile Hyaline Fibromatosis............22-12 Inclusion Body Fibromatosis (Infantile Digital Fibromatosis)......22-12 Lipofibromatosis...................................22-12 Calcifying Aponeurotic Fibroma.........22-12 Gardner Fibroma.................................22-12 Calcifying Fibrous Tumor....................22-12 Fibromatoses...................................................22-13 Superficial Fibromatoses......................22-13

Deep (Desmoid) Fibromatoses.............22-13 Inflammatory Myofibroblastic Tumor................................................22-14 Malignant........................................................22-15 Low Grade Myofibroblastic Sarcoma............................................22-15 Infantile and Adult Fibrosarcoma......22-15 Myxoinflammatory Fibroblastic Sarcoma............................................22-16 Myxofibrosarcoma................................22-16 Low Grade Fibromyxoid Sarcoma.....22-17

III. Fibrohistiocytic Tumors....................22-17 Classification of Fibrohistiocytic Tumors........................................................22-17 Benign..............................................................22-17 Benign Fibrous Histiocytoma..............22-17 Juvenile Xanthogranuloma..................22-18 Reticulohistiocytoma............................22-18 Xanthoma..............................................22-18 Giant Cell Tumor of Tendon Sheath...............................................22-18 Diffuse-Type Giant Cell Tumor...........22-19 Atypical Fibroxanthoma......................22-20 Giant Cell Tumor of Soft Tissue..........22-21 Malignant........................................................22-21 Undifferentiated Pleomorphic Sarcoma............................................22-21

IV. Lipomatous Tumors..........................22-22 Classification of Lipomatous Tumors...........22-22 Benign..............................................................22-22 Lipoma...................................................22-22 Angiolipoma..........................................22-22

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_22, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Spindle Cell/Pleomorphic Lipoma......22-23 Lipoblastoma(tosis)..............................22-23 Hibernoma.............................................22-24 Lipomatosis...........................................22-24 Malignant........................................................22-24 Well-Differentiated Liposarcoma/ Atypical Lipomatous Tumor...........22-24 Dedifferentiated Liposarcoma.............22-25 Myxoid Liposarcoma............................22-25 Pleomorphic Liposarcoma...................22-26

V. Smooth Muscle Tumors....................22-26 Classification of Smooth Muscle Tumors.....22-26 Benign..............................................................22-26 Leiomyoma............................................22-26 Peritoneal Leiomyomatosis (Leiomyomatosis Peritonealis Disseminata).....................................22-27 Palisaded Myofibroblastoma of Lymph Node.................................22-27 Malignant........................................................22-27 Leiomyosarcoma...................................22-27

VI. Skeletal Muscle Tumors....................22-28 Classification of Skeletal Muscle Tumors.....22-28 Benign..............................................................22-28 Rhabdomyomatous Mesenchymal Hamartoma......................................22-28 Cardiac Rhabdomyoma.......................22-28 Adult Rhabdomyoma...........................22-28 Fetal Rhabdomyoma............................22-28 Genital Rhabdomyoma........................22-28 Malignant........................................................22-28 Rhabdomyosarcoma.............................22-28 Embryonal Rhabdomyosarcoma.........22-29 Alveolar Rhabdomyosarcoma.............22-29 Pleomorphic Rhabdomyosarcoma......22-30

VII. Vascular Tumors...............................22-30 Classification of Vascular Tumors................22-30 Benign..............................................................22-30 Papillary Endothelial Hyperplasia (Masson “Tumor”)...........................22-30 Bacillary Angiomatosis........................22-30 Capillary Hemangioma (Infantile Hemangioendothelioma).................22-30 Lobular Capillary Hemangioma (Pyogenic Granuloma).....................22-31 Cavernous Hemangioma......................22-31 Epithelioid Hemangioma (Angiolymphoid H ­ yperplasia with Eosinophilia)............................22-31 Intramuscular Angioma.......................22-31 Angiomatosis (Diffuse Hemangioma)...................................22-32 Spindle Cell Hemangioma...................22-32

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Low Grade Malignant....................................22-32 Kaposiform Hemangioendothelioma (Kaposi-Like Hemangioendothelioma).................22-32 Retiform Hemangioendothelioma (Hobnail ­Hemangioendothelioma).................22-32 Papillary Intralymphatic Angioendothelioma..........................22-33 Composite Hemangioendothelioma....22-33 Kaposi Sarcoma....................................22-33 Malignant........................................................22-34 Epithelioid Hemangioendothelioma...................22-34 Angiosarcoma.......................................22-34 Perivascular Tumors......................................22-35 Glomus Tumor......................................22-35

VIII. Peripheral Neural Tumors.................22-36 Classification of Peripheral Neural Tumors........................................................22-36 Benign..............................................................22-36 Traumatic Neuroma (Amputation Neuroma)..........................................22-36 Morton Neuroma (Localized Interdigital Neuritis)........................22-36 Digital Pacinian Neuroma....................22-36 Mucosal Neuroma.................................22-36 Solitary Circumscribed Neuroma (Palisaded Encapsulated Neuroma)..........................................22-36 Schwannoma.........................................22-36 Solitary Neurofibroma.........................22-37 Diffuse Neurofibroma...........................22-37 Plexiform Neurofibroma......................22-38 Perineurioma.........................................22-38 Dermal Nerve Sheath Myxoma...........22-38 Ganglioneuroma...................................22-38 Granular Cell Tumor...........................22-38 Heterotopic Meningeal Lesions (Ectopic Meningioma).....................22-39 Heterotopic Glial Nodules (Nasal Gliomas)................................22-39 Malignant........................................................22-39 Malignant Peripheral Nerve Sheath Tumor (Malignant Schwannoma or Neurofibrosarcoma) . ......................22-39 Extraspinal (Soft Tissue) Ependymoma (See CNS Tumors)............................22-40

IX. Chondroosseous Tumors..................22-41 Classification of Chondroosseous Tumors........................................................22-41

Soft Tissue Tumors

Benign..............................................................22-41 Osteoma Cutis.......................................22-41 Myositis Ossificans................................22-41 Soft Tissue Chondroma........................22-41 Malignant........................................................22-41 Extraskeletal Osteosarcoma................22-41

X. Miscellaneous Tumors......................22-42 Classification of Tumors of Uncertain Histogenesis................................................22-42 Benign..............................................................22-42 Tumoral Calcinosis...............................22-42 Amyloidoma..........................................22-42 Myxoma.................................................22-43 Uncertain Biologic Potential..........................22-44

22-3

PEComa.................................................22-44 Ossifying Fibromyxoid Tumor............22-44 Malignant........................................................22-45 Alveolar Soft Part Sarcoma.................22-45 Epithelioid Sarcoma.............................22-47 Peripheral Primitive Neuroectodermal Tumor/ Extraosseous Ewing sarcoma..........22-47 Extrarenal Rhabdoid Tumor...............22-48 Desmoplastic Small Round Cell Tumor........................................22-49 Synovial Sarcoma.................................22-49

XI. Suggested Reading...........................22-50

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INTRODUCTION ♦♦ See Tables  22.1 and 22.2 for immunohistochemical profiles and cytogenetics findings in different lesions

♦♦ See Tables 22.3–22.11 for general classification of soft tissue tumors

FIBROBLASTIC/MYOFIBROBLASTIC TUMORS Classification of Fibroblastic/Myofibroblastic Tumors ♦♦ See Table 22.3

Benign Keloid Scar Clinical ♦♦ Keloid scarring is a reactive fibrous proliferation that almost invariably follows local trauma or surgery. It commonly affects young black people; there may be a familial tendency to developing keloid scars ♦♦ Any anatomic location may be affected but the head and neck region is most commonly involved ♦♦ Treatment is difficult and up to 50% of patients will show local recurrence after excision

Macroscopic ♦♦ Keloid scarring is characterized by an often polypoid cutaneous lesion showing excessive scar tissue extending beyond the boundaries of the site of initial tissue damage

Microscopic ♦♦ Keloid scars consist of hypocellular, thick, glassy, hyalinized, eosinophilic collagen fibers haphazardly arranged into broad bands or nodules, sometimes with associated calcifications

Differential Diagnosis ♦♦ Hypertrophic scar: less common than keloid scarring, is confined to the original site of tissue damage, is more cellular with a nodular configuration, and is less prone to local recurrence

Nodular Fasciitis (Fig. 22.1) ♦♦ Nodular fasciitis is a common, self-limiting, reactive fibroblastic/myofibroblastic proliferation that histologically is often mistaken for sarcoma

Clinical ♦♦ It typically presents in adults 20–40 years of age, with no sex predilection as a rapidly growing, often painful or tender subcutaneous nodule. Most lesions are usually present for less than 10–12 weeks ♦♦ Common sites of involvement include the upper extremities and trunk, and head and neck in children. A small percentage of lesions may develop in intravascular, intramuscular, and intraarticular sites

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♦♦ Nodular fasciitis is self-limiting, showing spontaneous regression (if untreated); less than 2% recur locally after excision, likely due to resection during active phase of growth

Macroscopic ♦♦ Grossly, nodular fasciitis is a well-circumscribed or stellate mass, usually measuring <3 cm in diameter and ­unencapsulated. The cut surface may show myxoid, cystic, or fibrous changes depending on the duration of the lesion

Microscopic ♦♦ Nodular fasciitis consists of a cellular myofibroblastic proliferation in short intersecting fascicles and variably loose, myxoid, or collagenous stroma (feathery appearance) containing delicate thin-walled vessels (granulation tissue-like) ♦♦ Neoplastic cells typically have plump nuclei with occasional prominent nucleoli; however, characteristically the cells lack nuclear atypia ♦♦ Normal mitotic forms may be numerous. Additional features include extravasated red blood cells, scattered inflammatory cells, keloidal-like collageneous ­hyalinization, osteoclastlike multinucleated giant cells and, rarely, reactive new bone formation

Immunohistochemistry ♦♦ Lesional cells stain positive with muscle-specific actin and smooth muscle actin, and are negative for desmin, keratin, and S-100 protein. CD68 expression may be seen in the osteoclast-like giant cells; however, it is neither sensitive nor specific for nodular fasciitis

Variants ♦♦ Fasciitis ossificans: usually periosteal in location and contains prominent reactive bone formation; it has features of both nodular fasciitis and myositis ossificans ♦♦ Cranial fasciitis: occurs predominantly in infants, and involves the soft tissue of the scalp and underlying skull and often results in bone erosion

Differential Diagnosis ♦♦ Sarcomas: rarely grow as rapidly as nodular fasciitis and are often of greater size with a deeper location ♦♦ Histologically, sarcomas are typically more cellular and densely packed with greater nuclear atypia and hyperchromasia and variable necrosis

Positive

Variable

Negative

Negative

Negative

Cytokeratin

S-100

Smooth muscle actin

Desmin

CD34

Negative

Negative

Variable

Negative

Negative

Positive

Cytokeratin

EMA

S-100

CD34

CD31

TFE-3

Pleomorphic undifferentiated sarcoma

Negative

Negative

Variable

Negative

Variable

Variable Negative Negative

Antibody

Cytokeratin

S-100

Smooth muscle actin

Desmin

MDM-2

CDK-4 Myo-D1 Myf-4

(c) Pleomorphic Soft Tissue Tumors

ASPS

Antibody

(b) Epithelioid Soft Tissue Tumors

Synovial sarcoma

Antibody

(a) Monomorphic Spindle Cell Tumors

Positive Negative Negative

Positive

Negative

Negative

Variable

Negative

Pleomorphic liposarcoma

Negative

Negative

Variable

Negative

Positive

Positive

Epithelioid sarcoma

Variable

Negative

Negative

Positive

Negative

MPNST

Negative Positive Positive

Negative

Positive

Positive

Rare

Rare

Pleomorphic rhabdomyosarcoma

Negative

Positive

Positive

Negative

Variable

Positive

Epithelioid angiosarcoma

Negative

Positive

Positive

Rare

Rare

Leiomyosarcoma

Negative Negative Negative

Negative

Negative

Negative

Positive

Negative

Pleomorphic MPNST

Negative

Negative

Negative

Positive

Variable

Variable

Epithelioid MPNST

Negative

Negative

Variable

Negative

Negative

Fibrosarcoma

Negative Negative Negative

Negative

Positive

Positive

Negative

Variable

Pleomorphic leiomyosarcoma

Negative

Negative

Negative

Variable

Positive

Positive

Biphasic synovial sarcoma

Negative

Variable

Positive

Negative

Negative

Fibromatosis

Table 22.1. Differentiating Soft Tissue Tumors Based on Morphologic Patterns and Immunohistochemical Profiles

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Table 22.2. Common Cytogenetic Changes in Soft Tissue Tumors Tumor

Cytogenetic change

Gene fusion

Frequency

Alveolar rhabdomyosarcoma

t(2;13)(q35;q14)

PAX3-FKHR

Clear cell sarcoma

t(12;22)(q13;q12)

EWS-ATF1

>90%

Dermatofibrosarcoma protuberans

t(17;22)(q21;q13)

COL1A1-PDGFB

>90%

Desmoplastic small round cell tumor

t(11;22)(p13;q12 )

EWS-WT1

>95%

Extraskeletal myxoid chondrosarcoma

t(9;22)(q22;q12)

EWS-NR4A3

75%

Ewing sarcoma/PNET

t(11;22)(q24;q12)

EWS-FLI1

90%

t(21;22)(q22;q12)

EWS-ERG

  5%

t(7;22)(p22;q12)

EWS-ETV1

<1%

t( 2;22)(q33;q12)

EWS-FEV

<1%

Infantile fibrosarcoma

t(12;15)(p13;q25)

ETV6-NTRK3

>95%

Inflammatory myofibroblastic tumor

t with 2p23

ALK fusions

>50%

Low grade fibromyxoid sarcoma

t(7;16)(q33;p11.2)

FUS-CREB3L2

>95%

Myxoid liposarcoma

t(12;16)(q13;p11)

FUS-CHOP

95%

t(12;22)(q13;q11)

EWS-CHOP

  5%

SYT-SSX1

65%

SYT-SSX2

35%

Synovial sarcoma t(X;18)(p11.2;q11.2)

Table 22.3. Fibroblastic/Myofibroblastic Tumors Pediatric Benign   Fibrous hamartoma of infancy   Keloid scar   Myofibroma(tosis)   Nodular fasciitis   Fibromatosis colli   Proliferative fasciitis   Juvenile hyaline fibromatosis   Proliferative myositis   Inclusion body fibromatosis   Ischemic fasciitis   Lipofibromatosis   Elastofibroma   Calcifying aponeurotic fibroma   Fibroma of tendon sheath   Gardner fibroma   Desmoplastic fibroma   Calcifying fibrous tumor  Mammary-type myofibroblastoma   Angiofibroblastoma   Cellular angiofibroma   Nuchal-type fibroma Fibromatoses   Solitary fibrous tumor  Inflammatory myofibroblastic   Superficial fibromatoses   Deep (desmoid) fibromatoses tumor Malignant  Low grade myofibroblastic sarcoma  Infantile and adult fibrosarcoma  Myxoinflammatory ­fibroblastic sarcoma   Myxofibrosarcoma  Low grade fibromyxoid sarcoma

1000

65%

Table 22.4. Fibrohistiocytic Tumors Benign   Benign fibrous histiocytoma   Juvenile xanthogranuloma   Reticulohistiocytoma   Xanthoma   Giant cell tumor of tendon sheath   Diffuse type giant cell tumor   Atypical fibroxanthoma   Giant cell tumor of soft tissue Intermediate   Dermatofibrosarcoma protuberans   Plexiform fibrohistiocytic tumor Malignant   Undifferentiated pleomorphic sarcoma

♦♦ Fibromatosis: usually larger with a more infiltrative growth pattern, often with skeletal muscle involvement. Histologically, they have a fascicular growth pattern with abundant collagen and slender fibroblasts, but may have areas of fasciitis-like architecture (especially when arising in intraabdominal and breast). Mitoses are usually rare ♦♦ Benign fibrous histiocytoma −− Characterized by storiform cellular proliferations, more polymorphous with usually only focal actin positivity

Soft Tissue Tumors

Table 22.5. Lipomatous Tumors Benign   Lipoma   Angiolipoma   Spindle cell/pleomorphic lipoma   Lipoblastoma(tosis)   Hibernoma   Lipomatosis Malignant   Atypical lipomatous tumor/well-differentiated liposarcoma   Dedifferentiated liposarcoma   Myxoid liposarcoma   Pleomorphic liposarcoma

Table 22.6. Smooth Muscle Tumors Benign   Leiomyoma   Peritoneal leiomyomatosis   Palisaded myofibroblastoma of lymph node Malignant   Leiomyosarcoma

Table 22.7. Skeletal Muscle Tumors Benign   Rhabdomyomatous mesenchymal hamartoma   Cardiac rhabdomyoma   Adult rhabdomyoma   Fetal rhabdomyoma   Genital rhabdomyoma Malignant   Embryonal rhabdomyosarcoma   Alveolar rhabdomyosarcoma   Pleomorphic rhabdomyosarcoma

Proliferative Fasciitis Clinical ♦♦ The most common presentation of proliferative fasciitis is a rapidly growing mass on the extremities (usually forearm and thigh), in patients between the ages of 40 and 70 years and no sex predilection ♦♦ Lesions rarely recur after excision

Macroscopic

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Table 22.8. Vascular Tumors Benign  Papillary endothelial hyperplasia   Bacillary angiomatosis   Capillary hemangioma  Lobular capillary hemangioma   Cavernous hemangioma   Epithelioid hemangioma   Intramuscular angioma   Angiomatosis   Spindle cell hemangioma

Intermediate grade  Kaposiform hemangioendothelioma   Retiform hemangioendothelioma  Papillary intralymphatic angioendothelioma  Composite hemangioendothelioma   Kaposi sarcoma Malignant  Epithelioid hemangioendothelioma   Angiosarcoma

Perivascular tumors   Glomus tumor

Table 22.9. Peripheral Neural Tumors Benign   Traumatic neuroma   Morton neuroma   Digital pacinian neuroma   Mucosal neuroma   Solitary circumscribed neuroma   Schwannoma   Solitary neurofibroma   Diffuse neurofibroma   Plexiform neurofibroma   Perineurioma   Dermal nerve sheath myxoma   Ganglioneuroma   Granular cell tumor   Heterotopic meningeal lesion   Heterotopic glial nodules Malignant   Malignant peripheral nerve sheath tumor   Extraspinal (soft tissue) ependymoma

Table 22.10. Chondroosseous Tumors Benign   Osteoma cutis   Myositis ossificans   Soft tissue chondroma Malignant   Extraskeletal osteosarcoma

♦♦ Grossly they consist of a poorly circumscribed, subcutaneous, gray-white mass, usually measuring 1–5 cm

Microscopic ♦♦ Histologically, this proliferation is similar to nodular fasciitis but contains numerous basophilic polygonal large cells with

one or more nuclei with prominent nucleoli, resembling ganglion cell and prominent admixed vessels, resembling granulation tissue. The edge of the lesion is usually ill-defined

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Table 22.11. Miscellaneous Tumors Benign   Tumoral calcinosis   Amyloidoma   Myxoma Uncertain biologic potential   PEComa   Ossifying fibromyxoid tumor Malignant   Alveolar soft part sarcoma   Epithelioid sarcoma   Primitive neuroectodermal tumor   Extrarenal rhabdoid tumor   Desmoplastic small round cell tumor   Synovial sarcoma

Microscopic ♦♦ The histologic appearance is similar to proliferative fasciitis, but growth between individual (uninvolved) muscle fibers results in a classic “checkerboard-like” appearance with slight atrophy, but preservation, of muscle fibers. Foci of metaplastic bone or cartilage may be present (approximately 10% of cases)

Differential Diagnosis ♦♦ Sarcomas: tend to show more localized growth, cytological atypia, and pleomorphism and do not preserve muscle fibers

Ischemic Fasciitis (Atypical Decubital Fibroplasia) Clinical ♦♦ This lesion occurs in debilitated, immobilized, or bedridden patients as the result of prolonged pressure and impaired circulation ♦♦ It produces a painless soft tissue mass, often mistaken for a neoplasm, in the subcutaneous areas over bony prominences such as at the shoulder, sacrum, and hip ♦♦ There is a slight female predilection, and the peak age is between 70 and 90 years ♦♦ Local recurrence after excision may occur

Macroscopic ♦♦ Ischemic fasciitis is a poorly circumscribed mass in the deep subcutis, which may extend into underlying skeletal muscle

Microscopic

Fig. 22.1. Nodular fasciitis: intervening short fascicles of ­spindle cells with a “tissue culture” appearance and extravazated red blood cells.

Differential Diagnosis ♦♦ Pleomorphic rhabdomyosarcoma: rarely subcutaneous and shows greater cytological atypia and abnormal mitoses. Immunohistochemistry shows consistent expression of desmin, actin, and myogenin (Myf-4)

Proliferative Myositis Clinical ♦♦ Proliferative myositis typically presents as a solitary, rapidly growing lesion of less than 4 weeks duration involving the muscles of trunk and shoulder girdle of middle aged adults, with no gender predilection. Recurrence of the lesion is rare after excision

Macroscopic ♦♦ Grossly proliferative myositis is poorly demarcated and usually measures 1–6  cm in diameter. There is often scar-like induration involving muscle and overlying fascia

1002

♦♦ The microscopic appearance is one of a lobular or zonal growth pattern of prominent vessels and inflamed granulation tissue with plump, atypical appearing fibroblasts. There is usually a prominent myxoid stroma with cystic change, diffuse fibrinoid necrosis, and variable fibrosis (especially in older lesions)

Elastofibroma Clinical ♦♦ Elastofibroma is an uncommon distinct lesion believed to be reactive; however, reports of clonal abnormalities raise the possibility that this is a true neoplasm; clustering of cases suggests a genetic predisposition ♦♦ The elderly are most commonly affected and there is a marked female predilection. Presentation is that of a slowgrowing, ill-defined mass attached to the periosteum of ribs ♦♦ Elastofibroma usually arises in the subscapular region and is bilateral in approximately 10% of cases ♦♦ There is no tendency for local recurrence or metastatic potential; surgery is curative

Macroscopic ♦♦ Elastofibroma has ill-defined lesional margins typically measure between 5 and 10 cm, and the cut surface has a dense fibrous appearance with infiltration of surrounding adipose tissue

Soft Tissue Tumors

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Microscopic

Desmoplastic Fibroblastoma

♦♦ Elastofibroma is composed of irregular bands of dense, hypocellular hyalinized collagenous fibrous tissue, with characteristically numerous thick, serrated, eosinophilic elastic fibers. There is often entrapped mature adipose tissue and a variably myxoid matrix

♦♦ Desmoplastic fibroblastoma is an uncommon neoplasm affecting mainly middle-aged males, with a male/female ratio of approximately 3:1. Patient usually presents with a painless subcutaneous nodule on the upper or lower extremities or back ♦♦ Tumors are typically hypocellular with spindled or stellateshaped fibroblasts/myofibroblasts embedded in a dense collagenous stroma. The lesion is usually well circumscribed but is unencapsulated ♦♦ Surgical excision is curative, and there is no propensity for local recurrence or metastasis

Fibroma of Tendon Sheath (Fig. 22.2) Clinical ♦♦ This entity is relatively common in adults and presents as a slow-growing, painless, hard nodule attached to the tendons of hands and feet (usually on the fingers) ♦♦ There is a peak age between 20 and 50 years and males are affected twice as commonly as females ♦♦ Up to 25% of cases recur after local excision

Macroscopic ♦♦ Well-circumscribed, firm, and rubbery nodules attached to tendons, 1–2 cm in size

Microscopic ♦♦ There is a lobular proliferation of bland-appearing fibroblasts/myofibroblasts within densely collagenized stroma and thin, slit-like vessels between the lobules ♦♦ Cellularity and mitosis vary with the duration of the lesion, with earlier lesions being more cellular and mitotically active

Differential Diagnosis ♦♦ Giant cell tumor of tendon sheath: these are more cellular and have less hyalinized stroma ♦♦ Nodular fasciitis: this is usually not attached to tendons, more cellular, and shows a zonation pattern ♦♦ Fibromatosis: this is typically not circumscribed or lobulated and lack slit-like vessels

Mammary-Type Myofibroblastoma Clinical ♦♦ Mammary-type myofibroblastoma occurs mainly in middleaged adults and shows a male predominance. Lesions are mostly subcutaneous. The most common locations include those along the putative “milk line,” mainly inguinal and groin areas ♦♦ Patients are usually asymptomatic and the lesion is commonly an incidental finding during a surgical procedure. If a mass is noted by the patient, it is usually painless ♦♦ Local excision is usually curative

Microscopy ♦♦ Mammary-type myofibroblastoma is morphologically identical to its breast counterpart ♦♦ It measures in average 6  cm, is well-circumscribed, and unencapsulated ♦♦ Morphologically, it is characterized by a proliferation of small, oval spindle cells, resembling those composing spindle cell lipoma, arranged in short fascicles. The background is collagenous with prominent hyalinized collagen bundles. Admixed mast cells are commonly present. Adipose tissue is frequently present in variable distribution and amounts. Vascularity is usually not prominent

Immunohistochemistry ♦♦ The neoplastic cells in mammary-type myofibroblastoma are characteristically positive for desmin and CD34

Differential Diagnosis ♦♦ Intradermal spindle cell lipoma: this is an ill-defined mass occurring within the dermis with no or minimal extension into the subcutaneous tissue ♦♦ Cellular angiofibroma: this usually has numerous prominent vessels showing hyalinization ♦♦ Fat-forming solitary fibrous tumors: these typically have frequent hemangiopericytoma-like vessels

Angiomyofibroblastoma Clinical ♦♦ Most cases of angiofibroblastoma arise in premenopausal adult females, and arise in the subcutaneous tissue of the pelFig.  22.2. Fibroma of tendon sheath: bland fibroblastic/­ viperineal region. The vulva is the most common site affected. myofibroblastic proliferation with slit-like vessels. Patients present with a painless, circumscribed mass

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♦♦ Angiomyofibroblastoma shows no potential for local recurrence or metastasis. Simple excision is curative

Microscopy ♦♦ Angiomyofibroblastoma is well demarcated with a thin fibrous pseudocapsule, and abundant, variably myxoid stroma ♦♦ The lesion is variably cellular and is composed of small round to spindled cells, which usually concentrate around vessels. Scattered binucleated and multinucleated tumor cells are noted. Occasionally, degenerative nuclear atypia is present. Fat is present in variable amounts

Immunohistochemistry ♦♦ Desmin is positive in all cases; however, expression of this marker may be decreased in tumors arising in ­postmenopausal women. Tumors commonly express estrogen and progesterone receptors. Actin is usually negative

Cellular Angiofibroma Clinical

Essentials of Anatomic Pathology, 3rd Ed.

sionally associated with diabetes mellitus (30–40% cases), and show marked preference for the posterior neck area; however, other locations may be affected ♦♦ Nuchal-type fibroma often recurs but has no potential for metastases

Microscopy ♦♦ Nuchal-type fibroma presents as an ill-circumscribed, dermal, and subcutaneous fibrous growth, with occasional entrapment of adnexa. It is composed of dense hypocellular, haphazardly arranged collagen ♦♦ Nuchal-type fibroma is histologically indistinguishable from Gardner fibroma

Solitary Fibrous Tumor (Fig. 22.3) Clinical ♦♦ Solitary fibrous tumor (SFT) was originally described as a neoplasm arising predominantly in the pleura; however, many isolated case reports as well as larger series have shown SFT to be a ubiquitous lesion arising anywhere in the body

♦♦ Cellular angiofibroma is a rare benign neoplasm that affects mainly middle-aged adults with no gender ­predilection. It commonly arises in the vulvovaginal and inguinoscrotal areas ♦♦ Patients present with a painless mass or hydrocele (males) ♦♦ Local recurrence occurs in rare cases. Simple excision is curative

Microscopy ♦♦ Cellular angiofibroma is usually well circumscribed and may have a thin fibrous pseudocapsule ♦♦ The neoplasm is variably cellular and composed of small spindle cells with oval nuclei, closely resembling the cells in spindle cell lipoma. Round vessels with some variation is size are present and have prominent hyalinized walls. Intratumoral adipose tissue may be present in variable amounts. Scattered mast cells are seen

Immunohistochemistry ♦♦ Cellular angiofibroma is variably positive for CD34 and almost always negative for desmin. Desmin expression may be seen in tumors arising in male patients

Differential Diagnosis ♦♦ Mammary-type myofibroblastoma: this has inconspicuous vessels, bundles of hyalinized collagen, and expresses desmin and CD34 in all cases ♦♦ Angiomyofibroblastoma: this typically contains abundant myxoid stroma and small thin-walled vessels ♦♦ Aggressive angiomyxoma: this is characterized by a myxoid stroma, small, thin-walled vessels, and bundles of myoid cells spinning off vessel walls

Nuchal-Type Fibroma Clinical ♦♦ Nuchal-type fibroma is a rare, benign fibroblastic ­proliferation that affects mainly young and middle-aged males, is occa-

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Fig.  22.3. Solitary fibrous tumor: “patternless” spindle cell n­ eoplasm with alternating hypercellular (A) and hypocellular (B) areas, and “HPC-like” vessels.

Soft Tissue Tumors

including visceral locations, peritoneum, retroperitoneum, ­mediastinum, and head and neck regions ♦♦ It usually affects adults, with no sex predilection, and often presents as a slowly enlarging mass located in deep soft tissues. It is rarely associated with systemic symptoms such as hypoglycemia and finger clubbing, and the clinical course is usually benign; however, malignant forms do exist

Microscopic ♦♦ SFTs are commonly large, well-circumscribed lobulated masses showing a “patternless” proliferation of spindled fibroblast-like cells with intervening collagen bundles. Typically, there is marked variation in cellularity within the lesion. The stroma is variably densely hyalinized and the neoplasm has a characteristic hemangiopericytoma-like vascular pattern ♦♦ The neoplastic cells are small, have ovoid nuclei, vesicular chromatin, inconspicuous nucleoli, and small to moderate amount of palely eosinophilic cytoplasm ♦♦ Variant: lipomatous SFT is characterized by a variable adipocytic component. Most components of this variant are benign ♦♦ Occasionally, cases of SFT demonstrating features suggestive of malignancy may be seen and include mitoses greater than 4 mitoses/10 high power fields, hypercellular areas, necrosis, and marked nuclear pleomorphism

Immunohistochemistry ♦♦ The neoplastic spindle cells are positive for CD34 and CD99, and occasionally express smooth muscle actin. They are usually negative for S-100 protein, desmin, and keratin

Pediatric Fibrous Tumors Fibrous Hamartoma of Infancy Clinical ♦♦ Fibrous hamartoma of infancy presents in the first 2 years of life, (usually patients are younger than 1 year of age) as a solitary freely movable, poorly circumscribed soft tissue mass (3–5 cm) involving the dermis and subcutis ♦♦ They are most common in the anterior or posterior axillary area, upper arm and shoulder regions, and show a marked male predilection ♦♦ Local excision is usually curative and recurrences are rare

Microscopic ♦♦ Fibrous hamartoma of infancy has an organoid growth pattern and is composed of three components in varying proportions: (1) myxoid foci with small round nests of undifferentiated spindle cells; (2) fascicles of myofibroblasts with wavy, tapering nuclei resembling fibromatosis; and (3) mature adipose tissue

Differential Diagnosis ♦♦ There is no real differential at this age and location with the typical morphologic appearance

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Myofibroma/Myofibromatosis ♦♦ Myofibroma and myofibromatosis are solitary or multicentric lesions, respectively, that form a morphologic continuum with myopericytoma and the so-called infantile hemangiopericytoma

Clinical ♦♦ There is a wide age range but infants and young children (less than 2 years of age) are commonly affected, with many cases being congenital; there is a male predominance. Most lesions in both adults and children are solitary (myofibroma) ♦♦ Solitary lesions affect superficial (dermal and subcutis) soft tissues of head and neck, trunk and extremities, or may arise in skeletal muscle and aponueroses. A small ­percentage of myofibroma may arise in the bones of the skull ♦♦ Multicentric cases may involve soft tissue and bone, and frequently arise in visceral locations, including gastrointestinal tract, lungs, kidneys, pancreas among others ♦♦ Although the etiology of myofibroma/myofibromatosis is unknown, the occurrence of familial cases is highly suggestive of a genetic component ♦♦ Lesions may show spontaneous regression. Patients are usually cured by simple excision, with rare recurrence. Visceral lesions may rarely lead to death, with pulmonary involvement carrying a particularly poor prognosis

Microscopic ♦♦ Most lesions are less than 3  cm, well-circumscribed, and unencapsulated with a lobulated or multinodular pattern. Lesions arising in deep locations and visceral sites tend to have less well-defined edges. Necrosis or cystic degenerations are common ♦♦ The neoplasm is characterized by a zonation pattern with whorling fascicles of bland appearing fibroblasts and myofibroblasts at the periphery of the nodules and primitive round cells around prominent hemangiopericytoma-like vessels toward the center of the nodules ♦♦ The stroma is often hyalinized and may have a pseudochondroid appearance with a light blue hue. Calcifications and necrosis are not uncommon. Mitoses are rare ♦♦ Characteristically, there is a prominent subendothelial proliferation of spindle cells with projection into vessels, which may mimic lymphovascular invasion; however, there is no association with metastasis

Immunohistochemistry ♦♦ Myofibroma/myofibromatosis is consistently positive for SMA and HHF-35, and negative for desmin, S-100 protein, EMA, and keratins

Fibromatosis Colli ♦♦ Fibromatosis colli is a fusiform, scar-like fibrous replacement of the distal sternocleidomastoid muscle that is seen in neonates usually by 2–4 weeks of age, with no gender predilection. It results in cervicofacial asymmetry (torticollis) ♦♦ It is often associated with abnormal positioning in utero and traumatic delivery, as well as with other musculoskeletal abnormalities

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♦♦ Microscopically, fibromatosis colli is characterized by a ­variably cellular fibroblastic/myofibroblastic proliferation embedded in a myxoid to collagenous stroma. Entrapment of skeletal muscle, evidenced by the presence of scattered multinucleated muscle fibers, is invariably present ♦♦ Most lesions will resolve with nonsurgical approaches, such as physical therapy and stretching exercises; however, approximately 10% of cases require surgical intervention. Most patients achieve complete cure if treated before 1 year of age

Juvenile Hyaline Fibromatosis ♦♦ This is an exceedingly rare, hereditary disorder of infants and children with an autosomal recessive pattern of inheritance. There is no sex predilection. Prognosis is dependent on the number, size, and location of nodules, as well as the patient’s overall functional status ♦♦ It is characterized by cutaneous, tumor-like lesions involving head and neck, gingiva, and periarticular soft tissue (leading to contractures), and bone, especially the skull, long bones and phalanges ♦♦ It is morphologically characterized by a proliferation of plump fibroblasts embedded in a hyaline nonfibrillary material. Neoplastic cells are negative for SMA and desmin ♦♦ Mutations of the gene encoding capillary morphogenesis protein 2 (CMG2) on chromosome 4q21 are implicated in the pathogenesis of this disorder

Inclusion Body Fibromatosis (Infantile Digital Fibromatosis) ♦♦ This is a distinct fibrous tumor that occurs on the dorsal aspect of fingers and toes of infants as a small nodule (usually measuring <2 cm), in the dermis and subcutis. Patients are usually less than 1 year of age and there is no gender predilection ♦♦ Histologically, inclusion body fibromatosis consists of an illdefined nodule of fascicles of myofibroblasts with characteristic scattered intracytoplasmic perinuclear round eosinophilic inclusions (trichrome and actin positive). There is no cytologic atypia and mitoses are scarce ♦♦ Surgery is the main treatment. Recurrence is seen in approximately 60% of cases and is directly correlated with the ­adequacy of the surgery

Lipofibromatosis Clinical ♦♦ Lipofibromatosis affects mainly infants and young children, with a male predominance. Patients usually present with an ill defined, slowly growing mass involving hands and feet ♦♦ Lipofibromatosis is composed of two main components in varying amounts: (1) adipose tissue and (2) spindle cells arranged in long fascicles traversing the fat component ♦♦ The major differential diagnosis is with fibrous hamartoma of infancy. Lipofibromatosis does not contain the myxoid nodules of primitive oval cells, which are characteristic of fibrous hamartoma of infancy

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Calcifying Aponeurotic Fibroma Clinical ♦♦ Calcifying aponeurotic fibroma is a rare, slowly growing fibroblastic proliferation that occurs in the distal extremities (palms and soles, wrist and ankle) of children and adolescents (median age 9 years), with a slight male predominance ♦♦ Clinical presentation is of a solitary, poorly defined, painless mass arising close to or involving aponeuroses and tendons ♦♦ There is a tendency for local recurrence in approximately half of the cases; however, the recurrence is neither aggressive nor destructive and therefore simple excision is usually the treatment of choice

Microscopic ♦♦ Tumors are usually less than 3  cm and have an infiltrative growth pattern, with entrapment of adjacent normal structures ♦♦ Histologically, they are characterized by islands of central calcification surrounded by small, round cells arranged in parallel arrays. Fascicles of fibroblasts/myofibroblasts are noted between these islands ♦♦ Osteoclast-like giant cells may be present around areas of calcification

Gardner Fibroma Clinical ♦♦ Gardner fibroma is an uncommon benign fibroblastic proliferation arising in infants, children, and teenagers, with no sex predilection. It affects mainly the paraspinal area, chest wall, flank, head and neck, and extremities ♦♦ Gardner fibroma is frequently associated with the development of desmoid-type fibromatosis and familial adenomatosous polyposis ♦♦ It usually presents as an asymptomatic plaque-like ­thickening in superficial and/or deep soft tissue locations

Microscopy ♦♦ Gardner fibroma is hypocellular and composed of ­haphazardly arranged thick collagen bundles with cleft-like spaces

Calcifying Fibrous Tumor Clinical ♦♦ Calcifying fibrous tumor is a benign fibrous neoplasm ­predominantly affecting children, but also less commonly arising in adults. There is no gender predilection ♦♦ Most patients seek medical attention due to a painless mass in the subcutaneous and deep soft tissues of extremities, trunk, and neck. Rarely, visceral locations may be affected ♦♦ An association with inflammatory myofibroblastic tumor (IMT) has been suggested; however, this association is still controversial

Microscopy ♦♦ Calcifying fibrous tumor is a hypocellular fibroblastic lesion characterized by a dense sclerotic background, variably

Soft Tissue Tumors

prominent chronic inflammatory component, including the formation of germinal centers, and variable amounts of calcifications, both dystrophic and psammomatous types. Examples with no calcifications do exist

Immunohistochemistry ♦♦ The spindle cells are positive for CD34. ALK is negative in calcifying fibrous tumor

Fibromatoses ♦♦ Fibromatoses are locally aggressive neoplasms that commonly recur; however, they do not metastasize. They are subclassified into two main superficial and deep types

Superficial Fibromatoses (Fig. 22.4) Clinical ♦♦ Superficial fibromatoses are small, slow growing, bland myofibroblastic proliferations, which most commonly arise in adults and are bilateral in approximately 50% of cases. They tend to involve superficial fascia or aponeurosis and may result in flexion contractures ♦♦ They are believed to be a multifactorial disease with a genetic component (familial cases) and association with trauma. In some cases, they may be associated with epilepsy, ­diabetes, or alcohol abuse ♦♦ Local excision, usually fasciectomy is the treatment of choice. Frequent local recurrences may occur; however, there is no potential for distant metastases

Microscopic ♦♦ Histologically, the lesions show variable cellularity and collagenization, depending on the growth phase. The lesions are usually ill defined and have infiltrative edges ♦♦ The early active growth phase is characterized by fascicles of plump fibroblasts/myofibroblasts. Although mitoses are not frequent, they may be seen. Older lesions show more

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hyalinized background and are hypocellular. Myxoid change may be present, and cartilaginous or osseous metaplasia occurs rarely

Variants ♦♦ Palmar fibromatosis (Dupuytren contracture): this involves the palmar surface of the hand or fingers of adults, more commonly in men and often results in flexion contractures. Cytogenetic studies have shown associated ­trisomies 7 and 8 ♦♦ Plantar fibromatosis (Ledderhose disease): this involves the feet, typically of children and young adults, and occurs more frequently in males. It tends not to result in contraction deformities. Local recurrence after surgery is common. Similar cytogenetic abnormalities to those present in palmar fibromatosis are seen in plantar fibromatosis ♦♦ Knuckle pad: this lesion comprises of bland cellular fibrous tissue in the dermis with overlying hyperkeratosis, no treatment is required ♦♦ Penile fibromatosis (Peyronie disease): Peyronie disease involves the shaft of the penis and results in pain and curvature of the penis on erection. It mainly affects men between 40 and 60 years of age, and is typically slow growing. The lesion is composed of hypocellular scar tissue with chronic inflammation and occasional metaplastic ossification. Surgical excision is the only effective treatment

Deep (Desmoid) Fibromatoses (Fig. 22.5) Clinical ♦♦ Desmoid fibromatosis arises in three clinical settings: sporadic, associated with familial adenomatous polyposis (FAP), and multicentric or familial types ♦♦ They are described on the basis of their anatomic location as follows: extraabdominal (60%), abdominal wall (25%), and intraabdominal (15%) ♦♦ The sporadic group of tumors are usually extraabdominal, commonly involving limb girdles and proximal extremities, as well as head and neck. Abdominal wall tumors usually occur on the anterior abdominal wall in women in the peripartum period, but may also arise in a preceding scar (e.g., cesarean section). Patients with FAP tend to have intraabdominal tumors, particularly involving the mesentery ♦♦ Peak incidence is between 15 and 40 years of age, with females being twice more commonly affected than males ♦♦ Desmoid fibromatosis requires wide complete excision with or without radiotherapy, yet still show a recurrence rate ranging from 25 to 80% ♦♦ Mutations in the APC gene (chromosome 5q) are seen in patients with FAP or familial desmoids and in some sporadic cases

Macroscopic Fig. 22.4. Plantar fibromatosis: long fascicles of myofibroblasts with tapered nuclei.

♦♦ Grossly, desmoid tumors are poorly circumscribed, infiltrative large lesions (>5 cm) with a pale, whorled and fibrous cut surface, and usually involve skeletal muscle and/or intraabdominal organs

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♦♦ The stroma is variably collagenous and sometimes focally myxoid, with thick-walled, elongated, compressed blood vessels and peripheral lymphoid aggregates, resembling nodular fasciitis. This phenomenon is particularly more common in tumors arising in the pelvis and mesentery. Keloidal hyalinization may also be present, especially in intraabdominal lesions. Cartilaginous or osseous metaplasia occurs rarely ♦♦ Tumor edges are often ill-defined and entrapment of adjacent structures is commonly seen

Immunohistochemistry ♦♦ Tumor cells express actin in most cases, and occasionally desmin and S-100 protein. b-catenin expression (nuclear positivity) due to APC mutations may also be identified in approximately 70% of cases

Differential Diagnosis ♦♦ Nodular fasciitis: looser stromal arrangement with microcystic degeneration, zonation pattern, inflammation, and hemorrhage ♦♦ Cellular neurofibroma and low grade malignant nerve sheath tumor: these neural tumors consist of wavy, elongated nuclei and show diffuse expression of S-100 protein and is negative for b-catenin stain

Inflammatory Myofibroblastic Tumor Clinical ♦♦ IMTs are most common in childhood and adolescence; however, the age range is quite wide. Females are slightly more affected ♦♦ The most common sites of involvement are the lungs and abdominal cavity (mesentery and omentum), but IMTs have been described in nearly all sites in the body ♦♦ Clinical presentation is quite variable with symptoms most often relating to the site of origin of the tumor. Occasionally, systemic symptoms such as weight loss, fever, and hematologic abnormalities may be seen ♦♦ In approximately one-quarter of cases, there is local recurrence, which is related to the location and extent of resection, and multinodularity. Metastases in cases that do not show definite features of malignancy are rare (<5% of cases); however, morphologic features are not reliable to predict the development of metastatic disease. Because of this potential of frank malignant transformation as well as metastasis, IMTs are best regarded as low grade sarcomas

Microscopy Fig.  22.5. Desmoid fibromatosis: long fascicles of fibroblasts/ myofibroblasts (A). Occasionally, keloidal hyalinization is noted (B). Intraabdominal desmoid fibromatosis often shows “fasciitis-like” features in some areas (C).

Microscopic ♦♦ Desmoid tumors are cellular neoplasms consisting of long fascicles of bland-appearing fibroblasts and myofibroblasts. Cellularity and mitotic activity are variable but usually low

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♦♦ The classic appearance of IMT is that of a fascicular spindle cell proliferation of plump fibroblasts and ­myofibroblasts with an associated prominent inflammatory infiltrate including mainly plasma cells but also lymphocytes and eosinophils ♦♦ The stroma is variably loosely myxoid or collagenous ♦♦ Frank malignant transformation is characterized by the presence of highly atypical and hyperchromatic large cells, as well as frequent mitoses

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♦♦ Scattered large ganglion-like cells may be seen throughout the neoplasm

Immunohistochemistry ♦♦ The spindle cells of IMT show variable positivity for actin, desmin, and occasionally keratin ♦♦ ALK-1 protein is immunohistochemically detected in approximately 30% of cases, correlates with rearrangements of the ALK gene, and is more commonly seen in tumors arising in childhood

Cytogenetics ♦♦ Rearrangement of ALK gene on chromosome 2p is ­characteristically present in a subset of IMTs

Malignant Low Grade Myofibroblastic Sarcoma Clinical

Fig.  22.6. Fibrosarcoma: note the herringbone pattern of the long fascicles of spindle cells.

♦♦ Low grade myofibroblastic sarcoma occurs predominantly in young to middle-aged adults, with a slight male predilection. It has a wide anatomic distribution, but is most common in the head and neck region, and is usually deep-seated ♦♦ Local recurrence is common; however, metastases are rare and may occur after long periods of time after initial diagnosis

♦♦ The prognosis of adult fibrosarcoma is directly related to morphologic tumor grade, tumor size, and depth of the lesion. Tumor shows a recurrence rate of 12–79% and metastatic rate of 9–63%. Most common metastatic sites include lungs and bones. Five-year survival rate is between 39 and 54%

Microscopy ♦♦ Histologically, the lesions are composed of hypercellular fascicles of elongated myofibroblasts, with at least mild nuclear atypia and often diffuse infiltration of skeletal muscle ♦♦ Tumors are variably positive for desmin, a-smooth muscle actin, and CD34, and negative for S-100 protein, keratins, and caldesmon

Infantile and Adult Fibrosarcoma (Fig. 22.6) Clinical ♦♦ Adult and infantile fibrosarcoma are histologically similar; however, they have distinct clinicopathologic, prognostic and genetic features. Although infantile fibrosarcoma is a well defined entity, adult fibrosarcomas are rare and difficult to diagnose, being mostly a diagnosis of exclusion ♦♦ Infantile fibrosarcoma: almost all cases arise within the first year of life, and are frequently congenital. There is a slight male predominance. The most commonly affected sites include distal extremities, trunk, and head and neck regions. Patients usually present with a painless, fast growing soft tissue mass ♦♦ Infantile fibrosarcoma may show spontaneous regression as well as prominent response to surgery and chemotherapy. Recurrence rate is between 5 and 50%, while metastases are rare. Mortality rate is approximately 15% ♦♦ Adult fibrosarcoma: this affects mostly middle-aged and older adults, with no gender predilection. Tumors present as a painful mass. It also may involve extremities, trunk, and head and neck

Macroscopic ♦♦ Infantile fibrosarcoma is usually a large poorly defined, lobulated mass with infiltrative edge. The cut surface is tan and soft with areas of myxoid and cystic degeneration, hemorrhage, and necrosis ♦♦ Adult fibrosarcoma is often a well-circumscribed large deep seated mass, with a tan and firm cut surface with hemorrhage and necrosis

Microscopic ♦♦ Infantile fibrosarcoma is a highly cellular neoplasm showing intersecting fascicles of primitive-appearing spindle or oval cells. There is minimal pleomorphism and mitoses are common. Stromal collagen is variable. Necrosis, hemorrhage, and dystrophic calcifications may be present ♦♦ Adult fibrosarcoma is composed of dense fascicles of spindle cells forming a characteristic herringbone growth pattern. Cells often have hyperchromatic nuclei and prominent nucleoli. Mitoses are frequent. Necrosis and hemorrhage are common ♦♦ Areas similar to fibrosarcoma may be encountered in other tumors such as dermatofibrosarcoma protuberans and solitary fibrous tumor; however, areas of typical morphology are often present and help in the differential diagnosis

Immunohistochemistry ♦♦ Infantile and adult fibrosarcoma shows variable, nonspecific positivity for actin, desmin, and cytokeratin

Cytogenetics ♦♦ Infantile fibrosarcoma is characterized by a t(12;15)(p13;q25), juxtaposing the ETV6 gene on chromosome 12 with the NTRK3 gene on chromosome 15. This is the same abnormality encountered in congenital mesoblastic nephroma

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♦♦ Adult fibrosarcoma is characterized by complex karyotypic abnormalities

Differential Diagnosis ♦♦ Fibrsoarcoma in adults has a wide differential diagnosis and is a diagnosis of exclusion, with characteristic morphology and lack of staining for multiple markers; the differential includes desmoid fibromatosis (less cellular), low grade myofibroblastic sarcoma, malignant peripheral nerve sheath tumor and synovial sarcoma (more stromal collagen; t(X;18) translocation)

Myxoinflammatory Fibroblastic Sarcoma ♦♦ Myxoinflammatory fibroblastic sarcoma is a rare sarcoma affecting middle-aged males and females. It shows predilection for the distal extremities, in particular hands and feets. Patients present with a slowly growing, painless mass in the dermis and subcutaneous tissue ♦♦ Morphologically, the neoplasm shows alternating hypocellular, myxoid areas and hypercellular, more collagenized areas. In addition, there is a prominent mixed inflammatory infiltrate and rare atypical cells that have large nuclei and prominent eosinophilic nucleoli, resembling Reed–Sternberg (RS) cells. Areas containing macrophages filled with mucin are also present. The vascularity of myxoinflammatory fibroblastic sarcoma is inconspicuous ♦♦ The large RS-like cells do not show any specific immunophenotypic profile, and are negative for CD30 and CD15, as well as for keratins, desmin, and S-100 protein ♦♦ The rate of local recurrence is as high as 70%; however, metastases are very rare (<2% of cases)

Myxofibrosarcoma (Fig. 22.7) Clinical ♦♦ Myxofibrosarcoma is the most common sarcoma of older adults and affects predominantly older adults (>60 year of age), with a slight male predominance. Tumors arise more commonly on limbs, in particularly lower limbs, and limb girdles ♦♦ Patients usually present with a subcutaneous or deep painless, slowly growing mass ♦♦ Surgery is the main treatment of myxofibrosarcoma, followed by radiotherapy to prevent local recurrence. The rate of local recurrence (50–60%) is directly related to the completeness of resection; while distant metastasis (20–35%) correlates with tumor depth and histologic grade ♦♦ Most common metastatic sites include lungs and bones

Fig. 22.7. Myxofibrosarcoma: alternation of hypercellular and myxoid areas (A) and presence of curvilinear vessels (B) are diagnostic of this entity. matrix, while high grade myxofibrosarcoma has frequent hypercellular areas, nuclear atypia, and necrosis ♦♦ Curvilinear vessels are typically present and readily identified within the myxoid areas. Neoplastic cells tend to converge and accumulate around these vessels ♦♦ Nuclear pleomorphism is characteristically present as well as frequent mitoses, including atypical forms and necrosis. Within the myxoid areas, pseudolipoblasts are noted and are characterized by macrophages containing mucin in the cytoplasm, pushing their nuclei to the side

Macroscopic

Immunohistochemistry

♦♦ The tumor presents as a subcutaneous (two-third cases) or deep (one-third cases) ill-defined, lobulated mass with poorly defined margins and variable myxoid areas. Necrosis and hemorrhage are common

♦♦ Neoplastic cells are rarely positive for SMA, desmin, and keratins, but negative for S-100, caldesmon, and myogenin

Microscopy ♦♦ Myxofibrosarcoma shows a lobulated architecture with nodules demonstrating alternating hypocellular and hypercellular areas. Low grade lesions show predominant myxoid

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Differential Diagnosis ♦♦ Pleomorphic liposarcoma: this is characterized by pleomorphism and large, atypical lipoblasts with indented nuclei and sharply punched-out cytoplasm vesicles ♦♦ Pleomorphic leiomyosarcoma: this shows fascicles of ­spindled cells with prominent pleomorphism; this neither

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contains myxoid areas nor has curvilinear vessels; neoplastic cells are positive for SMA, desmin, and caldesmon ♦♦ Pleomorphic rhabdomyosarcoma: this is characterized by scattered large pleomorphic rhabdomyoblasts, which are positive for desmin and myogenin

Low Grade Fibromyxoid Sarcoma ♦♦ Low grade fibromyxoid sarcoma is rare, occurs mostly in young adults with a peak age between 30 and 50 years, and affects mainly limbs and limb girdles. Most neoplasms are deeply seated, well-circumscribed, and painless ♦♦ Recurrence (60%) and metastasis (6–50%) may occur many years after initial diagnosis, and patients require

long clinical followup. Metastases are commonly seen in the lungs ♦♦ The tumor is composed of swirling fascicles of bland, uniform spindled fibroblasts and myofibroblasts with a variably dense fibrous and myxoid hypovascular stroma. The tumor cells are small with minimal nuclear pleomorphism and rare mitoses ♦♦ Some cases may have giant hyalinized rosettes (formerly known as hyalinizing spindle cell tumor with giant rosettes) ♦♦ Most cases are positive for EMA (scattered cells), and negative for actin, desmin, CD34, and S-100. A t(7;16)(q34;p11) translocation has recently been found to be associated with these lesions

FIBROHISTIOCYTIC TUMORS Classification of Fibrohistiocytic Tumors

Macroscopic

♦♦ See Table 22.4

♦♦ Grossly, deep variants are well-circumscribed, pseudoencapsulated and usually measure greater than 4  cm. Central ­hemorrhage or cystic change is occasionally present

Benign Benign Fibrous Histiocytoma (Fig. 22.8) Clinical ♦♦ Benign fibrous histiocytomas may be subdivided into two main types depending on their location −− Cutaneous type (dermatofibroma – see Chapter 18) −− Deep type (<5%), arising within subcutis, skeletal muscle or abdominal cavity ♦♦ The deep types principally arise in adults, between 20 and 40 years of age with a slight male predominance. The commonest sites of involvement are the lower limbs and head and neck regions. Up to 20–30% may recur after local excision

Fig. 22.8. Benign fibrous histiocytoma: polymorphous storiform spindle cell proliferation with peripheral entrapment of ­collagen fibers.

Microscopic ♦♦ Benign fibrous histiocytoma shows a storiform growth pattern consisting of short fascicles of polymorphous spindle cells with elongated or plump vesicular nuclei. Scattered foamy macrophages and giant cells are frequently present ♦♦ Mitoses are often present, but usually at a frequency of <5/10 HPF ♦♦ The stroma may be myxoid, focally hyalinized or hemorrhagic with hemosiderin deposition and admixed inflammatory cells or occasional foci of necrosis. Entrapment of peripheral hyaline collagen is noted at the edge of the lesion

Variants of Benign Fibrous Histiocytoma ♦♦ Aneurysmal fibrous histiocytoma: this occurs mainly in young and middle aged adults with a slight female predominance and may grow rapidly to a large size. Histologically, there are numerous blood-filled cavernous cavities that lack an endothelial lining in a background of cellular fibrous histiocytoma with abundant hemosiderin deposition and giant cells ♦♦ Atypical fibrous histiocytoma: this is a clinically, nondistinct variant with atypical cytological features including bizarre hyperchromatic giant cells and histiocytes. In addition, there are usually an increased number of mitoses, including atypical forms. They are mainly dermal, but occasionally extend into the subcutis. Although they may recur locally, they very rarely metastasize ♦♦ Epithelioid fibrous histiocytoma: neoplastic cells are epithelioid with abundant eosinophilic cytoplasm ♦♦ Cellular variant of benign fibrous histiocytoma: this variant accounts for 5% of cases and may be mistaken for malignancy. It is typically relatively monomorphic and fascicular but retains its circumscription. The importance in recogniz-

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ing this subtype lies in their increased risk of recurrence (up to 30% of cases locally recur)

Immunohistochemistry ♦♦ There are no particular helpful markers for benign fibrous histiocytoma, although IHC can be helpful in excluding other lesions in the differential diagnosis

Differential Diagnosis ♦♦ Nodular fasciitis: this consists of loosely arranged fascicles of myofibroblasts in a myxoid matrix ♦♦ Neurofibroma: this is composed of more uniform thick wavy collagen bundles which in turn are composed of tumor cells with slender wavy nuclei that are S-100 protein positive ♦♦ Leiomyoma: these have a more distinct fascicular pattern; the tumor cells have blunt-ended plumper nuclei and express actin and desmin ♦♦ Dermatofibrosarcoma protuberans (DFSP): there is more extensive dermal involvement with a uniform cellular population lacking giant cells, inflammatory cells, and xanthoma cells. The growth pattern is infiltrative and the cells are positive for CD34 and negative for Factor XIIIa

Juvenile Xanthogranuloma Clinical ♦♦ Juvenile xanthogranuloma (JXG) usually develops between 6 and 24 months of age; 20% are congenital and 15% of cases arise in adults. There is no sex predilection, and they are often multiple ♦♦ The head and neck region is commonly affected, and the lesions are usually cutaneous, with 5% occurring in deep soft tissue or other organs (e.g., eye) ♦♦ Lesions are usually self-limited and occasionally undergo spontaneous involution

Microscopic ♦♦ JXG consists of a diffuse, uniform population of histiocytes with eosinophilic, vacuolated, or xanthomatous (lipidized) cytoplasm. There is a variable admixture of Touton giant cells, lymphocytes, eosinophils, and plasma cells. The overlying epidermis tends to be atrophic and rarely ulcerated, but is usually uninvolved by tumor ♦♦ Mitotic figures are commonly seen and may be frequent

Differential Diagnosis ♦♦ Langerhans cell histiocytosis: this consists of a less cohesive population of S-100 positive and CD1a positive Langerhans cells and lacks Touton giant cells ♦♦ Benign fibrous histiocytoma: this has a storiform growth pattern with a more polymorphous cell population

Essentials of Anatomic Pathology, 3rd Ed.

may be multiple, and 20% are associated with a destructive arthritis, but they typically have a benign self-limiting course

Microscopic ♦♦ Reticulohistiocytoma consists of a well-circumscribed, ­uniform population of multinucleated histiocytes within the dermis with abundant, ground-glass, eosinophilic cytoplasm and peripherally located nuclei ♦♦ There are admixed mononucleate histiocytes, epithelioid cells, and mixed inflammatory cells, and in contrast to xanthogranulomas, the giant cells contain diastaseresistant PAS-positive material in the cytoplasm of the giant cells

Differential Diagnosis ♦♦ Pleomorphic sarcoma: this will have more cytological atypia, nuclear pleomorphism, and abnormal mitoses ♦♦ Malignant melanoma: this will show more cytological atypia and pleomorphism and expression of S-100 protein and HMB 45 within tumor cells

Xanthoma ♦♦ Xanthomas are reactive proliferations of histiocytes that contain intracytoplasmic lipid and are frequently associated with hyperlipidemia ♦♦ They usually occur in skin and subcutis and may involve tendons or synovium ♦♦ The various types are related to the underlying lipid disorder and anatomic location, i.e., eruptive, tuberous, tendinous, plain xanthomas and xanthelasmas

Giant Cell Tumor of Tendon Sheath (Fig. 22.9) Clinical ♦♦ Giant cell tumor of tendon sheath is a very common lesion that predominantly affects the digits of the hand, and presents as a painless, slow-growing mass fixed to the underlying tendon ♦♦ Lesions are usually associated with a tendon, bursa, or ­synovium of joints ♦♦ There is a peak incidence between 20 and 40 years and a female predominance. Up to 30% of cases may recur after local excision

Microscopic

Reticulohistiocytoma Clinical

♦♦ The tumor is composed of sheets and nests of round, mononuclear cells with varying numbers of multinucleated giant cells, xanthomatous foamy macrophages and mitotic activity ♦♦ Hemosiderin-laden macrophages and scattered chronic inflammatory cells may also be seen

♦♦ This is an uncommon cutaneous lesion that affects young or middle age adults with a female predominance ♦♦ It presents as a slow growing, solitary nodule (<1 cm) on the upper body or head and neck region. Less commonly they

♦♦ Clonal abnormalities involving the short arm of ­chromosome 1 have been described in many cases of giant cell tumor of tendon sheaths

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Cytogenetics

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Cytogenetics ♦♦ Diffuse-type giant cell tumor is a clonal process characterized by near- or pseudodiploid karyotype. Abnormalities of chromosomes 5 and 7 have been described in these lesions, as well as rearrangements of the 1p11-13 region

Dermatofibrosarcoma Protuberance (Fig. 22.10) Clinical ♦♦ DFSP involves the dermis and subcutaneous tissue of adults, between 20 and 50 years of age, without any sex or racial predilection. The most common sites of involvement are on the trunk, groin, and lower extremities. They are slow-growing tumors ♦♦ Local recurrences are very common (30–60%) and therefore complete local excision is required. Metastasis is very rare, but may be seen in lesions showing focal or diffuse fibrosarcomatous transformation

Fig. 22.9. Giant cell tumor of tendon sheath: mononuclear and rare multinucleated cells show similar nuclear morphology, and are admixed with chronic inflammatory cells and foamy macrophages.

Microscopic

Diffuse-Type Giant Cell Tumor Clinical

♦♦ Grossly DFSP may appear as a plaque-like lesion or a nodule (often as a solitary, protuberant whitish mass). The average size is 5 cm, but occasionally they can measure greater than 20 cm

♦♦ Diffuse-type giant cell tumor affects young adults and shows a slight female predominance ♦♦ Most patients present with pain, swelling, and limitation of joint movement. Hemorrhagic effusions may also be present. Lesions may arise in intraarticular sites, most commonly the knee, or less frequently, extraarticular locations, such as knee region, thigh, and foot ♦♦ Rare cases of malignant transformation have been identified ♦♦ Diffuse-type giant cell tumor has a propensity for local destructive recurrence (up to 50% of cases), which is correlated with the completeness of resection of the initial tumor. Metastases in benign cases have been reported but are extremely rare. Malignant cases are aggressive and may give rise to lung metastases

Microscopic ♦♦ Diffuse-type giant cell tumor is often a large mass with infiltrative edges ♦♦ Tumors are composed of four main cell types: small mononuclear cells with histiocyte-like cytomorphology, large cells with abundant eosinophilic cytoplasm and a rim of hemosiderin granules scattered to rare osteoclast-like giant cells, and foamy macrophages in clusters ♦♦ Areas of pseudovascular degeneration may be seen in a subset of cases. Scattered inflammatory cells are often present. Mitoses are common and easily identified ♦♦ Malignant cases are characterized by necrosis, nuclear atypia, presence of spindle cells and myxoid changes ♦♦ Neoplastic cells are positive for CD68 and CD163 (histiocytic markers). Scattered desmin-positive dendritic cells are present in approximately 50% of cases

Macroscopic ♦♦ DFSP is a poorly circumscribed dermal-based lesion with diffusely infiltrative margins and extension into subcutanous tissue with infiltration and isolation of fat lobules ­(honeycoming growth pattern); however, skeletal muscle involvement is uncommon ♦♦ The tumor is usually separated from the overlying ­epidermis by a Grenz zone and contains entrapped adnexal structures ♦♦ DFSP is composed of a uniform population of fibroblastlike spindle cells with a monomorphous ­storiform growth pattern. Neoplastic cells show minimal hyperchromasia and pleomorphism ♦♦ Foam cells, Touton giant cells, and/or granular cells are rarely present. DFSPs typically have a low mitotic index with usually <5 mitoses per 10 HPF. Myxoid or giant cell fibroblastoma-like areas may be present

Variants ♦♦ Bednar tumor (5% of cases): DFSP with heavy melaninpigmented dendritic spindle cells; this variant is more common in black patients ♦♦ Fibrosarcomatous variant: Foci of herringbone growth pattern, similar to fibrosarcoma with an increased mitotic rate and a significantly increased risk of metastasis (15%) ♦♦ DFSP with myoid nodules: DFSP with nodules and bundles of myofibroblasts, with myoid phenotype

Immunohistochemistry ♦♦ The neoplastic cells are positive for vimentin and CD34, and negative for desmin. They are also actin negative (except for

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Fig. 22.10. Dermatofibrosarcoma protuberans: monomorphic storiform proliferation with diffuse infiltration (“honeycombing”) of subcutaneous adipose tissue (A, H&E stain; B, CD34 stain). Occasionally, admixed pigmented dendritic cells are noted (C, Bednar tumor). Fibrosarcomatous, or higher grade, areas show herringbone pattern, reminiscent of fibrosarcoma (D). myofibroblasts in myoid variant) and S-100 negative (except in dendritic cells of the Bednar tumor variant)

Cytogenetics ♦♦ Ring chromosomes derived from portions of chromosomes 17 and 22 are frequently present in DFSP

Differential Diagnosis ♦♦ Benign fibrous histiocytoma: this is usually of smaller size, composed of a more heterogeneous cell population (negative for CD34) with lipid and hemosiderin deposition, and contains entrapped hyalinized collagen ♦♦ Classic fibrosarcoma: this is a deeply seated tumor with greater mitotic activity, and no evidence of classic DFSP

Plexiform Fibrohistiocytic Tumor ♦♦ Plexiform fibrohistocytic tumor is a rare mesenchymal neoplasm occurring in children and young adults with a female predominance. It usually involves the subcutis of the upper extremities and may extend to the dermis and into skeletal muscle

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♦♦ Wide local excision is advised as they are prone to recur locally (reported in up to 35% of cases) and may metastasize in rare cases ♦♦ Tumors consist of a plexiform proliferation of fibroblastlike, histiocyte-like, and multinucleated giant cells (all in variable amounts) with a collagenous stroma between the nodules ♦♦ There is usually mild cellular atypia but no significant cellular pleomorphism. Mitotic activity is usually in the range of 3/10 HPF. Vascular invasion is present in 20% of cases

Atypical Fibroxanthoma Clinical ♦♦ Atypical fibroxanthoma (AFX) is a superficial (cutaneous) tumor with an indolent course that arises in actinically damaged skin of the head and neck in older adults. It presents as a rapidly enlarging, solitary nodule, occasionally with ulceration ♦♦ Complete surgical excision provides a uniformly good prognosis, with local recurrences rare

Soft Tissue Tumors

Microscopic ♦♦ AFX usually measures 1–2 cm and is often circumscribed, but may be infiltrative at the edges; polypoid lesion in the dermis may have an epidermal collarette ♦♦ Most lesions have a Grenz zone but some may ulcerate the epidermis. Lesions do not extend into subcutaneous adipose tissue ♦♦ Tumors are composed of a haphazard, storiform, or fascicular arrangement of variably sized tumor cells with pleomorphic bizarre nuclei and abundant eosinophilic or amphophilic cytoplasm, and occasional Touton giant cells. Frequent mitotic figures are present. Stroma may be variably collagenized and/or myxoid

Immunohistochemistry ♦♦ Immunohistochemistry is very helpful in the diagnosis of AFX, by excluding other lesions in the differential diagnosis ♦♦ Tumor cells are vimentin positive, and 50% show positivity for actin; they should be negative for S-100 protein, HMB 45, desmin, and cytokeratin

Differential Diagnosis ♦♦ Spindle cell squamous cell carcinoma: this may be associated with epidermal dysplasia, may extend into subcutis and neoplastic cells, and show cytokeratin positivity ♦♦ Malignant melanoma: junctional component may be identified, neoplasm may extend into adipose tissue, S-100 protein and HMB 45 are often positive ♦♦ Leiomyosarcoma: this is usually a deep-seated large mass and cells express desmin and smooth muscle actin ♦♦ Pleomorphic sarcoma: extensive involvement of the subcutis, invasion of fascia and muscle, necrosis and vascular invasion are seen in pleomorphic sarcoma

Giant Cell Tumor of Soft Tissue Clinical

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cystic changes (similar to aneurismal bone cyst), stromal hemorrhage, and clusters of foamy macrophages ♦♦ Vascular invasion is present in 30% of tumors and does not correlate with malignancy

Malignant Undifferentiated Pleomorphic Sarcoma (Fig. 22.11) Clinical ♦♦ Undifferentiated pleomorphic sarcoma is a “wastebasket” for tumors that neither morphologically fit into a ­recognizable category nor show a specific line of ­differentiation with the aid of ancillary studies. They represent a group of tumors previously known as so-called “malignant fibrous histiocytoma” (MFH) ♦♦ These neoplasms are further classified as “undifferentiated high grade pleomorphic sarcoma,” “undifferentiated pleomorphic sarcoma with giant cells,” and ­“undifferentiated pleomorphic sarcoma with prominent inflammation” ♦♦ The prognosis of undifferentiated pleomorphic sarcoma is poor with a 5-year survival <50% ♦♦ Undifferentiated high grade pleomorphic sarcoma: storiform growth pattern of short fascicles of fibroblasts/myofibroblasts with bizarre pleomorphic nuclei and cytoplasm, atypical mitoses and admixed giant cells and spindle cells ♦♦ Undifferentiated pleomorphic sarcoma with giant cells: these usually occur in older patients in the deep soft tissue of the lower extremities and have a poor prognosis. Morphologically, it consists of conventional pleomorphic sarcoma with prominent osteoclast-like giant cells ♦♦ Undifferentiated pleomorphic sarcoma with prominent inflammation: this is composed of large cells with atypical nuclei, a prominent inflammatory component including neutrophils and eosinophils, and areas of more conventional pleomorphic sarcoma

♦♦ Giant cell tumor of soft tissues occurs primarily in young to middle-aged adults, with no gender predilection ♦♦ Patients usually present with a solitary painless mass in the dermis and/or subcutaneous tissue. Most commonly, tumors arise in the upper and lower extremities, followed by trunk, and head and neck regions ♦♦ Tumors may occasionally recur locally (approximately 10% of cases) but do not show potential for distant metastases

Microscopic ♦♦ Giant cell tumor of soft tissue shows a multinodular growth pattern with tumor nodules separated by fibrous septae containing hemosiderin-laden macrophages ♦♦ Tumor nodules are composed primarily of frequent multinucleated giant cells and scattered small mononuclear cells with cytomorphology identical to the multinucleated cells. The stroma demonstrates a rich vascular component ♦♦ Mitoses are frequent; however, nuclear atypia is not present. Metaplastic bone formation at the periphery of the lesion is noted in approximately 50% of cases. Other changes include

Fig. 22.11. Undifferentiated pleomorphic sarcoma: pleomorphic spindle and epithelioid neoplasm showing no particular lineage differentiation.

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LIPOMATOUS TUMORS Classification of Lipomatous Tumors ♦♦ See Table 22.5

Benign Lipoma (Fig. 22.12) Clinical ♦♦ Lipomas are the most common benign mesenchymal neoplasms and are composed of mature adipose tissue. They usually arise in subcutaneous tissue in adults between 40 and 60 years of age and show no sex predilection ♦♦ Lipomas may occur anywhere, but are most frequent in the trunk and proximal limbs. Although most lipomas arise in subcutaneous tissue, rare cases occur in deeper locations, such as intramuscular (a.k.a. intramuscular lipoma), subsynovial connective tissue (a.k.a. lipoma arborescens), bone surface (a.k.a parosteal lipoma), abdominal cavity, and retroperitoneum ♦♦ Most lesions are solitary, but 2–3% of patients have multiple lipomas. Patients usually present with a painless mass ♦♦ Local recurrence after excision is rare (1–2%), except for intramuscular lipoma, which carries a much higher recurrence rate. Lipomas do not show potential for malignant transformation or metastases

Macroscopic ♦♦ Lipomas are typically well-circumscribed, thinly encapsulated and lobulated with a homogenous yellow fatty cut surface. Tumor size is variable, but they are rarely >10 cm. The superficially located tumors are often smaller than the deeply seated tumors

Microscopic ♦♦ Histologically, lipomas are composed of mature adipocytes with intervening thin fibrous septa. There is minimal varia-

tion in adipocytes size and shape, and no cytologic atypia or hyperchromasia ♦♦ Myxoid change or fibrosis may be present to variable degrees, and when prominent the lesion can be classified as myxolipoma or fibrolipoma, respectively ♦♦ Intramuscular lipoma shows an infiltrative growth pattern with entrapment of individual skeletal muscle fibers, creating a characteristic “checkerboard” appearance ♦♦ Secondary microscopic fat necrosis and hemorrhage may also be present. Metaplastic bone and cartilage formation may also be seen

Cytogenetics ♦♦ The vast majority of lipomas show one of the following cytogenetic abnormalities: aberrations involving 12q13-15, aberrations involving 6p21-23, and loss of material from 13q

Differential Diagnosis ♦♦ Myxoma: this is a hypocellular lesion without adipose tissue and with a prominent myxoid matrix ♦♦ Intramuscular angioma: this is characterized by the presence of an intramuscular irregular vascular proliferation, often accompanied by an extensive adipocytic component ♦♦ Atypical lipomatous tumor/well-differentiated liposarcoma (see below): this is composed of scattered lipoblasts and adipocytes of variable size with atypical, hyperchromatic nuclei, and has a distinct cytogenetic profile ♦♦ Myxoid liposarcoma (MLS) (see below): this contains small lipoblasts, a characteristic vascular pattern and a distinct cytogenetic profile, which helps in differentiating lipomas from myxoid liposarcomas

Angiolipoma (Fig. 22.13) Clinical ♦♦ Angiolipoma is a common, painful, subcutaneous lesion that typically arises in young adults with a male predominance ♦♦ Angiolipomas commonly occur in the forearm, followed by the trunk and upper arm, and are multiple in 60% of cases (<5% are familial) ♦♦ They do not locally recur once completely excised, or undergo malignant transformation

Microscopic ♦♦ Angiolipomas are well-circumscribed lesions composed of mature adipose tissue and small vessels, which are typically more prominent at the periphery of the lesion; however, the amount of adipose tissue and small vessels is quite variable ♦♦ The vessels in angiolipomas are often capillary sized with fibrin microthrombi

Differential Diagnosis Fig.  22.12. Lipoma: neoplasm composed of mature adipose tissue.

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♦♦ Lipoma: conventional lipomas lack the prominent, small vessels with fibrin thrombi

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Fig.  22.14. Spindle cell lipoma: small primitive appearing s­ pindle cells with admixed mast cells and hyaline collagen.

Microscopic ♦♦ Spindle cell lipomas are composed of a variable admixture of mature fat and uniform small, slender spindle cells. They often have a variably myxoid matrix and contain scattered mast cells. Birefringent, eosinophilic, hyaline collagen fibers are also present ♦♦ Pleomorphic lipomas show variable amounts of ­multinucleated giant cells (“floret” cells)

Cytogenetics ♦♦ 13q and 16q abnormalities have been identified in some cases

Differential Diagnosis Fig. 22.13. Angiolipoma: mature adipose tissue with a vascular component of small vessels containing fibrin thrombi (A, B). ♦♦ Intramuscular angioma: this is characterized by ­intramuscular location and poor circumscription ♦♦ Kaposi sarcoma and angiosarcoma: these two lesions are typically larger, not encapsulated, and do not contain adipocytes or microthrombi

Spindle Cell/Pleomorphic Lipoma (Fig. 22.14) Clinical ♦♦ Spindle cell and pleomorphic lipomas are within the same histologic spectrum and present as a painless, slow-­growing, well-defined solitary mass, usually arising in males between the age of 45 and 65 years ♦♦ This variant of lipoma characteristically arises in the dermal or subcutaneous tissue of posterior neck and shoulder regions in subcutaneous tissue ♦♦ Surgical excision is curative

♦♦ Myxoma: hypocellular, less vascular, and lack adipocytes ♦♦ Schwannoma: do not contain adipocytes, and the lesional spindle cells will be diffusely S-100 positive ♦♦ Myxoid liposarcoma: location, characteristic vascularity, and the presence of lipoblasts will help with this differential ♦♦ Atypical lipoma/well-differentiated liposarcoma: deeper location, larger size, and more adipocytic nuclear atypia will be seen in the lesion

Lipoblastoma(tosis) Clinical ♦♦ Lipoblastoma is a tumor of infancy, usually arising in ­children less than 3 years of age, with a male predominance (M/F = 2:1) ♦♦ Tumors are usually superficial, well-circumscribed, slowly growing masses that involve limbs. Deeper lesions are larger and may be diffusely infiltrative (a.k.a., lipoblastomatosis) ♦♦ Lipoblastoma has no potential for malignant transformation or metastases. Local recurrences following excision are infrequent in superficial discrete lesions, and tend to occur in diffuse lipoblastomatosis

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Microscopic ♦♦ Histologically, there is a distinct lobular architecture to the adipocytes, with intervening fibrous septae. There is a variable admixture of mature and immature adipocytes; the immature cells range from primitive mesenchymal cells to univacuolated and multivacuolated cells (the presence and quantity of lipoblasts decreases with increasing age) ♦♦ No cellular atypia is appreciated in lipoblastoma ♦♦ Foci of extramedullary hematopoiesis, mast cells, and a variably myxoid matrix may be present

Cytogenetics ♦♦ Rearrangements and gains of chromosome 8 (8q11-13) are found in most cases of lipoblastoma

Differential Diagnosis ♦♦ Lipoma: they do not contain immature fat cells and lipoblasts ♦♦ Myxoid liposarcoma: although it may be impossible to distinguish on histological grounds to differentiate the two, MLS is very rare in children, and also usually does not have the lobulated architecture that is so typical of lipoblastoma

Hibernoma Clinical ♦♦ Hibernomas are rare, benign neoplasms that usually arise in young adults, with a slight male predominance, in the interscapular and back of neck regions ♦♦ Patients present with a slowly growing, painless, ­subcutaneous mass; occasionally lesions may be intramuscular ♦♦ Complete excision is curative, with no potential for local recurrence or distant metastases

Microscopic ♦♦ Microscopically, hibernoma is composed of variable amounts of three cell types: mature adipocytes, ­multivacuolated large cells, and large granular ­eosinophilic cells. The stroma may be myxoid or show areas resembling spindle cell lipoma ♦♦ Mitoses are usually not present

Cytogenetics

Fig. 22.15. Well-differentiated liposarcoma: variation of ­adipocyte size and shape with prominent fibrous septa ­containing atypical cells (A). Occasionally, lipoblasts are quite prominent (B).

♦♦

♦♦ 11q13 rearrangements are found in hibernomas

Lipomatosis ♦♦ Lipomatosis is a rare condition that usually affects adult males, but has many different clinical forms, including associations with several rare genetic disorders ♦♦ It consists of a diffuse overgrowth of mature adipose tissue involving large regions of the body

♦♦

Malignant

♦♦

Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor (Fig. 22.15) Clinical

♦♦

♦♦ Well-differentiated liposarcoma (WDLS)/atypical ­lipomatous tumor (ALT) is the most common sarcoma in adults, ­affecting

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mostly middle-aged males and females. Children are very rarely affected The terminology used depends on the surgical amenability of the lesion to complete resection −− ALT: tumors located on the extremities and trunk, i.e., sites amenable to wide complete excision −− WDLS: tumors arising in the retroperitoneum, spermatic cord, and mediastinum, i.e., sites where wide complete excision is difficult, if not impossible Most commonly, tumors arise in the deep soft tissues of extremities, retroperitoneum, paratesticular area, and mediastinum The most important prognostic factor is tumor location and amenability for surgical resection. When completely excised, ALT has a low propensity for local recurrence (<2%); while tumors arising in areas such as retroperitoneum have a high probability of local recurrence (>20%) ALT/WDLS have no propensity for distant metastasis; however, when lesions undergo dedifferentiation, they acquire a metastatic potential (see Dedifferentiated Liposarcoma)

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Macroscopy ♦♦ ALT/WDLS is usually a large, deeply seated mass with wellcircumscribed edges and a thin fibrous pseudocapsule. Focal myxoid change may be present, as well as areas of osseous metaplasia, necrosis, and fibrosis

Microscopic ♦♦ ALT/WDLS is composed of mature adipocytes showing variation in cell size and shape. Lipoblasts may be seen; however, their presence is not a requirement for the diagnosis. Importantly, scattered atypical and hyperchromatic cells are noted within fibrous septae, vessel walls, and associated with adipocytes ♦♦ Fat necrosis may be present, as well as osseous metaplasia and foci of myxoid change. Mitoses are rare

Variants ♦♦ Sclerosing liposarcoma: this is more commonly seen in the retroperitoneum or paratesticular regions and consists of collagenous, hypocellular fibrous tissue with scattered mature adipocytes and bizarre hyperchromatic stromal cells ♦♦ Inflammatory type: this is a rare subtype that usually occurs in the retroperitoneum, where it may simulate an inflam­matory pseudotumor or lymphoma. It consists of WDLS with an infiltrate of numerous prominent lymphoplasmacytic aggregates ♦♦ Spindle cell type: this is usually located in the subcutis and contains a population of bland spindle cells amidst otherwise classical atypical lipomatous tumor

Fig.  22.16. Dedifferentiated liposarcoma: abrupt transition between well-differentiated liposarcoma (left) and nonlipogenic sarcoma (right).

♦♦ Heterologous differentiation including rhabdomyosarcomatous, leiomyosarcomatous, or osteosarcomatous differentiation occurs in up to 10% of cases and does not impart a worse prognosis

Cytogenetics

Immunohistochemistry

♦♦ Ring and giant chromosomes derived from 12q, similar to ALT/WDLS are seen

♦♦ ALT/WDLS is consistently positive for MDM2 and CDK4, with a specificity and sensitivity of >95%

Prognosis

Cytogenetics ♦♦ Supernumerary ring and giant marker chromosomes resulting from amplification of the 12q13-15region, which includes the MDM2 and CDK4 genes, are the most commonly observed chromosomal abnormalities in ALT/WDLS

Dedifferentiated Liposarcoma (Fig. 22.16) ♦♦ Dedifferentiated liposarcoma is defined as an abrupt transition from well-differentiated liposarcoma to an unclassifiable nonlipogenic sarcoma, either in the primary tumor (90%) or in a recurrence (10%) ♦♦ Dedifferentiation is more common in retroperitoneal locations than in the extremities, most likely due to the longer duration of retroperitoneal lesions prior to clinical detection

Macroscopic ♦♦ Both the dedifferentiated and well-differentiated components are often easily distinguished ♦♦ It is crucial that the well-differentiated component is sampled to allow identification of the lipomatous component and thus the correct diagnosis made in a primary tumor

Microscopic ♦♦ The dedifferentiated component usually has a morphologic appearance of an unclassified sarcoma, and may be of low, intermediate, or high morphologic grade

♦♦ Local recurrence is extremely common, and occurs in almost all cases by 20 years. Distant metastases are seen in 15–20% of cases. The extent of dedifferentiation does not seem to have prognostic significance

Myxoid Liposarcoma (Fig. 22.17) Clinical ♦♦ Myxoid liposarcoma (MLS) is the second most common liposarcoma ♦♦ It occurs primarily in younger patients, with a peak incidence between 30 and 40 years of age, and classically involves the deep soft tissue of the extremities ♦♦ MLS has a tendency for local recurrence and up to one-third of patients develop metastases, often to unusual sites, including other soft tissue sites and the retroperitoneum, and lung

Microscopic ♦♦ MLS has a multilobular architecture with copious myxoid matrix and mucin pools, within which is a population of univacuolated and multivacuolated small lipoblasts and variable numbers of primitive round to angulated nonlipogenic cells ♦♦ There is a characteristic prominent, delicate branching (“chicken-wire”) capillary network in the background ♦♦ Focal chondroid, smooth muscle or osseous metaplasia occurs rarely

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Cytogenetics ♦♦ A reciprocal chromosomal translocation t(12;16) (q13;p11) resulting in FUS/CHOP fusion protein is present in 90% of cases

Differential Diagnosis ♦♦ Intramuscular myxoma: less vascular and lacks lipoblasts ♦♦ Myxofibrosarcoma: typically has more nuclear pleomorphism and curvilinear vessels

Pleomorphic Liposarcoma

Fig. 22.17. Myxoid liposarcoma: small round to ovoid cells in a myxoid background with thin-walled vessels and small uni- or bivacuolated lipoblasts. ♦♦ “Round cell liposarcoma” refers to the presence of ­hypercellular areas composed of sheets of primitive round cells of a higher tumor grade with increased metastatic potential

♦♦ Pleomorphic liposarcoma is rare, accounting for 5% of all liposarcomas, affecting mostly older adults with no gender predilection, and arising most often in the deep soft tissue of extremities ♦♦ It is a high grade sarcoma with propensity for local recurrence and metastases occurring in up to 50% of patients ♦♦ The tumor is composed of variable numbers of pleomorphic multivacuolated lipoblasts with marked cytological pleomorphism and sometimes numerous intracytoplasmic eosinophilic globules or droplets ♦♦ No unique cytogenetic profile has been identified and they tend to have very complex karyotypes

SMOOTH MUSCLE TUMORS Classification of Smooth Muscle Tumors ♦♦ See Table 22.6

Benign Leiomyoma (Fig. 22.18) Microscopic ♦♦ Leiomyomas are well-circumscribed neoplasms composed of interlacing bundles and fascicles of smooth muscle cells with blunt-ended cigar-shaped nuclei and brightly ­eosinophilic cytoplasm ♦♦ Mitotic activity is generally absent or very rare. Degenerative pleomorphism is variable and may result in “smudged” nuclei ♦♦ Fibrosis and calcification may be present to varying degrees ♦♦ Immunoperoxidase staining shows positivity for the muscle markers actin, desmin, and h-caldesmon

Variants ♦♦ Pilar leiomyoma: this mainly occurs on the limbs and trunk of young adults with no sex predilection. Presentation is usually as multiple, slow-growing, painful dermal-based nodules associated with hair follicles; they tend to have irregular, ill-defined margins histologically ♦♦ Genital leiomyoma: this involves the nipple, vulva, or scrotum

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Fig. 22.18. Leiomyoma: long fascicles composed of elongated spindle cells. ♦♦ Deep leiomyoma: this is uncommon, and presents as a solitary, painless, slow-growing mass in middle-aged adults. The most common sites of involvement are the extremities, abdominal cavity, and retroperitoneum. Lesions are wellcircumscribed and often >5 cm in diameter. In females, <10 mitoses/50 HPF are accepted; however, in males, no mitotic activity is accepted

Soft Tissue Tumors

♦♦ Angioleiomyomas: most commonly arise on the extremities, especially the lower leg, of women 40–60 years of age. They are usually solitary, painful, subcutaneous well-­circumscribed nodules <3  cm in diameter. Histologically, they are composed of mature smooth muscle cells surrounding thickwalled blood vessels that lack elastic laminae

Peritoneal Leiomyomatosis (Leiomyomatosis Peritonealis Disseminata) ♦♦ This lesion is composed of multiple peritoneal nodules of benign smooth muscle cells ♦♦ It is a rare entity and is usually an incidental finding, ­occurring in premenopausal women, especially pregnant women and black women ♦♦ Lesions regress with removal of estrogen and progesterone sources

Palisaded Myofibroblastoma of Lymph Node ♦♦ This is a benign myofibroblastic proliferation arising in lymph nodes, usually in the groin region ♦♦ They often resemble schwannomas due to their palisading pattern, but contain distinctive amianthoid fibers or thick collagen mats and the lesional cells express actin but not S-100

Malignant Leiomyosarcoma (Fig. 22.19) Clinical ♦♦ Clinical features and presentation depends on the location (see variants)

Microscopic ♦♦ Leiomyosarcomas are often well-circumscribed, with the exception of cutaneous lesions ♦♦ Deep-seated tumors tend to be larger and exhibit more necrosis

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♦♦ Although the appearance varies with the degree of ­differentiation (or grade), overall these tumors are ­composed of interlacing fascicles and bundles of spindled cells with vesicular, ovoid to cigar-shaped nuclei and eosinophilic cytoplasm ♦♦ In low grade lesions, the spindle cells are easily ­recognizable as smooth muscle; whereas, in high grade lesions, it is more difficult to recognize the tumor cells as  being of smooth muscle origin and thus ­immunohistochemistry may be ­necessary to confirm the diagnosis ♦♦ Nuclear pleomorphism and mitoses are present to varying degrees ♦♦ Epithelioid or round cells may rarely be present, and multinucleated, osteoclast-like giant cells are even less commonly found. Areas of hyalinization and myxoid change may be present within the tumor

Immunohistochemistry ♦♦ Leiomyosarcomas show variable expression of muscle-specific actin, smooth muscle actin, desmin, h-caldesmon and S-100 protein. They may also show variable focal expression of keratin and/or EMA

Variants ♦♦ Intraabdominal leiomyosarcoma: occurs in the retroperitoneum, mesentery, or omentum in adults with a peak incidence between 50 and 70 years, and is more comon in men. Tumors typically measure between 7 and 35  cm and wide excision is often not possible. Metastases occur to the lungs and liver, and the 5-year survival rates are approximately 20–30% ♦♦ Subcutaneous leiomyosarcoma (deep soft tissue of limbs): is most common in the thigh and also occurs in adults with a peak incidence between 50 and 70 years and a slight male predominance; 50% of lesions metastasize, and the 5-year survival is approximately 60% ♦♦ Cutaneous leiomyosarcoma: occurs in younger adults, usually on the limbs, especially the lower leg, and is often painful. There is a definite male predilection. Lesions commonly recur locally, but rarely, if ever, metastasize ♦♦ Vascular leiomyosarcoma: usually arises from the inferior vena cava or large leg veins. It occurs in older adults, and the IVC tumors are much more common in women. Metastases to liver, lymph nodes, and lungs are frequent, and the 5-year survival rate is approximately 20%

Cytogenetics ♦♦ Leiomyosarcomas usually exhibit a complex karyotype

Differential Diagnosis

Fig.  22.19. Leiomyosarcoma: cells with cigar-shaped nuclei, pleomorphism, and frequent necrosis, including atypical forms.

♦♦ Leiomyoma: these are smaller with less nuclear pleomorphism, rare mitoses, no necrosis and a simple karyotype ♦♦ Postoperative (reactive) myofibroblastic nodules: this consists of a haphazard arrangement of spindle cells with basophilic cytoplasm in the setting of recent injury, e.g., post TURBT ♦♦ Malignant peripheral nerve sheath tumor: this is composed of spindled tumor cells with wavy, buckled, asymmetrical nuclei, and variable S-100 positivity; they will lack expression of actin and desmin

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SKELETAL MUSCLE TUMORS Classification of Skeletal Muscle Tumors ♦♦ See Table 22.7

Benign Rhabdomyomatous Mesenchymal Hamartoma ♦♦ This is an extremely rare, bizarre striated muscle proliferation that presents as cutaneous nodules in the head and neck of neonates and infants

Cardiac Rhabdomyoma (See Chapter 27) ♦♦ Hamartomatous process often associated with tuberous sclerosis

Adult Rhabdomyoma ♦♦ Adult rhabdomyoma (AR) is a rare, slow-growing lesion with an overwhelming predilection for the head and neck region ♦♦ AR typically occurs in middle-aged adults, and is more common in men ♦♦ Most cases are solitary, but 10% of patients have multifocal rhabdomyomas ♦♦ ARs occasionally recur after local excision, usually following incomplete excision ♦♦ Grossly, these tumors are well circumscribed, unencapsulated, and usually <5 cm with a soft red/brown cut surface ♦♦ Histologically, the lesion is composed of large, polygonal cells with eosinophilic or vacuolated cytoplasm (glycogen rich) and central or peripheral small nuclei with prominent nucleoli, so-called “spider cells.” Cytoplasmic cross-striations and inclusions are variably present and usually focal ♦♦ Strong diffuse desmin and myoglobin immunopositivity is typically present, reflecting skeletal muscle differentiation

Fetal Rhabdomyoma ♦♦ Fetal rhabdomyoma (FR) is even less common than AR, and has a presumed hamartomatous origin ♦♦ Unlike its adult counterpart, fetal rhabdomyoma shows immature skeletal muscle differentiation ♦♦ It may occur at any age; however, the peak age is 3 years. There is an association between fetal rhadomyoma and nevoid basal cell carcinoma syndrome ♦♦ FR typically occurs in head and neck locations as a solitary mass, in particular behind the ear and in submucosal locations where it is usually polypoid ♦♦ Complete excision is curative and recurrences are very rare ♦♦ FR demonstrates a zonation pattern, with central primitive spindle cells in myxoid matrix and more mature eosinophilic rhabdomyoblasts at the periphery ♦♦ Mitoses are rare and nuclear atypia is absent; the latter is the most important factor in differentiating FR from rhabdomyosarcoma

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♦♦ Strong diffuse desmin and myoglobin immunopositivity is demonstrated in most cases

Genital Rhabdomyoma ♦♦ Genital rhabdomyoma (GR) is a rare benign neoplasm with skeletal muscle differentiation that occurs as a solitary, polypoid mass in the vagina, vulva, or cervix of young or middleaged women ♦♦ Most lesions are slow-growing and usually measure less than 3 cm ♦♦ GRs do not recur after local excision ♦♦ Histologically, these lesions consist of a submucosal proliferation of elongated, eosinophilic rhabdomyoblasts with conspicuous cytoplasmic cross-striations, embedded in a fibrous stroma ♦♦ Mitoses are typically absent ♦♦ Strong diffuse desmin and myoglobin immunopositivity is demonstrated in all cases ♦♦ Distinguishing GR from botyroid rhabdomyosarcoma relies on the presence of nuclear atypia, greater mitotic activity, and more myxoid areas in the latter

Malignant Rhabdomyosarcoma ♦♦ Rhabdomyosarcomas encompass a group of malignant neoplasms showing evidence of skeletal muscle differentiation. They are the most common sarcomas of children and adolescents, and rarely affect adults (with the exception of pleomorphic rhabdomyosarcoma) ♦♦ The three main types of rhabdomyosarcoma include −− Embryonal rhabdomyosarcoma (ERMS) −− Alveolar rhabdomyosarcoma (ARMS) −− Pleomorphic rhabdomyosarcoma (PRMS) ♦♦ Immunohistochemically, these tumors show varying degrees of staining for muscle markers depending on their degree of differentiation, including desmin, muscle-specific actin, and myogenin (Myf-4) ♦♦ In addition, some cases may show expression of vimentin, cytokeratin, S-100 protein, CD99/MIC2 (15%), and smooth muscle actin (10%) ♦♦ Prognosis varies with age, subtype, and location −− Younger patients have a better prognosis than older patients −− In children, the alveolar subtype has a worse prognosis than embryonal; spindle cell and botyroid have a better prognosis than embryonal and alveolar; and orbital and paratesticular tumors have a better prognosis than parameningeal and extremity tumors −− In adults, the relationship of histological subtype to prognosis is unclear; however, the spindled cell type carries a particularly poor prognosis in this age group

Soft Tissue Tumors

Embryonal Rhabdomyosarcoma (Fig. 22.20) Clinical ♦♦ ERMS occurs in infants and children less than 15 years of age, with a peak incidence at 4 years of age, and a slight male predominance ♦♦ The most commonly involved sites are the head and neck and paratesticular regions

Macroscopic ♦♦ Grossly, ERMS is usually poorly circumscribed with infiltration of adjacent normal structures and a pale fleshy cut surface

Microscopic ♦♦ ERMS shows an infiltrative and haphazard growth pattern, with alternating hypercellular areas and loose myxoid hypocellular areas. At the most primitive end of the spectrum, the neoplastic cells are undifferentiated, ­hyperchromatic, round or spindle-shaped ♦♦ There is typically a variable amount of more differentiated rhabdomyoblasts with eosinophilic fibrillary cytoplasm,

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so called “strap cells”; cross-striations are variably present (30–60% of cases) ♦♦ The tumors are mitotically active with varying degrees of nuclear pleomorphism; an anaplastic variant of RMS exists and is composed of enlarged bizarre tumor cells with marked nuclear pleomorphism

Cytogenetics ♦♦ Most cases show 11p deletions, which possibly result in the loss of an as yet unknown tumor suppressor gene. Alterations in the same area on chromosome 11 are found in BeckwithWiedemann syndrome

Variants ♦♦ Botyroid rhabdomyosarcoma: submucosal variant of ERMS that classically forms a polypoid (grape-like) mass of tumor nodules, and occurs at mucosal sites such as the bladder or oropharyngeal cavity. This variant is much more hypocellular with myxoid areas and condensation of tumor cells just below the mucosa forming a “cambium-layer” (present in greater than 50% of cases) ♦♦ Spindle cell rhabdomyosarcoma: this is associated with a favorable clinical outcome (90% 5-year survival). It occurs in children in paratesticular and head and neck regions, but also in adults in non-paratesticular locations. Histologically, it is characterized by a fascicular or storiform growth pattern. The tumor cells are spindled rhabdomyoblasts, which resemble smooth muscle cells; however, cross-striations and eosinophilia indicate skeletal muscle differentiation

Alveolar Rhabdomyosarcoma (Fig. 22.21) Clinical ♦♦ This variant of rhabdomyosarcoma mainly occurs in adolescents and young adults ♦♦ It typically presents as a rapidly growing deep-seated mass involving limbs. Less commonly it arises in the paranasal region

Fig.  22.20. Embryonal rhabdomyosarcoma: small round blue cell tumor with evidence of myogenic differentiation (A, B).

Fig.  22.21. Alveolar rhabdomyosarcoma: larger cells with d­ yscohesive pattern, producing alveolar appearance. Note the presence of prominent rhabdomyoblasts (top).

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♦♦ ARMS carries the worse prognosis when compared with embryonal rhabdomyosarcoma

Microscopic ♦♦ ARMS has a variable appearance depending on the histologic subtype ♦♦ The typical subtype is composed of small round cells in illdefined aggregates with fibrous septae separating the tumor cells into a dyscohesive alveolar pattern ♦♦ Multinucleated giant cells with peripheral wreath-like nuclei may be present, and cross-striations are identified in 16–30% of cases

Cytogenetics ♦♦ t(2;13)(q35;q14) is the most common translocation seen in ARMS, followed by t(1;13)(p36;q14), resulting in PAX3/ FKHR and PAX7/FKHR fusion products, respectively

Variants ♦♦ Solid variant of alveolar RMS: densely packed tumor cells lacking the fibrous septae and thus the alveolar pattern of the typical subtype. They may resemble embryonal RMS; however, the cells are larger and a focal alveolar pattern may be identified ♦♦ Mixed embryonal alveolar RMS: Hybrid features between ERMS and ARMS

Pleomorphic Rhabdomyosarcoma Clinical ♦♦ Pleomorphic rhabdomyosarcoma is the rarest type of rhabdomyosarcoma ♦♦ It occurs in older patients, (men more than women) typically over the age of 45 years, and has a very poor prognosis

♦♦ The tumors are usually located in the deep soft tissue of the lower extremities and typically present as a rapidly growing painful mass

Microscopic ♦♦ PRMS has an infiltrative growth pattern with a haphazard, loose arrangement of neoplastic cells within a variably collagenous stroma ♦♦ The neoplastic cells are large, pleomorphic round, or ­spindleshaped eosinophilic rhabdomyoblasts that very rarely show cross-striations

Differential Diagnosis ♦♦ Ewings sarcoma/primitive neuroectodermal tumor (PNET): CD99+ ♦♦ Neuroblastoma: chromogranin and synaptophysin+ ♦♦ Angiosarcoma: CD31 and Factor VIII+ ♦♦ Synovial sarcoma: cytokeratin and EMA+ ♦♦ Malignant melanoma: S-100 and HMB 45+ ♦♦ Granulocytic sarcoma: CD45, myeloperoxidase, CD43, and CD68+ ♦♦ Malignant lymphoma: CD45+ ♦♦ Small cell carcinoma: low molecular weight cytokeratin (CAM 5.2) +; location, age and lack of rhabdomyoblasts are also helpful features in this differential ♦♦ Rhabdoid tumor: cytokeratin+, desmin, and myoglobin♦♦ Alveolar soft part sarcoma (ASPS): alveolar pattern with intervening thin-walled vessels and intracytoplasmic PAS with diastase-positive crystalline material ♦♦ Myxoma: age and location usually provide correct diagnosis

VASCULAR TUMORS Classification of Vascular Tumors

Bacillary Angiomatosis

♦♦ See Table 22.8

♦♦ Bacillary angiomatosis (BA) usually occurs in immunocompromised hosts and is caused by Bartonella henselae (rickettsial organism) infection ♦♦ This is also a reactive vascular proliferation composed of granulation tissue, endothelial cells with an epithelioid appearance, and an admixed neutrophilic infiltrate ♦♦ The bacilli are identified with a Warthin–Starry stain

Benign Papillary Endothelial Hyperplasia (Masson “Tumor”) ♦♦ Papillary endothelial hyperplasia is a reactive lesion representing an unusual form of an organizing thrombus. It may arise in a dilated blood vessel or in an underlying vascular lesion ♦♦ Clinically, it usually arises on the head and neck or fingers of young adults, is <2 cm in size, and does not recur ♦♦ Histologically, it is a well-circumscribed and commonly intravascular lesion and is composed of anastomosing endothelial-lined channels with a papillary configuration. Thrombosis and fibrosis may be present to varying degrees

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Capillary Hemangioma (Infantile Hemangioendothelioma) ♦♦ This is the most common benign vascular tumor of childhood and typically involves the superficial soft tissue of head and neck region. It usually presents soon after birth and grows rapidly with 70% of tumors showing spontaneous regression

Soft Tissue Tumors

♦♦ The lesion has a multilobulated architecture and is cellular, composed of closely packed capillaries lined by plump endothelial cells with variable mitotic activity. Interstitial fibrosis may be present to varying degrees

Variants ♦♦ Tufted angioma occurs in children on the trunk or neck ♦♦ Cherry angioma (senile angioma) occurs on the trunk of adults

Lobular Capillary Hemangioma (Pyogenic Granuloma) (Fig. 22.22) ♦♦ Pyogenic granuloma is a common variant of capillary hemangioma ♦♦ It usually present as a solitary, ulcerated, polypoid nodule <2 cm, typically involving the skin of fingers and skin and mucosa of head and neck with no age or sex predilection ♦♦ They do not regress and 10–15% may recur ♦♦ They are characterized by a well-circumscribed, lobular proliferation of capillaries associated with an inflamed granulation tissue-like stroma ♦♦ There is usually an overlying epithelial collarette and ulceration, but the appearances may vary depending on the age of the lesion

Variants ♦♦ Intravascular pyogenic granuloma: rare variant, usually occurring in adults ♦♦ Granuloma gravidarum: this usually occurs on the gingivae of pregnant women and regresses in the postpartum period

Cavernous Hemangioma ♦♦ Cavernous hemangiomas are less common than capillary hemangiomas ♦♦ They are usually larger and more deep-seated than capillary hemangiomas, do not regress, and may involve any organ

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♦♦ They may be associated with: −− Mafucci syndrome (multiple enchondromas, lymphangiomas, and spindle cell hemangiomas) −− Kasabach–Merritt syndrome (consumption coagulopathy) −− Blue rubber bleb nevus syndrome (skin and GI hemangiomas) ♦♦ Histologically, cavernous hemangiomas are composed of a poorly circumscribed proliferation of dilated, thin-walled blood vessels, and may show areas of thrombosis, secondary dystrophic calcification and capillary hemangioma

Epithelioid Hemangioma (Angiolymphoid ­Hyperplasia with Eosinophilia) ♦♦ Epthelioid hemangioma usually presents as subcutaneous red nodular lesions arising in the head and neck region and extremities of adults, usually between 30 and 60 years of age, with a predilection for females ♦♦ Tumors are usually solitary and involve the subcutis, but can involve the dermis ♦♦ Whether they represent a reactive process or a true benign neoplasm remains unclear ♦♦ Approximately 30% of cases recur and therefore complete local excision is recommended; however, there is no potential for metastasis ♦♦ Histologically, they comprise a relatively well-­circumscribed proliferation of small and medium-sized vessels lined by plump epithelioid endothelial cells with eosinophilic cytoplasm and prominent nucleoli. There is usually a larger vessel associated with the lesion, typically a muscular artery, which itself may be lined by epithelioid endothelial cells ♦♦ The background stroma is rich in inflammatory cells and typically composed of a mixed infiltrate of lymphocytes, prominent lymphoid follicles with germinal center formation, eosinophils, plasma cells, and mast cells ♦♦ Dermal-based lesions tend to show less circumscription and less lymphoid follicle formation

Differential Diagnosis ♦♦ Kimura disease: deeper lesions on the posterior neck, which may involve lymph nodes, associated with eosinophilia and have a flat endothelial lining (more common in Japan) ♦♦ Epithelioid hemangioma may resemble a lymph node because of their circumscription and prominent lymphoid infiltrate with lymphoid follicle formation

Intramuscular Angioma

Fig. 22.22. Lobular capillary hemangioma: lobular proliferation of small capillaries.

♦♦ These lesions can arise in patients of any age, but most patients are usually <30 years and there is no sex predilection ♦♦ They typically present as a slowly growing sometimes painful mass involving the lower limbs, especially the musculature of the thigh ♦♦ The calcifications frequently seen radiographically probably represent phleboliths within the lesion ♦♦ Recurrences are common and are seen in up to 50% of patients, thus wide resection is advised

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♦♦ Histologically, these lesions consist of an ill-defined proliferation of thin and thick-walled (capillary and cavernous) vessels within skeletal muscle and with variable amounts of admixed adipose tissue

Differential Diagnosis ♦♦ Intramuscular lipoma: no vascular component and a more indolent clinical course ♦♦ Angiosarcoma: no lobular architecture and greater endothelial atypia

Angiomatosis (Diffuse Hemangioma) ♦♦ This is a rare lesion of childhood and adolescence characterized by a diffuse proliferation of blood vessels, most likely representing a malformative process ♦♦ The proliferation involves large areas of the body, most commonly limbs or visceral organs ♦♦ Surgical treatment is difficult due to the extensive nature of the process and persistence of disease is common ♦♦ Histologically, a diffuse infiltration of dermis, subcutis, skeletal muscle and bone by a mixture of veins, capillaries, and cavernous vascular spaces is present, depending on the site of involvement ♦♦ Mature adipose tissue is typically present to a variable extent and accounts for the fatty appearance of these lesions grossly

Differential Diagnosis ♦♦ Intramuscular hemangioma: usually involves one muscle group ♦♦ Arteriovenous hemangioma: shunting clinically and a mixture of arteries and veins histologically

Spindle Cell Hemangioma (Fig. 22.23) ♦♦ Spindle cell hemangioma was initially described as a low grade malignant lesion, but increasing evidence suggests that is most likely nonneoplastic

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ It arises as solitary or multiple red nodules on the distal extremities (especially the hands) of adolescents and young adults with no sex predilection ♦♦ The lesion has an indolent clinical course, but patients may develop new lesions over many years ♦♦ Microscopically, the lesion is ill-defined and involves the dermis and subcutis. There are irregular cavernous vascular spaces with a flat endothelial lining, often containing organizing thrombi, and solid areas of bland spindle cells with eosinophilic cytoplasm ♦♦ The endothelial cells may have an epithelioid appearance and contain intracytoplasmic vacuoles, and may form papillary projections focally ♦♦ The vascular lining and epithelioid cells are positive for CD34 and CD31, and the spindle cells are positive for vimentin and negative for CD34 and CD31

Differential Diagnosis ♦♦ Kaposi sarcoma: no cavernous spaces, no epithelioid endothelial cells, and positive staining for HHV-8

Low Grade Malignant Kaposiform Hemangioendothelioma (Kaposi-Like Hemangioendothelioma) ♦♦ This is a rare tumor of childhood that usually occurs in the retroperitoneum and skin, but can involve deeper soft tissues ♦♦ It carries a significant risk of mortality and morbidity because of its infiltrative growth and locally aggressive behavior, particularly with intraabdominal lesions ♦♦ It is commonly associated with Kasabach–Merritt syndrome (consumption coagulopathy) ♦♦ The lesion is usually quite infiltrative with fibrous septae separating ill-defined nodules of bland spindled cells forming slit-like vascular spaces, with an interspersed proliferation of capillaries ♦♦ Additional features may include scattered epithelioid endothelial cells, hemosiderin deposition, and hyaline globules ♦♦ The spindled cells show positivity for CD34 and CD31 and are negative for Factor VIII-related antigen

Differential Diagnosis ♦♦ Kaposi sarcoma: rare in children, is usually multicentric, contains a prominent inflammatory infiltrate and lacks a lobular growth pattern ♦♦ Capillary hemangioma: solid nodules of capillary ­proliferations without a spindle cell component

Retiform Hemangioendothelioma (Hobnail ­Hemangioendothelioma) Fig. 22.23. Spindle cell hemangioma: spindle cell proliferation with evidence of vascular differentiation.

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♦♦ Retiform hemangioendothelioma is an uncommon, locally aggressive, vascular neoplasm that affects predominantly young adults with no sex predominance

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♦♦ Tumors usually arise in the skin and subcutaneous tissue of the distal extremities, and present as small plaques or nodules ♦♦ This neoplasm is characterized by frequent local ­recurrences. Rare metastatic cases have been described ♦♦ It is microscopically characterized by elongated, arborizing blood vessels resembling the rete testis. The cells lining the neoplastic vessels are often protuberant with a hobnail appearance. Pleomorphism and mitoses are not present ♦♦ Intravascular and stromal small lymphocytes are frequently present ♦♦ Neoplastic cells are usually positive for the vascular markers CD31, CD34, and vWF; HHV-8 is negative

Papillary Intralymphatic Angioendothelioma ♦♦ Papillary intralymphatic angioendothelioma is a rare, locally aggressive vascular neoplasm that affects mainly children, but may also occur in adults. Males and females are equally affected ♦♦ Lesions arise mainly as cutaneous and/or subcutaneous lesions in the limbs ♦♦ It may recur if not completely excised. Since the number of studied cases so far is limited, the exact potential for metastasis remains unknown ♦♦ Morphologically, it shows thin-walled dilated spaces with intraluminal papillary tufts containing hyaline cores and hobnail endothelial cells

Composite Hemangioendothelioma ♦♦ Composite hemangioendotheioma is an extremely rare, locally aggressive tumor that affects predominantly adults with equal gender distribution ♦♦ Hands and feet are more often affected and patients present with a painless nodule or an ill-defined swelling. Approximately one-quarter of patients have a history of lymphedema ♦♦ Approximately half of the published cases show local recurrence, and rare cases have shown metastasis ♦♦ Microscopically, there is a complex variable mixture of vascular components: epithelioid hemangioendothelioma, spindle cell hemangioma, “angiosarcoma-like” areas, retiform hemangioendothelioma, and benign vascular abnormalities

Kaposi Sarcoma (See Chapter 18) (Fig. 22.24) ♦♦ Kaposi sarcoma (KS) is typically a locally aggressive vascular neoplasm that typically affects the skin and lymph nodes (mainly in children), but, in immunosuppressed patients, may also affect mucosal sites and visceral sites ♦♦ There are four distinct clinical groups in which KS is noted: (1) classic indolent form affecting older men of Mediterranean decent, (2) endemic African KS that affect non-HIV infected children, (3) iatrogenic KS arising in the setting of organ transplant and immunosuppressive therapy, and (4) AIDS associated KS (most common and aggressive form)

Fig. 22.24. Kaposi sarcoma: spindle cell vascular neoplasm that shows close relationship to HHV-8. Note intracytoplasmic hyaline globules (A, B, H&E stain; C, HHV-8 stain). ♦♦ All groups have similar histologic features with three growth stages: patch, plaque, and nodular ♦♦ HHV-8 is present in all cases of KS and is believed to play an important oncogenic role in the pathogenesis of the disease

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Malignant

Differential Diagnosis

Epithelioid Hemangioendothelioma (Fig. 22.25) Clinical

♦♦ Metastatic carcinoma: more prominent nuclear atypia and mitotic activity, which is usually not angiocentric. EMA and keratins will be positive, and CD31 negative, in carcinoma ♦♦ Melanoma: more nuclear atypia and mitotic activity, and is usually not angiocentric. CD31 immunostain will be negative in tumor cells, which will instead express ­melanocytic markers such as S-100+ and HMB 45 ♦♦ Epithelioid angiosarcoma: composed of irregular anastomosing channels with necrosis and tumor cells showing more nuclear atypia and mitoses than EHE ♦♦ Epithelioid sarcoma (ES): usually arises on the distal extremity of young patients and has a nodular growth pattern with central necrosis and dense collagenous stroma, which blends with epithelioid cells

♦♦ Epithelioid hemangioendothelioma (EHE) is a rare, malignant vascular tumor that may involve any organ, but usually presents as a solitary often painful mass in the superficial and deep soft tissue of extremities, and is associated with a blood vessel ♦♦ EHE occurs in adults over a wide age range; the male:female ratio is equal for tumors arising in soft tissue, but for tumors arising in the lungs and liver there is a slight female predilection ♦♦ The reported local recurrence rate is approximately 15% and the metastatic rate is greater than 30%, with metastases usually to lymph nodes, lung, liver, and bone

Microscopic ♦♦ EHE is an ill-defined and infiltrative lesion, which can often be seen to be originating within a vessel and centrifugally extending into adjacent soft tissue ♦♦ EHE is composed of nests and trabeculae of epithelioid or spindled endothelial cells within a prominent myxohyaline stroma. Neoplastic cells typically have vesicular nuclei and eosinophilic cytoplasm with intracytoplasmic lumina containing red blood cells ♦♦ Cytological atypia and mitoses are usually not prominent ♦♦ Approximately one-third of cases show malignant features (viz., marked nuclear atypia, increased mitotic activity, spindling of cells, and necrosis) and behave in a more ­aggressive fashion

Immunohistochemistry ♦♦ The vascular markers CD31, CD34, FLI1, and Factor VIII are usually positive in EHE. Cytokeratin positivity may be seen in up to 50% of cases; EMA is usually absent

Angiosarcoma (Fig. 22.26) Clinical ♦♦ Primary angiosarcoma may be divided into five clinical groups (see below)

Cutaneous angiosarcoma

♦♦ This variant usually arises on the head and neck of the elderly as multiple erythematous plaques and nodules and shows a male predilection. It is highly associated with UV exposure ♦♦ It carries a poor prognosis with widespread dissemination and an aggressive clinical course

Lymphedema-associated angiosarcoma

♦♦ Also known as Stewart–Treves syndrome, this variant usually arises in the arms of females 1–30 years postradical mastectomy +/− radiation (outside the radiation field). However, with the advent of conservative options for  the treatment of breast carcinoma, lymphedema-­associated angiosarcoma is now very rare ♦♦ It is also associated with a poor prognosis

Radiation-induced angiosarcoma

♦♦ This variant is rare and often occurs 5 years after radiation therapy. Its incidence has been gradually increasing due to conservative treatment of breast carcinoma. It is associated with a poor prognosis

Angiosarcoma of breast parenchyma

♦♦ Also rare, this subtype is more common in females with a peak between 20 and 40 years of age; however, this ­subtype is not associated with radiation or treatment or lymphedema

Angiosarcoma of deep soft tissue

♦♦ Angiosarcoma of deep soft tissue is rare ♦♦ It occurs in older adults, is more common in men, affects the lower limbs and retroperitoneum, and carries a poor prognosis

Microscopic

Fig. 22.25. Epithelioid hemangioendothelioma: epithelioid cells with intracytoplasmic vacuoles.

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♦♦ All forms have similar histologic features and are infiltrative tumors, usually multifocal, containing numerous, irregular, anastomosing vascular channels with a dissecting pattern between collagen bundles, adipose tissue, and other native structures

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bacillary angiomatosis, ES, malignant melanoma, spindle cell sarcoma, and sarcomatoid carcinoma

Variants ♦♦ Epithelioid angiosarcoma −− This is composed exclusively of epithelioid cells, some with intracytoplasmic vacuoles containing red blood cells, and focal blood vessel formation. Brisk mitotic activity, necrosis, and hemorrhage are typically present −− The differential diagnosis includes carcinoma and melanoma, and immunohistochemistry is helpful in distinguishing between these three categories of tumors −− Epithelioid angiosarcoma has an aggressive clinical course with systemic metastases and death within 2–3 years

Perivascular Tumors Glomus Tumor Clinical ♦♦ Glomus tumors are rare and usually occur in adults 30–50 years of age. Male to female ratio is equal, except for subungual types, which are more common in women ♦♦ Tumors typically arise as solitary, painful nodules in the dermis or subcutis of fingers ♦♦ About 10% may recur after excision ♦♦ Malignant examples of glomus tumor (glomangiosarcoma) are very rare, and carry a poor prognosis

Microscopic Fig. 22.26. Angiosarcoma: low grade breast angiosarcoma may be low grade with a prominent dissecting pattern (A). Epithelioid morphology may mimic carcinoma and melanoma (B).

♦♦ Typically, there is endothelial multilayering, pleomorphism, and hyperchromasia to varying degrees. In addition, the endothelial cells are often tufted and have a papillary configuration ♦♦ Mitoses and necrosis are present to a variable extent ♦♦ Solid areas without vascular architecture may also be identified and usually represent more poorly differentiated areas

Immunohistochemistry ♦♦ The tumor cells express CD31, CD34, Fli-1, and less commonly Factor VIII

Electron Microscopy ♦♦ Weibel–Palade bodies are characteristic of endothelial cell differentiation

Differential Diagnosis ♦♦ The differential diagnosis may include many other vascular and nonvascular lesions, e.g., hemangioma, angiomatosis,

♦♦ Glomus tumors are well-circumscribed and variably cellular, comprising varying amounts of blood vessels, smooth muscle, and glomus cells ♦♦ Glomus cells may be in solid sheets or nests and are round, uniform cells with pale, eosinophilic cytoplasm and central, round hyperchromatic nuclei with well-defined cell margins. Mitoses are rare ♦♦ The stroma may be edematous with myxoid change

Variants ♦♦ Glomangioma: cavernous vascular spaces with clusters of glomus cells around and lining vessels ♦♦ Glomangiomyoma: features of glomangioma and glomus tumor with smooth muscle proliferation

Immunohistochemistry ♦♦ Glomus cells express smooth muscle actin, muscle-specific actin, and are negative for desmin, cytokeratins, and S-100 protein

Differential Diagnosis ♦♦ Adnexal tumors: focal ductal differentiation will usually be seen and cytokeratin positivity demonstrated ♦♦ Intradermal nevus: focal nesting pattern, maturation, S-100 protein expression

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PERIPHERAL NEURAL TUMORS Classification of Peripheral Neural Tumors ♦♦ See Table 22.9

Benign Traumatic Neuroma (Amputation Neuroma) ♦♦ Traumatic neuroma is a reparative process that arises from the proximal end of a nerve following trauma ♦♦ It may occur in any location where a peripheral nerve is severed and does not heal, e.g., post trauma or surgery, in amputations ♦♦ It usually presents as a small, painful nodule in superficial soft tissue ♦♦ Histologically, it is composed of a poorly circumscribed disorderly arrangement of nerve fascicles with admixed fibroblasts, Schwann cells, and axons within a collagenous stroma with variable myxoid change

Morton Neuroma (Localized Interdigital Neuritis) ♦♦ Morton neuroma is a reactive, sclerosing process involving peripheral nerves in the region of the metatarsal heads. Resection is curative ♦♦ Morton neuroma usually affects adult females and results in severe lancinating pain ♦♦ The lesion has irregular edges and consists of marked endoneurial, perineurial, and epineurial fibrosis with resultant loss of axons. The fibrosis may extend to involve adjacent fat and vessel walls

Digital Pacinian Neuroma ♦♦ Digital pacinian neuroma is an uncommon type of Pacinian neuroma and consists of an unencapsulated collection of hyperplastic Pacinian corpuscles

♦♦ The Schwann cell component will be S-100 protein positive and the admixed axons neurofilament positive. The capsule will be highlighted by EMA positivity

Schwannoma (Fig. 22.27) Clinical ♦♦ Schwannomas commonly occur in adults as a superficial or deep solitary, slow-growing mass, with a peak age of 20–50 years and no sex predilection ♦♦ Common sites of involvement include the head and neck region and the extremities ♦♦ They usually do not recur after excision ♦♦ Bilateral acoustic schwannomas are one of the diagnostic criteria for neurofibromatosis type 2

Macroscopic ♦♦ Schwannomas arise from peripheral nerves but are usually easily separated at the time of surgery ♦♦ The majority are <5 cm in diameter and encapsulated

Microscopic ♦♦ The lesions are of variable cellularity with a biphasic fascicular or swirling pattern. The two components, Antoni A and Antoni B, describe the appearances of differing areas within schwannomas, and are present in varying proportions ♦♦ Antoni A areas consist of compact, cellular areas with monomorphic eosinophilic spindled Schwann cells, often with nuclear palisading resulting in the formation of Verocay ­bodies, in a background of collagenous stroma ♦♦ Antoni B areas are hypocellular and comprise spindled Schwann cells with little cytoplasm in a background of copious myxoid stroma and blood vessels with thick hyalinized walls

Mucosal Neuroma ♦♦ This is a rare lesion and arises almost always in the setting of MEN type 2b (Gorlin syndrome). It consists of a haphazard arrangement of hyperplastic nerve fibers

Solitary Circumscribed Neuroma (Palisaded Encapsulated Neuroma) Clinical ♦♦ Solitary circumscribed neuroma typically presents as a longstanding, solitary, painless nodule, with a mean size of 3 mm, on the face of adults between 30 and 60 years of age ♦♦ They are well circumscribed, partially encapsulated lesions, usually in the dermis, and composed of bland, spindle cells with small, wavy nuclei in a fascicular growth pattern within a fibrous stroma ♦♦ They tend not to show nuclear palisading or zonation, features that help distinguish them from schwannomas (see below)

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Fig.  22.27. Schwannoma: alternating Antoni A and B zones with hyalinized blood vessels. Occasional Verocay bodies may be seen.

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♦♦ Mitoses are present to a variable degree but are usually few in number and not atypical. Nuclear hyperchromasia and mild pleomorphism may also be present ♦♦ Degenerative changes including hyalinization, stromal hemorrhage, calcifactions, and cystic change

Immunohistochemistry ♦♦ The Schwann cell component will be strongly S-100 protein positive, and the capsule will be highlighted by EMA positivity. Neurofilament protein (NFP) should be negative as there is a distinct absence of axons within schwannomas

Variants ♦♦ Ancient (degenerated) schwannoma: benign schwannoma with prominent degenerative changes, which may include significant nuclear atypia, but not atypical mitoses ♦♦ Cellular schwannoma: this variant usually presents as a large deep tumor in the retroperitoneum or mediastinum, and may be mistaken for sarcoma, both clinically and histologically. They are hypercellular with a predominant Antoni A fascicular pattern, increased mitotic activity (>10/10 HPF) and increased nuclear pleomorphism (usually degenerative). They may show infrequent microfoci of necrosis (not geographic like MPNST), a peripheral lymphocytic infiltrate and foamy macrophages ♦♦ Plexiform schwannoma: this uncommon type occurs in younger adults and is usually not associated with neurofibromatosis; it consists of encapsulated nodules of Antoni A areas of schwannoma ♦♦ Melanotic schwannoma: this is a rare variant that occurs in older patients, often involving spinal nerve roots (psammomatous melanotic schwannoma is associated with the Carney complex)

Solitary Neurofibroma (Fig. 22.28) Clinical ♦♦ Solitary neurofibroma usually presents as a solitary localized, painless, nodular skin lesion. It may be sporadic or associated with neurofibromatosis type 1 (NF-1) ♦♦ It may affect patients of any age, but the incidence peaks between the ages of 20 and 30 years ♦♦ They are usually situated in the dermis and subcutis; deeper lesions may be associated with NF-1 and may rarely undergo malignant change ♦♦ Solitary neurofibromas arise within nerves and there is no tendency for local recurrence

Microscopic ♦♦ Neurofibromas are circumscribed but not encapsulated and may appear as a fusiform expansion of nerve trunk (variable) ♦♦ They are usually of uniform cellularity comprising ­elongated spindle cells with eosinophilic processes in a variable fibromyxoid stroma with admixed small nerve fibers, Schwann cells, mast cells, perineural cells, and fibroblasts. The nuclei of the spindle cells are tapering or wavy, slightly hyperchromatic, and may show degenerative changes

Fig.  22.28. Solitary neurofibroma: small spindly cells with tapered nuclei (A). Immunostain for neurofilament protein highlight admixed axons (B). ♦♦ The stroma may show variable hyalinization or myxoid change ♦♦ The presence of atypical cells in a patient with NF-1 should prompt a thorough search for mitoses, as mitotic activity is generally not accepted in solitary neurofibroma and raises the possibility of a malignant peripheral nerve sheath tumor (MPNST) ♦♦ S-100 positivity is detected in 30–50% of cells, and there is admixed neurofilament positivity, unlike schwannomas

Diffuse Neurofibroma ♦♦ This is a superficial variant of neurofibroma that occurs in younger patients (10–30 years) as an ill-defined, indurated subcutaneous lesion. Approximately 10% of cases are associated with NF-1 ♦♦ The tumor population is the same as that seen in solitary neurofibromas; however, there is an infiltrative growth pattern that involves the dermis and subcutaneous tissue; Meissnerian differentiation is frequently identified ♦♦ Overall there is no tendency to undergo malignant transformation

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Plexiform Neurofibroma

Immunohistochemistry (All Types)

♦♦ Plexiform neurofibromas usually arise in childhood and are pathognomonic for NF-1 ♦♦ They are most common in head and neck regions where they are usually superficially located and may be large and disfiguring ♦♦ They consist of a diffuse enlargement and distortion of nerves by neurofibromatous tissue in cords and nodules with associated myxoid change ♦♦ Large and deep-seated lesions have a risk of malignant change, and it is thus essential to look for mitoses, atypia, and areas of increased cellularity

♦♦ EMA is positive in most cases and a subset of cases will also be positive for claudin

Perineurioma (Fig. 22.29) Clinical ♦♦ Soft tissue perineurioma – arises on the limbs and trunk as a painless subcutaneous mass in adults, with a female predominance; there is no association with NF-1 ♦♦ Intraneural perineurioma – arises in young adults and tends to be associated with motor deficits ♦♦ Sclerosing perineurioma – presents as solitary small nodules on fingers and palms of young adults ♦♦ Complete excision is curative and perineuriomas tend not to recur

Microscopic (Soft Tissue Perineurioma) ♦♦ Perineuroma is well-circumscribed, nodular or ovoid, ­usually 1.5–2.0 cm in size, and is not associated with identifiable nerves ♦♦ The histologic features are variable and include growth of wavy spindle cells in elongated bundles, interweaving fascicles, loose whorls, or a storiform pattern that dissects through a collagenous stroma ♦♦ Mild nuclear hyperchromasia may be present and mitoses are rare ♦♦ Myxoid change is infrequently present

Cytogenetics (All Types) ♦♦ Rearrangement of chromosome 22 is associated with perineuriomas

Dermal Nerve Sheath Myxoma Clinical ♦♦ Presentation is as a slow-growing, solitary, painless lesion in young adults. Common sites of involvement include the hands, back, arm, face, and neck ♦♦ There is no association with NF-1; local recurrence is common

Microscopic ♦♦ The histologic pattern is of a circumscribed multilobular lesion, 0.5–3  cm in size, composed of a loose network of stellate, spindle, and epithelioid cells with eosinophilic, thin cytoplasmic processes, within an abundant myxoid stroma ♦♦ Mitoses, if present, are usually rare ♦♦ S-100 and GFAP are usually positive within the tumor cells

Ganglioneuroma Clinical ♦♦ Ganglioneuromas arise in patients between 10 and 20 years of age with a female predominance, and most lesions occur in the mediastinum, retroperitoneum, and adrenal medulla ♦♦ Symptoms are due to mass effects and rarely due to endocrine activity ♦♦ Most arise de  novo; however, in a few cases, tumors may represent matured neuroblastoma/ganglioneuroblastoma, or may arise in association with schwannoma or pheochro­ mocytoma ♦♦ Resection is typically curative

Microscopic ♦♦ Ganglioneuromas consist of a well-circumscribed mass with a fibrous capsule; usually <15  cm in greatest dimension, within which is a loose network of bundles of axonal processes with Schwann cells (resembling neurofibroma) and nests or scattered mature ganglion cells ♦♦ Multinucleated cells, nuclear pleomorphism, vacuolation, and degenerative changes may all be present to varying degrees ♦♦ Adequate sampling is required to rule out ganglio­ neuroblastoma

Granular Cell Tumor (Fig. 22.30) Clinical Fig. 22.29. Soft tissue perineurioma: note the whorled growth pattern of the neoplastic cells, closely resembling meningioma.

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♦♦ Granular cell tumors are common lesions that usually arise on the skin or subcutis of any anatomic site, but are most common on the trunk, tongue, and arms

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Differential Diagnosis ♦♦ Adult rhabdomyoma: this is distinguished by the lack of cytoplasmic granules and presence of cross-striations and cytoplasmic glycogen in rhabdomyomas ♦♦ Hibernoma and fibroxanthoma: distinguished by the presence of lipid droplets within the cytoplasm of the lesional cells in the former two entities ♦♦ Reactive processes: no nested or trabecular arrangement, presence of inflammatory cells and necrosis ♦♦ Squamous cell carcinoma (vs. pseudoepitheliomatous hyperplasia of granular cell tumor): no underlying granular cells and more marked nuclear atypia within the squamous epithelium

Fig.  22.30. Granular cell tumor: large eosinophilic cells with small centrally located nuclei.

♦♦ They occur at a peak age of 40–70 years and show a slight female predominance. Although most are solitary, 10% of patients have multiple granular cell tumors. The vast majority of tumors are benign, <3 cm in size and rarely recur after local excision

Microscopic ♦♦ Granular cell tumors are poorly circumscribed with infiltrative margins and are composed of nests, trabeculae or sheets of monomorphic round to polygonal cells with copious granular, palely eosinophilic cytoplasm. Neoplastic cells contain uniform, central, pyknotic nuclei with minimal nuclear pleomorphism and scattered mitoses ♦♦ The granular appearance of the cytoplasm is due to the presence of PAS positive diastase resistant intracytoplasmic granules ♦♦ Pseudoepitheliomatous hyperplasia of overlying squamous epithelium is often present and can distract from the underlying proliferation of granular cells and result in the erroneous diagnosis of a squamous lesion ♦♦ The granular cells show S-100, neuron-specific enolase (NSE), and NKI-C3 positivity

Variants ♦♦ Gingival granular cell tumor of newborn infants (congenital epulis): arise on the maxilla almost exclusively in female infants. Show similar histologic features with prominent vessels, inflammatory cells, and entrapped nests of odontogenic epithelium; however, S-100 is typically negative in this variant, suggesting a probable distinct origin of to these lesions ♦♦ Malignant granular cell tumor: this represents 2–3% of all cases, and usually occurs in deeper soft tissue locations. 50% of patients have a metastasizing, fatal clinical course. They have similar morphologic features to the benign type, but with increased cellular atypia with prominent nucleoli and frequent mitoses

Heterotopic Meningeal Lesions (Ectopic Meningioma) ♦♦ Consists of three types −− Ectopic meningothelial hamartoma – usually occurs over the scalp and spinal column of children and has a pseudoangimatous appearance −− Cutaneous meningioma – occurs in adults and usually arises on the head −− Type III – spread of a central nervous system meningioma to overlying skin or subcutis

Heterotopic Glial Nodules (Nasal Gliomas) ♦♦ Nasal gliomas are the result of misplaced glial tissue in the subcutis of the head and neck (most common in the nose). The nodules consist of a circumscribed mass of mature glial tissue (GFAP positive); neurons are absent

Malignant Malignant Peripheral Nerve Sheath Tumor (Malignant Schwannoma or Neurofibrosarcoma) (Fig. 22.31) Clinical ♦♦ MPNST occurs in three principal forms: sporadic, radiotherapy-associated (10% cases) and in the setting of NF-1 (30–50% cases) ♦♦ It shows a peak incidence in patients aged 20–50 years, but tends to occur 10–15 years earlier in patients with NF-1. MPNST may arise in a neurofibroma in the presence of NF-1 ♦♦ In the sporadic form, men and women are affected at a similar frequency; however, in NF-1, there is a strong male predominance (M/F = 4:1) ♦♦ Common sites of involvement include the proximal limbs and trunk, and less commonly retroperitoneum and posterior mediastinum ♦♦ The 5-year survival rate in sporadic cases is approximately 50% and in NF-1 associated cases 20–25% ♦♦ Metastases usually occur to the lung, liver, subcutis, and bone

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Macroscopic ♦♦ MPNST is usually a large, fusiform, eccentric mass arising in association with a nerve and most are >10 cm in diameter. The cut surface has a fleshy, white appearance with variable areas of hemorrhage and necrosis

Microscopic ♦♦ The growth pattern of MPNST is that of a fascicular spindle cell proliferation with an abrupt transition between cellular and myxoid areas. Perivascular whorling of tumor cells is a characteristic feature of MPNST ♦♦ The tumor cells are elongated with tapering or wavy, hyperchromatic nuclei and pale, ill-defined cytoplasm. Nuclear pleomorphism and mitoses are present in various amounts ♦♦ The background stroma is variably myxoid and fibrotic. Geographic necrosis may also be present ♦♦ Heterologous differentiation is seen in approximately 10–15% of cases and includes rhabdomyosarcoma (Malignant Triton tumor, worse prognosis), osteosarcoma, chondrosarcoma, angiosarcoma, and/or glandular differentiation

Immunohistochemistry ♦♦ S-100 positivity is present in less than 50% of cases, and usually in just 20–30% of cells. GFAP and EMA positivity may also be seen

Variants ♦♦ Epithelioid MPNST: these represent approximately 5% of MPNSTs, are often superficial, and carry a better prognosis. The differential diagnosis from carcinoma or melanoma is difficult, but they are usually S-100+, HMB 45-, and keratin-

Differential Diagnosis ♦♦ Synovial sarcoma (SS): usually has a uniform fascicular pattern, lacks neural differentiation, and often contains calcifications. Immunohistochemistry in synovial sarcomas shows cytokeratin and EMA expression in the tumor cells ♦♦ Leiomyosarcoma: tumor cells of leiomyosarcoma have more eosinophilic cytoplasm and central blunt-ended nuclei. In addition, immunohistochemistry may also help, in that leiomyosarcomas are positive for actin and desmin and negative for S-100

Extraspinal (Soft Tissue) Ependymoma (See CNS Tumors) Fig. 22.31. Malignant peripheral nerve sheath tumor: alternating hypercellular and myxoid areas composed of spindle cells with tapered nuclei (A). Perivascular accentuation of tumor cells is a frequent feature seen in MPNST (B). Occasionally, heterologous differentiation, such as chondrosarcomatous may be seen (C).

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♦♦ These are rare tumors that occur in the subcutaneous tissue over the sacrum and coccyx, and have a greater tendency to metastasize than their intraspinal counterpart, usually with late metastasis (>10 years) to lung ♦♦ The most common types are myxopapillary

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CHONDROOSSEOUS TUMORS Classification of Chondroosseous Tumors ♦♦ See Table 22.10

Benign Osteoma Cutis ♦♦ The majority of bony nodules in skin arise due to secondary ossification of preexisting lesions such as pilomatrixoma or nevi ♦♦ Osteoma cutis refers to the rare occurrence of multiple cutaneous nodules of mature bone in the absence of any preceding lesion, most commonly arising in the superficial skin of the face ♦♦ The pathogenesis of such lesions remains obscure and there is no equivalent entity in deeper soft tissue

Myositis Ossificans Clinical ♦♦ Myositis ossificans is a reactive, usually solitary, self-­limiting lesion of soft tissue ♦♦ A history of trauma is found in approximately 30% of patients, reflecting the reactive nature of this process ♦♦ Myositis ossificans most commonly affects young adults and shows a male predominance; it is uncommon in children ♦♦ Patients typically present with a rapidly enlarging mass in the quadriceps or brachialis muscles ♦♦ Imaging studies show a well-circumscribed lesion with a characteristic pattern of peripheral calcification and central lucency (variable with duration)

Macroscopic ♦♦ The gross appearance of myostis ossificans reflects that seen by imaging, in that it is a well-circumscribed lesion with edematous muscle in the center and bone formation at the periphery

Microscopic ♦♦ The central zone of the lesion is composed of a myofibroblastic proliferation with a nodular fasciitis-like pattern and a variable degree of hemorrhage ♦♦ Mitoses are usually abundant within this central area, but nuclear atypia should be minimal ♦♦ The distinctive “zonation pattern” refers to the maturation of the lesion toward the periphery, with osteoid seams calcifying into trabecular-appearing bone ♦♦ Entrapped, atrophic skeletal muscle fibers are seen, and endochrondral calcification may be present

Variants ♦♦ Panniculitis Ossificans: this represents myositis ossificans in the subcutis; usually the upper limbs of women

♦♦ Fibroosseous pseudotumor of the digits (florid reactive periostitis): this entity describes rare heterotopic ossification occurring in the subcutis of digits of young adults that resembles myositis ossificans but lacks the zonation pattern ♦♦ Fibrodysplasia (myositis) ossificans progressiva: this extremely rare entity describes a subset of patients who develop disseminated myositis ossificans lesions as a hereditary lesion. This form of disease affects children less than 10 years of age and is typically associated with skeletal abnormalities. It is slowly progressive and associated with a poor long-term prognosis

Differential Diagnosis ♦♦ Extraskeletal osteosarcoma: the typical “zonation pattern” of maturation is not seen in extraskeletal osteosarcoma, which instead shows a “reversed” zonation pattern whereby bone is more commonly seen in the center of the lesion, with the more cellular areas located at the periphery. In addition, there is usually marked nuclear pleomorphism and necrosis in extraskeletal osteosarcoma, in contrast to myositis ossificans, which shows at most minimal nuclear atypia and does not typically show necrosis

Soft Tissue Chondroma (See Chapter 21) Clinical ♦♦ Soft tissue chondroma is a benign, predominantly cartilaginous lesion, most likely neoplastic in origin, which occurs almost exclusively on the hands and feet ♦♦ It is the soft tissue counterpart of enchondroma and periosteal chondroma ♦♦ Soft tissue chondromas are usually solitary painless masses, which are often associated with tendons, the most common presentation being on the finger of adults ♦♦ Excision is curative in most cases; however, up to 20% of lesions locally recur

Microscopic

♦♦ The microscopic appearance is of nodules of mature hyaline cartilage with clusters of chondrocytes showing mild to moderate nuclear atypia and occasional mitoses ♦♦ Additional features that may be seen include fibrosis, myxoid change, ossification, calcification, and cystic degeneration

Malignant Extraskeletal Osteosarcoma Clinical ♦♦ About 5% of all osteosarcomas arise in soft tissue, and are thus classified as extraskeletal osteosarcomas ♦♦ Extraskeletal osteosarcoma (EO) occurs most commonly in adults within the age range of 60–90 years, and affects men more frequently than women. The most common sites for EO to arise are the limbs, in particular, the thigh, followed by the retroperitoneum

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♦♦ EO is associated with prior radiation treatment in approximately 10% of patients, in which case they usually develop more than 4 years after radiation treatment ♦♦ EO has an extremely poor prognosis with an aggressive, metastasizing clinical course, and an overall mortality approaching 80% at 5 years

Macroscopic ♦♦ EOs are usually large (average 8–10  cm) circumscribed masses with focal hemorrhage and necrosis and a gritty texture. Bone is most prominent in the center of the lesion, in contrast to myositis osssficians

Microscopic ♦♦ EO shows the same wide spectrum of morphologic appearances as osteosarcomas arising in bone, with the common feature being the presence of neoplastic bone intimately associated with tumor cells ♦♦ Tumor cells are typically spindled or polyhedral with atypia and abundant mitoses including atypical forms ♦♦ The most common type is the osteoblastic variant, followed by the fibroblastic, chondroid, telangiectatic, small cell and well differentiated types

MISCELLANEOUS TUMORS Classification of Tumors of Uncertain Histogenesis

Cellular Neurothekeoma (Fig. 22.32) Clinical

♦♦ See Table 22.11

♦♦ This is usually a solitary, cutaneous lesion affecting children and young adults and occurring on the face, arm, and shoulder with a female predominance

Benign Tumoral Calcinosis ♦♦ Tumoral calcinosis is an idiopathic disorder that results in tumor-like calcium deposition in periarticular soft tissue. It is not associated with chronic renal failure or collagen vascular disorders

Clinical ♦♦ It occurs with a peak age of 10–30 years, and is more common in men and people of African descent; siblings of affected patients are affected in 50% of cases ♦♦ The most common sites of involvement are those around large joints-hips, shoulders, and elbows ♦♦ The deposits present as slow-growing, firm, subcutaneous masses, with multiple lesions present in two-third of cases

Microscopic ♦♦ Grossly, they consist of an unencapsulated, firm, rubbery mass, ranging in size from 5 to15 cm, with a calcified, chalky fibrotic cut surface ♦♦ Microscopically, the deposits consist of a proliferation of multinucleated and osteoclast-like giant cells and macrophages within dense fibrous tissue surrounding dystrophic calcifications. Psammomatous calcifications are rare

Amyloidoma ♦♦ Rare in soft tissue; there may be solitary or multiple lesions of extensive amyloid deposition ♦♦ May be primary or secondary arising in association with myeloma

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Fig.  22.32. Cellular neurothekeoma: dermal nests of short s­ pindle cells.

Soft Tissue Tumors

♦♦ There is no association with neurofibromatosis, and local recurrence is uncommon

Microscopic ♦♦ It has a multilobular growth pattern and is usually 0.5–3 cm in size ♦♦ The tumor is hypercellular, composed of fascicles and whorls of spindle or epithelioid cells with focally myxoid stroma. Multinucleated cells are often present and mitoses frequent

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♦♦ Myxofibrosarcoma: this is hypercellular with greater nuclear pleomorphism and mitotic activity

Juxtaarticular Myxoma

Immunohistochemistry

♦♦ This is an uncommon variant that typically arises in males, adjacent to large joints, usually knee, shoulder, elbow, and hip. It is often associated with cysts and degenerative joint disease ♦♦ They may involve subcutis, tendons, and joints and are more cellular and more vascular than intramuscular myxoma ♦♦ They often recur locally

♦♦ The lesional cells are positive for NKI-C3, NSE, and SMA, and are negative for S-100 protein

Digital Myxoma (Cutaneous Myxoid Cyst)

Myxoma (Fig. 22.33) Cellular/Intramuscular Myxoma Clinical ♦♦ Intramuscular myxomas usually arise in the musculature of the thigh, with a peak incidence between 30 and 70 years of age and a female predominance ♦♦ They present as a slow growing painless mass; up to 5% are multiple and associated with fibrous dysplasia (Mazabraud syndrome) ♦♦ Local recurrences are rare after excision

Microscopic ♦♦ Intramuscular myxoma is usually well circumscribed but extends between muscle fibers ♦♦ The lesions are paucicellular and have minimal vascularity ♦♦ The tumor is composed of small, bland, spindle or stellate cells with hyperchromatic nuclei floating in a background of myxoid matrix. The cells lack pleomorphism and mitotic activity

Differential Diagnosis ♦♦ Myxoid liposarcoma: this has a plexiform capillary network and contains lipoblasts

♦♦ Digital myxoma is an uncommon lesion that occurs as a small nodule on the finger of adults with a marked female predominance ♦♦ They are poorly circumscribed intradermal lesions composed of bland fibroblasts within a myxoid matrix ♦♦ Local recurrence occurs frequently

Superficial Angiomyxoma (Fig. 22.34) ♦♦ Superficial angiomyxoma is usually sporadic and may occur as multiple lesions in association with Carney complex ♦♦ The lesions usually affect adults and present as a superficial nodule involving dermis and subcutis, on the head and neck, trunk, or vulvovaginal region ♦♦ Local recurrence is common ♦♦ The tumors usually measure less than 4  cm and are composed of multiple, poorly defined myxoid nodules of scattered plump fibroblasts, numerous thin-walled vessels, a neutrophilic infiltrate (without associated necrosis or ulceration), and entrapped epithelial elements ♦♦ Local recurrence is common

Ganglion Cyst ♦♦ Ganglion cysts are common, and typically arise on the dorsum of the wrist in young adults ♦♦ They are frequently attached to a joint capsule and tendon sheath and may arise as a protrusion of synovium ♦♦ Histologically, they consist of bland fibrous tissue in a myxoid matrix, often without a true cyst lining

Angiomatoid “MFH” Clinical

Fig.  22.33. Intramuscular myxoma: hypocellular spindle cell neoplasm with small spindle cells.

♦♦ Angiomatoid MFH arises most often in children or adolescents with no sex predilection ♦♦ It occurs in the subcutis and deep dermis of upper extremities, and may be associated with systemic features including pyrexia, anemia, weight loss, or paraproteinemia ♦♦ They usually present as a slow-growing, fluctuant subcutaneous mass and have an excellent prognosis, provided the mass is completely excised ♦♦ There is a 10–15% local recurrence rate and <1% metastasize to lungs and lymph nodes

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Fig. 22.35. PEComa: nests of epithelioid cells with eosinophilic to clear cytoplasm.

Differential Diagnosis ♦♦ Aneurysmal benign fibrous histiocytoma: more superficial, more polymorphous cell population, and lack desmin expression ♦♦ Pleomorphic sarcoma: more cytologic atypia and pleomorphism with abnormal mitoses ♦♦ Metastatic melanoma: S-100 protein and HMB 45 ­expression will be seen in melanoma

Uncertain Biologic Potential PEComa (Fig. 22.35) Fig.  22.34. Superficial angiomyxoma: similar morphology with scattered neutrophils and no association with necrosis or ulceration (A, B).

Microscopic ♦♦ Tumors are composed of multiple nodules and sheets of uniform histiocytoid cells within a collagenous stroma surrounded by a fibrous pseudocapsule ♦♦ Neoplastic cells have vesicular, spindled nuclei and pale eosinophilic cytoplasm, mild pleomorphism and infrequent mitoses ♦♦ Large blood-filled pseudovascular spaces (no endothelial lining) with cystic hemorrhage and extensive hemosiderin deposition account for the name “angiomatoid” MFH ♦♦ Prominent lymphoid hyperplasia (peripheral) may be present, simulating a lymph node ♦♦ Focal myxoid change is sometimes present and rarely giant cells are seen

Immunohistochemistry ♦♦ Neoplastic cells are usually positive for EMA and desmin in approximately 50% of cases

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♦♦ The PEComa family of tumors demonstrate myomelanocytic differentiation and and include angiomyolipomas and lymphangioleomyomatosis ♦♦ Most PEComas occur in adults with a female ­predominance; common sites of involvement include soft  tissue sites and viscera, such as uterus ♦♦ Most tumors have a benign clinical course but malignant cases also exist ♦♦ PEComas have a broad range of morphological features, but are usually nested and composed of epithelioid cells with granular eosinophilic or clear cytoplasm. In some cases, the tumor cells may be spindled with a myoid appearance ♦♦ The background stroma usually contains a thin walled vascular network ♦♦ The presence of marked nuclear pleomorphism, high mitotic activity, or necrosis are features worrisome for malignancy ♦♦ The tumor cells express SMA and HMB 45, and less frequently Melan-A, desmin, and S-100

Ossifying Fibromyxoid Tumor Clinical ♦♦ This is a recently described tumor of uncertain lineage that presents as a subcutaneous nodule involving the extremities of adults with a male predominance

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♦♦ Tumors may recur locally, and rare cases may show malignant potential

♦♦ Children and those with smaller primary tumors seem to have a better prognosis

Microscopic

Microscopic

♦♦ Ossifying fibromyxoid tumor (OFMT) is a well-circumscribed, multinodular lesion, usually <5 cm in diameter, with a fibrous capsule and a shell of mature lamellar bone (90% of cases). Nonossifying examples have been recognized ♦♦ Neoplastic cells are arranged in nests and cords, and have round, monomorphic, vesicular nuclei with pale cytoplasm with minimal pleomorphism and rare mitoses within an abundant fibromyxoid stroma ♦♦ Chondroid metaplasia is occasionally present ♦♦ Atypical OFMT is characterized by irregular bone distribution, increased cellularity and mitosis, common recurrence, and rarely metastases (to lung) ♦♦ The round cells are positive for S-100 protein (80% cases), desmin (60%), and actin (50%)

♦♦ Although grossly these tumors are often poorly circumscribed, histologically they are composed of a lobulated organoid pattern of nests or sheets of large epithelioid cells ♦♦ Neoplastic cells are usually arranged in nests, may be solid, or may have an alveolar pattern due to central dyscohesion and necrosis of tumor cells. These nests are separated by delicate fibrovascular septa containing small blood vessels ♦♦ Neoplastic cells are typically monomorphic large, round cells with clear to eosinophilic granular cytoplasm and eccentric round nuclei with prominent nucleoli ♦♦ PAS positive diastase resistant intracytoplasmic crystals and granules and intracytoplasmic glycogen are present to variable degrees ♦♦ Nuclear pleomorphism is usually mild and mitotic activity low. ♦♦ Vascular invasion, especially of dilated peripheral veins, is identified in nearly all cases

Malignant

Immunohistochemistry

Alveolar Soft Part Sarcoma (Fig. 22.36) Clinical

♦♦ Positive staining for the carboxy terminal of TFE3 is seen in most cases, reflecting the characteristic cytogenetic abnormality seen in ASPS (see below) ♦♦ The tumor cells are usually negative for keratins

Immunohistochemistry

♦♦ ASPS accounts for <1% of all sarcomas, affects predominantly adolescents or young adults and shows a female predominance ♦♦ In adults, the lower extremities are the most common sites of involvement, whereas in children, the head and neck region is the most common site of involvement ♦♦ Clinically, ASPS usually presents as a slow-growing and painless mass; however, it is not uncommon for patients to present with metastases to lungs or brain ♦♦ Although an indolent growing tumor, the prognosis for patients with ASPS is poor due to an extremely high frequency of metastatic disease

Cytogenetics ♦♦ The characteristic abnormality in ASPS is a t(X;17)(p11;q25), which results in the fusion protein ASPL/TFE3

Differential Diagnosis ♦♦ Metastatic renal cell carcinoma: this will usually show more pleomorphism, lack intracytoplasmic crystals, and will express cytokeratin ♦♦ Melanoma: this is usually more pleomorphic and express HMB 45 and S-100 protein ♦♦ Paraganglioma: lacks intracytoplasmic glycogen, and contains chromogranin and synaptophysin

Clear Cell Sarcoma of Soft Tissue (Malignant Melanoma of Soft Parts) (Fig. 22.37) Clinical

Fig.  22.36. Alveolar soft part sarcoma: large polygonal cells with central degeneration and alveolar pattern.

♦♦ Clear cell sarcoma of soft tissue is a rare tumor that is intimately associated with tendons and aponeuroses, most commonly in the distal extremities, especially at the foot and ankle ♦♦ There is a peak incidence between the ages of 20 and 40 years, and a slight female predominance ♦♦ Tumors present as a slow growing, painful mass, usually with repeated local recurrences due to incomplete excision ♦♦ About 50% of patients develop late metastases to lungs, lymph nodes, or bone, and there is a poor long-term prognosis despite adjuvant therapy

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polygonal to spindle cells separated by fibrous septa with ­infiltration into fibrotendinous tissue, subcutis, or deep dermis ♦♦ Tumor cells have pale eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. Only rarely do tumor cells show clear cytoplasm. Multinucleated giant cells with wreath-like nuclei are often present ♦♦ Despite the aggressive nature of this tumor, nuclear pleomorphism and mitotic activity is usually low

Immunohistochemistry ♦♦ Tumor cells are usually S-100 protein and HMB 45 positive, reflecting melanocytic differentiation. Neuron-specific enolase (NSE), keratin, and actin positivity have also been reported

Cytogenetics ♦♦ The reciprocal translocation t(12; 22) (q13; q13), which results in an EWS/ATF1 fusion transcript is detected in most cases of clear cell sarcoma

Differential Diagnosis ♦♦ Cutaneous melanoma: this will usually have a junctional component and show a more irregular growth pattern and greater nuclear pleomorphism. In cases with no junctional component, cytogenetics studies are needed for the diagnosis ♦♦ MPNST: this is associated with peripheral nerves and/or NF-1. Tumor cells do not contain glycogen, are more hyperchromatic nuclei, and show greater mitotic activity. In addition, they should be negative for HMB 45 ♦♦ Metastatic renal cell carcinoma: this shows less prominent nucleoli, lacks the fusiform appearance, and shows diffuse positivity for cytokeratin (low molecular weight) and EMA

Extraskeletal Myxoid Chondrosarcoma (Fig. 22.38) Clinical ♦♦ Extraskeletal myxoid chondrosarcoma (EMC) usually presents as a painless, slow-growing, deep-seated mass. The most common sites of involvement are the lower limb (70%), trunk (20%), and upper limb (10%) ♦♦ Adults are most commonly affected with a peak age of 30–60 years, and a slight male predominance ♦♦ EMC is prone to local recurrences and metastases (40–50% of cases) to lungs, lymph nodes, bone, and brain. Poor prognostic factors include advanced age at presentation and size greater than 10 cm Fig. 22.37. Clear cell sarcoma: small spindled cells with monotonous cytomorphology and prominent nucleoli, similar to malignant melanoma (A). These tumors show positivity for S-100 protein (B) and HMB 45 (C).

Microscopic ♦♦ Tumors are usually <5 cm, associated with fascial and tendinous tissue, and composed of nests or fascicles of uniform round,

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Microscopic ♦♦ Histologically, these tumors show a lobular growth pattern with fibrous septa separating areas with copious myxoid matrix and with greater cellularity at the periphery of the lobules ♦♦ Neoplastic cells tend to grow in anastomosing cords and strands, and are usually small uniform ovoid cells with eosinophilic cytoplasm. The cells may also have a spindled or epithelioid appearance and may contain cytoplasmic hyaline (rhabdoid) inclusions

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50% metastasize to lymph nodes, lung and soft tissue; ES is one of the few sarcomas that metastasize to lymph nodes ♦♦ Tumors measuring less than 5  cm, younger age and more superficial tumors impart a better prognosis

Microscopic ♦♦ ES usually have diffusely infiltrative edges. Tumor is composed of nodules of monomorphic, eosinophilic, and epithelioid to spindle-shaped cells arranged in a granulomatous-like pattern ♦♦ Neoplastic cells typically show minimal nuclear pleomorphism and variable mitotic activity ♦♦ The milieu of ES is usually necrosis or myxohyaline degeneration within the tumor nodules (accounting for the granulomatous appearance) and dense fibrous stroma ♦♦ Perineural and vascular invasion are often present Fig.  22.38. Extraskeletal myxoid chondrosarcoma: anasto­ mosing cords of small ovoid cells in a prominent myxoid background.

♦♦ Mitoses and necrosis is present to varying extents but usually the mitotic activity of these tumors is low ♦♦ Well formed hyaline cartilage is rarely found within EMC

Immunohistochemistry ♦♦ EMC shows focal S-100, cytokeratin, and EMA positivity in a minority of cases

Cytogenetics ♦♦ The most common translocation seen in extraskeletal myxoid chondrosarcoma is t(9;22)(q22;q12), which results in the formation of an EWS/NR4A3 fusion transcript with oncogenic function

Differential Diagnosis ♦♦ Myoepithelioma of soft tissue: more superficial location, epithelial differentiation an expression of keratin, actin, and S-100 protein favors the latter

Epithelioid Sarcoma Clinical ♦♦ ES occurs in adolescents and young adults with a male predominance, and is of unknown lineage ♦♦ The most common sites of involvement are the distal extremities, especially the hand and wrist region (flexor surfaces) ♦♦ Clinically, it presents as a solitary (occasionally multiple) multinodular, slow-growing, superficial mass with involvement of the dermis and subcutis, sometimes with fascial or tendoninous attachments. Pain and ulceration are common ♦♦ Tumor spreads along fascial planes or neurovascular bundles, and thus surgical resections must be done with a wide excision margin, often requiring limb amputation ♦♦ The natural history of this tumor is one of a slow, relentless course with multiple local recurrences and eventual metastases and death, even with initial radical treatment. Approximately

Immunohistochemistry ♦♦ Tumor cells are typically cytokeratin and EMA positive, and show expression of CD34 in 50% of cases ♦♦ Most cases of ES show loss of INI-1 expression, which can help in the differential diagnosis with carcinomas, which nearly always have intact INI-1 expression

Differential Diagnosis ♦♦ Infections or necrobiotic granuloma: absence of nuclear pleomorphism, vascular and perineural invasion and negative staining for keratin and EMA and positive staining for CD68 all favor a benign process ♦♦ Nodular fasciitis, fibrous histiocytoma, and fibromatosis: these proliferations usually lack nodularity and the lesional cells do not have epithelioid features or cytokeratin expression ♦♦ Squamous cell carcinoma: epidermal involvement, dyskeratosis, keratin pearls, more cytological pleomorphism and lack of CD34 expression all favor squamous cell carcinoma ♦♦ Malignant melanoma: more nuclear pleomorphism, expression of melanocytic markers, and lack of cytokeratin expression helps resolve this differential in most cases

Variant ♦♦ Proximal-type ES: this variant of ES arises in older adults in the pelvis, perineum, or groin, usually as a deep-seated lesion. It has a more aggressive clinical course than the typical variant with earlier metastases and disease related deaths. Histologically, it is also multinodular with focal necrosis but tends not to show a granulomatous-like appearance. Tumor cells are usually more pleomorphic with carcinomalike cytology including prominent nucleoli and rhabdoid features

Peripheral Primitive Neuroectodermal Tumor/Extraosseous Ewing sarcoma (Fig. 22.39) ♦♦ PNET/Ewing tumors are a family of tumors with specific and reproducible translocations, most commonly t(11; 22) (q24;q12), and variable neuroectodermal differentiation

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ing light and dark areas, scant stroma, and a prominent capillary network. Necrosis is commonly present ♦♦ Neoplastic cells are primitive with scant pale to eosinophilic cytoplasm and round hyperchromatic nuclei with fine chromatin and sometimes prominent nucleoli ♦♦ Mitotic activity is variable but is often high, and apoptotic cells may also be frequent ♦♦ Homer–Wright rosettes and pseudorosettes occur in more well differentiated tumors

Immunohistochemistry ♦♦ Classically, PNET/Ewing tumors show diffuse strong membranous positivity (“Olympic ring”) for MIC2/CD99; although CD99 is not specific for PNET/Ewing tumors, this pattern of staining with the appropriate morphology and clinical setting is highly suggestive of a Ewing tumor

Cytogenetics/Molecular Genetics ♦♦ The most common translocation seen is t(11;22)(q24;q12), resulting in an EWS-FLI-1 fusion protein. Other translocations also occur, most of which involve the EWS region on chromosome 22 ♦♦ The EWS/FLI-1 fusion protein occurs in two types, and the Type 1 transcript is reported to be associated with an improved prognosis

Differential Diagnosis

Fig.  22.39. Ewing sarcoma: small round cell neoplasm with primitive appearance (A) and characterized by membranous positivity for CD99 (B).

Clinical ♦♦ Tumors occur over a wide age range, with a peak incidence between 10 and 30 years and a male predilection. Ewing sarcoma is the second most common sarcoma of bone and soft tissue in childhood ♦♦ Common sites of involvement include the trunk and lower limbs, and occasionally they arise in association with a nerve trunk ♦♦ They are usually rapidly enlarging, deep-seated masses that are, for the most part, unresectable. However, they usually are responsive to chemotherapy ♦♦ The Ewing family of tumors are high grade tumors, with metastases occurring to the lungs and lymph nodes; the overall 5-year survival is 20–30%

Microscopic ♦♦ At low power examination, PNET/Ewing sarcoma shows lobules, trabeculae, and sheets of cells, often with alternat-

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♦♦ Neuroblastoma: the presence of neuropil, ganglionic differentiation and calcifications, and lack of MIC2/CD99 staining in neuroblastoma aid in the differential diagnosis with Ewing tumors ♦♦ Rhabdomyosarcoma: typically express the muscle markers actin, desmin, and myogenin to varying extents ♦♦ Lymphoma: typically grow without any specific growth pattern, and express lymphocytic markers such as CD45 ♦♦ Neuroendocrine carcinoma: this shows cytokeratin positivity and will lack MIC2/CD99 expression

Extrarenal Rhabdoid Tumor ♦♦ Extrarenal rhabdoid tumor is a rare malignant neoplasm of childhood, usually arising in infancy ♦♦ While tumors may occur at any location, the trunk and proximal extremities are most commonly involved ♦♦ This tumor has a very aggressive clinical course with a median survival of 6 months; metastases occur to lungs, liver, lymph nodes, and soft tissue ♦♦ Tumor is composed of sheets of cells with large nuclei, prominent nucleoli and eccentric cytoplasm often containing hyaline globular inclusions ♦♦ Neoplastic cells usually express cytokeratin, EMA, and vimentin, and immunohistochemistry is essential to exclude other tumors that may have a rhabdoid phenotype ♦♦ Loss of INI-1 (SMARCB-1) expression is seen in most cases of extrarenal rhabdoid tumor, and is also helpful in the differential diagnosis

Soft Tissue Tumors

Desmoplastic Small Round Cell Tumor (Fig. 22.40) Clinical ♦♦ Desmoplastic small round cell tumor (DSRCT) arises in adolescents and young adults and shows a marked male predominance ♦♦ Tumor almost exclusively involves the peritoneal surfaces of the abdomen, pelvis, and omentum, with involvement of extraabdominal sites occurring rarely. There are often widespread peritoneal implants, with or without a dominant mass ♦♦ Clinical presentation may be with abdominal distension, a mass, constipation, obstruction, or ascites ♦♦ DSRCT is a highly aggressive neoplasm with a poor prognosis ♦♦ Tumors are normally not amenable to surgical excision and widespread metastases are common, with death within a few years despite treatment

Microscopic ♦♦ Grossly, the tumor exists as solid, large multilobulated mass, often as multiple discrete nodules, with or without areas of necrosis ♦♦ Microscopically, there are nests or sheets of varying sizes composed of small rounded cells within an abundant fibrotic, desmoplastic stroma ♦♦ Tumor cells may often be in a trabecular or cord-like arrangement, are hyperchromatic with inconspicuous nucleoli, scant cytoplasm and brisk mitotic activity. The cells may be vacuolated or contain PAS + eosinophilic inclusions

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♦♦ Reflecting the characteristic translocation, positive staining for the C-terminal of WT-1 (polyclonal antibody) is usually demonstrable

Cytogenetics ♦♦ The characteristic translocation associated with DSRCT is t(11;22)(q13;q12), and results in an EWS-WT1 fusion protein

Differential Diagnosis ♦♦ Although the appearances of DSRCT in the appropriate clinical setting is quite characteristic, in biopsies or limited specimens, the differential may include primitive neuroectodermal tumor (Ewing sarcoma), neuroblastoma, rhabdomyosarcoma, neuroendocrine carcinoma, seminoma or lymphoma

Synovial Sarcoma (Fig. 22.41) Clinical ♦♦ Initially believed to originate from synoviocytes, synovial sarcoma actually shows no relationship with synovium ♦♦ It may arise at any age, but there is a peak between 10–35 years, with a slight male predominance

Immunohistochemistry ♦♦ DSRCT is a tumor of unknown lineage and shows a polyphenotypic immunoprofile, with expression of cytokeratin, EMA, desmin (usually paranuclear dot-like staining), and occasionally S-100 protein

Fig. 22.40. Desmoplastic small round cell tumor: nests of small spindle cells with intervening desmoplastic stroma.

Fig. 22.41. Synovial sarcoma: monophasic (A) and biphasic (B).

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♦♦ Clinical presentation is usually with a deep-seated painful, slow-growing mass, often close to a large joint, with the most common sites being the lower limbs, abdomen, and head and neck region ♦♦ The 5-year survival rate is approximately 50%, and the clinical course is marked by late recurrences and metastases to lungs, lymph nodes, and bone marrow ♦♦ Good prognostic features include size <5 cm, early clinical stage and age less than 10 years

Macroscopic ♦♦ Grossly, synovial sarcoma is usually well-circumscribed and multilobular with a pseudocapsule

Microscopic ♦♦ Two histologic patterns may be identified: biphasic or monophasic ♦♦ Monophasic synovial sarcoma consists of a hypercellular, monomorphic proliferation of spindle cells arranged in fascicles and whorls with high nuclear to cytoplasmic ratio and tapering nuclei and variable mitotic activity ♦♦ Focal stromal calcification is seen in one-third of cases, and less commonly foci of ossification ♦♦ Additional features include stromal mast cells, collagenous stroma, and a branching, hemangiopericytoma-like vascular pattern

♦♦ Biphasic synovial sarcoma consists of both the spindle cell component and an epithelial component, usually in the form of glandular structures lined by cuboidal to columnar epithelium ♦♦ Round cell morphology can be seen in poorly differentiated synovial sarcoma and carries a worse prognosis

Immunohistochemistry ♦♦ Tumor cells express cytokeratins, EMA, S-100 (30%), and CD99 (60%)

Cytogenetics ♦♦ A t(X;18)(p11.2; q11.2) is seen in synovial sarcoma and results in two fusion genes: SYT-SSX1 and SYT-SSX2. The association between the fusion type and histologic pattern or prognosis is controversial

Differential Diagnosis ♦♦ ES: this has a superficial location usually in the upper limbs, and a multinodular growth pattern with central necrosis ♦♦ Clear cell sarcoma of soft parts: this has a nesting pattern and is composed of tumor cells with pale nuclei with macronucleoli and intracellular glycogen that are ­cytokeratin negative and S-100 protein positive ♦♦ Malignant peripheral nerve sheath tumor: this is usually associated with a large nerve, neurofibroma or NF-1 ♦♦ Carcinosarcoma: the epithelial and sarcomatous ­components in carcinosarcomas are usually of higher grade

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Billings SD, McKenney JK, Folpe AL, et  al. Cutaneous angiosarcoma ­following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol 2004;28:781–188.

Chbani L, Guillou L, Terrier P, et al. Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol 2009;131:222–227.

Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcomasubtype: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005;29:1340–1347.

Dalal KM, Antonescu CR, Singer S. Diagnosis and management of lipomatous tumors. J Surg Oncol 2008;97:298–313.

Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin Cancer Res 2003;9:1941–1956.

Deyrup AT, McKenney JK, Tighiouart M, et  al. Sporadic cutaneous angiosarcomas: a proposal for risk stratification based on 69 cases. Am J Surg Pathol 2008;32:72–77.

Bowne WB, Antonescu CR, Leung DH, et  al. Dermatofibrosarcoma ­protuberans: a clinicopathologic analysis of patients treated and followed at a single institution. Cancer 2000;88:2711–2720.

Drilon AD, Popat S, Bhuchar G, et al. Extraskeletal myxoid chondrosarcoma: a retrospective review from 2 referral centers emphasizing long term outcomes with surgery and chemotherapy. Cancer 2008;113: 3364–3371.

Brimo F, Robinson B, Guo C, et al. Renal epithelioid angiolipoma with atypia: a series of 40 cases with emphasis on clinicopathologic prognostic indicators of malignancy. Am J Surg Pathol 2010;34:715–722.

Evans HL. Atypical lipomatous tumor, its variants, and its combined forms: a study of 61 cases, with a minimum follow-up of 10 years. Am J Surg Pathol 2007;31:1–14.

Brown FM, Fletcher CD. Problems in grading soft tissue sarcomas. Am J Clin Pathol 2000;114:S82–S89.

Fayette J, Martin E, Piperno-Neumann S, et  al. Angiosarcomas, a ­heterogenous group of sarcomas with specific behavior depending on ­primary site: a retrospective study of 161 cases. Ann Oncol 2007;18: 2030–2036.

Cany L, Stoeckle E, Coindre JM, et al. Prognostic factors in superficial adult soft tissue sarcomas: analysis of a series of 105 patients. J Surg Oncol 1999;71:4–9. Carlson JW, Fletcher CD. Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature. Histopathology 2007;51:509–514.

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Folpe AL, Goldblum JR, Rubin BP, et al. Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically ­confirmed cases. Am J Surg Pathol 2005;29:1025–1033. Folpe AL, Lane KL, Paull G, et al. Low grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high grade areas. Am J Surg Pathol 2000;24:1353–1360. Folpe AL. Practical applications of immunohistochemistry in the diagnosis of soft tissue neoplasms. Surg Oncol 1999;8:197–203. Gebhard S, Coindre JM, Michels JJ, et  al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol 2002;26:601–616. Giovannini M, Biegel JA, Serra M, et al. EWS-erg and EWS-Fli1 fusion transcripts in Ewing’s sarcoma and primitive neuroectodermal tumors with variant translocations. J Clin Invest 1994;94:489–496. Guillou L, Benhattar J, Bonichon F, et  al. Histologic grade, but not ­SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol 2004;22:4040–4050. Guillou L, Wadden C, Coindre JM, et  al. “Proximal-type” epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol 1997;21:130–146. Hawkins WG, Hoos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer 2001;91: 794–803.

Lewis JJ, Antonescu CR, Leung DH, et  al. Synovial sarcoma: a ­multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremities. J Clin Oncol 2000;18: 2087–2094. McMenamin ME, Fletcher CD. Mammary-type myofibroblastoma of soft tissue: a tumor closely related to spindle cell lipoma. Am J Surg Pathol 2001;25:1022–1029. Mentzel T, Dry S, Katenkamp D, et  al. Low grade myofibroblastic ­sarcoma: analysis of 18 cases in the spectrum of myofibroblastic tumors. Am J Surg Pathol 1998;22:1228–1238. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest 2005;85:408–415. Michal M, Fetsch JF, Hes O, et al. Nuchal-type fibroma: a clinicopathologic study of 52 cases. Cancer 1999;85:156–163. Nascimento AF, Raut CP, Fletcher CD. Primary angiosarcoma of the breast: clinicopathologic analysis of 49 cases, suggesting that grade is not prognostic. Am J Surg Pathol 2008;32:1896–1904. Nascimento AF, Raut CP. Diagnosis and management of pleomorphic ­sarcomas (so-called “MFH”) in adults. J Surg Oncol 2008;97:330–339. Oliveira AM, Sebo TJ, McGrory JE, et al. Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and ploidy analysis of 23 cases. Mod Pathol 2000;13:900–908. Oliveira AM, Fletcher CD. Molecular prognostication for soft tissue ­sarcomas: are we there yet? J Clin Oncol 2004;22:4031–4034.

Hornick JL, Fletcher CD. Criteria for malignancy in nonvisceral smooth muscle tumors. Ann Diagn Pathol 2003;7:60–66.

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Hostein I, Audraud-Fregeville M, Guillou L, et al. Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded ­specimens. Cancer 2004;101:2817–2824.

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Singer S, Demetri GD, Baldini EH, et  al. Management of soft tissue ­sarcomas: an overview and update. Lancet Oncol 2000;1:75–85. Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer 2001;92: 359–368. Zagars GK, Ballo MT, Pisters PW, et al. Prognostic factors for patients with localized soft tissue sarcoma treated with conservation surgery and radiation therapy: an analysis of 1225 patients. Cancer 2003;97: 2530–2543.

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23 Tumor of the Salivary Glands Diana M. Bell, md and Adel K. El-Naggar, md

Contents

I. Introduction to Salivary Gland Tumors....................................23-3

II. Tumor-Like and Cystic Lesions...........23-6

Tumor-Like Lesions.........................................23-6 Sialolithiasis............................................23-6 Sialadenitis..............................................23-6 Sialadenosis.............................................23-6 Necrotizing Sialometaplasia..................23-6 Oncocytosis.............................................23-6 Lymphoepithelial Lesions......................23-6 Sjögren Syndrome..................................23-7 Küttner Tumor (Chronic Sclerosing Sialadenitis of Submandibular Gland)................23-7 Cystic Lymphoid Hyperplasia (HIV+ Subjects) . ..............................23-7 Inflammatory Pseudotumors................23-7 Salivary Gland Cysts........................................23-8 Benign Cysts of Salivary Gland: An Overview......................................23-8 Cystic Neoplasms....................................23-8 Inflammatory, Specific, and Nonspecific..................................23-8 Benign Cystic Lesions of the Neck........23-9

III. Benign Tumors.................................23-10 Epithelial.........................................................23-10 Pleomorphic Adenoma (Mixed Tumor)................................23-10 Myoepithelioma....................................23-11 Oncocytoma..........................................23-11 Warthin Tumor (Adenolymphoma)...........................23-12 Sebaceous Lymphadenoma.................23-12

Sebaceous Adenoma.............................23-13 Basal Cell Adenoma.............................23-13 Membranous Adenoma (Dermal Analog Tumor) ................23-13 Canalicular Adenoma..........................23-14 Nonepithelial...................................................23-14

IV. Malignant Epithelial Tumors.............23-15 Malignant Mixed Tumor...............................23-15 Carcinoma Ex Pleomorphic Adenoma..........................................23-15 Carcinosarcoma (Concomitant Epithelial and Mesenchymal Malignancy).....................................23-16 Metastasizing Pleomorphic Adenoma..........................................23-17 Myoepithelial Carcinoma..............................23-17 Oncocytic Carcinoma.....................................23-18 Carcinoma in Warthin Tumors.....................23-18 Sebaceous Carcinoma....................................23-18 Basal Cell Adenocarcinoma...........................23-19 Acinic Cell Carcinoma...................................23-20 Adenoid Cystic Carcinoma............................23-21 Mucoepidermoid Carcinoma........................23-23 Salivary Duct Carcinoma..............................23-24 Epithelial–Myoepithelial Carcinoma............23-25 Terminal Duct Carcinoma (Polymorphous Low Grade Adenocarcinoma)......................................23-26 Primary Squamous Cell Carcinoma.............23-26 Undifferentiated Carcinoma.........................23-27 Small Cell Carcinoma..........................23-27 Large Cell Carcinoma..........................23-27 Lymphoepithelial Carcinoma..............23-28 Rare Types of Adenocarcinoma....................23-28

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_23, © Springer Science+Business Media, LLC 2002, 2006, 2011

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V. Salivary Gland Carcinomas: Other VI. Metastasis to Salivary Gland............23-31 General Features............................................23-31 Tumors.............................................23-29 Primary Lymphomas of Salivary Gland.......................................23-29 Mesenchymal Tumors of Salivary Glands.....................................23-29 Salivary Gland Tumors in Children.............23-29 General Features..................................23-29 Juvenile Capillary Hemangioma........23-30 Sialoblastoma (Embryoma).................23-31 Malignant Epithelial Tumors..............23-31

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VII. Immunohistochemistry in the Assessment of Salivary Gland Tumors..................................23-32 VIII. TNM Classification of Major Salivary Gland (2010 Revision)........23-33 IX. Suggested Reading...........................23-33

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INTRODUCTION TO SALIVARY GLAND TUMORS ♦♦ Salivary gland tumors are predominantly epithelial (Tables 23.1–23.6). Mesenchymal tumors most often involve glands by extension rather than arising within the gland. The latter are also found predominantly in children and adolescents. The most commonly encountered tumors in surgical pathology will be highlighted in this chapter. The nonpleo-

morphic salivary adenomas can be placed under the domain of monomorphic adenoma. These, in turn, can be divided into basaloid and nonbasaloid tumors (Tables 23.7 and 23.8). There is also an inverse relationship between site of the affected salivary gland and the frequency of malignancy (Table 23.15).

Table 23.1. Categorical Classification of Salivary Gland Lesions

Reactive/Developmental

Tumor-like

Primary Neoplasms

Metastasis

Cysts

Benign

Malignant

Table 23.2. Tumor-Like and Cystic Lesions

Tumor-like 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Sialolithiasis Sialadenitis Sialadenosis Ductal adenoma/ hamartoma Oncocytosis Necrotizing sialometaplasia Benign lymphoepithelial lesions and Sjogrens syndrome Chronic sclerosing sialadenitis of the submandibular gland (Kuttner tumor) Cystic lymphoid hyperplasia in AIDS Inflammatory pseudo tumor Others: nodular fasciitis, sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease), Wegener granulomatosis.

Cystic lesions A) Benign cysts B) Cystic neoplasms C) Inflammatory, specific and non-specific

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Table 23.3. Incidence and Location of Nonneoplastic Salivary Gland Cysts (Batsakis and Raymond 1989) Type Mucocele Salivary duct Lymphoepithelial Ranula Congenital sialectasis Polycystic (dysgenetic)

Site

Frequency (%)

Minor glands Parotid Parotid and oral cavity Sublingual gland Parotid Parotid

76.0 9.0 7.0 6.0 1.5 <1.0

Table 23.4. Frequency of Retention Mucoceles by Site (Modified from S. Seifert) Site

Frequency (%)

Lower lip Cheek Floor of mouth Upper lip Palate Tongue Other areas No information

23.5 13.2 12.6 15.4 8.8 4.4 16.1 5.9

Table 23.5. Salivary Gland Neoplasms

Benign

Epithelial

• • • • • • • •

Pleomorphic adenoma (benign mixed tumor) Basal cell adenoma/ canalicular adenoma Warthin tumor Oncocytoma Myoepithelioma Sebaceous adenoma Ductal papilloma Cystadenoma

Malignant

Mesenchymal

• • • •

Angioma Sialolipoma Fibrous histiocytoma Neurofibroma and neurilemmoma

Epithelial

• • • •

Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Terminal duct carcinoma (polymorphous low grade adenocarcinoma)

• • • • • •

Epithelial-myoepithelial carcinoma Salivary duct carcinoma Basal cell adenocarcinoma Sebaceous carcinoma Oncocytic carcinoma Adenocarcinoma, NOS (not otherwise classified) Squamous cell carcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma (sarcomatoid carcinoma) Myoepithelial carcinoma Undifferentiated carcinoma (small and large cells) Lymphoepithelioma (undifferentiated carcinoma with lymphoid stroma)

• • • • • •

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Nonepithelial

• Sarcomas • Lymphomas

Tumor of the Salivary Glands

23-5

Table 23.6. Incidence of Primary Epithelial Salivary Gland Neoplasms in Different Sites (%) Diagnosis

Parotid

Benign   Pleomorphic adenoma   Adenolymphoma   Monomorphic adenoma Malignant   Mucoepidermoid ca.   Acinic cell ca.   Adenoid cystic ca.   Adenocarcinoma (NOS)   Squamous ca.   Undifferentiated ca.   Carcinoma Ex-PA

Submandibular

Sublingual

Minor

63.3 14.0 8.0

59.5 0.8 2.3

0 0 14.0

42.9 0 11.0

1.5 2.5 2.0 2.6 1.1 1.8 3.2

1.6 0.4 16.8 5.0 1.9 3.9 7.8

0 0 28.6 14.2 0 14.2 28.6

8.9 1.8 13.1 12.2 1.2 2.1 7.1

Table 23.7. Types of Monomorphic Adenomas Basal

Nonbasal Warthin tumor Oncocytoma Sebaceous lymphadenoma Sebaceous adenoma Ductal adenoma (Fig. 23.1)

Tubulotrabecular Solid Canalicular Dermal analog

Table 23.8. Differential Characteristics Between Basal Adenomas and Canalicular Adenoma (Modified from Eveson and Cawson 1985) Feature Sex   Female/male Age (years)   Range   Mean  Synchronous dermal lesions Site (%)   Parotid   Submandibular   Upper lip   Other minor site Multicentricity Recurrences Malignant transformation

Basal adenoma

Other types

Canalicular

1:10

1:1

  1.7:1

34–74 58.1 37.7%

  1–83 58.6 0

  34–88 65.1 0

86.2   6.8  0   6.8 48% 24% 28%

90.1   4.9   1.9  0   0.9  0    3.9%

  1.6  0 87.2 24.7 24.0 0 0

Fig. 23.1. Ductal adenoma.

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Essentials of Anatomic Pathology, 3rd Ed.

TUMOR-LIKE AND CYSTIC LESIONS Tumor-Like Lesions (See Table 23.2) Sialolithiasis ♦♦ Predominantly in submandibular gland ♦♦ Undulant and tender swelling ♦♦ Parotid less frequent and difficult to diagnose clinically

Microscopic ♦♦ Dilated ducts ♦♦ Squamous metaplasia ♦♦ Acinar atrophy and inflammation

Sialadenitis ♦♦ Acute and chronic nonspecific inflammation −− Bacterial: Staphylococcus aureus −− Viral: cytomegalovirus, paramyxovirus, Epstein–Barr virus, para and influenza viruses, and coxsackievirus ♦♦ Granulomatous −− Obstructive sialadenopathy

−−

−− −− −−

−−

(a) Ruptured mucoceles (b) Extravasated mucin Infectious (a) Mycobacterial, cat-scratch, disease, tularemia, ­fungal, toxoplasmosis, and others Sarcoidosis Associated with systemic disease (a) Wegener granulomatosis, Crohn disease, and others Associated with salivary gland tumor (a) Acinic cell carcinoma (b) Mucoepidermoid carcinoma (c) Warthin tumor (d) Lymphoepithelial lesions Foreign body granulomas (a) Iatrogenic (sialography)

Fig. 23.2. Necrotizing sialometaplasia. ♦♦ Uncertain etiology, vascular origin?

Macroscopic ♦♦ Mucosal site, ulceration, and painful swelling ♦♦ Nonulcerated: one-third of lesions

Microscopic (Fig. 23.2) ♦♦ Lobular distribution ♦♦ Central ductal squamous metaplasia ♦♦ Peripheral necrotic and inflamed acini

Differential Diagnosis ♦♦ Squamous carcinoma −− Infiltrative, keratinization, cellular features of malignancy −− Lacks lobular preservation ♦♦ Mucoepidermoid carcinoma −− Mucinous cells, infiltrative intermediate cells, and cystic formations

Sialadenosis

Oncocytosis (Fig. 23.3)

♦♦ ♦♦ ♦♦ ♦♦

♦♦ ♦♦ ♦♦ ♦♦

Hypertrophy and hyperplasia of acini Associated with systemic and neural disorders Presents as bilateral painless and recurrent swelling Etiology: neurogenic, metabolic, or hormonal

Oncocytic hyperplasia of ductal and acinar structure Unilateral or bilateral enlargement Preservations of lobular architecture Old age

Necrotizing Sialometaplasia (Fig. 23.2) Clinical

Lymphoepithelial Lesions Clinical

♦♦ Benign self-limiting reactive inflammatory process ♦♦ Sites: palate, 81.7%; other oral sites, 7.0%; major glands, 7.8%; and other, 3.5% ♦♦ Age: 40–60 years ♦♦ More men than women

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

1052

Idiopathic, autoimmune disease, HIV infection Localized, systemic Older women Recurrent painful swelling Epimyoepithelial islands

Tumor of the Salivary Glands

Fig. 23.3. Oncocytosis.

23-7

Fig. 23.5. Cystic lymphoid hyperplasia.

−− High incidence of non-Hodgkin lymphoma in women −− Nonlymphoid malignancy, low frequency

Differential Diagnosis ♦♦ Lymphoepithelial carcinoma ♦♦ Lymphoma (MALT) −− Both tumors may arise in this setting

Küttner Tumor (Chronic Sclerosing Sialadenitis of Submandibular Gland) ♦♦ Unilateral ♦♦ Lymphoplasmacytic periductal infiltrate with fibrosis ♦♦ Clinically tumor-like Fig. 23.4. Lymphoepithelial lesion.

Microscopic (Fig. 23.4) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Focal periductal lymphoreticular proliferation Partial or total obliteration of the acinar structure Epimyoepithelial islands Marked lymphoreticular infiltrate with germinal centers Hyaline-like material deposits

Sjögren Syndrome Clinical ♦♦ Associated with −− Keratoconjunctivitis sicca −− Xerostomia −− Connective tissue disease ♦♦ Assessed by labial minor salivary gland biopsy −− Focus score: number of inflammatory foci/4 mm of gland (focus is defined as ³50 lymphocytes)

Cystic Lymphoid Hyperplasia (HIV+ Subjects) (Fig. 23.5) Clinical ♦♦ ♦♦ ♦♦ ♦♦

HIV-infected patients Nodular or diffuse enlargement of salivary glands Unknown pathogenesis (p24) Antigen infection

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Glandular atrophy Intense lymphocytic proliferation with follicular hyperplasia Cystic formation with epithelial lining from ductal inclusion Epimyoepithelial islands

Inflammatory Pseudotumors Clinical ♦♦ Firm, nodular swelling in the parotid

Microscopic ♦♦ Myofibroblastic proliferation and chronic inflammatory cells

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Fig. 23.6. Congenital cyst.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 23.7. Dysgenetic polycystic lesion.

Immunohistochemistry ♦♦ SMA, MSA, and CD68+

Salivary Gland Cysts (See Tables 23.3 and 23.4) Benign Cysts of Salivary Gland: An Overview ♦♦ ♦♦ ♦♦ ♦♦

Congenital cyst – rare (2%) (Fig. 23.6) Secondary acquired, pseudocysts Most secondary pseudocysts are mucocele Parotid duct cyst (11%), lymphoepithelial cyst (7%), and ranula (5%)

Cystic Neoplasms ♦♦ ♦♦ ♦♦ ♦♦

Cystic mucoepidermoid carcinoma Warthin tumor Cystadenocarcinoma Sebaceous lymphadenoma

Fig. 23.8. Sclerosing polycystic adenosis.

Inflammatory, Specific, and Nonspecific Dysgenetic Cysts ♦♦ Polycystic dysgenetic lesions (Fig. 23.7) −− Rare −− Mainly parotid −− Multiple cysts lined by simple epithelial lining −− Female predominance −− Delayed clinical manifestation −− Bilateral −− Fluctuating, nontender parotid swelling −− Diagnosis: sialogram, spare main salivary duct −− Surgical excision for diagnosis and treatment −− Etiology: most likely developmental ♦♦ Sclerosing polycystic adenosis (Figs. 23.8 and 23.9)

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Fig. 23.9. Sclerosing polycystic adenosis.

Tumor of the Salivary Glands

−− Resemblance of fibrocystic disease of breast in its diversity −− Preservation of lobular architecture −− Duct ectasia, with or without epithelial hyperplasia, apocrine-like metaplasia −− Occasional collagenous spherulosis −− Uncapsulated but often demarcated, limitation of nodules from adjacent salivary tissue −− Differential diagnosis: dysgenetic polycystic parotid gland, obstructive sialadenitis −− Surgical excision for diagnosis and treatment −− Etiology: unclear, pseudoneoplastic benign entity versus neoplastic ♦♦ Cyst of submandibular gland −− Benign cyst lined by flattened epithelium −− Etiology: duct segmentation

23-9

Fig. 23.10. Subepithelial encapsulated mucin leakage (ranulas).

Secondary Cysts ♦♦ Salivary duct cyst −− Mainly parotid −− 10% of all nonneoplastic cysts −− More than two-thirds male in 2nd decade of life −− Multilayered, cuboidal epithelial lining −− Occasional oncocytic and squamous metaplastic changes −− Cystic contents, spheroliths or crystalline precipitate −− Pathogenesis: ductal obstruction ♦♦ Lymphoepithelial cyst −− Locations: parotid, intraparotid lymph nodes, floor of mouth −− Lining: flattened or multilayered epithelium surrounded by lymphocytes and lymphoid follicles −− Sebaceous glands and goblet cells may be present −− Pathogenesis: displacement of epithelium into lymphoid tissue or proliferation of bronchial pouch epithelium −− Related to benign lymphoepithelial lesions, chronic myoepithelial sialadenitis, and HIV-related cystic lymphoid hyperplasia

Mucoceles, Retention, and Extravasation ­(Ranula) (Fig. 23.10) ♦♦ Retention mucocele −− Less common, 15% −− Older age, >20 years −− Site: minor salivary glands −− Cyst lined by flat, cuboidal, or multilayered epithelium surrounded by thick fibrous capsule −− Pathogenesis: obstruction ♦♦ Extravasation

−− −− −− −− −−

Most common, 85% Sites: lip, cheek, and floor of mouth More in men (60%) Peak incidence: 2nd decade Initially ill-defined mucus lakes, followed by granuloma formation and muciphages, finally mucin-filled pseudocysts (no epithelial lining)

Benign Cystic Lesions of the Neck ♦♦ Thyroglossal duct cyst −− Midline, two-third below hyoid bone, one-third off midline, anteromedial to carotid artery and jugular vein ♦♦ Branchial cleft cyst −− Lateral neck, unrelated to hyoid, majority near angle of mandible; if small, anterior to sternomastoid and lateral to carotid artery and internal jugular vein ♦♦ Parathyroid cyst −− 95% near inferior thyroid margin, off midline; anterior to carotid artery and internal jugular vein ♦♦ Cervical thymic cyst −− Off midline; low neck; anterior to carotid artery and internal jugular vein ♦♦ Cystic hygroma ♦♦ Dermoid cyst −− Near midline, usually in upper neck −− Benign teratoma −− Usually near thyroid gland. ♦♦ Cervical ranula −− Off midline and suprahyoid in submental and submandibular triangle

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Essentials of Anatomic Pathology, 3rd Ed.

BENIGN TUMORS (SEE TABLES 23.5 AND 23.6) Epithelial Pleomorphic Adenoma (Mixed Tumor) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Comprised of 55–70% of all salivary neoplasms More in females in the 4th decade Painless, slow-growing mass In parotid: 90% superficial lobe, 10% deep lobe

Macroscopic ♦♦ Well-defined lobulated mass ♦♦ Multifocal in 0.5% of cases ♦♦ Variegated appearance, cartilaginous

Microscopic (Figs. 23.11–23.14)

Cytogenetics and Molecular Genetics ♦♦ Alteration, rearrangements, and LOH at 8q21 and 12q 14–15 regions

Differential Diagnosis ♦♦ Adenoid cystic carcinoma −− Lacks mesenchymal elements; clear demarcation between collagenous, epithelial, and mucoid materials −− Propensity for perineural invasion ♦♦ Myoepithelioma −− Lacks ductal and mesenchymal elements ♦♦ Terminal duct carcinoma −− Variegated epithelial patterns −− Lacks mesenchymal features

♦♦ Biphasic epithelial and mesenchymal elements ♦♦ Epithelial cells −− Tubules, nests, ribbons, and files with occasional squamous, oncocytic, or sebaceous differentiation ♦♦ Myoepithelial cells −− Spindle or plasmacytoid cells ♦♦ Stroma −− Mucoid, myxoid, hyaline, or chondroid −− Rarely adipose tissue and bone ♦♦ Crystals −− Tyrosine-calcium oxalate, collagenous spherules

Immunohistochemistry ♦♦ Generally noncontributory ♦♦ S-100 protein and smooth muscle actin (SMA) + in stroma and myoepithelial cells Fig. 23.12. Pleomorphic adenoma (myxoid stroma).

Fig.  23.11. Pleomorphic adenoma cartilaginous and ductal components.

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Fig. 23.13. Pleomorphic adenoma (squamous differentiation).

Tumor of the Salivary Glands

Fig. 23.14. Pleomorphic adenoma with crystals.

23-11

Fig. 23.15. Myoepithelioma (organoid pattern).

Recurrent Mixed Tumor ♦♦ Histologically similar to original tumor ♦♦ Multiple nodules ♦♦ Extension to surrounding tissue

Myoepithelioma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Uncommon, 1.5% of all salivary tumors 2.2–5.7% of all benign tumors Male:female ratio, 1:1 Most common sites: palate and parotid

Macroscopic ♦♦ Well-demarcated mass ♦♦ Tan, homogenous, and solid

Microscopic (Figs. 23.15 and 23.16) ♦♦ ♦♦ ♦♦ ♦♦

Comprised of >90% myoepithelial cells Cellular, mucoid, or hyalinized stroma may be present Lacks ductal differentiation Cell types: spindle, plasmacytoid, epithelioid, and clear cells

Immunohistochemistry ♦♦ Keratin (CK14)+, SMA+, S-100 protein+

Electron Microscopy ♦♦ Microfilaments, 50–100 Å in size ♦♦ Pinocytic vesicles

Differential Diagnosis ♦♦ Spindle cell myoepithelioma −− Leiomyoma, nerve sheath tumors, synovial sarcoma, nodular fasciitis − − Keratin immunoreactivity excludes mesenchymal tumors ♦♦ Plasmacytoid myoepithelioma

Fig. 23.16. Myoepithelioma (spindle cell). −− Plasmacytoma, positive for monoclonal light chain reaction and negative keratin– ♦♦ Clear cell myoepithelioma −− Metastatic renal cell carcinoma: vascular, cellular atypia, hemorrhage, history of RCC −− Myoepithelial carcinoma: cellular atypia, infiltrative growth

Oncocytoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Rare, 1% of all salivary tumors Women slightly more than men Bilaterality, in 7% of cases Main presentation, swelling

Macroscopic ♦♦ Solitary, encapsulated ♦♦ Reddish brown, smooth, and homogenous cut surface

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Fig. 23.17. Oncocytoma.

Microscopic (Fig. 23.17) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Large polygonal eosinophilic cells with central round nuclei Cord, ribbon, and acinar formation Focal mucinous or squamous metaplasia may be present Clear cell variant (clear cell oncocytoma) Oncocytic hyperplasia may occasionally be found at periphery

Immunohistochemistry ♦♦ AMA (antimitochondrial antibody)

Electron Microscopy

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  23.18. Warthin tumor oncocytic ductal proliferation with lymphoid stroma. ♦♦ ♦♦ ♦♦ ♦♦

Superficial, slow-growing mass Exclusively parotid, 2–15% of all parotid tumors Bilaterality not uncommon Male:female ratio, 8:1

Macroscopic ♦♦ Well-circumscribed and cystic ♦♦ Brownish, creamy materials

Microscopic (Fig. 23.18)

Special Stains

♦♦ Oncocytic epithelial lined spaces with occasional papillary formation ♦♦ Lymphoid stroma, with germinal centers ♦♦ Occasional goblet, squamous, and sebaceous cells

♦♦ Phosphotungstic acid hematoxylin stain (PTAH)+

Immunohistochemistry

Differential Diagnosis

♦♦ Noncontributory

♦♦ Conventional oncocytoma −− Pleomorphic adenoma with oncocytic metaplasia: features of pleomorphic adenoma −− Mucoepidermoid carcinoma: PTAH–, mucinous, intermediate, and squamous differentiation −− Acinic cell carcinoma: acinar differentiation, PTAH−, granules −− Oncocytosis and oncocytic hyperplasia: diffuse, lacks fibrous encapsulation, retains architecture ♦♦ Clear cell oncocytoma −− Epimyoepithelial carcinoma: dual cellular differentiation (myoepithelial and ductal) −− Metastatic renal cell carcinoma: high vascularity, history of renal cell carcinoma

Electron Microscopy

♦♦ Large accumulation of mitochondria with lamellar structure ♦♦ Occasionally large glycogen particles

Warthin Tumor (Adenolymphoma) Clinical ♦♦ Second most common benign tumor

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♦♦ Enlarged mitochondria in oncocytes

Cytogenetics ♦♦ Structural alteration in chromosome 7 ♦♦ A subset of WT (t11;19)

Differential Diagnosis ♦♦ Oncocytoma (in stroma-deficient Warthin tumor) −− Lack cystic formation ♦♦ Sebaceous adenoma, squamous carcinoma, and mucoepidermoid carcinoma −− Lack lymphoid stroma −− Minimal oncocytic features

Sebaceous Lymphadenoma Clinical ♦♦ Rare, 0.1% of all adenomas ♦♦ Parotid is the most common site

Tumor of the Salivary Glands

23-13

Microscopic (Figs. 23.20 and 23.21) ♦♦ Trabecular, solid, mixed, and membranous cellular patterns ♦♦ Mixed variant common ♦♦ Monotonous, small, dark nuclei with scant circumscribed and encapsulated nodules in basophilic cytoplasm ♦♦ Cords and nests with peripheral palisading ♦♦ Tubular pattern in minor glands ♦♦ Basement membrane materials between cell nests and stroma, marked in membranous type

Membranous Adenoma (Dermal Analog Tumor) (See Table 23.8) Clinical Fig. 23.19. Sebaceous lymphadenoma.

♦♦ Mainly parotid and peri- or intraparotid lymph nodes ♦♦ High recurrence rate

♦♦ Male:female ratio, 1:1 ♦♦ Painless mass

Macroscopic ♦♦ Circumscribed and encapsulated mass

Microscopic (Fig. 23.19) ♦♦ Solid sebaceous or cystic nests and metaplastic ducts in lymphoid stroma ♦♦ Giant cell reaction to extravasated cystic content

Sebaceous Adenoma Clinical ♦♦ Rare, 0.1% of all salivary gland tumors ♦♦ Males slightly more than females ♦♦ Parotid, submandibular, and oral cavity glands are most common sites

Macroscopic

Fig.  23.20. Basaloid salivary adenoma (note palisading p­ eripheral cells).

♦♦ Solid, gray, well-circumscribed mass

Microscopic ♦♦ Benign irregular sebaceous cellular nests in lymphoid stroma ♦♦ Large cystic formation

Basal Cell Adenoma (See Table 23.7) Clinical ♦♦ ♦♦ ♦♦ ♦♦

1–3% of all major salivary gland tumors Mostly in women Parotid is most common site May present within cervical lymph node

Macroscopic ♦♦ ♦♦ ♦♦ ♦♦

Encapsulated, round, or oval mass Grayish or white homogenous cut surface Average size 2 cm Occasional cystic formation

Fig.  23.21. Basaloid salivary adenoma with concurrent p­ leomorphic adenoma.

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Fig. 23.22. Dermal analog tumor.

Fig. 23.23. Canalicular adenoma.

♦♦ Synchronous or metachronous skin adnexal tumors (e.g., dermal cylindromas, trichoepitheliomas, eccrine spiradenomas) not uncommon

♦♦ Occasionally multinodular and multicentric ♦♦ Homogeneous tan soft mass

Macroscopic ♦♦ Multicentric ♦♦ Unencapsulated nodule

Microscopic (Fig. 23.22) ♦♦ Hyaline materials between cellular nests ♦♦ Morula-like structure with keratinization

Immunohistochemistry ♦♦ Noncontributory

Electron Microscopy ♦♦ Reduplicated basal laminae ♦♦ Ductal, myoepithelial, and basal cells features

Differential Diagnosis ♦♦ Adenoid cystic carcinoma −− Manifests invasive pattern; lacks vascularity ♦♦ Basal cell adenocarcinoma −− Similar cytomorphology but shows invasive features

Canalicular Adenoma (See Table 23.8) Clinical ♦♦ ♦♦ ♦♦ ♦♦

1% of all salivary gland tumors, 4% of all minor gland >73% in upper lip and buccal mucosa Male:female ratio, 1.0:1.7 Painless swelling

Microscopic (Figs. 23.23) ♦♦ Cords of columnar cells with abundant cytoplasm ♦♦ Loose vascular stroma ♦♦ Cystic and papillary projection

Immunohistochemistry ♦♦ Noncontributory

Electron Microscopy ♦♦ Nondiagnostic ♦♦ Desmosomes, polysomes, and endoplasmic reticulum

Differential Diagnosis ♦♦ Basal cell adenoma: lacks columnar cell features ♦♦ Adenoid cystic carcinoma: lacks circumscription and vascularity ♦♦ Other benign adenomas

Nonepithelial Types ♦♦ Angioma, lipoma, neurofibroma, hemangiopericytoma

Clinical ♦♦ Incidence: <5.0% ♦♦ Mainly involves major glands

Macroscopic ♦♦ Poorly demarcated

Macroscopic

Microscopic

♦♦ Circumscribed and encapsulated nodules (0.5–2 cm in size, mean 1.7 cm)

♦♦ Similar to those of other locations

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MALIGNANT EPITHELIAL TUMORS Malignant Mixed Tumor (See Tables 23.5, 23.9–23.15)

♦♦ Facial nerve paralysis (38%) ♦♦ Fixation to surrounding structure is common

♦♦ Incidence: 3–12% of all malignancies and 2% of all salivary tumors ♦♦ Types −− Carcinoma ex pleomorphic adenoma −− Carcinosarcoma −− Metastasizing pleomorphic adenoma

Macroscopic

Carcinoma Ex Pleomorphic Adenoma Clinical ♦♦ Painless, rapidly growing mass ♦♦ 5–10% of pleomorphic adenomas, 11.6% of all malignant tumors ♦♦ Mainly major salivary glands: parotid (82%), submandibular (18%), sublingual (0.3%) ♦♦ Minor glands: palate, sinonasal tract

Table 23.9. Site and Ethnic Distribution of Lymphoepithelial Carcinoma of Major Salivary Glands Feature

Incidence (%) 83.7 15.0 1.25

Ethnicity:   Eskimo-Greenlander   Southern Chinese   White   Indian   Japanese   Black   Others

52.5 20.0 11.25 2.5 2.5 2.5 8.75

Table 23.10. Incidence of Local Recurrence in Salivary Gland Carcinoma

Undifferentiated carcinoma Adenoid cystic carcinoma Carcinoma Ex-PA Adenocarcinoma, NOS Acinic cell carcinoma Mucoepidermoid carcinoma

Table 23.11. Incidence of Lymph Node Metastasis by Diagnosis of Salivary Gland Carcinoma Histology Mucoepidermoid carcinoma Adenocarcinoma, NOS Undifferentiated carcinoma Carcinoma Ex-PA Acinic cell carcinoma Adenoid cystic carcinoma

Recurrence (%) 64 61 60 48 15  5

Metastasis (%) 44 36 23 21 13  5

Table 23.12. Incidence of Distant Metastasis by Diagnosis of Salivary Glands Carcinomas Histology

Site:   Parotid   Submandibular   Unstated

Diagnosis

♦♦ Poorly circumscribed and infiltrative mass ♦♦ Variegated cut surface, soft to firm ♦♦ Hemorrhage and necrosis

Adenoid cystic carcinomas Undifferentiated carcinoma Adenocarcinoma, NOS Carcinoma Ex-PA Squamous cell carcinoma Acinic cell carcinoma Mucoepidermoid carcinoma

Metastasis (%) 42 36 27 21 15 14  9

Table 23.13. Prognostic Factors in Salivary Gland Carcinoma 1. Favorable features:   Low grade histology   Low stage   Parotid location 2. Unfavorable features:   High grade histology   High stage   Submandibular gland site   Cervical nodes metastasis   Facial nerve paralysis   Skin involvement   Recurrence

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Table 23.14. Staging of Salivary Gland Malignancies 1. Primary tumor (T)   TX: (cannot be assessed)   T0: (no tumor detected)   T1: £2.0 cm   T2: >2.0 <4.0 cm   T3: >4.0   T4a: moderately advanced   T4b: very advanced 2. Regional lymph nodes (N)   NX: (cannot be assessed)   N0: (no node metastasis)   N1: £3.0 cm in one lymph node   N2: subtypes:     N2a: one ipsilateral lymph node >3.0 £ 6.0 cm     N2b: multiple ipsilateral lymph nodes £ 6.0 cm     N2c: bilateral or contralateral, £ 6.0 cm in diameter   N3: metastasis in lymph node > 6.0 cm

Fig. 23.24. Carcinoma Ex-PA (salivary duct type).

3. Distant metastasis (M)   MX: metastasis (cannot be assessed)   M0: no metastasis   M1: distant metastasis

Table 23.15. Frequency of Epithelial Malignancy in Different Salivary Gland Sites Site Parotid Submandibular Sublingual Minor Unknown

Malignant (%) 14.7 37.0 85.7 46.1 ?

Microscopic (Figs. 23.24 and 23.25) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Malignant features Cellular atypia Infiltrative growth Necrosis Hemorrhage Hyalinization Calcification

Histologic Types ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Adenocarcinoma, NOS Squamous carcinoma Terminal duct carcinoma Undifferentiated carcinoma Mucoepidermoid carcinoma Salivary duct carcinoma

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Fig. 23.25. Carcinoma Ex-PA (poorly differentiated).

Subtypes ♦♦ Noninvasive (intratumoral carcinoma) ♦♦ Invasive

Immunohistochemistry ♦♦ Noncontributory

Differential Diagnosis ♦♦ Benign mixed tumors ♦♦ Carcinosarcoma

Carcinosarcoma (Concomitant Epithelial and Mesenchymal Malignancy) Clinical ♦♦ Rapid onset ♦♦ Parotid is most common site ♦♦ Rare, 0.06% of salivary neoplasms and 0.16% of malignant tumors

Tumor of the Salivary Glands

23-17

Macroscopic

Myoepithelial Carcinoma

♦♦ Large mass ♦♦ Unencapsulated

Clinical

Microscopic (Fig. 23.26) ♦♦ Biphasic epithelial and mesenchymal cells ♦♦ Cellular pleomorphism and mitosis ♦♦ Adenocarcinoma, chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, and unclassified sarcoma may be seen

Immunohistochemistry ♦♦ Keratin+, EMA+, desmin+, SMA+

DNA Content ♦♦ High proliferation and DNA aneuploidy

Differential Diagnosis ♦♦ Spindle cell carcinoma: keratin+, desmin–, and SMA– ♦♦ Primary sarcoma: keratin– ♦♦ Synovial sarcoma: uniform spindle and glandular components

♦♦ 0.2% of all epithelial neoplasms ♦♦ Parotid is most common site ♦♦ Male:female ratio, 1:1

Macroscopic ♦♦ Unencapsulated ♦♦ Hemorrhage, necrosis, and cystic degeneration

Microscopic (Figs. 23.27 and 23.28) ♦♦ Malignant spindled, plasmacytoid, clear, and epithelioid cells ♦♦ Marked pleomorphism, mitosis, and necrosis ♦♦ Invasive borders

Immunohistochemistry ♦♦ S-100 protein and actin+, keratin+/–

Metastasizing Pleomorphic Adenoma Clinical ♦♦ History of multiple recurrent pleomorphic adenoma ♦♦ Latent, average 16 years after primary excision

Microscopic ♦♦ Similar to benign mixed tumor

Macroscopic ♦♦ Nonencapsulated nodules

Differential Diagnosis ♦♦ Chondroid hamartomas of lung: lacks myoepithelial cells ♦♦ Chondroid chordoma: usually afflicts vertebra; lacks duct component

Flow Cytometry ♦♦ Diploid with low proliferative activity

Fig.  23.26. Carcinosarcoma: distinct carcinoma and sarcoma components.

Fig. 23.27. Myoepithelial carcinoma spindle palisading form.

Fig. 23.28. Myoepithelial carcinoma (clear cell type).

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Electron Microscopy ♦♦ Microfilaments with focal dense bodies ♦♦ Desmosomes and pinocytic vesicles

Flow Cytometry ♦♦ Abnormal DNA content (aneuploidy)

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Leiomyosarcoma: keratin–, SMA– Nerve sheath tumor: S-100 protein+, keratin– Spindle cell carcinoma: keratin+, S-100 protein– Metastatic melanoma: HMB 45+, keratin– Synovial sarcoma: biphasic features

Essentials of Anatomic Pathology, 3rd Ed.

−− Cribriform and apocrine features ♦♦ PTAH–

Carcinoma in Warthin Tumors Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Extremely rare Typically parotid or intraparotid lymph nodes Male:female ratio, 4.5:1 Middle and old age individuals History of prior irradiation not uncommon

Macroscopic

Oncocytic Carcinoma

♦♦ Solid, cystic, ill-defined mass ♦♦ Gray to light pink

Clinical

Microscopic

♦♦ ♦♦ ♦♦ ♦♦

Rare, 5% of all oncocytic tumors 0.005% of all epithelial neoplasms Major salivary glands, parotid is most common site Male:female ratio, 1:1 −− Pain, paralysis (one-third of patients) −− Old age

Macroscopic ♦♦ Ill-defined, infiltrative mass ♦♦ Necrosis, hemorrhage

Microscopic (Fig. 23.29) ♦♦ Large cells with oncocytic cytoplasm ♦♦ Nuclear and cellular atypia with pleomorphism, mitosis ♦♦ Vascular and soft tissue invasion

♦♦ Oncocytic carcinoma, most common ♦♦ Squamous and adenocarcinoma, occasionally ♦♦ Mucoepidermoid carcinoma can arise and/or coexist with Warthin tumor ♦♦ Warthin adenocarcinoma, representing the malignant epithelial counterpart of Warthin tumor (Fig. 23.30) ♦♦ Undifferentiated carcinoma is rare

Immunohistochemistry ♦♦ Noncontributory

Differential Diagnosis ♦♦ Metastatic carcinoma −− History of primary tumor elsewhere ♦♦ Concomitant primary salivary gland tumor

Immunohistochemistry

Sebaceous Carcinoma

♦♦ Noncontributory

Types

Differential Diagnosis

♦♦ Sebaceous carcinoma

♦♦ Oncocytoma −− Lacks invasion or cellular atypia ♦♦ Salivary duct carcinoma

Fig. 23.29. Oncocytic carcinoma.

1064

Fig. 23.30. Malignant Warthin tumor.

Tumor of the Salivary Glands

Fig. 23.31. Sebaceous carcinoma.

23-19

Fig. 23.32. Basaloid salivary adenocarcinoma.

♦♦ Sebaceous lymphadenocarcinoma

Clinical ♦♦ ♦♦ ♦♦ ♦♦

Very rare Exclusively parotid Male:female ratio, 1:1 Occasionally painful mass

Macroscopic ♦♦ Infiltrative, ill-defined mass ♦♦ Necrosis and hemorrhage

Microscopic (Fig. 23.31) ♦♦ Undifferentiated malignant cells with evidence of sebaceous differentiation ♦♦ Nerve invasion and soft tissue extension not infrequent

Special Studies ♦♦ Immunohistochemistry −− Lactoferrin+ −− EMA+ −− Adipophilin+ ♦♦ Electron microscopy −− Lipid vacuoles and glandular features

Differential Diagnosis ♦♦ High grade salivary gland carcinoma −− Lacks any sebaceous features ♦♦ Adnexal skin tumors

Basal Cell Adenocarcinoma (Figs. 23.32 and 23.33) Types ♦♦ De novo ♦♦ Carcinoma ex basal cell adenoma

Fig. 23.33. Basal cell salivary adenocarcinoma.

Clinical ♦♦ 2% of malignant epithelial tumors, 1.6% of all salivary tumors ♦♦ Mainly parotid, occasionally in submandibular and minor glands ♦♦ Male:female ratio, 1:1 ♦♦ Adults, average 60 years ♦♦ Swelling, occasional pain, and tenderness

Macroscopic ♦♦ Unencapsulated but well-circumscribed mass ♦♦ Occasionally infiltrative ♦♦ Homogenous tan cut surface, rarely cystic

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Microscopic ♦♦ Small, round-to-ovoid cells with dark hyperchromatic nuclei with −− Scant cytoplasm −− Peripheral palisading −− Minimal nuclear atypia −− Mitotic figures: 1–10/10 HPF −− Focal squamous metaplasia (25%) −− Infiltrative growth −− Perineural invasion (30%), vascular invasion (20%)

Special Studies ♦♦ Noncontributory

Differential Diagnosis ♦♦ Basal cell adenoma −− Lacks invasive features ♦♦ Basal cell carcinoma of skin −− History of BCC ♦♦ Solid adenoid cystic carcinoma −− High grade solid areas with foci of cribriform and tubular patterns ♦♦ Undifferentiated small cell carcinoma −− Neuroendocrine markers+ ♦♦ Basaloid squamous carcinoma −− Comedonecrosis, origin from dysplastic squamous epithelium

Fig. 23.34. Acinic cell carcinoma (classic form).

Acinic Cell Carcinoma Clinical ♦♦ Parotid 99%, rarely in submandibular and oral cavity ♦♦ Ectopic: may present in middle and lower cervical lymph nodes

Macroscopic

Fig. 23.35. Acinic cell carcinoma (microcystic form).

♦♦ Circumscribed or infiltrative ♦♦ Homogenous mass with gray cut surface ♦♦ Multinodular

Microscopic (Figs. 23.34–23.37) (See Table 23.16) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Large cells with small, centralized nuclei Abundant basophilic cytoplasm with coarse granules Vacuolation and clear cytoplasm not uncommon Lymphoid infiltrate with germinal center Dedifferentiated component

Electron Microscopy ♦♦ Three types of cells −− Ductal, with few organelles and luminal microvilli −− Serous with abundant granules −− Undifferentiated

Special Stains ♦♦ Periodic acid Schiff diastase resistant granules

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Fig. 23.36. Acinic cell carcinoma (macrocytic form).

Tumor of the Salivary Glands

23-21

Fig. 23.37. Acinic cell carcinoma with dedifferentiated component.

Fig. 23.38. Adenoid cystic carcinoma (predominantly tubular type).

Table 23.16. Characteristics of Acinic Cell Carcinoma

−− Metastatic renal cell carcinoma: vascular, history of RCC −− Epimyoepithelial carcinoma: ductal and myoepithelial cells, S-100 protein+ ♦♦ Tumors with papillary features −− Cystadenocarcinoma: mucin+ −− Metastatic papillary thyroid carcinoma: thyroglobulin+, nuclear inclusion

Feature

Frequency (%)

1. Pattern   Solid   Microcystic   Follicular   Papillary – cystic

50 30 15  5

2. Cell type   Serous-acinar   Ductal   Vacuolated, clear

75 20  5

3. Female/male

  2:1

4. Incidence   All parotid tumor   All parotid malignancies

  2–4 12–17

5. Bilaterality

 3

6. Local recurrence

45

7. Metastasis

20

Adenoid Cystic Carcinoma Clinical ♦♦ 6.5–10% of all epithelial salivary gland tumors, 2–4% of parotid tumors, 15% of submandibular tumors, and 30% of minor gland tumors ♦♦ Slightly more in women and in submandibular gland ♦♦ Slow-growing mass ♦♦ Pain in approximately 18% of patients ♦♦ Facial nerve paralysis in 4% of cases

Macroscopic ♦♦ Circumscribed, but uncapsulated, size 1.5–4 cm ♦♦ Firm, monolobular mass ♦♦ Gray and homogenous cut surface

Immunohistochemistry

Microscopic

♦♦ Noncontributory

♦♦ Features and grades −− Tubular form (Fig. 23.38) (a) Low grade (b) Monotonous cellular features, two cell types −− Cribriform, cylindromatous (Fig. 23.39) (a) Intermediate grade (b) Tumor nests with “sieve-like” or “Swiss cheese” configuration (c) Pseudoglandular spaces with hyaline materials −− Solid (Fig. 23.40) (a) Nests of basaloid high grade tumor cells

Differential Diagnosis ♦♦ Terminal duct carcinoma −− Most common in minor salivary glands −− Perineural invasion −− Variegated patterns −− Uniform cell populations ♦♦ Tumors with clear cell features −− Mucoepidermoid carcinoma: epidermoid features, mucinous and intermediate cells, and glandular formation

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Fig. 23.39. Adenoid cystic carcinoma (cribriform type).

Fig. 23.40. Adenoid cystic carcinoma (solid type). (b) Focal areas of tubular and cribriform patterns (c) Hyalinized stroma, mucinous, and myxoid forms may be present −− Variants (Figs. 23.41 and 23.42) (a) Dedifferentiated (b) Hyalinizing

Immunohistochemistry ♦♦ Ductal cells: CEA, EMA, and keratin+; S-100 protein and SMA– ♦♦ Myoepithelial cells: SMA+, S-100 protein, and keratin+

Flow Cytometry ♦♦ DNA aneuploid and high S-phase tumors, aggressive

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  23.41. Adenoid cystic carcinoma with dedifferentiated component.

Fig.  23.42. Adenoid cystic carcinoma with dedifferentiated component.

♦♦

♦♦

♦♦

Cytogenetics ♦♦ Translocation of t(6;9) chromosomes

Differential Diagnosis ♦♦ Terminal duct carcinoma

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♦♦

−− Variegated patterns −− Lacks solid and cribriform pattern Basal cell adenoma −− One cell type −− Lacks infiltration Basaloid squamous carcinoma −− Squamous differentiation −− Necrosis −− Origin from squamous dysplasia Small-cell undifferentiated carcinoma −− Immunostaining positivity to neuroendocrine markers and EM granules Poorly differentiated mucoepidermoid carcinoma −− Mucin+ −− Epidermoid features

Tumor of the Salivary Glands

23-23

Mucoepidermoid Carcinoma Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Most common malignant tumor, 15.5% of all salivary tumors Parotid 60–70%, oral cavity 15–20%, submandibular 6–10% Most common malignancy in children May present in mandible and paraparotid lymph node Average time to diagnosis: 6.8 years in low grade tumors and 1.5 years in high grade tumors

Macroscopic ♦♦ Low grade: well-circumscribed, cystic, and mucoid, rarely exceed 3.0 cm ♦♦ Intermediate and high grades: poorly circumscribed, infiltrative, and solid

Microscopic ♦♦ Grade I (Fig. 23.43) −− Macro- or microcystic −− Mucin-producing cells abundant −− Lacks pleomorphism and mitosis −− Broad borders −− Mucin pools ♦♦ Grade II (Fig. 23.44) −− Lacks cystic formation −− Intermediate cells, with or without epidermoid features −− Moderate nuclear pleomorphism −− Invasive borders −− Inflammation and fibrosis ♦♦ Grade III (Fig. 23.45) −− Rare mucin cells −− Poorly differentiated epidermoid and glandular components −− Cellular pleomorphism −− Invasive border ♦♦ Variants (Figs. 23.46 and 23.47) −− Sclerosing mucoepidermoid carcinoma with eosinophilia

Fig. 23.43. Mucoepidermoid carcinoma (low grade cystic).

Fig. 23.44. Mucoepidermoid carcinoma (intermediate grade).

Immunohistochemistry ♦♦ Rarely required ♦♦ Proliferation markers, elevated in high grade

Cytogenetics ♦♦ Deletion of -5q, t(11;19)

Differential Diagnosis ♦♦ Benign mixed tumors with squamous differentiation −− Stroma of mixed tumor and myoepithelial cells ♦♦ Squamous cell carcinoma −− Keratinization −− Lacks intermediate and mucinous cells ♦♦ Necrotizing sialometaplasia

Fig. 23.45. Mucoepidermoid carcinoma (high grade).

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Table 23.17. Clinicopathologic Characteristics of Salivary Duct Carcinoma Incidence Feature   All epithelial neoplasms (%)   All malignant tumor (%)   Parotid malignancy (%) Male/female Age Site   Parotid (%)   Submandibular (%)   Minor glands (%) Lymph node metastasis (%) Outcome   Death (%)

Fig. 23.46. Mucoepidermoid carcinoma (sclerotic type).

0.2 0.5 1–6 4:1 27–83 (Median 63 years) 83.3 11.7 5.0 56.6 53.3

Table 23.18. Differential Clinicopathologic Characteristics Between TDC and SDC (Modified from Batsakis and Luna 1989) Category Sex   Female/male Age   Range   Mean Salivary gland site (%) Behavior   Recurrence (%)   Cervical node (%)   Metastasis (%)   Distant metastasis (%)

Fig. 23.47. Mucoepidermoid carcinoma (sclerotic type). −− Preservation of lobular pattern −− Lacks malignant cellular features

Salivary Duct Carcinoma (See Tables 23.17 and 23.18) Clinical ♦♦ Swelling and mass formation, common presentation

Macroscopic ♦♦ Poorly demarcated and infiltrative ♦♦ Light tan and firm

Microscopic (Figs. 23.48–23.50) ♦♦ Intraductal and infiltrative features, mimics mammary duct carcinoma −− Intraductal: comedo, cribriform, and solid forms ♦♦ Desmoplasia and hyalinization in invasive tumors ♦♦ Lacks myoepithelial and epidermoid cells

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TDC

SDC

2:1

1:4

23–79 (49) Palate (65.5)

27–83 (64) Parotid (83.3)

(12) (10) 0 1:4

55 66 66 70

TDC Terminal duct carcinoma, SDC Salivary duct carcinoma ♦♦ Vascular and neural permeation not uncommon ♦♦ Goblet cells may be seen

Special Studies ♦♦ ♦♦ ♦♦ ♦♦

Mucin: generally negative CK7, AR, ER-beta+; variable Her2 neu Ki-67: high-growth fraction Flow cytometry: predominantly DNA aneuploid with ­elevated S-phase

Differential Diagnosis ♦♦ Mucoepidermoid carcinoma

Tumor of the Salivary Glands

Fig. 23.48. Salivary duct carcinoma (cystic).

23-25

Fig. 23.50. Salivary duct carcinoma. −− Lacks comedonecrosis and intraductal component ♦♦ Metastatic breast carcinoma −− Most challenging differential diagnosis (a) Male predominance, favor primary (b) History of breast carcinoma

Epithelial–Myoepithelial Carcinoma Clinical ♦♦ 1% of all salivary tumors ♦♦ Predominantly major glands: parotid 75%, submandibular and minor glands 25% ♦♦ Male:female ratio, 1:2 ♦♦ Painless mass

Macroscopic ♦♦ Solitary, well-defined, circumscribed or lobulated, gray mass ♦♦ Size ranges from 2 to 8 cm ♦♦ Recurrent tumors: lobulated, ill-defined borders with necrosis Fig. 23.49. Salivary duct carcinoma. −− Lacks cribriform and intraductal component −− Shows intermediate and epidermoid cells −− Contains goblet cells ♦♦ Acinic cell carcinoma −− Monotonous cells −− No intraductal features −− Lacks comedonecrosis −− Characteristic granules ♦♦ Oncocytic carcinoma −− Large cells with granular cytoplasm −− No papillary or cribriform features ♦♦ Mucin-producing adenopapillary carcinoma −− Columnar, goblet, and signet-ring cells

Microscopic (Fig. 23.51) ♦♦ Variable intra- and intertumoral patterns ♦♦ Dual cell layers: inner ductal and outer myoepithelial cells ♦♦ Ductal cells: cuboidal or columnar with eosinophilic cytoplasm ♦♦ Myoepithelial cells: ovoid with abundant clear cytoplasm surrounded by basal materials

Special Stains ♦♦ Mucin – ♦♦ PAS diastase resistant+

Immunohistochemistry ♦♦ Myoepithelial cells: SMA+, S-100 protein+, keratin weakly– ♦♦ Ductal: keratin +

Differential Diagnosis ♦♦ Mucoepidermoid carcinoma

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Fig. 23.52. Polymorphous low grade adenocarcinoma (tubular and cribriform pattern). Fig. 23.51. Epimyoepithelial carcinoma.

♦♦ Lacks dual cellular composition ♦♦ Cystic features in low grade ♦♦ Acinic cell carcinoma −− Clear cell type −− PAS+, diastase+ −− Characteristic basophilic granules ♦♦ Sebaceous carcinoma −− Fat stain+ −− Occasional squamous differentiation ♦♦ Metastatic renal cell carcinoma: −− High vascularity −− Necrosis −− History of renal cell carcinoma

Terminal Duct Carcinoma (Polymorphous Low Grade Adenocarcinoma) Clinical (See Table 23.18) ♦♦ Incidence: 7.4% of all minor salivary gland tumors, 19.6% of malignant tumors ♦♦ Hard palate is most common site ♦♦ Occurs occasionally in major salivary gland

Macroscopic ♦♦ Small, lobulated mass ♦♦ Yellow-tan and firm

Microscopic (Figs. 23.52 and 23.53) ♦♦ Uniform cytology, but heterogeneous patterns ♦♦ Patterns: tubular, cribriform, papillary, solid, and fascicular features ♦♦ Mitosis, low; necrosis, rare ♦♦ Mucoid, hyaline, and mucohyaline stroma ♦♦ Perineural invasion, common

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Fig. 23.53. Polymorphous low grade adenocarcinoma (solid form).

Immunohistochemistry ♦♦ Noncontributory

Differential Diagnosis ♦♦ Pleomorphic adenoma −− Epithelial and stromal elements ♦♦ Basal and canalicular adenomas −− Well-circumscribed −− Uniform basal or columnar cellular pattern ♦♦ Adenoid cystic carcinoma −− Most difficult differential diagnosis, especially in low grade tumors −− Lacks varied patterns of terminal duct carcinoma −− Manifests cribriform and solid features

Primary Squamous Cell Carcinoma Clinical ♦♦ 0.9–4.7% of all malignancies; parotid gland, 0.3–1.5% and submandibular, 2.4–7.0%

Tumor of the Salivary Glands

23-27

♦♦ Male:female ratio, 3:1 ♦♦ Symptoms: mass (50%), pain (33%), and nerve paralysis (17%)

Macroscopic ♦♦ Infiltrative, ill-defined, and firm mass ♦♦ Necrosis, not uncommon

Microscopic ♦♦ Well to poorly differentiated squamous cells with keratinization ♦♦ Dysplastic ductal epithelium may be found

Differential Diagnosis ♦♦ Metastatic squamous cell carcinoma −− Circumscribed nodule within gland −− History of squamous carcinoma ♦♦ Mucoepidermoid carcinoma −− Mucin-producing cells −− Lacks keratinization ♦♦ Necrotizing sialometaplasia −− Lobular preservation of salivary structure −− Lacks atypia and keratinization

Fig. 23.54. Small cell carcinoma.

Undifferentiated Carcinoma ♦♦ Incidence: 1–30% of epithelial malignancy

Types ♦♦ Small cell ♦♦ Large cell ♦♦ Undifferentiated carcinoma ­(lymphoepithelial carcinoma)

with

lymphoid

stroma

Differential Diagnosis ♦♦ Metastasis −− Merkel cell carcinoma: history of Merkel cell carcinoma, keratin dot-like+ −− Basal cell carcinoma: history of skin lesions ♦♦ Solid adenoid cystic carcinoma −− Focal tubular and cribriform patterns

Small Cell Carcinoma Clinical ♦♦ Very rare: 1.7% of malignant parotid tumors, 2.2% of malignant submandibular tumors ♦♦ Mainly parotid ♦♦ Male:female ratio, 6:1

Fig. 23.55. Large cell neuroendocrine carcinoma.

Differential Diagnosis ♦♦ Lymphoma −− Keratin–, leukocyte common antigen (LCA)+ ♦♦ Adenoid cystic carcinoma, solid type −− Tubular and cribriform components may be present −− Negative staining for neuroendocrine markers ♦♦ Merkel cell carcinoma −− History of primary tumor −− Keratin immunostaining

♦♦ Light tan and soft nodule

Large Cell Carcinoma Clinical

Microscopic (Fig. 23.54)

♦♦ Predominantly parotid

♦♦ Identical to small cell carcinoma of lung

Microscopic (Fig. 23.55)

Immunohistochemistry

♦♦ Cells larger than small cell carcinoma ♦♦ Abundant cytoplasm

Macroscopic

♦♦ Keratin, synaptophysin, and chromogranin+

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Fig. 23.56. Lymphoepithelial carcinoma.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 23.57. Adenocarcinoma not otherwise classified.

♦♦ Cords and nests may be seen

Immunohistochemistry ♦♦ Keratin+, LCA– ♦♦ Neural markers occasionally+

Differential Diagnosis ♦♦ Melanoma −− S-100 protein and HMB-45+, keratin– ♦♦ Undifferentiated carcinoma −− Neuroendocrine markers–

Lymphoepithelial Carcinoma Clinical (See Table 23.18) ♦♦ ♦♦ ♦♦ ♦♦

0.4% of all salivary gland tumors Male:female ratio, 1.5:1 Evidence of familial clustering Evidence of EBV-association

Fig. 23.58. Papillary cystadenocarcinoma.

Microscopic (Fig. 23.56) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Indistinguishable from nasopharyngeal carcinoma Lymphoid content varies Occasional squamous differentiation Carcinoma demarcated from surrounding nonepithelial elements Epimyoepithelial islands of lymphoepithelial lesions

Differential Diagnosis ♦♦ Metastasis from conventional sites

Rare Types of Adenocarcinoma ♦♦ ♦♦ ♦♦ ♦♦

Adenopapillary carcinoma Cystadenocarcinoma (Figs. 23.57 and 23.58) Adenosquamous carcinoma Adenocarcinoma (NOS), not otherwise classified (Fig. 23.59) −− Moderately differentiated adenocarcinoma −− Lack any resemblance to know salivary gland carcinomas

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Fig. 23.59. Papillary cystadenocarcinoma.

Tumor of the Salivary Glands

23-29

SALIVARY GLAND CARCINOMAS (SEE TABLE 23.19): Other Tumors

Table 23.19. Stage Grouping Stage I: Stage II: Stage III: Stage IV:

T1 N0 M0 T2 N0 M0 T3 N0 M0 T1 N1 M0 T2 N1 M0 T4 N0 M0 T3 N0 M0 T4 N1 M0 Any T N2 M0 Any T N2 M1

Table 23.20. Characteristics of Primary Salivary Gland Lymphoma

Fig. 23.60. Granular cell tumor.

5% of all extranodal lymphomas 40% of all head and neck lymphomas 85% non-Hodgkin B-cell lymphoma (2/3 well differentiated). 15% Hodgkin lymphoma Majority extranodal and parenchymal (MALT) Primary intraparotid lymph node, occasionally

Primary Lymphomas of Salivary Gland (See Table 23.20) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Rare More frequent in parotid than submandibular glands (8:1) Mainly older patients, 6th to 7th decade of life Intraparotid lymph node involvement staged as in cervical lymphoma

Microscopic ♦♦ Sclerosis, common in large type ♦♦ Small cell type arise in a background of benign lymphoepithelial lesions ♦♦ Plasmacytoma, very rare

Mesenchymal Tumors of Salivary Glands ♦♦ 5% of all tumors ♦♦ Benign −− Types: angiomas, lipomas, neurofibromas, and hemangiopericytomas (undetermined malignant potential), granular cell tumor (Figs. 23.60 and 23.61) −− Except for neurofibroma, they are exclusively parotid in origin

Fig. 23.61. Sialolipoma. −− Usually ill-defined lesions −− Histologically identical to soft tissue counterpart ♦♦ Sarcoma (see Table 23.21) −− Rare −− Ill-defined mass −− Comparable microscopic characteristics to soft tissue counterparts (Fig. 23.62)

Salivary Gland Tumors in Children General Features (See Table 23.22) ♦♦ Comprise 5% of childhood tumors ♦♦ High incidence of benign nonepithelial tumors

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Table 23.21. Primary Sarcomas of Major Salivary Gland (Modified from Luna et al. 1991) Characteristic Sex   Male/female Age (years)   Range   Mean Site   Parotid   Submandibular Most frequent subtypes   Rhabdomyosarcoma   MFH   Fibrosarcoma   Neurosarcoma   Angiosarcoma Recurrence Metastasis DOD

Table 23.22. Histologic Types of Salivary Gland in Children Under 16 years of Age (Modified from Luna et al. 1998)

Incidence 12:1 10–91 36.0 91.8   8.2 21.6 16.2 12.1   9.4   6.7 22.9 32.4 36.4

Incidence (%) 1. Epithelial (total #394)   (a) Benign (50%)     Pleomorphic adenoma     Embryoma (sialoblastoma)     Warthin tumor     Cystadenoma     Lymphoepithelial lesions     Monomorphic adenoma   (b) Malignant (50%)     Mucoepidermoid carcinoma     Acinic cell carcinoma     Adenocarcinoma     Undifferentiated carcinoma     Adenoid cystic carcinoma     Carcinoma ex pleomorphic adenoma     Squamous cell carcinoma     Unclassified carcinoma 2. Mesenchymal (total #274)   (a) Benign (93.8%)     Hemangioma     Lymphangioma     Neurogenic     Lipoma     Xanthoma     Fibromatosis   (b) Malignant mesenchymal (6.2%)     Sarcoma     Ganglioneuroblastoma

46.0 2.0 0.7 0.7 0.7 0.25 27.3 6.8 5.6 3.8 2.8 2.3 1.0 0.25

69.7 17.5 4.0 1.5 0.7 0.7 5.5 0.4

Fig. 23.62. Myxoid liposarcoma. ♦♦ High incidence of epithelial malignancy ♦♦ Predominantly in parotid ♦♦ Vasoformative tumors, most common in neonates and infants ♦♦ Pleomorphic adenoma, mucoepidermoid, and acinic cell carcinomas in children between 10 and 16 years

Juvenile Capillary Hemangioma (Figs. 23.63 and 23.64) Clinical ♦♦ Most common postnatal tumor

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Figs. 23.63. Juvenile capillary hemangioma. ♦♦ Commonly in girls, with a left-side predilection ♦♦ Spontaneous involution, not uncommon

Tumor of the Salivary Glands

23-31

Fig. 23.64. Juvenile capillary hemangioma.

Fig. 23.65. Sialoblastoma.

♦♦ Angle of the mandible, common ♦♦ Recurrence, uncommon ♦♦ 50% undergo spontaneous involution

Microscopic (Fig. 23.65)

Macroscopic ♦♦ Enlarged gland ♦♦ Purple-red and spongy

Primitive basaloid cells, resembling primitive epithelium Focal sebaceous differentiation, occasionally Peripheral palisading is common Necrosis, perineural, or vascular invasions are not uncommon

Immunohistochemistry

Microscopic

♦♦ Noncontributory

♦♦ Similar to other sites

Electron Microscopy

Sialoblastoma (Embryoma) Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ ♦♦ ♦♦ ♦♦

♦♦ Primitive features, free ribosomes, sparse endoplasmic reticulum

Differential Diagnosis

Congenital or prenatal Newborn and first year of life Low grade malignancy Major salivary glands 1.5–15 cm in size No gender preference Typically asymptomatic

♦♦ Basal cell adenoma −− Less primitive cells, less mitotic activities, and primitive stroma ♦♦ Adenoid cystic carcinoma and basal cell adenocarcinoma are very rare in this age

Malignant Epithelial Tumors

Macroscopic ♦♦ Well-circumscribed, encapsulated, and lobulated mass ♦♦ Yellowish-tan and firm

♦♦ Mucoepidermoid and acinic cell carcinomas account for 60% of salivary gland malignancy in children ♦♦ Adenoid cystic carcinoma, adenocarcinoma, and undifferentiated carcinomas are very rare

METASTASIS TO SALIVARY GLAND General Features (See Tables 23.23–23.26) ♦♦ Routes −− Lymphatic −− Hematogenous

−− Local spread (sarcomas of the facial bones or soft tissue and skin cancer) ♦♦ Parotid metastasis: lymphatic and hematogenous ♦♦ Submandibular gland metastasis, rare ♦♦ Parotid is the most common site because of lymphatic content

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Table 23.23. Infraclavicular Primary of Parotid and Parotid Lymph Node Metastasis Primary

Incidence (%)

Lung Kidney Breast Colorectal Others

34.3 31.4 11.4 11.4 11.4

Site Skin and mucous membrane Nasopharynx Thyroid gland

Table 23.24. Metastasis to Major and Minor Salivary Gland Site

Incidence (%)

Intraoral Parotid Submandibular Submandibular space

Table 23.25. Supraclavicular Primary Tumor with Metastasis to Parotid Gland and Intraparotid Lymph Node Diagnosis

Incidence (%)

Squamous carcinoma Melanoma Carcinoma Carcinoma

68.9 25.3   4.9   0.9

Table 23.26. Metastasis Infraclavicular Primary to Submandibular Gland Primary

  85.7    7.1 807    1.5

Incidence (%)

Breast Lung Kidney Other

38.9 27.7 22.3 11.1

IMMUNOHISTOCHEMISTRY IN THE ASSESSMENT OF SALIVARY GLAND TUMORS (SEE TABLES 23.27–23.29) Table 23.27. Immunohistochemical Analysis of Tumors with Myxohyalinized Stroma Marker GFAP S-100 Keratin SMA Desmin

PA

ADCC

BCA

+ + ± ± −

− ± + + −

− − + + −

PA pleomorphic adenoma, ADCC adenoid cystic carcinoma, BCA basal cell adenoma

Table 23.28. Tumors with Carcinoma with Basaloid Features Marker Keratin S-100 Chromogranin SMA

Small cell

Adenoid cystic

Basaloid

+ ± + −

+ ± − ±

+ − − −

SMA smooth muscle actin 1078

Table 23.29. Immunohistochemistry in the Differential Diagnosis of Salivary Gland Tumors with Clear Cell Features Marker

CCC

ME/MC

EMC

CK CK-CAM CEA EMA S-100 SMA MSA

+ + ± + − − −

+ + − ± + + +

+ + + + + + +

CCC clear cell carcinoma, ME myoepithelioma, MC myoepithelial carcinoma, CK cytokeratin, CEA carcinoembryonic antigen, EMA epithelial membrane antigen, SMA smooth muscle actin, MSA muscle-specific antigen

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TNM CLASSIFICATION OF MAJOR SALIVARY GLAND (2010 REVISION) ♦♦ T: Primary Tumor −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor £2  cm in greatest dimension without extraparenchymal extension −− T2: Tumor >2  cm but <4  cm in greatest dimension. No extraparenchymal extension −− T3: Tumor having extraparenchymal extension and/or >4 cm in greatest dimension −− T4a: Moderate advanced disease; tumor invades skin, mandible, ear canal, and/or facial nerve −− T4b: Very advanced disease; tumor invades skull base and/ or pterygoid plates and/or encases carotid artery ♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Metastasis in a single ipsilateral node, £3 cm in greatest dimension

−− N2: Metastasis in a single ipsilateral lymph node, >3 cm but <6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none >6  cm in greatest dimension, or in bilateral or contra-lateral lymph nodes, none >6  cm in greatest dimension −− N2a: Metastasis in a single ipsilateral lymph node >3 cm but <6 cm in greatest dimension −− N2b: Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension −− N2c: Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension −− N3: Metastasis in lymph node >6  cm in greatest dimension ♦♦ M: Distant Metastasis −− MX: Metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis

Suggested Reading Auclair PL, Langloss JM, Weiss SW, Corio RL. Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature. Cancer 1986;58:1305–1315. Batsakis JG, El-Naggar AK. Sebaceous lesions of salivary glands and oral cavity. Ann Otol Rhinol Laryngol 1990;99:416–418. Batsakis JG, Frankenthaler R. Embryomas (sialoblastoma) of salivary glands. Ann Otol Rhinol Laryngol 1992;101:958–960. Batsakis JG, Luna MA. Histopathologic grading of salivary gland ­neoplasms: I. Mucoepidermoid carcinoma. Ann Otol Rhinol Laryngol 1990;99:835–838. Batsakis JG, Raymond AK. Sialocysts of the parotid glands. Ann Otol Rhinol Laryngol 1989;98:487–489. Batsakis JG, Brannon RB, Sciubba JJ. Monomorphic adenomas of major salivary glands: a histologic study of 96 tumours. Clin Otolaryngol 1981;6:129–143. Batsakis JG, Luna MA, El-Naggar AK. Histopathologic grading of salivary gland neoplasms: II. Acinic cell carcinomas. Ann Otol Rhinol Laryngol 1990;99:929–933. Batsakis JG, Luna MA, El-Naggar A. Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas. Ann Otol Rhinol Laryngol 1990;99:1007–1009. Batsakis JG, Luna MA, El-Naggar AK. Basaloid monomorphic adenomas. Ann Otol Rhinol Laryngol 1991;100:687–690. Batsakis JG, McClathey KD, Johns ME, Regezi JA. Primary squamous cell carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg 1976;102:355–357.

Batsakis JG, Pinkston GR, Luna MA, Byrs RM, Sciubba JJ, Tillery GW. Adenocarcinomas of the oral cavity: a clinicopathologic study of terminal duct carcinomas. J Laryngol Otol 1983;97:825–835. Brandwein MS, Jagirdar J, Patil J, Biller H, Kaneko M. Salivary duct carcinoma (cribriform salivary carcinoma of excretory ducts). A clinicopathologic and immunohistochemical study of 12 cases. Cancer 1990;65:2307–2314. Callender DL, Frankenthaler RA, Luna MA, Lee SS. Salivary gland neoplasms in children. Arch Otolaryngol Head Neck Surg 1992;118: 472–476. Caselitz J, Schulze I, Seifert G. Adenoid cystic carcinoma of the salivary glands: an immunohistochemical study. J Oral Pathol Med 1986;15: 308–318. Cheuk W, Chan JK. Advances in salivary gland pathology. Histopathology 2007;51:1–20. Croitoru CM, Mooney JE, Luna MA. Sebaceous lymphadenocarcinoma of salivary glands. Ann Diagn Pathol 2003;7:236–239. Ellis GL, Corio RL. Acinic cell adenocarcinoma. A clinicopathologic analysis of 294 cases. Cancer 1983;52:542–549. Ellis GL, Wiscovitch JG. Basal cell adenocarcinomas of the major ­salivary glands. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1990;69: 461–469. Ellis GL, Auclair PL, Gnepp DR, Goode RK. Other malignant ­epithelial neoplasms. In: Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the salivary glands. Philadelphia: W.B. Saunders Co., 1991;455–488.

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Evans HL. Mucoepidermoid carcinoma of salivary glands: a study of 69 cases with special attention to histologic grading. Am J Clin Pathol 1984;81:696–701.

Luna MA, Batsakis JG, Tortoledo MF, del Junco GW. Carcinomas ex monomorphic adenoma of salivary glands. J Laryngol Otol 1989;103: 756–759.

Evans HL, Batsakis JG. Polymorphous low grade adenocarcinoma of minor salivary glands. A study of 14 cases of a distinctive neoplasm. Cancer 1984;53:935–942.

Luna MA, Ordóñez NG, Mackay B, Batsakis JG, Guillamondegui O. Salivary epithelial-myoepithelial carcinomas of intercalated ducts: a  clinical, electron microscopic, and immunocytochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1985;59:482–490.

Eveson JW, Cawson RA. Tumours of the minor (oropharyngeal) salivary glands: a demographic study of 336 cases. J Oral Pathol 1985;14:500–509. Everson JW, Speight PM. Non-neoplastic lesions of the salivary glands: new entities and diagnostic problems. Current Diagnostic Pathology 2006;12;22–30. Felix A, El-Naggar AK, Press MF, et al. Prognostic significance of biomarkers (c-erbB-2, p53, proliferating cell nuclear antigen, and DNA content) in salivary duct carcinoma. Hum Pathol 1996;27:561–566. Gnepp DR. Metastatic disease to the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the salivary glands. Philadelphia: W.B. Saunders Co., 1991;560–569. Gnepp DR, Corio RL, Brannon RB. Small cell carcinoma of the major salivary glands. Cancer 1986;58:705–714. Headington JT, Batsakis JG, Beals TF, Campbell TE, Simmons JL, Stone WD. Membranous basal cell adenoma of parotid gland, dermal cylindromas, and trichoepitheliomas. Comparative histochemistry and ultrastructure. Cancer 1977;39:2460–2469.

McDaniel RK. Benign mesenchymal neoplasms. In Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the salivary glands. Philadelphia: W.B. Saunders Co., 1991;489–513. Seifert G. Histological typing of salivary gland tumors. World Health Organization. International Histological Classification of Tumours, 2nd ed. Berlin: Springer-Verlag, 1991. Seifert G. Classification and differential diagnosis of clear and basal cell tumors of the salivary glands. Semin Diagn Pathol 1996;13:95–103. Seifert G, Donath K. Classification of the pathology of diseases of the ­salivary glands: review of 2,600 cases in the Salivary Gland Register. Beitrage zur Pathologie 1976;159:1–32. Seifert G, Donath K. Multiple tumours of the salivary glands. Terminology and nomenclature. Eur J Cancer B Oral Oncol 1996;32:3–7. Simpson RH, Sarsfield PT, Clarke T, Babajews AV. Clear cell carcinoma of minor salivary glands. Histopathology 1990;17:433–438.

Hui KK, Batsakis JG, Luna MA, Mackay B, Byers RM. Salivary duct adenocarcinoma: a high grade malignancy. J Laryngol Otol 1986; 100:105–114.

Skalova A, Gnepp DR, Simpson RH, Lewis JE, DiPalma S, Michal M. Clonal nature of sclerosing polycystic adenosis of salivary glands demonstrated by using the polymorphism of the human androgen receptor (HUMARA) locus as a marker. Am J Surg Pathol. 2006;30:939–944.

Kapadia S. Newly recognized salivary gland tumours. Pathology International 2004;54:S245–S255.

Spiro RH, Huvos AG, Strong EW. Acinic cell carcinoma of salivary origin. A clinicopathologic study of 67 cases. Cancer 1978;41:924–935.

Kemp BL, Batsakis JG, El-Naggar AK, Kotliar SN, Luna MA. Terminal duct adeno­carcinoma of the parotid gland. J Laryngol Otol 1995;109: 466–468.

Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of  adenoid cystic carcinoma of the salivary glands. Cancer 1984;54: 1062–1069.

Krolls SG, Trodahl NJ, Boyers RC. Salivary gland lesions in children: a survey of 430 cases. Cancer 1972;30:459–469.

Takata T, Ogawa I, Nikai H. Sebaceous carcinoma of the parotid gland. An immunohistochemical and ultrastructural study. Virchows Arch 1989;414:459–464.

Luna MA. Salivary mucoepidermoid carcinoma: revisited. Adv Anat Pathol 2006;13:293–307. Luna MA, Tortoledo ME, Allen M. Salivary dermal analogue tumors arising in lymph nodes. Cancer 1987;59:1165–1169.

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Waldron CA. Mixed tumor (pleomorphic adenoma) and myoepithelioma. In: Ellis GL, Auclair PL, Gnepp DR, eds. Surgical pathology of the ­salivary glands. Philadelphia: W.B. Saunders, 1991;165–186.

24 Head and Neck John D. Henley, md and Don-John Summerlin, md

Contents

I. Oral Cavity........................................24-4

Infection............................................................24-4 Candidiasis..............................................24-4 Herpes Simplex Virus.............................24-4 Oral Hairy Leukoplakia........................24-4 Human Papillomavirus..........................24-5 Disseminated Fungal Infection..............24-5 Immune-Mediated Disease..............................24-5 Lichen Planus..........................................24-5 Benign Mucous Membrane (Cicatricial) Pemphigoid...................24-6 Pemphigus Vulgaris................................24-6 Inflammatory/Nonneoplastic Lesions.............24-6 Peripheral Ossifying Fibroma...............24-6 Peripheral Giant Cell Granuloma........24-7 Verruciform Xanthoma..........................24-7 Traumatic Ulcerative Granuloma with Stromal Eosinophilia................24-7 Mucous Extravasation Phenomena (Mucocele/Ranula).............................24-8 Necrotizing Sialometaplasia..................24-8 Benign Neoplasms............................................24-8 Granular Cell Tumor.............................24-8 Congenital Gingival Granular Cell Tumor (Congenital Epulis).......24-8 Premalignant/Malignant Neoplasms..............24-9 “Leukoplakia”........................................24-9 Squamous Dysplasia/Carcinoma In Situ.................................................24-9 Proliferative Verrucous Leukoplakia........................................24-9 Squamous Cell Carcinoma..................24-10 Verrucous Carcinoma..........................24-10

Sarcomatoid (Spindle Cell) Carcinoma........................................24-11 Papillary Squamous Cell Carcinoma........................................24-11 Malignant Melanoma...........................24-11 Miscellaneous Lesions....................................24-12 Adenomatoid Hyperplasia...................24-12 Amalgam Tattoo...................................24-12 Aphthous Stomatitis.............................24-12 Dermoid Cyst........................................24-12 Geographic Tongue (Erythema Migrans)........................24-12 Lingual Thyroid....................................24-12 Lymphoepithelial Cyst.........................24-12 Melanoacanthoma................................24-12 Nicotine Stomatitis...............................24-12 Oral Focal Mucinosis...........................24-12 Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma...............24-12 Salivary Duct Cyst................................24-13 Smokeless Tobacco-Induced Keratosis...........................................24-13

II. Jaws.................................................24-13 Nonodontogenic Cysts/Pseudocysts..............24-13 Nasopalatine Cyst.................................24-13 Traumatic Bone Cavity........................24-13 Odontogenic Cysts..........................................24-13 Dentigerous Cyst...................................24-13 Odontogenic Keratocyst (Keratocystic Odontogenic Tumor)..............................................24-14 Apical Periodontal Cyst.......................24-14

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_24, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Calcifying Odontogenic Cyst (Gorlin Cyst)....................................24-14 Dentinogenic Ghost Cell Tumor (Included Here Given Similarity to Gorlin Cyst).................................24-15 Reactive/Nonneoplastic Disease....................24-15 Cementoosseous Dysplasia..................24-15 Odontoma..............................................24-15 “Giant Cell” and Giant Cell-Rich Lesions........................................................24-15 Central Giant Cell Granuloma...........24-15 Giant Cell Tumor..................................24-16 Aneurysmal Bone Cyst.........................24-16 Cherubism.............................................24-16 Benign Neoplasms..........................................24-16 Ameloblastoma.....................................24-16 Adenomatoid Odontogenic Tumor.....24-17 Calcifying Epithelial Odontogenic Tumor (Pindborg Tumor)...............24-17 Squamous Odontogenic Tumor...........24-17 Ameloblastic Fibroma..........................24-18 Cementoblastoma.................................24-18 Central Cementoossifying Fibroma............................................24-18 Odontogenic Fibroma..........................24-18 Malignant Neoplasms.....................................24-19 Ameloblastic Carcinoma......................24-19 Squamous Cell Carcinoma..................24-19 Clear Cell Odontogenic Carcinoma........................................24-19 Osteosarcoma........................................24-19 Chondrosarcoma..................................24-20 Mesenchymal Chondrosarcoma..........24-20 Metastatic Disease................................24-20 Melanotic Neuroectodermal Tumor of Infancy..........................................24-20 Miscellaneous Lesions....................................24-20 Stafne Defect.........................................24-20 Tori.........................................................24-20 Gingival Cyst/Lateral Periodontal Cyst...................................................24-21 Central Mucoepidermoid Carcinoma........................................24-21

III. Oro/Hypopharynx...........................24-21 Malignant Neoplasms.....................................24-21 Squamous Cell Carcinoma..................24-21 Lymphoepithelial Carcinoma..............24-21 Basaloid Squamous Carcinoma..........24-21 Papillary Squamous Cell Carcinoma................................24-22

IV. Nasal Cavity, Paranasal Sinuses, and Nasopharynx.............................24-22 Infection..........................................................24-22

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Rhinosinusitis........................................24-22 Allergic Fungal Sinusitis......................24-23 Invasive Fungal Sinusitis.....................24-23 Other Forms of Infectious Sinusitis.............................................24-23 Inflammatory/Nonneoplastic Lesions...........24-23 Mucocele................................................24-23 Wegener Granulomatosis....................24-24 Sarcoidosis.............................................24-24 Myospherulosis.....................................24-24 Polyps.....................................................24-24 Benign Neoplasms..........................................24-25 Lobular Capillary Hemangioma (Granuloma Pyogenicums).............24-25 Hyperkeratotic Squamous Papilloma..........................................24-25 Sinonasal Papilloma (Schneiderian Papilloma)........................................24-25 Hemangiopericytoma-Like Tumor of the Nasal Cavity...........................24-26 Juvenile Nasopharyngeal Angiofibroma...................................24-27 Malignant Neoplasms.....................................24-27 Squamous Cell Carcinoma..................24-27 Malignant Lymphoma..........................24-28 Adenoid Cystic Carcinoma..................24-28 Olfactory Neuroblastoma (Esthesioneuroblastoma).................24-29 Sinonasal Undifferentiated Carcinoma (SNUC).........................24-29 Malignant Melanoma (Sinonasal Melanoma).....................24-30 Small Cell (Neuroendocrine) Carcinoma (SCNC).........................24-30 Adenocarcinoma...................................24-31 Rhabdomyosarcoma.............................24-31 Nasopharyngeal Carcinoma (NPC)....24-32 Miscellaneous Lesions....................................24-32 Respiratory Epithelial Adenomatoid Hamartoma......................................24-32 Necrotizing Sialometaplasia................24-32 Cholesterol Granuloma........................24-32 Chondromesenchymal Hamartoma......................................24-32 Extranodal Sinus Histiocytosis (Sinus Histiocytosis with Massive Lymphadenopathy, Rosai–Dorfman Disease).............................................24-32 Fibromatosis.........................................24-33 Hemangioma of Nasofacial Bones.......24-33 Meningioma..........................................24-33 Mesenchymal Chondrosarcoma..........24-33 Osteoma.................................................24-33 Metastatic Tumors................................24-33 Pituitary Adenoma...............................24-33

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Salivary Gland Tumors........................24-33 Sarcoma.................................................24-33 Solitary Fibrous Tumor.......................24-33 Teratoid Carcinosarcoma (Teratocarcinosarcoma)..................24-33

V. Larynx and Trachea..........................24-34 Infection..........................................................24-34 Disseminated Fungal Infection............24-34 Inflammatory/Nonneoplastic Lesions...........24-34 Laryngocele...........................................24-34 Oncocytic Cyst......................................24-34 Vocal Cord Polyp (Laryngeal Polyp)............................24-34 Contact Ulcer........................................24-35 Benign Neoplasms..........................................24-35 Laryngeal Papillomatosis (Squamous Papillomas)...................24-35 Premalignant/Malignant Neoplasms............24-35 Squamous Cell Hyperplasia (Hyperkeratosis)..............................24-35 Squamous Dysplasia/Carcinoma In Situ...............................................24-36 Squamous Cell Carcinoma..................24-36

Verrucous Carcinoma..........................24-36 Basaloid Squamous Cell Carcinoma........................................24-36 Sarcomatoid Carcinoma (Spindle Cell Carcinoma)................24-36 Papillary Squamous Cell Carcinoma................................24-37 Lymphoepithelioma-Like Carcinoma........................................24-37 Small Cell (Neuroendocrine) Carcinoma (SCNC).........................24-37 Large Cell Neuroendocrine Carcinoma (LCNC).........................24-37 Adenoid Cystic Carcinoma..................24-38 Chondrosarcoma..................................24-38 Mesenchymal/Soft Tissue Tumors......24-38

VI. TNM Classifications for the Lip and Oral Cavity (2010 Revision)......24-38 VII. TNM Classifications for the Larynx (2010 Revision)....................24-39 VIII. Suggested Readings..........................24-40

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ORAL CAVITY Infection Candidiasis Clinical ♦♦ This represents the most common opportunistic infection in the oral cavity. It may be caused by a variety of species, most commonly Candida albicans. This can occur at any age, including infancy; however, it is usually secondary to underlying disease (immunosuppression, diabetes), immunosuppressive therapy, or local factors (ill-fitting dentures). It may appear as a curd-like pseudomembrane (pseudomembranous candidiasis), tissue hyperplasia (hyperplastic candidiasis), or erythema (atrophic candidiasis)

Microscopic ♦♦ In most instances, perpendicularly oriented (relative to mucosa) pseudohyphae and spores are located in the superficial parakeratin accompanied by neutrophilic exocytosis. Visualization of the organisms and spores may be aided by GMS and PAS stains

Oral Hairy Leukoplakia Clinical ♦♦ This condition represents a peculiar manifestation of Epstein–Barr virus (EBV) infection, mostly in immunosuppressed hosts. Usually, bilateral linear striations are seen on the lateral border of tongue. Oral hairy leukoplakia may be seen in AIDS, organ transplant patients, diabetics, and cancer patients. On rare occasions, this infection can be seen in immunocompetent hosts

Microscopic ♦♦ Upon microscopic examination, hyperkeratosis is seen beneath, which is a linear band of cells with edematous cytoplasm and nuclei that demonstrate chromatin margination (Fig. 24.2A,B). In situ hybridization will illuminate EBV within these cells. Superimposed candidiasis is present in most cases

Herpes Simplex Virus Clinical ♦♦ Most herpetic lesions of the oral cavity are caused by Herpes simplex virus, type I or type II. Typically, herpetic infections present as localized vesicles or ulcers on keratinized mucosa or lip vermilion. Mucosal eruptions can be widespread in children not previously exposed (gingivostomatitis)

Microscopic ♦♦ The histopathologic features include vesicles with acantholytic cells (Tzanck cells). Commonly, the lesions are biopsied once they have ulcerated. If so, cells on margin of the ulceration often demonstrate viral cytopathic effect (multinucleate cells with “ground glass” chromatin, angular nuclear outlines, and intranuclear eosinophilic inclusions) (Fig. 24.1)

Fig. 24.1. Multinucleate cells with ground glass nuclear change characterize infection with Herpes simplex virus.

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Fig. 24.2. The hyperkeratotic lesions of oral hairy leukoplakia usually present on the lateral border of the tongue in immunosuppressed patients (A). Cellular changes characterized by edematous cytoplasm and nuclei that demonstrate chromatin margination are secondary to Epstein-Barr virus (B).

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Differential Diagnosis ♦♦ Morsicatio linguarum (tongue chewing) −− This condition demonstrates thickened parakeratin with a ragged surface and adherent bacterial colonies but lacks candidal infection and EBV

Human Papillomavirus Clinical ♦♦ Human papillomavirus infection will produce papillary lesions of the oral cavity – papillomas, condylomas, and verrucae. Commonly, these are seen in young patients on tongue, gingiva, and soft palate complex. These possess a papillary growth pattern and are generally small, localized lesions

Microscopic ♦♦ The squamous papilloma demonstrates a papillary epithelial proliferation arising from stalk or pedunculated base. Verrucae demonstrate coarse keratohyaline granules, hyperkeratosis, and axial inclination of rete ridges. Condylomas demonstrate koilocytes and broader papillations and branching. The presence of condylomas in children may suggest child abuse. Although not thought to be a significant risk factor for carcinomas of the oral cavity proper, HPV types 16 and 18 are highly associated with squamous cell carcinomas of tonsil/oropharynx

Fig. 24.3. Oral manifestations of histoplasmosis reflect disseminated disease. Inset: GMS stain highlights yeast.

Disseminated Fungal Infection Clinical ♦♦ A variety of disseminated fungal infections may have oral manifestations, including histoplasmosis, ­blastomycosis, cryptococcosis, and coccidioidomycosis. Most, but not all, patients demonstrate a definable immunodeficient state (i.e., HIV, diabetes, status postorgan transplantation, malignancy). These infections are accompanied by oral ulceration, weight loss, and fevers. In many instances, oral lesions are preceded by pulmonary infection

Microscopic ♦♦ Typically granulomatous inflammation is seen, including histiocytes, giant cells, and necrosis (Fig. 24.3). The presence of a neutophilic infiltration with giant cells is characteristic of blastomycosis. Blastomycosis is notorious for associated pseudoepitheliomatous hyperplasia, simulating squamous cell carcinoma. Discrete granulomas may be absent in histoplasmosis (i.e., organism-laden, foamy histiocytes with necrosis and nonspecific inflammation). Fungal stains (GMS and PAS) may aid identification of microorganisms

Fig. 24.4. Band-like inflammatory infiltrates and spike-shaped rete ridges characterize lichen planus.

Microscopic ♦♦ A band-like infiltrate of lymphocytes obscuring epithelial/ connective tissue junction represents the seminal microscopic feature (Fig. 24.4). Spike-shaped rete ridges and dissolution of basal epithelial layer are also apparent

Immune-Mediated Disease Lichen Planus Clinical

Immunofluorescence

♦♦ This mucocutaneous disease is characterized by bilateral, symmetrical white striations (striae of Wickham) superimposed upon an erythematous background. Most commonly this is seen in perimenopausal females on the buccal mucosa, tongue, or gingiva. In the erosive form, it presents as an erythematous lesion with faint peripheral striations

Differential Diagnosis

♦♦ Should direct immunoflurescent testing be undertaken, granular deposition of fibrinogen is observed at the basement membrane level ♦♦ Lichenoid mucositis −− Histologically this is similar to lichen planus but typically is not symmetrical. This may be due to a variety of stimuli – dental products, dental materials, systemic medication

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♦♦ Epithelial dysplasia with lichenoid inflammation −− Epithelial alterations consistent with irreversible, precancerous change, probably accounts for most cases of “malignant transformation” of lichen planus

Benign Mucous Membrane (Cicatricial) Pemphigoid Clinical ♦♦ This immunologically mediated disease demonstrates generalized sloughing of epithelium leaving a bleeding erythematous base. The typical population is peri/postmenopausal females. Often sloughing can be elicited with gauze or a gloved finger. Ocular and genital mucosal involvement may also be seen

Microscopic ♦♦ Subbasilar separation of the epithelium is characteristic of this condition (Fig.  24.5). A diffuse chronic inflammatory infiltrate of lymphocytes is seen with a smattering of neutrophils

Immunofluorescence ♦♦ Linear deposition of C3 and IgG along the basement membrane zone is seen in almost all cases in which direct immunofluorescence is performed

Differential Diagnosis ♦♦ Lichen planus −− Can demonstrate separation but basal layer is lost. The lymphocytic infiltrate is typically more band like ♦♦ Pemphigus vulgaris −− Separation occurs above the basal layer, and Tzanck cells may be present

Pemphigus Vulgaris Clinical

Essentials of Anatomic Pathology, 3rd Ed.

commonly afflicted individuals. This can manifest primarily as gingival desquamation without cutaneous lesions

Microscopic ♦♦ Suprabasilar separation of the epithelium is seen, possibly with evidence of Tzanck cells. The inflammatory infiltrate is composed mostly of lymphocytes

Immunofluorescence ♦♦ Intraepithelial (desmosomal) deposition of C3 and IgG in a spider web pattern is characteristic of pemphigus when viewed with immunofluorescence (Fig. 24.6)

Differential Diagnosis ♦♦ Lichen planus, see above ♦♦ Cicatricial pemphigoid, see above ♦♦ Drug-induced pemphigus −− Can be seen in particular with penicillamine ♦♦ Paraneoplastic pemphigus −− Supra and subbasilar splits are seen in patients with lymphoma and leukemia

Inflammatory/Nonneoplastic Lesions Peripheral Ossifying Fibroma Clinical ♦♦ This represents a reactive mesenchymal proliferation of periodontal ligament origin that retains the capacity to form bone or cementum-like product. Most commonly seen in the second to third decade, the peripheral ossifying fibroma demonstrates a female predilection. Occurring exclusively on the gingiva, it presents as a broad-based nodule that is typically ulcerated and asymptomatic

♦♦ Widespread sloughing and ulceration of mucosa is the typical manifestation. Young adult males and females are the

Fig. 24.5. Subbasilar separation of the epithelium with chronic inflammation.

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Fig. 24.6. Direct immunofluorescence revealing IgG positivity in the desmosomal areas.

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Fig. 24.7. Peripheral ossifying fibroma is a gingival-based nodule exhibiting matrix (i.e., bone or cementum) production.

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Fig. 24.8. The connective tissue papillae are filled with lipid-laden macrophages in verruciform xanthoma.

Microscopic ♦♦ The microscopic features include a cellular mesenchymal tissue with intermixed calcifications that can resemble bone or cementum (Fig. 24.7). It often extends to the base because of its origin in the periodontal ligament, resulting in recurrence

Peripheral Giant Cell Granuloma Clinical ♦♦ Considered a reactive proliferation of vascular mesenchymal tissue with intermixed osteoclasts, the peripheral giant cell granuloma has a propensity to occur in older adults in the fourth to sixth decades. It appears as a lobular, blue to purple mass on the gingiva/alveolar ridge. It may erode bone superficially, resulting in an alveolar radiolucency

Microscopic ♦♦ The peripheral giant cell granuloma consists of an exuberant mass of spindle-shaped cells with numerous extravasated erythrocytes, hemosiderin pigment (especially at the periphery), and multinucleated giant cells. Because of its location, it can recur with frequency

Verruciform Xanthoma Clinical

Fig. 24.9. The ulcer bed in traumatic ulcerative granuloma with stromal eosinophilia can be extremely cellular and mistaken for a neoplastic process.

Traumatic Ulcerative Granuloma with Stromal Eosinophilia Clinical

♦♦ This interesting entity represents a peculiar reactive proliferation of lipid-laden macrophages with a papillary surface configuration. Typically occurring on the gingiva or palatal mucosa in adults, it can appear red to yellow in coloration with a granular surface that may look like a volcano crater

♦♦ This peculiar exuberant reactive process can mimic squamous cell carcinoma in its clinical presentation. Typically present on the dorsolateral tongue in adults, it manifests as an ­exophytic ulcerative mass usually of several weeks duration. This may be painful and persist even after multiple surgeries

Microscopic

Microscopic

♦♦ The histologic appearance is that of papillary proliferations of epithelium with brightly eosinophilic keratin beneath, which the connective tissue papillae are filled with lipidladen macrophages (Fig. 24.8). These cells will be confined to papillary lamina propria

♦♦ Surface ulceration is seen overlying a proliferation of inflamed granulation tissue with prominent, reactive endothelial cells (Fig.  24.9). Eosinophils and macrophages are prominent in the deeper aspects approximating and involving muscle

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Differential Diagnosis ♦♦ Squamous cell carcinoma, but only from a clinical perspective ♦♦ Lymphoma −− Atypical lymphoid cells, clonal −− Aside from NK/T-cell lymphomas, which may be polymorphous, most lymphomas are monomorphic infiltrates, contrasted to mixed infiltrate of traumatic ulcerative granuloma. Lymphoma will generally lack prominent eosinophils

Mucous Extravasation Phenomena (Mucocele/Ranula) Clinical ♦♦ This is a reactive lesion representing spillage of mucin into tissue due to duct damage. Typically young patients, first to second decade, represent the common population. Mucoceles occur most commonly in the lower lip, ranulae in the floor of mouth. The clinical appearance is that of a dome-shaped, fluid-filled lesion that may wax and wane with rupture. A “plunging ranula” presents as neck mass and may simulate thyroglossal duct cyst

Microscopic ♦♦ Pseudocystic accumulations of mucin surrounded by macrophages, a wall of compressed granulation tissue and inflammation represent the salient diagnostic features (Fig. 24.10)

Necrotizing Sialometaplasia Clinical ♦♦ An ulcerative lesion involving salivary gland, necrotizing sialometaplasia can mimic malignancy. Although its etiology is unclear, it is possibly due to underlying ischemic event. Younger adults are most commonly affected, with the

Essentials of Anatomic Pathology, 3rd Ed.

palate representing the most common site. Swelling with pain, followed by a sharply demarcated ulceration over a 2-week period represents the typical clinical progression

Microscopic ♦♦ Necrotizing sialometaplasia is characterized by coagulative necrosis of acinar units with surface ulceration and squamous metaplasia of salivary ducts. However, there is maintenance of lobular architecture of salivary gland. Because of the squamous metaplasia, it can mimic squamous cell carcinoma or mucoepidermoid carcinoma

Differential Diagnosis ♦♦ Squamous cell carcinoma −− Infiltrative growth, cytologic atypia, nonlobular growth pattern, surface epithelial features ♦♦ Mucoepidermoid carcinoma −− Infiltrative growth, prominent appearance to goblet cells, no necrosis of acinar units

Benign Neoplasms Granular Cell Tumor Clinical ♦♦ This is a benign, nonneoplastic proliferation of probable perineural sheath cells. Seventy percent occur on the tongue, primarily dorsum, as a deep mass with maintenance of surface architecture. These often represent longstanding processes

Microscopic ♦♦ Ill-defined collections of cells with granular cytoplasm, eccentric nuclei, and indistinct cytoplasmic boundaries constitute the primary histologic feature (Fig.  24.11). Many cases have superimposed pseudoepitheliomatous hyperplasia, mimicking squamous cell carcinoma. Granular cell tumors tend not to recur, even with incomplete removal

Immunohistochemistry ♦♦ S-100 protein+

Differential Diagnosis ♦♦ Squamous cell carcinoma −− Lacks the subepithelial granular cells that accompany pseudoepitheliomatous hyperplasia. Rare on the dorsum of the tongue where granular cell tumor is common

Congenital Gingival Granular Cell Tumor (Congenital Epulis) Clinical

Fig. 24.10. Disruption of salivary gland ducts results in mucin extravasation into connective tissue.

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♦♦ The congenital gingival granular cell tumor is a benign proliferation of granular cells on the alveolar ridge in newborns. This manifests as an exophytic mass, often large (greater than 5 cm), on the maxillary alveolar ridge most commonly. As the name implies, it is typically present at birth

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Fig.  24.12. The most apparent atypical changes of severely dysplastic epithelium in the oral cavity may be limited to lower aspect of the epithelium.

Fig.  24.11. Granular cell tumors are notorious for inducing pseudoepitheliomatous hyperplasia of the overlying epithelium.

Microscopic ♦♦ This appears as a mass of cells with granular cytoplasm, often demonstrating distinct cell boundaries. The overlying epithelium is typically atrophic

Immunohistochemistry ♦♦ S-100−

Premalignant/Malignant Neoplasms “Leukoplakia” ♦♦ This represents strictly a clinical term and should never be used as a microscopic diagnosis. All it confers is a white patch and, as such, carries no histologic implications. The clinical location, symptoms, and risk factors are far more important in assessing the risk of preneoplasia/carcinoma. The microscopic diagnosis ranges from hyperkeratosis to squamous cell carcinoma. It is recommended that the use of the term be discouraged

Squamous Dysplasia/Carcinoma In Situ Clinical ♦♦ As with other sites, the oral epithelium tends to demonstrate precursor lesions prior to frank invasion. Most classifications grade squamous dysplasia to carcinoma in situ dependent

upon the degree and thickness of epithelial involvement. This may present as a white patch, red patch (erythroplasia), or ulcer. Typically squamous dysplasia/carcinoma in situ is seen in patients over 40 who are also smokers and drinkers. Females now represent approximately 50% of cases. Ventrolateral tongue, floor of mouth, and soft palate complex represent high risk sites for these squamous cell carcinoma precursors

Microscopic ♦♦ The histologic features include nuclear enlargement, hyperchromatism, pleomorphism, loss of polarity, and architectural changes (i.e., formation of bulbous rete ridges) (Fig. 24.12) ♦♦ WHO Classification of oral dysplasia −− Mild – lower one-third abnormalities −− Moderate – lower one-half abnormalities −− Severe – lower two-thirds abnormalities −− Carcinoma in situ – full-thickness abnormalities ♦♦ The grade of dysplasia does correlate with risk of squamous cell carcinoma (i.e., the higher the grade, the greater the risk). Reproducibility of grading oral dysplasia (both intra- and interobserver) is generally poor

Proliferative Verrucous Leukoplakia Clinical ♦♦ Proliferative verrucous leukoplakia represents a relatively recently described progressive condition involving multiple sites in the oral cavity. It occurs in the fifth decade or later and has a female predilection. No strong tobacco association is apparent. Multiple white patches are seen that tend to enlarge, become verrucous and coalesce over time. It usually progresses to squamous cell carcinoma in less than a decade. It has yet to be successfully managed with consistency by any means

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Microscopic ♦♦ Within a given patient, it can vary from site to site in the oral cavity from verrucous hyperkeratosis to epithelial dysplasia to verrucous carcinoma to squamous cell carcinoma

Squamous Cell Carcinoma Clinical ♦♦ This represents the most common malignancy in the oral cavity. Ventrolateral tongue, floor of mouth, and gingiva are the common sites of origin. Mostly seen in smokers and/or drinkers over age of 40, some studies suggest an increasing element of cases in younger patients without known risk factors. Although often suspected, HPV has yet to be shown to play a major role in oral cavity proper carcinomas. Once predominantly a male disease, females are increasing in incidence to 50% of cases. It manifests as white patch, red patch, ulcer, or exophytic mass

Microscopic ♦♦ Characteristically, invasive and proliferative squamous epithelium is seen demonstrating the cytologic and morphologic alterations seen in epithelial dysplasia, with the addition of

keratin pearls. The level of differentiation is graded as well, moderately, or poorly differentiated. Histologic grade does correlate with disease aggressiveness, although not as directly as clinical stage. Depth of invasion (>4  mm) and perineural invasion represent negative predictors. Currently, ~50% of patients survive 5 years, relatively unchanged over the last half century

Differential Diagnosis ♦♦ See Table 24.1

Verrucous Carcinoma Clinical ♦♦ This represents a low grade, well-differentiated variant of squamous cell carcinoma. Usually seen over the age of 60, it is more commonly seen in smokeless tobacco users than smokers. Characterized by a large (>4  cm) papillary mass with a broad base, verrucous carcinoma is often snow white due to hyperkeratosis. Generally, it is seen on tongue, alveolar mucosa, buccal mucosa and is often of long-standing duration. As it is usually nonmetastazing, neck dissection is not indicated

Table 24.1. Differential Diagnosis of the Poorly/Undifferentiated Sinonasal Neoplasm Squamous cell carcinoma

Squamous differentiation: keratin, intercellular bridges and/or dyskeratotic cells

Lymphoma NK/T lymphoma: midline B-cell lymphoma: paranasal sinuses

Lymphoid markers+ (CD45RO, CD56, CD3, CD20) Cytokeratin−

Sinonasal undifferentiated carcinoma (SNUC)

Cytokeratin +, neuroendocrine markers – prominent nucleoli Scant cytoplasm Prominent mitotic figures

Malignant melanoma

S-100 protein+, cytokeratin−Melanoma markers+ (HMB 45, MelanA)

Olfactory neuroblastoma

Synaptophysin+, chromogranin + S-100 protein + sustentacular cells Cytokeratin−

Basaloid squamous cell carcinoma

Undifferentiated basaloid cells Squamous differentiation, “mosaic pattern” of keratinization

Lymphoepithelioma-like carcinoma

Cytokeratin+ Lymphoma and melanoma markers− Histologically indistinguishable from nasopharyngeal carcinoma

Adenoid cystic carcinoma, solid pattern or so-called “dedifferentiated”

Evidence of glandular differentiation as tubular and/or cribriform structures Myoepithelial differentiation (S-100, actin+)

Pituitary adenoma

Synaptophysin+ Cytokeratin +/− No (rare) mitotic figures

Rhabdomyosarcoma

MyoD1+, myogenin+, desmin+, muscle-specific actin+ CD99− Children

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Fig. 24.13. Verrucous carcinoma is a broad-based, hyperkeratotic tumor that infiltrates in a “pushing” fashion.

Fig.  24.14. Spindle cell carcinoma, surrounding a focus of malignant basaloid cells, simulates sarcoma.

Microscopic

Papillary Squamous Cell Carcinoma Clinical

♦♦ Verrucous carcinoma varies from standard squamous cell carcinoma by exhibiting broad papillations of squamous epithelium exhibiting minimal atypia with deeply invaginated folds of parakeratin (“parakeratin plugging”) (Fig.  24.13). If cytologic atypia is present, the diagnosis of “verrucous” type carcinoma should be doubted as it probably represents a papillary keratinizing well-differentiated squamous cell carcinoma. This malignancy has an excellent prognosis with a 95% 5-year survival rate

♦♦ A relatively recent addition to the literature, this represents an exophytic variant of squamous cell carcinoma that is highly associated with HPV types 16 and 18. There is a predilection for tonsil–oropharynx and hypopharynx. The prognosis is generally more favorable and probably relates to depth of stromal invasion more than size of exophytic component

Differential Diagnosis

Microscopic

♦♦ Papillomas −− Typically smaller, well-confined lesions with a pedunculated base

♦♦ A branching papillary architecture is seen with little tendency to keratinize (Fig. 24.15). Brisk mitotic activity and notable cytologic atypia are commonly present

Sarcomatoid (Spindle Cell) Carcinoma Clinical ♦♦ This represents a poorly differentiated variant of squamous cell carcinoma. Usually, sarcomatoid carcinoma manifests after age of 40 and can occur in a history of radiation or burns, particularly electrical. Usually, it occurs as a polypoid, ulcerated mass on posterior tongue or in oropharynx

Microscopic ♦♦ The microscopic appearance is that of an exuberant proliferation of anaplastic spindle-shaped cells that appear to ‘drop off’ from atypical surface epithelium (Fig. 24.14)

Immunohistochemistry ♦♦ Cytokeratin 5/6+, vimentin+, p63+

Differential Diagnosis ♦♦ Spindle cell sarcomas −− Cytokeratin− −− Most superficial spindle cell malignancies in the oral cavity are carcinomas

Differential Diagnosis ♦♦ Squamous papilloma −− Lacks the cytologic atypia and architectural complexity of papillary squamous cell carcinomas

Malignant Melanoma Clinical ♦♦ This is a rare malignancy arising from mucosal melanocytes. Typically, it is seen in adults throughout the mucosa although more commonly in the nasal cavity and paranasal sinuses. It may present as a lesion of long-­standing duration with widespread discoloration. In addition, it also can occur as an exophytic pigmented mass

Microscopic ♦♦ The cells are typically large with prominent red nucleoli and abundant cytoplasm. Although often amelanotic, some dusky pigment can be seen with diligent searching. It is imperative to determine whether the lesion primary or metastatic. It is useful to identify atypical cells within the mucosal epithelium. Mucosal melanosis has a poor ­prognosis due to its aggressive nature and delay in diagnosis

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Fig. 24.16. Subcorneal abscess formation is prominent in geographic tongue. Fig. 24.15. Papillary squamous cell carcinoma has a predilection for the oropharynx, including the tonsil, and is associated with human papillomavirus.

Miscellaneous Lesions Adenomatoid Hyperplasia ♦♦ This represents enlarged mucous glands in a tumor-like pattern seen in the palate. It may actually represent normal glands overlying a neoplasm and thus should be investigated thoroughly

Amalgam Tattoo ♦♦ The amalgam tattoo is a localized discolored area demonstrating granular, black foreign material aligned along ­collagen fibers and staining basement membrane. It is typically seen in area of dental restorations

Aphthous Stomatitis ♦♦ These are ulcerations seen primarily in the lining mucosa in a variety of patterns. Minor aphthae are less than 1 cm ulcers with a fibrinous membrane and halo of erythema. Herpetiform aphthae consist of multiple punctate erythematous ulcerations. Major aphthae are large, greater than 2 cm, ulcerations with significant pain. No distinctive histopathology is seen with these lesions, rather they are clinical diagnoses

Lingual Thyroid ♦♦ This represents residual thyroid remaining on posterior dorsum or within the substance of the tongue, left from the embryologic descent of the thyroid enlarge

Lymphoepithelial Cyst ♦♦ This developmental anomaly is lined by squamous epithelium and surrounded by lymphoid follicles and is commonly seen in floor of the mouth, posterior/lateral tongue, and tonsillar region

Melanoacanthoma ♦♦ A suddenly progressing and regressing pigmented lesion of the buccal mucosa in African Americans, melanoacanthoma histologically demonstrates the presence of dendritic melanocytes within the spinous layer of epithelium

Nicotine Stomatitis ♦♦ Characterized by punctate erythematous areas surrounded by white zones on the palate of primarily pipe smokers, nicotine stomatitis demonstrates a surface proliferation of squamous epithelium around a central salivary duct with associated inflammation

Oral Focal Mucinosis

Dermoid Cyst

♦♦ This represents a localized mass seen at any site in the mucosa characterized by the presence of abundant ground substance and flattening of the rete ridges of the epithelium

♦♦ This developmental anomaly is seen in the midline floor of the mouth and exhibits a keratinized lining with adnexal structures. True teratomas are rarely seen

Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma

Geographic Tongue (Erythema Migrans) ♦♦ An inflammatory condition of the tongue primarily characterized by superficial microabscesses, this may represent a form of psoriasis (Fig. 24.16)

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♦♦ A discrete nodule usually less than 1 cm seen most frequently on lip vermilion and hard palate, the palisaded, encapsulated neuroma is characterized by well-demarcated proliferation of Schwann cells with faint palisaded arrangements and has axons present (Fig. 24.17)

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Fig. 24.17. Palisaded encapsulated neuroma is a circumscribed neural lesion and, thus, may be mistaken for schwannoma. Inset: Axonal proliferation distinguishes neuroma from nerve sheath tumor.

Salivary Duct Cyst ♦♦ The salivary duct cyst is a focal, small cystic lesion lined by salivary ductal epithelium seen most commonly in upper lip, buccal mucosa, and palate

Fig. 24.18. Smokeless tobacco-induced keratosis is notable for acellular, subepithelial hyalinization.

Smokeless Tobacco-Induced Keratosis ♦♦ This represents a somewhat unique lesion occurring as a corrugated white patch seen in the location of placement of tobacco that demonstrates superficial epithelial necrosis and an amorphous hyalinized material histologically (Fig. 24.18)

JAWS Nonodontogenic Cysts/Pseudocysts Nasopalatine Cyst Clinical ♦♦ Because it represents cystic degeneration of epithelial remnants of the nasopalatine duct, this cyst is seen in the anterior maxilla, midline between the maxillary central incisors. It occurs in adults and may produce a swelling in the anterior hard palate

Radiograph ♦♦ The radiographic features are that of a pear or heart-shaped well-demarcated radiolucency between the roots of the maxillary central incisors

Microscopic ♦♦ The lining consists of simple cuboidal, respiratory, or stratified squamous epithelium with prominent ­neurovascular bundles in the wall

Traumatic Bone Cavity Clinical ♦♦ The traumatic bone cavity is exactly that, a cavity in bone possibly due to trauma with subsequent lysis of clot. It is most commonly seen in the posterior mandibular body with possible expansion and is often filled with serosanguineous fluid. Young adults are the typical population with a male predilection

Radiograph ♦♦ This represents a demarcated lucency with scalloping between tooth roots

Microscopic ♦♦ The microscopic features demonstrate a thin fibrous connective tissue wall with or without inflammation

Odontogenic Cysts Dentigerous Cyst Clinical ♦♦ This represents a developmental odontogenic cyst occurring around the crown of impacted tooth. It occurs most commonly in mandibular third molar region. The lining of this cyst can give rise to ameloblastoma, squamous cell carcinoma, or intraosseous mucoepidermoid carcinoma

Radiograph ♦♦ The radiographic presentation is that of a unilocular radiolucency around the crown of an impacted tooth

Microscopic ♦♦ Histologically, a bilayer of cuboidal cells or stratified squamous lining with myxomatous connective tissue containing small islands of odontogenic epithelium is seen (Fig. 24.19)

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Fig. 24.19. A bland lining of squamous cells with a loose connective tissue wall constitute the diagnostic features of a dentigerous cyst.

Odontogenic Keratocyst (Keratocystic Odontogenic Tumor) Clinical ♦♦ This entity represents a peculiar keratinized odontogenic cyst arising from prefunctional dental lamina. The WHO currently classifies this as an odontogenic tumor rather than a cyst due to mutational features. It is most common in the second to third decades and the posterior mandible. It can occur as multiple lesions, perhaps forming “daughter” cysts, making complete removal more difficult. This may be the feature that contributes to a 30% recurrence rate ♦♦ It is associated with the nevoid basal cell carcinoma syndrome (Gorlin–Goltz syndrome) that possesses the following characteristics −− Autosomal dominant, defect in ptch gene (chromosome 9) −− Multiple basal cell carcinomas on non- or minimally sunexposed skin −− Palmar and plantar pits −− Skeletal anomalies – bifid ribs, brachymetacarpalism, kyphoscoliosis, calcified falx cerebri −− Other tumors including medulloblastoma

Radiograph ♦♦ The common radiographic pattern is that of a multilocular radiolucency with possible expansion although it may be unilocular. The odontogenic keratocyst tends to demonstrate linear growth pattern within the jaw

Microscopic ♦♦ The odontogenic keratocyst demonstrates squamous epithelium with a luminal layer of corrugated parakeratin (Fig. 24.20). A uniform thickness of 6–8 cell layers is apparent with a prominent basal layer with palisading nuclei

Differential Diagnosis ♦♦ Keratinizing odontogenic cyst

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Fig.  24.20. Odontogenic keratocysts are cytologically bland, locally aggressive cystic lesions. −− This cyst demonstrates a luminal layer orthokeratin, an indistinct basal layer and no association with the nevoid basal cell carcinoma syndrome

Apical Periodontal Cyst Clinical ♦♦ This is an inflammatory cyst due to a pulpally infected tooth, seen at the apex of a nonvital tooth

Radiograph ♦♦ The apical periodontal cyst appears as a unilocular lucency at the apex of tooth

Microscopic ♦♦ Histologically, proliferative squamous epithelial lining is seen with a wall of inflamed granulation tissue

Calcifying Odontogenic Cyst (Gorlin Cyst) Clinical ♦♦ This developmental odontogenic cyst may demonstrate questionable neoplastic potential. It is seen in the second to third decade and the anterior aspects of the jaws. It may also occur in an extraosseous fashion on the gingiva. It has a low ­recurrence rate of 10% and may be associated with ameloblastomas

Radiograph ♦♦ The Gorlin cyst appears as a unilocular or multilocular expansile radiolucency with intermixed calcifications and may be associated with an odontoma

Microscopic ♦♦ A lining of odontogenic epithelium is seen with a basal layer of columnar cells with palisading nuclei. Prominent in this epithelium is the presence of “ghost” cells, squamous cells with abundant cytoplasm and central voids lacking nuclei (Fig.  24.21). Variable amounts of odontogenic product, “dentinoid,” may also be present

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require removal, only identification. However, patients are at risk for osteomyelitis as the lesions calcify and become avascular

Radiograph ♦♦ These lesions appear as relatively well-demarcated, mixed radiolucent/radiopaque lesions

Microscopic ♦♦ Cementoosseous dysplasia appears as curetted fragments with high cellularity of spindle-shaped mesenchymal cells. These cells are mixed with calcified product, often small sphericals of cementum and/or bone

Differential Diagnosis ♦♦ Central cementoossifying fibroma −− Field for field this is a histologically identical lesion although it represents a benign neoplasm. It can be distinguished by radiographic (well-demarcated, expansile lucency) and surgical findings (avascular, delineated solid mass)

Odontoma Clinical ♦♦ The odontoma is a hamartomatous process of the ­odontogenic apparatus that is seen primarily in the first two decades of life. It presents as two types: compound, which forms toothlike structures most commonly in the anterior maxilla, and complex, which forms a mass of calcified product in the posterior jaws Fig.  24.21. “Ghost” cells, prematurely keratinizing epithelial cells without nuclei, are the hallmark of the calcifying odontogenic cyst.

Dentinogenic Ghost Cell Tumor (Included Here Given Similarity to Gorlin Cyst) ♦♦ This represents a noncystic neoplasm with microscopic characteristics similar to the Gorlin cyst. These represent more aggressive lesions and rare malignant counterparts have been reported

Reactive/Nonneoplastic Disease Cementoosseous Dysplasia Clinical ♦♦ This peculiar condition is a nonneoplastic proliferation of periodontal ligament origin. Typically asymptomatic, it is found on routine radiographic survey. It demonstrates a predilection for African American females in the third to fifth decade. It occurs in a variety of clinical settings including periapical, which is seen around apices of mandibular anterior teeth; focal which is a single lesion seen in the posterior mandible; and florid which are multiple lesions seen in at least two quadrants. It does not

Radiograph ♦♦ The compound odontoma demonstrates multiple tooth-like structures with radiolucent rim. The complex odontoma exhibits a central mass of opaque material surrounded by radiolucent rim

Microscopic ♦♦ Odontomas contain a mixture of enamel, enamel matrix, dentin, pulp, and follicular tissue, either in appropriate context or haphazardly arranged

“Giant Cell” and Giant Cell-Rich Lesions Central Giant Cell Granuloma Clinical ♦♦ This represents a central lesion seen most commonly in females in the early second decade. It demonstrates a propensity to occur in the anterior mandible crossing the midline. Its etiology is unknown and it exhibits a recurrence rate of 15%. Peripheral variant is seen most commonly on the mandibular gingiva or alveolar mucosa as a purplish, exophytic mass

Radiograph ♦♦ Typically, this occurs as a multilocular radiolucency although it can be unilocular. Expansion, tooth movement, and resorption are all possible sequelae

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Microscopic ♦♦ Large pools of extravasated erythrocytes surrounded by cellular mesenchymal tissue with giant cells bordering the cavities are the salient histologic features. The cavities are not lined by endothelial cells

Cherubism Clinical

Fig.  24.22. Osteitis fibrosa cystica (“brown tumor”) results from hyperparathyroidism and is histologically indistinguishable from giant cell reparative granuloma. Inset: Reactive osteoid may be prominent.

♦♦ Cherubism represents an inherited disorder, transferred as an autosomal dominant condition due to a defect on chromosome 4p16. It exhibits complete penetrance in males and incomplete penetrance in females. The usual age at diagnosis is 5 years. Bilateral expansion of the maxilla and mandible is seen clinically, producing chubby cheeks, hence the name. Cherubism typically regress at puberty without surgery, although it may require surgical intervention if grossly deforming

Radiograph ♦♦ Bilateral, expansile multilocular radiolucencies in the posterior mandible and maxilla are the hallmarks of this disease

Microscopic Microscopic ♦♦ Microscopically, the giant cell granuloma is characterized by a cellular spindle-cell framework with clusters of multinucleated giant cells (osteoclasts), extravasated erythrocytes, and hemosiderin

Differential Diagnosis ♦♦ Giant cell lesions of the jaws constitute an area of confusion −− Much has been written as to whether giant cell granulomas, giant cell tumors, and aneurysmal bone cysts represent the same lesion, entities on a continuum or separate and distinct conditions ♦♦ The brown tumor of hyperparathyroidism is indistinguishable from the central giant cell granuloma and, accordingly, this systemic disease must be excluded (Fig. 24.22)

Giant Cell Tumor

♦♦ Cellular, myxomatous mesenchymal tissue with intermixed giant cells comprises the majority of the lesion, whereas perivascular cuffing of hyaline material represents a useful clue to the diagnosis

Benign Neoplasms Ameloblastoma Clinical ♦♦ This is the most common epithelial odontogenic neoplasm, recapitulating the enamel organ. Ameloblastoma occurs most commonly in the third to fifth decade of life and presents as painless expansion usually in the posterior mandible. Typically aggressive, the ameloblastoma demonstrates up to a 90% recurrence rate with curettage and a 15–20% recurrence rate with resection. Rare examples of metastasis have been reported (malignant ameloblastoma). Peripheral variant represents an ameloblastoma occurring in an extraosseous location (Fig. 24.23)

♦♦ This is a true neoplasm that rarely occurs in the oral cavity and is discussed in detail in Chapter 21

Radiograph

Aneurysmal Bone Cyst Clinical

♦♦ Either an expansile unilocular or multilocular (soap bubble) radiolucency is the classic radiographic presentation. Perforation of the cortical plate is often seen

♦♦ The aneurysmal bone cyst is seen most commonly before the age of 20 and does not exhibit a gender predilection. The mandible is more commonly afflicted by this rapidly ­expansile lesion. Often substantial recurrence is due to incomplete removal. This may occur in concert with other pathologic entities including fibroosseous lesions and osseous neoplasms. Its etiology is unknown although trauma is suspected

Microscopic

Radiograph ♦♦ A symmetrically expansile, unilocular radiolucency with a thin rim of residual bone is the typical manifestation although it can be multilocular

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♦♦ Two histologic variants are typically seen. The unicystic ameloblastoma demonstrates cystic areas with luminal proliferation of the plexiform pattern of ameloblastoma. The conventional ameloblastoma may exhibit a variety of patterns including follicular, plexiform, acanthomatous, granular cell, basal cell, and desmoplastic (Fig. 24.24). Both are typically characterized by a peripheral layer of columnar cells with reverse polarization and nuclear palisading. Central zones of stellate cells with exaggerated intercellular spacing are seen in more solid areas although the conventional ameloblastoma can be predominantly cystic

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Microscopic ♦♦ Microscopically, this neoplasm is characterized by a cystic lesion with proliferation of epithelial cells demonstrating whorls and focal gland-like spaces lined by columnar cells. Dentinoid and amyloid may also be present

Calcifying Epithelial Odontogenic Tumor (Pindborg Tumor) Clinical ♦♦ This benign epithelial odontogenic neoplasm can mimic malignancy due to its cellular pleomorphism. It is seen mostly as a slowly progressing expansile mass in the posterior mandible in the fourth to sixth decades. It demonstrates a 15% recurrence rate after removal Fig. 24.23. Peripheral ameloblastoma resembles its intraosseous counterpart. Note overlying mucosa.

Radiograph ♦♦ The Pindborg tumor appears as a well-demarcated ­multilocular radiolucency with calcifications (“driven snow” appearance)

Microscopic ♦♦ The microscopic appearance is that of sheets of polygonal epithelial cells with prominent intercellular bridging. Marked pleomorphism is often seen but without mitotic activity. Spherical laminated calcifications (Liesegang rings) and amyloid are also present

Differential Diagnosis ♦♦ Squamous cell carcinoma −− Mitoses, invasive growth, and an ill-defined radiographic appearance differentiate the two entities

Squamous Odontogenic Tumor Clinical

Fig. 24.24. Ameloblastoma may show prominent cystic change. Peripheral cells exhibit nuclear palisading with reverse polarization; the latter is not conspicuous in this example.

♦♦ This, too, is a benign epithelial odontogenic neoplasm that can mimic squamous cell carcinoma at the histologic level. Present in the third to fourth decades, it occurs in the posterior jaws as an expansile mass. Treated appropriately, it rarely recurs

Radiograph ♦♦ The characteristic appearance is that of a semilunar radiolucency arising in alveolar bone

Microscopic Adenomatoid Odontogenic Tumor Clinical ♦♦ This benign neoplasm of the odontogenic apparatus forms gland-like spaces surrounded by odontogenic epithelium. Most commonly, it is seen in the anterior maxilla associated with an impacted canine tooth and demonstrates a 2:1 female predilection. Enucleation tends to be a curative surgical procedure

Radiograph ♦♦ The radiographic presentation is that of a pericoronal lucency with or without calcification

♦♦ Islands of squamous epithelial cells without a prominent basal layer are the histologic signature. Although worrisome, no atypia, mitotic figures, or central keratinization is seen (Fig.  24.25). The islands may demonstrate central cystic degeneration

Differential Diagnosis ♦♦ Squamous cell carcinoma −− Should demonstrate pleomorphism, mitoses, keratinization, all of which are lacking in squamous odontogenic tumor ♦♦ Ameloblastoma, acanthomatous type −− Prominent palisading arrangement of basal cell layer is the distinguishing characteristic

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Fig. 24.25. Squamous odontogenic tumors demonstrate islands of squamous epithelium without atypical features or mitoses.

Ameloblastic Fibroma Clinical ♦♦ This represents a mixed odontogenic tumor with coexistent epithelial and mesenchymal components. It occurs in the first and second decades, with the majority in the posterior mandible impeding the eruption of the permanent first molar. Even with appropriate surgery, a 10–20% recurrence rate is seen

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 24.26. Bilayers of ameloblastic cells embedded in a myxomatous mesenchymal framework characterize ameloblastic fibroma.

Central Cementoossifying Fibroma Clinical

Radiograph

♦♦ The central cementoossifying fibroma is a benign productforming neoplasm of periodontal ligament origin. It occurs in the second to fourth decades with a female predilection. The posterior mandibular is most common and it manifests as a slowly progressing swelling. It rarely recurs when surgically removed

♦♦ Radiographically, a unilocular or multilocular radiolucency associated with an impacted tooth is the typical presentation

Radiograph

Microscopic ♦♦ A bilayer of odontogenic epithelium embedded within cellular myxomatous mesenchymal tissue constitutes the diagnostic features (Fig. 24.26)

Cementoblastoma Clinical ♦♦ This represents the benign odontogenic counterpart to the osteoblastoma. Most common in the first two decades, it occurs in the mandibular first molar area and is characterized by pain and swelling. It can recur if incompletely removed

Radiograph ♦♦ An opaque symmetrical mass merging imperceptibly with the root of the tooth and possessing a radiolucent peripheral rim are the reproducible radiographic features

Microscopic ♦♦ Peripheral radiation of cemental product punctuated by prominent cementoblasts, cementoclasts, and vascularity are the salient characteristics. Because of these features, it is thought to represent the odontogenic analog of osteoblastoma

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♦♦ Typically, this is a well-demarcated unilocular radiolucency with characteristic bowing of the inferior border of the mandible. Although product-forming histologically, it usually demonstrates only small flecks of calcification at the radiographic level

Microscopic ♦♦ This is an avascular, well-delineated mass of cellular mesenchymal tissue demonstrating spindle-shaped cells arranged in whorls and fascicles. Usually, only limited punctate calcifications are interspersed within the cellular tissue

Odontogenic Fibroma Clinical ♦♦ This benign neoplasm is comprised primarily of odontogenic mesenchymal tissue with variable epithelium and calcification. It can be central or peripheral and occurs at an average age of 40. A prominent female propensity is seen and the posterior maxilla is most commonly afflicted. On rare occasions, it may be associated with a peculiar cleft defect in the maxilla. Only rare recurrences have been reported

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Radiograph ♦♦ The radiographic appearance is that of a unilocular or multilocular radiolucency, often with expansion

Microscopic ♦♦ The simple type appears as a collagenous mesenchymal proliferation with evenly dispersed bland spindle cells. The WHO type demonstrates cellular mesenchymal tissue with strands of odontogenic epithelium and variable calcified product

Malignant Neoplasms Ameloblastic Carcinoma Clinical ♦♦ This is an odontogenic epithelial malignancy with ameloblastic differentiation. It occurs most commonly in the fourth decade with a mandibular predilection. It metastasizes preferentially to the lungs and demonstrates a <50% 5-year survival rate

Radiograph ♦♦ It manifests as an ill-defined, lytic lesion with a variable growth rate

Microscopic ♦♦ The microscopic appearance is that of an epithelial proliferation with peripheral cells demonstrating columnar morphology with reverse polarization (Fig.  24.27). Prominent pleomorphism and mitotic activity are usually seen

Squamous Cell Carcinoma Clinical ♦♦ This is a central odontogenic carcinoma demonstrating squamous differentiation. Seen in adults, it demonstrates a

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mandibular predilection. Its overall behavior is dependent on grade and stage. However, most of them represent local disease and are amenable to surgery

Radiograph ♦♦ This may occur as a poorly defined lytic lesion or arise from a preexisting, long-standing odontogenic cyst

Microscopic ♦♦ This entity demonstrates the typical features of squamous cell carcinoma; accordingly, one must rule out metastasis or an antral primary if occurring in the maxilla

Clear Cell Odontogenic Carcinoma Clinical ♦♦ This odontogenic malignancy is composed of odontogenic epithelium with prominent cytoplasmic clearing. Occurring in the sixth decade or later, it is most common in the mandible. Although metastasis is known to occur, it is not common. However, multiple recurrences with locally aggressive behavior is the typical pattern

Radiograph ♦♦ The clear cell odontogenic carcinoma manifests as an ill-defined lucency with bone destruction

Microscopic ♦♦ Strands and sheets of cells with odontogenic differentiation and cytoplasmic clearing are seen. These clear cells may or may not demonstrate glycogen with PAS stains. The stroma is often cellular with hyalinization around the epithelium

Differential Diagnosis ♦♦ Metastatic renal cell carcinoma −− Prominent vascular stroma without the stromal cellularity should help delineate the two

Osteosarcoma Clinical ♦♦ Osteosarcoma of the jaws demonstrates a different character relative to osteosarcoma of the long bones in the following ways −− Tends to occur at a later age, average ~33 years −− Tends to be lower grade −− Tends to be chondroblastic ♦♦ The survival rate has remained relatively unchanged even with the newer modalities of treatment. Osteosarcomas of the mandible demonstrate a 40% 5-year survival, and the maxilla demonstrates a 25% 5-year survival

Radiograph Fig. 24.27. Cellular pleomorphism, as seen here, distinguishes ameloblastic carcinoma from ameloblastoma.

♦♦ Osteosarcomas tend to be ill-defined mixed radiolucent/ opaque lesions, perhaps with a radiating calcified product (sunburst effect). Localized widening of the periodontal ligament space may be an early manifestation

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Microscopic ♦♦ As in the long bones, osteosarcoma is characterized by tumor bone punctuated by a frankly sarcomatous mesenchymal proliferation. Cartilage is often seen in osteosarcoma of the jaws and should always be treated with suspicion

Chondrosarcoma Clinical ♦♦ Some have speculated otherwise, but these do occur in the jaws. The average age at diagnosis is ~30 years. Chondrosarcomas of the jaws tend to be slow-growing lesions and tend to be low grade

Radiograph ♦♦ Chondrosarcomas demonstrate many of the same radiographic features of osteosarcoma although the product tends to be less linear and more rounded

Fig. 24.28. Larger pigmented cells surround small blue cells in the melanotic neuroectodermal tumor of infancy.

Microscopic ♦♦ Generally, mature type cartilage is seen with minimally atypical chondrocytes and chondroblasts. Because of this, chondrosarcomas of the jaws are often underdiagnosed as benign conditions

Mesenchymal Chondrosarcoma Clinical ♦♦ A rare tumor, the mesenchymal chondrosarcoma is seen in the jaws as one of its more preferential locations. It may also arise in soft tissue and is seen most commonly in the second and third decades

Microscopic ♦♦ Undifferentiated stromal cells with islands of mature cartilage are the histologic hallmarks. The stromal component may resemble “small blue cell tumors” and/or hemangiopericytoma (“staghorn” vascular pattern). Mitotic figures may be scarce to frequent and the cartilaginous foci vary from prominent to scarce

Differential Diagnosis ♦♦ Distinction from Ewing sarcoma, hemangiopericytoma, and others relies upon recognition of cartilaginous foci

Metastatic Disease Clinical ♦♦ Carcinomas of breast, lung, prostate, renal origin represent the most common metastases to the jaws. Fully one-third of patients are unaware of primary tumor at time of diagnosis. These often present with pain and/or paresthesia

Melanotic Neuroectodermal Tumor of Infancy Clinical ♦♦ This neoplastic process of neuroectodermal origin usually manifests in the first year of life as an expansile lesion in the anterior maxilla. Often, elevated levels of urinary vanillylmandelic acid can be demonstrated. A 15% recurrence rate is seen, with 6% demonstrating malignant behavior

Radiograph ♦♦ The melanotic neuroectodermal tumor of infancy presents as a demarcated radiolucency of the anterior maxilla with a primary tooth “floating in space”

Microscopic ♦♦ This tumor is an epithelial lesion with two cell types: a small cell with hyperchromatic nucleus and scant cytoplasm and a large cell with vesicular nucleus, abundant cytoplasm, and melanin pigment (Fig. 24.28). These are typically arranged in small islands and cords with the melanin occurring centrally

Miscellaneous Lesions Stafne Defect ♦♦ This is a bony defect present at the posterior inferior margin of the mandible occupied by the submandibular gland – it should be recognized radiographically with no surgery necessary

Radiographic

Tori

♦♦ Presenting most commonly as lytic, ill-defined lesions, exceptions include prostatic and breast metastases that can be dramatically osteoblastic

♦♦ These represent bony outcroppings seen in the midline of the hard palate and bilaterally on the medial mandible – they represent variations of anatomic normal

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Gingival Cyst/Lateral Periodontal Cyst ♦♦ These cystic lesions of odontogenic apparatus are lined by a bilayer of cuboidal to flattened epithelium with focal plaque-like thickenings and a single cavity. The gingival cyst is seen in mucosa, the lateral periodontal cyst in bone. The botryoid odontogenic cyst represents a multiple compartmented cyst in bone with similar histology but more aggressive clinical course. The glandular odontogenic cyst demonstrates a luminal layer of cuboidal cells and duct-like structures with behavior much like ameloblastoma with a high recurrence rate and significant expansion

Central Mucoepidermoid Carcinoma ♦♦ This is a mucoepidermoid carcinoma arising within the mandible primarily, probably from pluripotential odontogenic epithelium (Fig. 24.29). It is usually low grade with a good prognosis

Fig.  24.29. Central mucoepidermoid carcinoma arises within the mandible and resembles a salivary gland primary.

ORO/HYPOPHARYNX Malignant Neoplasms Squamous Cell Carcinoma Clinical ♦♦ This is most commonly seen in the base of tongue and tonsil and is typically large (T3–T4) by time of diagnosis. Dysphagia, exophytic mass, and otalgia are presenting complaints. Stage III and IV diseases have 5-year survival rates below 30%

Microscopic ♦♦ Typically, these squamous cell carcinomas are less differentiated with limited to no keratin production. HPV may be present in up to 50% of oropharyngeal squamous cell carcinomas

Lymphoepithelial Carcinoma Clinical ♦♦ A malignant epithelial neoplasm that is essentially undifferentiated with prominent lymphoid component (evidence of squamous differentiation seen via electron microscopy). Related to EBV although evidence may be somewhat equivocal. Seen in adults, it rarely occurs in the tonsil and base of tongue. A fairly aggressive neoplasm, it demonstrates a less than 50% 5-year survival

Microscopic ♦♦ Sheets of undifferentiated epithelial cells are seen embedded within lymphoid stroma. The nuclei tend to be vesicular and

large with prominent nucleoli. Cytokeratins generally will illuminate the epithelium

Basaloid Squamous Carcinoma Clinical ♦♦ This represents a peculiar high grade variant of squamous cell carcinoma demonstrating both basaloid and squamous components. Occurring in the sixth to eighth decades, it exhibits a male predilection. It is seen primarily in the base of tongue when occurring in the oropharynx. The overall survival rate is poor with less than a 30% 5-year survival, although this may be due to overall stage, rather than more aggressive behavior ♦♦ See section “Larynx and Trachea”

Microscopic ♦♦ A biphasic tumor (“mosaic pattern” of cells), basaloid squamous carcinoma exhibits lobules and cords of cells with hyperchromatic nuclei and scanty cytoplasm, often surrounded by prominent hyalinization (Fig. 24.30). Peripheral palisading and central necrosis are common, and it often merges with typical squamous cell carcinoma. Surface epithelial alterations may be evident

Differential Diagnosis (See Table 24.1) ♦♦ Adenoid cystic carcinoma −− Lacks squamous differentiation and surface epithelial involvement

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Papillary Squamous Cell Carcinoma Clinical ♦♦ This represents an exophytic HPV-associated variant of squamous cell carcinoma. It preferentially involves the tonsil/oropharynx, larynx, and sinonasal tract. The prognosis likely relates to extent of invasion

Microscopic ♦♦ Papillary condylomatous-like architecture is seen with cytologic atypia that exceeds what is seen in papillomas/ condylomas (Fig. 24.15). Keratinization is generally scant

Differential Diagnosis

Fig. 24.30. Basaloid squamous carcinoma is an aggressive malignancy with a predilection for the base of tongue and larynx.

♦♦ Squamous papillomas with or without dysplasia −− Exhibit less cytologic atypia and koilocytes are readily present

NASAL CAVITY, PARANASAL SINUSES, AND NASOPHARYNX Infection Rhinosinusitis Clinical ♦♦ Classified into acute, subacute, and chronic based on the duration of sign and symptoms. Chronic rhinosinusitis, one of the most commonly reported chronic diseases in the USA, is defined as the presence of nasal cavity and paranasal sinus inflammation for greater than 12 weeks. The pathophysiology comprises a spectrum of inflammatory and infectious diseases. Limited coronal computed tomography is the most definitive technique for the diagnosis ♦♦ Allergy, fungus, and bacteria are potential causes, with the latter giving rise to purulent sinusitis. Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are more common offending agents. Ongoing inflammation, decreased in ostial size, retention of secretions, and decrease in mucociliary action contribute to the pathogenesis

Microscopic ♦♦ Edema, hyperplastic seromucinous glands, thickened basement membrane, and inflammatory cells (neutrophils, lymphocytes, plasma cells, and eosinophils) are typical findings. Retention cysts (Fig.  24.31) are common, and obstruction may lead to mucocele (frontal and ethmoid sinuses most commonly affected) formation

Differential Diagnosis ♦♦ The infiltrates of sinusitis are distinguished from lymphoma by their mature appearance. They are rich with plasma cells and Russell bodies are common. High grade angiotropic

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Fig. 24.31. Retention cysts are a common finding in the mucosa of individuals with chronic sinusitis. NK/T-cell lymphoma has larger cells with atypical nuclei and often ­exhibits angiotropic growth accompanied by thrombosis and necrosis ♦♦ Allergic fungal sinusitis contains fungal hyphae (highlighted via GMS stain) within dense, eosinophilic-rich exudates. Fungal elements are absent in nonspecific chronic sinusitis ♦♦ The presence of necrosis, granulomatous inflammation, and/ or vasculitis raises the specter ozf Wegener granulomatosis (WG). The histopathology of WG is typically incompletely developed, requiring serologic support (c-ANCA) for diagnosis

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Allergic Fungal Sinusitis Clinical ♦♦ Allergic fungal sinusitis is a noninvasive mycosis and the most common form of fungal rhinosinusitis. Patients are immunocompetent and often young and asthmatic. Bony erosion, ­rupture of the sinus walls, and/or orbital extension are not uncommon. The offending organisms are ubiquitous; dematiaceous fungi are common (i.e., Curvularia and Bipolaris species). Eradication is difficult and recurrence is common

Microscopic ♦♦ The hallmark is thick eosinophil-rich “allergic mucin” which contains with fungal hyphae (highlighted via GMS stain). Charcot–Leyden crystals are common. There is no tissue invasion by organisms and the mucosal exhibits nonspecific changes of sinusitis with or without polyps

Differential Diagnosis ♦♦ Invasive fungal sinusitis shows angiotropic growth of ­fungus  with thrombosis and necrosis. Fungus is found in ­viable and/or necrotic tissue and not confined to a mucinous or inflammatory exudate. Patients are generally diabetic or immunodeficient ♦♦ Sinus mycetoma or “fungus ball” is a rare, noninvasive colonization of a sinus cavity by fungus. These lesions lack the eosinophilic-rich infiltrate of allergic fungal sinusitis

Invasive Fungal Sinusitis Clinical ♦♦ Rhinocerebral disease due to Zygomycetes (Rhizopus– Mucor–Absidia) presents with headache, pain, and fever. Patients with diabetic ketoacidosis experience rapidly progressive disease with extension into the CNS. The turbinates appear necrotic ♦♦ Nasoorbital disease due to Aspergillus species is typically seen in immunocompromised patients with AIDS, neutropenia, and/or hematologic malignancies

Microscopic ♦♦ Angioinvasive growth of fungus (highlighted on GMS stain) with thrombosis, hemorrhage, and infarction is ­characteristic. Zygomycetes exhibit irregular ribbon-like hyphae (generally 10–20 mm in width) devoid of septa, whereas Aspergillus has smaller hyphae (3–6 mm in width) with 45° branching and distinct cross-septa

Other Forms of Infectious Sinusitis Scleroma (Rhinoscleroma) ♦♦ Microscopically, histiocytic foam cells (Mikulicz cell) contain coccobacilli (Klebsiella rhinoscleromatis). Bacteria are highlighted on Warthin–Starry and Giemsa stains. The differential diagnosis includes Rosai–Dorfman disease, leprosy, and metabolic storage disease

Rhinosporidiosis ♦♦ Polypoid mucosal lesions containing large sporangia (100– 400  mm) resemble “coccidioides immitis though bigger”

Fig. 24.32. Sporangia are numerous in the mucosal lesions of Rhinosporidiosis. Inset: Sporangium containing spores.

(Fig. 24.32). The etiology fungus is Rhinosporidium seeberi, which is endemic to India. These lesions can simulate angiomatous nasal polyp

Mycobacterial Infection ♦♦ Etiologic bacteria include Mycobacterium tuberculosis and rarely atypical mycobacteria; the latter is typically encountered in HIV patients. The histologic findings include caseating and/or noncaseating granulomas, ulceration, histiocytic inflammation, and destruction of septal cartilage

Leprosy ♦♦ Involvement of paranasal sinuses is common and of epidemiological significance in lepromatous-type leprosy. Ulceration is accompanied by perivascular histiocytes, which contain the acid fact bacillus Mycobacterium leprae

Syphilis ♦♦ Primary, secondary, and tertiary syphilis can all cause intranasal pathology. Warthin–Starry staining may fail to reveal the pathogenic spirochetes, Treponema pallidum. Microscopic findings include plasma cell endarteritis, ulceration, and septal perforation

Inflammatory/Nonneoplastic Lesions Mucocele Clinical ♦♦ With progressive expansion these lesions can simulate a neoplasm and. They have a predilection for the mastoid, frontal, and ethmoid sinuses. A potential complication of sinusitis, they result from ostial obstruction and impaired lymphatic drainage

Microscopic ♦♦ An epithelial lining may or may not be apparent and goblet cells may be hyperplastic. Degenerating debris, mucous, and muciphages are present

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Fig. 24.33. Consider the possibility of Wegener granulomatosis, lymphoma, and fungal infection in sinonasal specimens with prominent necrosis.

Wegener Granulomatosis Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  24.34. Extracellular fluid and inflammation, particularly eosinophils, are features of nasal polyps. should be ruled out via appropriate methodologies (i.e., ­special stains and culture)

Differential Diagnosis ♦♦ Infectious and noninfectious causes of granulomatous inflammation warrant histologic and clinical consideration. Granulomatous vasculitis should be ruled out

♦♦ The sinonasal tract is involved in 60–95% of patients with Wegener granulomatosis (WG). Features include ulceration of the nasal septum, sinus mucosa, oral mucosa or destruction of the vocal cord. Histologically, the diagnosis of WG is largely one of exclusion as other causes of granulomas and necrosis must be ruled out. Multiple biopsies of diseased mucosa are not uncommonly required to establish the diagnosis. Corroborating the histologic findings with serologic studies is extremely important since most patients (70–90%) are c-ANCA positive (c-ANCA negative cases occur)

Myospherulosis Clinical

Microscopic

Microscopic

♦♦ A histologic spectrum may be seen from neutrophilic microabscesses to the signature triad of necrosis, granulomatous inflammation, and vasculitis (Fig. 24.33). Typically, the triad is incomplete and the histologic specificity for WG decreases as fewer elements of the triad are represented

Differential Diagnosis

Differential Diagnosis ♦♦ Malignant lymphoma and infection commonly warrant consideration in cases of WG. Failure to identify atypical, neoplastic cells and microorganisms aids to exclude these possibilities

Sarcoidosis Clinical ♦♦ Approximately 5% of patients with sarcoidosis have sinonasal involvement. Clinical features are nonspecific and include nasal obstruction and chronic sinusitis. Grossly, lesions manifest as mucosal crusting, studding, plaque-like changes, or polyps in the nose

Microscopic ♦♦ Noncaseating granulomas (small foci of central caseous nec­ rosis can be seen) are present. The presence of ­microorganisms

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♦♦ This lesion of iatrogenic origin consists of a foreign body/ granulomatous reaction to petrolatum-based material used for nasal packing

♦♦ Large spherules simulating fungi contain altered erythrocytes

♦♦ If the diagnosis is in doubt, negative GMS staining can aid ­distinction from fungal infection

Polyps Clinical ♦♦ Sinonasal polyps are common, affecting from up to 4% of the population. They are typically multiple and bilateral. Their pathogenesis is poorly understood. Associations include sinusitis, allergy, immune deficiency, cystic fibrosis, ciliary dyskinesia, and aspirin hypersensitivity −− Grossly, they are soft, edematous, and semitranslucent

Microscopic ♦♦ Large quantities of extracellular fluid-edema separate bland stromal cells (Fig. 24.34). Eosinophils are prominent in most cases. Seromucinous glands may be hyperplastic or inapparent and retention cysts common. A minority develop extensive vascular proliferation and ectasia with deposition of pseudoamyloid, see angiomatous variant below

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Variants ♦♦ A choanal polyp is a clinically defined variant originating in a paranasal sinus that is histologically indistinguishable from typical polyps. They solitary, more prevalent in children and may undergo torsion/infarction ♦♦ Repeated vascular compromise/insult and repair of an otherwise typical sinonasal polyp can result in prominent angiomatous changes (i.e., so-called angiomatous polyp). Choanal polyps at particularly predisposed to such change and may undergo complete infarction ♦♦ Polyp with stromal atypia has atypical stromal cells analogous to atypical polyps that can occur in the vagina, esophagus, and mouth

Differential Diagnosis ♦♦ Lobular capillary hemangioma has densely packed capillarysized vessels with a lobular or “organized” configuration, which polyps lack. Sinonasal papillomas are defined by their characteristic proliferative epithelium, again lacking in ­polyps. Juvenile angiofibroma, specific to young males and the nasopharynx, has a stroma that is densely collagenous; polyps are typically edematous and inflamed

Benign Neoplasms Lobular Capillary Hemangioma (Granuloma Pyogenicums) Clinical ♦♦ This benign capillary proliferation can grow rapidly and is associated with microtrauma and pregnancy. Epistaxis can be problematic necessitating emergent care

Microscopic ♦♦ A lobular proliferation of small capillaries defines these tumors (Fig.  24.35A,B). The mucosa is commonly ulcerated

Differential Diagnosis ♦♦ A lobular architecture of the vasculature and the less collagenous stroma aid to distinguish hemangioma from juvenile nasopharyngeal angiofibroma, although occasional hemangiomas may have a more fibrotic stroma ♦♦ Angiomatous polyp has vessels, which are congested, often large and ectatic that lack the uniformity and organization of hemangioma

Hyperkeratotic Squamous Papilloma Clinical ♦♦ These lesions arise from nasal vestibule in contrast to sinonasal papilloma, which arises from the respiratory mucosa or Schneiderian membrane. They are analogous to their counterpart occurring elsewhere on the skin

Microscopic ♦♦ This papillary squamous proliferation typically exhibits ­hyperkeratosis and lacks significant cytologic atypia. Coexistent dysplasia is rare

Fig. 24.35. A lobular distribution of cells is extremely useful in recognizing lobular capillary hemangioma of the nasal cavity (A). Lobular capillary hemangioma is uncapsulated, abuts the mucosa, and often ulcerates (B).

Sinonasal Papilloma (Schneiderian Papilloma) Clinical ♦♦ These locally aggressive, progressive tumors arise from the Schneiderian membrane and require surgical removal. The WHO separates into three types: exophytic, inverted and oncocytic. There is a significant risk of recurrence, especially for incompletely resected lesions. Coexistent carcinoma or progression to carcinoma with recurrence may occur and mandates careful histologic examination. Barnes found 11% of cases complicated by carcinoma in a large collective review ♦♦ Patients may present with nasal obstruction, epistaxis, and headaches. Proptosis and diplopia may reflect invasion of the orbit ♦♦ Tumors arising on the nasal septum tend to be exophytic (i.e., exophytic or fungiform papilloma) in appearance, while

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tumors occurring laterally and in the paranasal sinuses commonly exhibit an inverted pattern of growth (i.e., inverted papilloma). Microscopically, a mixed pattern of growth is not uncommon ♦♦ Human papilloma virus DNA has been detected in up to 38% and 57% of fungiform and inverted papillomas, respectively

Microscopic ♦♦ These lesions are composed of basement membrane-bound proliferations of cytologically bland squamous, transitional, and/or columnar cells, which grow in an exophytic papillary or “inverted” manner. Architecturally, both inverted and fungiform growth patterns are often present in a given lesion (Fig.  24.36A). Inverted growth occurs as the proliferative epithelium colonizes and expands the underlying seromucinous glands of the sinus mucosa ♦♦ Mucous cells, microcytic change, and infiltration of the proliferative epithelium by neutrophils is common and characteristic (Fig. 24.36B) ♦♦ Surface parakeratin and koilocytic-like changes may be observed. Dysplasia is not particularly common but occurs and evaluation for its presence, particularly severe dysplasia or carcinoma in situ should be made. Coexistent invasive carcinoma must be ruled out

Differential Diagnosis ♦♦ Polyps with squamous metaplasia can simulate inverted papilloma. Metaplastic changes are surface based, limited, and accompanied by injury and repair, including ulceration and inflammation ♦♦ Inverted papilloma must be distinguished from carcinoma. Papilloma lacks the atypia of carcinoma and the inverted growth is smooth bordered and basement membrane confined. Carcinoma shows irregular or jagged, invasive growth and incites desmoplasia. Abundant keratin production and/or well-developed squamous differentiation should raise the index of suspicion for carcinoma

Hemangiopericytoma-Like Tumor of the Nasal Cavity Clinical

Fig.  24.36. Inverted papilloma derives its name from its “inverted” pattern of growth; however, both inverted and exophytic growth patterns are often present in a given lesion (A). Intraepithelial cysts with clusters of neutrophils are common in inverted papilloma (B).

♦♦ These interesting tumors occur in adults (mean age: ~60 years) who present with obstruction and/or epistaxis. Surgical excision is generally curative as the vast majority behave benignly

Immunohistochemistry

Microscopic

Differential Diagnosis

♦♦ These submucosal tumors are unencapsulated (Fig. 24.37A) and composed of plump spindle cells. The latter exhibits fascicular and solid to focally whorled patterns of growth. Cell borders are indistinct. Nuclei are round, oval, and/or spindle shaped with vesicular or mildly hyperchromatic chromatin. Nuclear pleomorphism is minimal. A delicate vasculature commonly exhibits a staghorn pattern

♦♦ Solitary fibrous tumor (SFT) has a wiry collagenous background and a tendency for variable cellularity from field to field; however, this latter feature is often subtle and not constant. Moreover, SFT is CD34 positive ♦♦ Hemangioma exhibits richer vascularity, typically arranged in lobular or segmented architecture and tends to be less ­cellular. Nonetheless, distinction may be difficult

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♦♦ Only vimentin is consistently positive. CD34 is negative which aids distinction from solitary fibrous tumor

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(Fig.  24.37B). Mitotic figures are scarce and generally not seen. The vascular component may be inconspicuous on biopsy material and, in such cases, the diagnosis is aided by clinicopathologic correlation

Immunohistochemistry ♦♦ Tumor cells stain positively for vimentin and androgen receptor, the latter in up to 75% of cases. CD34 is negative

Molecular Biology ♦♦ Beta-catenin mutations have been reported in a significant percentage of JNAs

Differential Diagnosis ♦♦ Hemangioma is less fibrous and more cellular with densely packed vascular channels. Angiomatous nasal polyp is typically edematous, less fibrous and may be hemorrhagic and/or infarcted. The specific clinicopathologic features (i.e., characteristic age, sex, and location) of angiofibroma is very useful in their distinction for other entities

Malignant Neoplasms Squamous Cell Carcinoma Clinical ♦♦ Squamous cell carcinoma is the most common malignancy of nasal cavity and paranasal sinuses. This tumor principally arises in adults and the elderly. Associations include smoking, human papilloma virus infection, and exposure to nickel and chromium-refining processes

Microscopic Fig. 24.37. (A) Hemangiopericytoma-like tumor is biologically indolent and composed of isomorphic cells with no consistent pattern of immunohistochemical staining, aside from vimentin positivity. (B) The typical appearance of juvenile nasopharyngeal angiofibroma is present, including thin-walled blood ­vessels, a densely collagenous stroma and spindled to stellate, mesenchymal cells.

♦♦ Generally, aside from a few special variants, squamous cell ­carcinomas exhibit cytologic atypia and invasive growth within desmoplastic stroma. Squamous differentiation is defined by the presence of keratin production, intracellular bridges, and/or dyskeratotic cells. Endophytic, exophytic, and mixed patterns of growth may be encountered. Tumors are graded as well, moderately or poorly differentiated. Several variants occur (see below)

Juvenile Nasopharyngeal Angiofibroma Clinical

Variants

♦♦ Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign tumor that occurs exclusively in males in the second and third decades (mean age 16 years, range 10–26 years) of life. They arise in the pterygopalatine fossa and have a significant recurrence rate with incomplete surgical excision and potential for intracranial extension. Notorious for profuse intraoperative bleeding preoperative embolization is desirable ♦♦ JNA occurs up to 25 times more frequently in patients with familial adenomatous polyposis

Microscopic ♦♦ Thin-walled blood vessels, a densely collagenous stroma and spindled to stellate, mesenchymal cells comprise this tumor

♦♦ Verrucous carcinoma, as encountered more commonly in the oral cavity, rarely occurs in the nasal cavity and paranasal sinuses. These nonmetastasizing, progressive tumors exhibit a “pushing” margin of invasion with minimal cytologic atypia ♦♦ Basaloid squamous cell carcinoma, as more commonly encountered in the oropharynx and larynx, can arise in the nasal cavity and paranasal sinuses. Immunostains are diffusely and strongly positive for p63 ♦♦ Papillary squamous cell carcinoma is an HPV-associated variant of squamous cell carcinoma. Sinonasal tract tumors have poorest prognosis relative to papillary squamous cell carcinoma arising elsewhere ♦♦ Rarely, a spindle cell or sarcomatoid morphology may be encountered

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Malignant Lymphoma ♦♦ The majority sinonasal lymphomas are represented by NK/ T-cell, B-cell type, and peripheral T-cell type lymphomas. Hodgkin disease is very rare in sinonasal region. See the chapter on lymphoma ♦♦ NK/T-cell lymphoma preferentially involves the midline of the nasal cavity and is highly associated with EBV. A histologic spectrum may be seen from small to large lymphoid cells with irregular nuclei, often with clear/pale cytoplasm (Fig. 24.38). Angiocentric growth is accompanied by thrombosis and necrosis. Tumor cells marked positively for CD45RO, CD2, and CD56 ♦♦ In contrast to NK/T-cell lymphoma, B-cell lymphoma is more common in paranasal sinuses. Sheets of large atypical B-cells show positivity for CD45RO and CD20 (Fig. 24.39)

Essentials of Anatomic Pathology, 3rd Ed.

Adenoid Cystic Carcinoma Clinical ♦♦ Adenoid cystic carcinoma (AdCC) is the second most common malignancy of the paranasal sinuses. These tumors are aggressive with a high incidence of local recurrence and distant metastasis. CNS extension is common and most cases are ultimately fatal. Solid variant tumors progress more quickly

Microscopic ♦♦ AdCC may exhibit a cribriform, tubular, and/or solid pattern of growth (Fig. 24.40A,B). Tumor cells are small and basophilic with scant cytoplasm and inconspicuous nucleoli. Myoepithelial cells are detectable (via light microscopy or immunohistochemistry) peripherally within cribriform nests and tubular profiles ♦♦ Ducts profiles in the tubular pattern can show a particularly prominent bilayer of peripheral myoepithelial cells and luminal

Fig.  24.38. NK/T-cell lymphomas exhibit angiotropic growth, thrombosis, and necrosis. These tumors are typically polymorphous; malignant cells may have clear cytoplasm.

Fig. 24.39. Diffuse large cell lymphoma shows sheets of atypical lymphoid cells with conspicuous mitotic figures.

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Fig.  24.40. Adenoid cystic carcinoma is the most common malignant gland forming tumor of the nasal cavity and paranasal sinuses. The cribriform pattern of adenoid cystic carcinoma is well recognized (A). Predominant tubular patterns of adenoid cystic carcinoma can be challenging diagnostically (B).

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cuboidal cells. Perineural invasion/spread is characteristic. Mitotic figures, nucleoli, and necrosis common in the solid and dedifferentiated variants

Immunohistochemistry ♦♦ Tumor cells are positive for cytokeratin and c-kit. Peripheral myoepithelial cells stain for actin, p63, calponin, and S-100

Differential Diagnosis (See Table 24.1) ♦♦ The presence of myoepithelial differentiation aids to distinguish tubular AdCC from adenocarcinoma-NOS, which lacks such differentiation (actin-, ca lponin-). Polymorphous low grade adenocarcinoma is a potential consideration, but its occurrence in the nasonasal region is exceeding rare

Olfactory Neuroblastoma (Esthesioneuroblastoma) Clinical ♦♦ These rare neuroectodermal tumors account for ~1–5% of the malignant nasal cavity neoplasms. Tumors likely arise from the olfactory membrane or placode. Thus, involving or near the cribriform plate they carry a risk for intracranial extension. Patients (mean age: ~50 years) may present with obstructive symptoms, bleeding, pain, an optic disorder, and impaired sense of smell ♦♦ Paraneoplastic syndromes (i.e., Cushing syndrome, SIADH, etc.) can accompany these tumors

Microscopic ♦♦ A histologic spectrum may be encountered: from uniform, “small blue” cells embedded in fibrillary matrix to nests of epithelioid polygonal cells having a paraganglioma or carcinoid-like appearance (Fig. 24.41A). Tumor cell nests contain peripherally located S-100 positive sustentacular cells (Fig. 24.41B). The mitotic rate is variable; however, mitotic figures are often inconspicuous and few ♦♦ Prominent vascular proliferation typically accompanies nests of tumor cells. Homer Wright pseudorosettes, when present, reflect neuroblastic differentiation. Melanin can occasionally be present. Immunohistochemical corroboration of the diagnosis is very useful

Immunohistochemistry ♦♦ Tumor cells are positive for synaptophysin and chromogranin. Cytokeratin should be negative; however, unusual keratin positivity is rarely encountered. S-100 positive sustentacular cells are present peripherally in tumor cell nests

Molecular Findings ♦♦ These tumors lack the characteristic t(11;22)(q24;q12) translocation of Ewing sarcoma/PNET. Comparative genomic hybridization results have shown complex, manifold gains, and losses; high stage tumors have shown frequent gains at 13q14.2–q14.3, 13q31.1, and 20q11.21–q11.23, and loss of Xp21.1

Differential Diagnosis (See Table 24.1) ♦♦ Other sinonasal “small blue cell tumors” must be considered. High grade carcinomas, such as sinonasal undifferentiated and neuroendocrine carcinoma, are cytokeratin positive.

Fig. 24.41. A nested pattern of growth, isomorphic cells, and a prominent vasculature are features of olfactory neuroblastoma (A). S-100 protein positive sustentacular cells are a signature feature of olfactory neuroblastoma (B). Rhabdomyosarcoma shows immunohistochemical evidence of myogenic differentiation. The possibility of sinonasal involvement by pituitary adenoma should not be forgotten

Sinonasal Undifferentiated Carcinoma (SNUC) Clinical ♦♦ Patients affected by these aggressive tumors may present with pain, obstruction, and epistaxis. Diplopia and proptosis are features of advanced stage disease

Microscopic ♦♦ Nests, trabeculae, and sheets of medium-sized cells with hyperchromatic nuclei and variably prominent nuclei have small to moderate amounts of eosinophilic cytoplasm. (Fig. 24.42) The mitotic rate is high, necrosis is typical, and vascular invasion can be prominent

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Fig. 24.42. This sinonasal undifferentiated carcinoma was metastatic to the skin of the neck and negative for neuroendocrine markers.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 24.43. Malignant melanoma. Cytokeratin and S-100 immunohistochemistry is crucial in the workup of any undifferentiated sinonasal tumor in which melanoma is a diagnostic consideration.

Immunohistochemistry ♦♦ Cytokeratin is positive while neuroendocrine markers are generally negative

Differential Diagnosis ♦♦ Immunohistochemistry is useful is distinguishing from other considerations, such as olfactory neuroblastoma (S-100+ sustentacular cells, synaptophysin+, chromogranin+), ­neuroendocrine carcinoma (cytokeratin+, synaptophysin+, chromogranin+), rhabdomyosarcoma (desmin+, musclespecific actin+, ­myogenin+, MyoD1+) malignant lymphoma (lymphoid ­markers+), and malignant melanoma (S-100+, cytokeratin−) ♦♦ The presence of readily discernable nucleoli in SNUC aids distinction from small cell neuroendocrine carcinoma

Malignant Melanoma (Sinonasal Melanoma) Clinical ♦♦ Primary melanoma of the sinonasal cavity affects older individuals (mean age ~70 years). Patients present with epistaxis, obstruction, and mass. The prognosis is poor with a 5-year survival less than 50%

Microscopic ♦♦ Tumor cells can be either epithelioid and/or spindled (Fig. 24.43). Small and pleomorphic cell types are less common. Prominent eosinophilic nucleoli are common and neoplastic cells are frequently arranged in a peritheliomatous distribution. Sinonasal melanoma is commonly amelanotic

Immunohistochemistry ♦♦ These tumors stain similar to their cutaneous counterparts. Positive stains include S-100 protein, HMB 45, Melan A, tyrosinase, microphthalmia transcription factor, and vimentin

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♦♦ Cytokeratin is negative and useful in distinguishing melanoma from carcinoma

Differential Diagnosis ♦♦ Immunohistochemistry is extremely useful is establishing the diagnosis and excluding other considerations such as carcinoma (cytokeratin+, vimentin−), olfactory neuroblastoma (synaptophysin+, chromogranin+/−, S-100+ sustentacular cells), and lymphoma (lymphoid cell markers+, S-100 protein−)

Small Cell (Neuroendocrine) Carcinoma (SCNC) Clinical ♦♦ The mean age is ~50 years. Recurrences and metastasis occur in 70% and may be seen later than the third year beyond diagnosis

Microscopic ♦♦ Tumors resemble small cell carcinoma of the lung. Cellular nests, cords, and trabeculae are comprised of hyperchromatic cells with scanty cytoplasm. Nuclei are oval or round and nucleoli inconspicuous. Necrosis and hemorrhage are common, as is nuclear molding and crush artifact. Ultrastructurally, dense core granules are present

Immunohistochemistry ♦♦ Immunohistochemistry is extremely useful in establishing the diagnosis. Tumor cells should express cytokeratin (AE1/ AE3 and CAM 5.2) and neuroendocrine markers (i.e., synaptophysin and/or chromogranin). 34betaE12 is generally negative, and if positive only weakly so

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Differential Diagnosis

Molecular Findings

♦♦ Other undifferentiated and “blue cell” tumors should be considered. Olfactory neuroblastoma is cytokeratin negative, neuroendocrine marker positive, S-100 positive in sustentacular cells are present in most cases. Malignant melanoma is cytokeratin negative and melanoma marker positive. Sinonasal undifferentiated carcinoma is cytokeratin positive and neuroendocrine marker negative

♦♦ H-ras mutation has been found in a minority of ITACs and appears to be associated with poor prognosis. K-ras-2 mutation, common in colorectal adenocarcinoma, is absent in ITAC

Adenocarcinoma Clinical ♦♦ These are relatively rare tumors. Variants include low grade tubulopapillary and intestinal-type adenocarcinoma (ITAC) ♦♦ Intestinal-type adenocarcinoma occur both sporadically and as a result of occupation exposure to wood dust. Woodworkers with nasal exposure to wood dust have 70–500 times the risk for these tumors relative to the general population

Microscopic ♦♦ The low grade tubulopapillary variant is the most common pattern. These tumors exhibit unencapsulated papillary or tubular proliferations of cytologically bland cuboidal to columnar cells with uniform round nuclei. Tubular proliferations consist of back-to-back glandular profiles with little to no intervening stroma. Mitotic figures are typically few. Necrosis is generally not present and goblet cells are not common ♦♦ Intestinal-type adenocarcinoma can be divided into four subtypes: papillary tubular cylinder cell, alveolar goblet cell, signet-ring cell, and transitional or mixed pattern. Most belong to the first subtype. Tumors are histologically diverse and resemble the iterations of adenocarcinoma encountered throughout the gastrointestinal tract. Tumor cells can have a nondescript columnar, goblet cell, or signet-ring appearance. Necrosis and karyorrhexic debris are common. Mitotic activity is variable

Rhabdomyosarcoma Clinical ♦♦ Generally, this is a tumor of childhood with a mean age of 4 years. The nasopharynx is the second most common site in head and neck after the orbit. They may occur in nasal cavity and paranasal sinuses. The embryonal variant is the most common subtype (85% of cases)

Microscopic ♦♦ These “small blue cell” tumors are highly cellular and composed of small cells, variably spindled, with scant cytoplasm and hyperchromatic nuclei. Mitotic figures are numerous (Fig.  24.44). Larger cells with opaque eosinophilic cytoplasm with cross-­striations may be present. The stroma is commonly myxoid ♦♦ Ultrastructurally, Z-bands and myofilaments are demonstrated

Immunohistochemistry ♦♦ Immunohistochemistry is fundamental in establishing the diagnosis. Tumor cells are positive for MyoD1, myogenin, desmin, and muscle-specific actin. CD99 is negative

Differential Diagnosis ♦♦ Other small round blue cell tumors of childhood, see the chapter on soft tissue

Molecular Findings ♦♦ See the chapter on soft tissue

Immunohistochemistry ♦♦ The majority of ITACs are positive for CK7, CD20, and CDX2; a minority is MUC2 positive. Low grade adenocarcinomas are CK7 positive and negative for CD20, CDX2, and MUC2

Differential Diagnosis ♦♦ Low grade adenocarcinoma can be sufficiently bland to simulate an adenoma of salivary gland type; however, aside from pleomorphic adenoma such tumors are virtually nonexis­tent in this location ♦♦ Metastatic prostate carcinoma to the nasal sinus can simulate primary low grade adenocarcinoma. Enteric-type carcinomas must be distinguished from metastatic carcinoma of colonic origin ♦♦ Cytokeratin 7 may be useful in aiding distinction between intestinal-type adenocarcinoma of the sinus, which often shows some CK7 positivity, and adenocarcinoma of the colon (CK7−)

Fig. 24.44. Immunohistochemistry is fundamental in the diagnosis of small blue cell tumors. This rhabdomyosarcoma of the head and neck was metastatic to lymph node.

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Nasopharyngeal Carcinoma (NPC) Clinical ♦♦ The WHO most recent classification of NPC −− Keratinizing squamous cell carcinoma −− Nonkeratinizing carcinoma (a) Undifferentiated (b) Differentiated −− Basaloid squamous cell carcinoma ♦♦ All types of NPC are considered variants of squamous cell carcinoma ♦♦ High risk populations for NPC include southern Chinese, Eskimos and other natives of the Arctic region. NPC is the most common head and neck malignancy in southeastern China and Taiwan. Ethnic background, EBV exposure, and ingestion of volatile nitrosamines are thought to determine risk for NPC ♦♦ HLA-A2 and HLA-B-Sin 2 histocompatibility loci have been identified as possible markers for genetic susceptibility. There is a bimodal age incidence with peaks occurring near 20 and 65 years of age in low risk populations. High risk populations lack an early peak ♦♦ Patients commonly present with otitis media and hearing loss. Metastatic disease is the first presentation of disease (i.e., neck mass) in ~50% ♦♦ Undifferentiated and differentiated nonkeratinizing carcinomas have a strong association with EBV. EBV-associated tumors are highly sensitive to radiation therapy and have a 5-year survival of greater than 60% ♦♦ Keratinizing squamous cell carcinoma has a weaker association with EBV, arise in older patients, and have a 5-year survival of less than 40%. They are generally larger tumors at presentation

Microscopic ♦♦ Keratinizing squamous cell carcinoma has histology similar to tumors occurring elsewhere in the upper aerodigestive tract ♦♦ Differentiated nonkeratinizing carcinoma manifests nests and sheets of epidermoid appearing cells lacking keratinization. Nuclei are large, oval, and vesicular with prominent nucleoli. Robust lymphoplasmacytic inflammation accompanies the tumor cells ♦♦ Undifferentiated nonkeratinizing carcinoma exhibits polygonal cells with indistinct cytoplasmic membranes imparting a syncytical appearance. Dense lymphoplasmacytic inflammation dominants the histology and may obscure tumor cells. Vesicular nuclei exhibit little chromatin and distinct nuclei membranes. Nucleoli are prominent ♦♦ Basaloid squamous cell carcinoma appears similar to tumors occurring elsewhere

Immunohistochemistry ♦♦ These tumors are positive for cytokeratin

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Differential Diagnosis ♦♦ Immunohistochemistry aids distinction from lymphoma (lymphoid marker+ and cytokeratin−) and melanoma (S-100+, HMB 45+, and cytokeratin−)

Molecular Findings ♦♦ EBER (EBV-encoded RNA) positivity via in situ hybridization is present in greater than 90% of nonkeratinizing NPC and is a favorable prognostic indicator ♦♦ Cell proliferation may be upregulated via alterations of mitogen-activated protein kinases, and Akt and Wnt pathways. p16, cyclin D1, and cyclin E, among others, have been implicated in cell cycle abnormalities ♦♦ Polymorphism of a nitrosamine metabolizing gene, CYP2A6, may play a fundamental role in NPC susceptibility in certain populations

Miscellaneous Lesions Respiratory Epithelial Adenomatoid Hamartoma ♦♦ These are benign polypoid, nonneoplastic proliferations of ciliated respiratory epithelium. They most commonly arise on the posterior septum. Their cause is unknown. They may be mistaken for inverted papilloma

Necrotizing Sialometaplasia ♦♦ Infarction or necrosis of seromucinous glands at any site of upper aerodigestive tract can lead to squamous metaplasia, often extensive with cytologic atypia, that mimics squamous cell carcinoma

Cholesterol Granuloma ♦♦ Cholesterol granuloma may be encountered in the frontal and maxillary sinuses, less commonly in the paranasal sinuses. Cholesterol clefts, giant cells, foam cells, hemosiderin, and macrophages are present within fibrous granulation tissue. The changes are the result of resorbing hemorrhage

Chondromesenchymal Hamartoma ♦♦ These intranasal/paranasal tumors occur in infants. Bland spindle cells, fibrous stroma, and foci of cartilage comprise these tumors. Aneurysmal bone cyst-like change with giant cells may be present

Extranodal Sinus Histiocytosis (Sinus Histiocytosis with Massive Lymphadenopathy, Rosai–Dorfman Disease) ♦♦ The nasal and paranasal cavities are, after the skin, the second most common site of extranodal involvement by Rosai– Dorfman disease. The defining lesional cells are large foamy S-100 positive histiocytes that may contain intact intracytoplasmic lymphocytes (emperiopolesis)

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Fibromatosis ♦♦ These tumors are rare and histologically similar to fibromatosis occurring elsewhere. The differential diagnosis includes solitary fibrous tumor and low grade sarcomas

Hemangioma of Nasofacial Bones ♦♦ Osseous hemangioma commonly produces bony irregularities. Cavernous thin-walled vessels fill and expand cancellous bone

Meningioma ♦♦ Sinonasal meningioma is rare. The histology is similar to those of conventional intracranial lesions, including nuclear pseudoinclusions and psammoma bodies. Immunostains for EMA and vimentin are positive

Mesenchymal Chondrosarcoma ♦♦ These primitive appearing spindle cell tumors often have a hemangiopericytoma-like appearance with foci of cartilaginous matrix. A paucity of cartilaginous matrix makes the diagnosis difficult

Fig.  24.45. Pituitary adenoma may rarely present as a sinus tumor as in this case.

Osteoma ♦♦ Osteomas are dense tumor-like lesions of lamellar bone and are relatively common in the craniofacial skeleton. Patients with Gardner syndrome are at increased risk for craniofacial osteomas, gastrointestinal adenomas, fibromatosis, and keratinous cysts

Metastatic Tumors ♦♦ The most common metastatic tumor found in the nasal cavity-paranasal sinus region is renal cell carcinoma followed by lung, breast, thyroid, and prostate primaries

Pituitary Adenoma ♦♦ Sinus involvement may occur via extension from an intrasellar lesion or as primary ectopic tumor (Fig. 24.45)

Salivary Gland Tumors ♦♦ While adenoid cystic carcinoma is relatively common, other types of salivary gland tumors rarely involve the sinuses

Sarcoma ♦♦ A wide array of sarcomas may involve the nasal cavity-sinus region including, fibrosarcoma, osteosarcoma, chondrosarcoma, and Ewing sarcoma/PNET

Solitary Fibrous Tumor ♦♦ There are many recent reports of sinonasal solitary fibrous tumor. Immunohistochemistry is useful in establishing the ­diagnosis as these tumors are positive for CD34 and vimentin. CD99 is positive in 60–70% of cases

Fig. 24.46. Teratocarcinosarcoma is an unusual sinus tumor that is reminiscent of germ cell neoplasia. Primitive or blastema-like elements are common and may accompany malignant squamous and/or glandular components.

Teratoid Carcinosarcoma (Teratocarcinosarcoma) ♦♦ The histopathology of these highly malignant tumors is complex with features of an immature teratoma mixed with carcinoma. Carcinomatous elements can be gland forming and/or squamoid. Primitive neuroectodermal elements (including rosette-like structures), rhabdomyoblasts, and cartilaginous areas are typical (Fig.  24.46). Three of three tested cases were negative for chromosome 12p amplification is a recent study

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LARYNX AND TRACHEA Infection Disseminated Fungal Infection Clinical ♦♦ A variety of disseminated fungal infections may have laryngeal manifestations, including histoplasmosis, blastomycosis, cryptococcosis, and coccidioidomycosis. Infection of the larynx is typically preceded by pulmonary infection. The clinical impression is often laryngeal carcinoma or tuberculosis

Microscopic ♦♦ A granulomatous inflammatory response, including histiocytes, giant cells, and necrosis, is generally present. Welldefined granulomas may or may not be present. Bug-laden, foamy histiocytes with necrosis and nonspecific inflammation, with limited evidence of giant cells or granulomas, may be encounter with histoplasmosis ♦♦ Blastomycosis is notoriously for inducing pseudoepitheliomatous hyperplasia and associated neutrophilic inflammation with giant cells (Fig. 24.47)

Inflammatory/Nonneoplastic Lesions Laryngocele Clinical ♦♦ This lesion is represented by either congenital or an acquired air-filled (can accumulate fluid) dilatation of the laryngeal saccule

Microscopic ♦♦ They are lined by respiratory-type epithelium, which may undergo oncocytic metaplasia. The presence of neutrophils indicates secondary infection (i.e., laryngopyocele)

Fig.  24.47. In blastomycosis, granulomatous inflammation is typically rich with neutrophils. Inset: GMS stain showing broadbased budding yeast.

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Oncocytic Cyst Clinical ♦♦ Oncocytic cysts arise in elderly patients and most common occur within the ventricle. Patients present with complaints of hoarseness

Microscopic ♦♦ These cysts are lined by large oncocytic cells and arise within and involve the seromucinous glands of the larynx (Fig.  24.48). Variable papillary infoldings are encountered and maybe so prominent that a diagnosis of papillary cystadenoma is entertained

Differential Diagnosis ♦♦ Other benign cysts occur in the larynx including small ductal cysts lined by cuboidal cells of no special type and tonsillar retention cysts. The latter have the appearance of dilated, cystic tonsillar crypts, are squamous lined, and rich in lymphoid follicles

Vocal Cord Polyp (Laryngeal Polyp) Clinical ♦♦ These appear as sessile or pedunculated, raspberry-like lesions involving the true vocal cords. Their occurrence is associated with chronic voice abuse and heavy smoking

Microscopic ♦♦ These polypoid lesions vary in appearance. Typical stromal changes include vascular congestion, hemorrhage, myxoid change, perivascular hyalinization, thrombosis, and increased stromal cellularity (Fig.  24.49). A given lesion may have many or few of the above findings. The overlying squamous epithelium may show atypia, which may be related to ischemia and should not be mistaken for dysplasia

Fig.  24.48. Oncocytic cysts laryngeal cysts are nonneoplastic lesions that occur with increasing frequency in the elderly.

Head and Neck

Fig.  24.49. Laryngeal polyps are characterized by myxoid stroma and are often exhibit hemorrhage and thrombosis as seen in this case.

Contact Ulcer Clinical ♦♦ These lesions involve the posterior commissure of the vocal folds. They often recur and gastric reflux has been implicated in their pathogenesis

Microscopic ♦♦ The mucosa is typically ulcerated; however, squamous hyperplasia maybe seen adjacent to the ulcer. The signature portion of this lesion is the exuberant granulation tissue comprising the ulcer base, which can be extremely cellular and mimic neoplasia

Differential Diagnosis ♦♦ The characteristic location and clinical features aid distinction from potential histologic mimics such as hemangioma, spindle cell carcinoma, and granulomatous inflammation

Benign Neoplasms Laryngeal Papillomatosis (Squamous Papillomas) Clinical ♦♦ Resulting from the vertical transmission of human papilloma virus (HPV) types 6 and 11, the onset of juvenile laryngeal papillomatosis is, as the name suggests, generally in childhood or adolescence. The lesions are centered upon true cords and extension to false cords, vestibule and subglottis is not uncommon. They rarely involve trachea and bronchi. Adult cases tend to be solitary, recur less often, and have the same HPV association ♦♦ While multiple recurrences are typical, most cases eventually regress. Nonetheless, progressive disease occurs and can lead to death

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Fig.  24.50. Numerous HPV-induced squamous papillomas are encountered in laryngeal papillomatosis.

Microscopic ♦♦ Delicate fibrovascular cores are lined by relatively bland squamous epithelium exhibiting basal cell hyperplasia. While parakeratosis is common, hyperkeratosis can be present. There is basal cell hyperplasia and mild nuclear enlargement ♦♦ Koilocytic and koilocytic-like changes, including perinuclear halos and hyperchromatic, raisinoid nuclei, are present. Atypia is common and manifests as loss of polarity, mild nuclear enlargement and pleomorphism, binucleation, apoptosis, individual cell keratinization, and increased mitotic figures (Fig. 24.50) ♦♦ These lesions grow exophytically although extension into respiratory glands can be seen

Immunohistochemistry ♦♦ Immunohistochemical positivity for HPV antigen and in situ hybridization positivity for HPV 6/11 is common

Differential Diagnosis ♦♦ Histologically, invasive papillomatosis is identical to typical papillomatosis. Recognition of the former is based upon an invasive growth beyond the larynx into adjacent soft tissues ♦♦ Papillary squamous cell carcinoma exhibits greater cytologic atypia than papilloma, affects older individuals, and lacks the koilocytic changes of papilloma

Premalignant/Malignant Neoplasms Squamous Cell Hyperplasia (Hyperkeratosis) Clinical ♦♦ While hyperkeratosis manifests clinically as whitish mucosa plaques or thickenings, microscopically these lesions show hyperkeratosis accompanied by acanthosis or squamous hyperplasia. The true cords and interarytenoid area are the

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most commonly affected areas. Such change is associated with hoarseness and encountered in smokers and voice abusers

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Diagnosis can be difficult on biopsy (due to lack of atypia and difficulty in establishing invasion) and requires cooperation between the pathologist and the clinician

Microscopic

Microscopic

♦♦ The mucosa shows hyperkeratosis and typically acanthosis. Squamous cells are cytologically bland and maintain polarity ♦♦ Verrucous hyperkeratosis (verrucous hyperplasia) is a variant exhibiting verrucoid or papillary architecture. These lesions lack the papillary branching of papilloma and the pushing invasion of verrucous carcinoma

♦♦ See above section “Oral Cavity.” A diagnosis of verrucous carcinoma should not be made when there is notable or prominent cytologic atypia. Moreover, broad-based, ‘pushing’ invasion beyond the limits of the nonneoplastic mucosa should be demonstrated

Squamous Dysplasia/Carcinoma In Situ ♦♦ Keratotic lesions show spectrum of dysplasia ranging from mild squamous dysplasia to squamous cell carcinoma in situ. The WHO grades dysplasia into mild, moderate, severe, and carcinoma in situ ♦♦ There is correlation between degree of dysplasia and progression to invasive carcinoma. Progression to invasion may take years. The reproducibility of dysplasia grading is poor ♦♦ Cytologic atypia induced by previous radiation therapy may simulate dysplasia/carcinoma in situ

Squamous Cell Carcinoma Clinical ♦♦ Squamous cell carcinoma is the most common neoplasm of the larynx. Over 90% of carcinomas are squamous type. The mean age at diagnosis is 60 years. Smoking is the dominant risk factor for all types, including variants ♦♦ Segregating tumors according to laryngeal subsite has relevant prognostic import. Most tumors are glottic (65%), followed by supraglottic (35%) and subglottic (<5%). Glottic tumors have the best survival followed by supraglottic and then subglottic

Microscopic ♦♦ Recapitulating squamous epithelium tumors manifest keratin production, intracellular bridges, and/or dyskeratotic cells. Endophytic, exophytic, and mixed patterns of growth may be encountered. Stromal invasion is reflected by the presence of desmoplasia. Tumors are graded as well, moderately, or poorly differentiated. Several variants occur (see below)

Molecular Findings ♦♦ Implicated genetic abnormalities in the development of head and neck squamous cell carcinoma are complex and numerous, including alterations of p16ink4A, p53, cyclin D1, p14ARF, FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb

Verrucous Carcinoma Clinical ♦♦ This low grade variant of squamous cell carcinoma occurs most frequently in the oral cavity. The clinicopathologic features similar to those occurring elsewhere (i.e., nonmetastasizing) −− Grossly, these are gray-white, warty, broadly implanted mucosal growths. They represent no more than 2% of glottic carcinomas

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Differential Diagnosis ♦♦ Verrucous hyperkeratosis (verrucous squamous hyperplasia) lacks “pushing” invasion. Any large and/or broadly implanted lesion raises suspicion for carcinoma and warrants clinical input prior to diagnosis

Basaloid Squamous Cell Carcinoma Clinical ♦♦ This biologically high grade, variant of squamous cell carcinoma has a predilection for the supraglottic larynx, hypopharynx, and tongue base. There is a propensity for nodal as well as systemic metastases. The 5-year survival rate is ~18%

Microscopic ♦♦ These highly cellular neoplasms are composed of nests of hyperchromatic, basaloid-appearing cells exhibiting peripheral nuclear palisading. Squamous differentiation is encountered more centrally. Lobular, solid, trabecular, and cribriform patterns are encountered. Nuclei are hyperchromatic and variably pleomorphic with inconspicuous to prominent nucleoli ♦♦ Cytoplasm, likewise, is variable and single dyskeratotic cells are typical and have been noted to impart a “mosaic” pattern upon the tumor ♦♦ Central necrosis within tumor nests is common. Intercellular basement membrane-like material is often encountered in thin membranous structures or as droplets

Immunohistochemical ♦♦ Immunostains are positive for cytokeratin and p63. Neuroendocrine markers and TTF-1 are negative

Differential Diagnosis ♦♦ The solid variant of adenoid cystic carcinoma can mimic basaloid squamous cell carcinoma (BSCC); however, the former lacks squamous differentiation and is less pleomorphic than BSCC ♦♦ Immunohistochemically, small cell neuroendocrine carcinoma is positive for neuroendocrine markers and negative for p63

Sarcomatoid Carcinoma (Spindle Cell Carcinoma) Clinical ♦♦ The larynx is the most common site for this variant of squamous cell carcinoma, which is also encountered in the oral and nasal cavities, paranasal sinus, hypopharynx, and esophagus ♦♦ The average age at presentation is 66 years. Most tumors are glottic with a mean tumor size of less than 2  cm.

Head and Neck

Exophytic growth is a characteristic and may simulate a benign polyp. Recurrences may develop in up to ~50% of patients. Survival is related to the depth of invasion

Microscopic ♦♦ These malignant spindle cell tumors may be cytologically bland or markedly atypical. Coexistent foci of obvious squamous differentiation may or may not be present and when present confirm the diagnosis. Such foci can be quite limited, and diligent search for squamous differentiation should be made. Foci of benign or malignant-appearing cartilage and/or bone may be present (so-called “carcinosarcoma”). The presence of adjacent carcinoma in situ may also be present and aids in the diagnosis

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lymph node metastasis occurring in most patients. Visceral dissemination of disease occurs in up to 25% of patients

Microscopic ♦♦ Large, poorly to undifferentiated, nonkeratinized tumor cells intermingled with small nonneoplastic lymphocytes and plasma cells

Immunohistochemical ♦♦ If in doubt, cytokeratin positivity aids to distinguish from ­lymphoma and melanoma

Immunohistochemistry

Small Cell (Neuroendocrine) Carcinoma (SCNC) Clinical

♦♦ Immunostains are extremely useful in establishing the diagnosis when in doubt. Malignant spindle cells are anticipated to be positive for cytokeratin and vimentin. EMA may also be positive

♦♦ Laryngeal SCNC is histologically identical to it pulmonary counterpart. As with SCNC occurring at most sites there is early development of metastatic disease. There is a strong association with smoking and mean survival is 11 months

Differential Diagnosis

Microscopic

♦♦ Spindle cell carcinoma can be cytologically quite bland and easily mistaken for a benign mesenchymal process. Cytokeratin positivity argues for a diagnosis of carcinoma. Recurrent masses in a field of prior radiation should be viewed with a very high index of suspicion despite bland cytology ♦♦ Sarcomas lack immunohistochemical evidence of epithelial differentiation (i.e., cytokeratin negative) and lack a precursor lesion (i.e., carcinoma in situ)

♦♦ Hyperchromatic, small cells with scant cytoplasm show nuclear molding and crush artifact. Mitotic activity is high, and apoptotic nuclei debris is conspicuous. Nucleoli are not readily apparent and small if seen

Papillary Squamous Cell Carcinoma Clinical

Immunohistochemical ♦♦ Immunohistochemistry is extremely useful in establishing the diagnosis as cells are expected to be positive for cytokeratin, neuroendocrine markers, and TTF-1 (i.e., synaptophysin and/or chromogranin positive)

Differential Diagnosis

♦♦ These exophytic tumors are HPV-associated variants of squamous cell carcinoma (see section “Oropharynx”). Laryngeal primary tumors have the best prognosis relative to papillary squamous cell carcinoma arising elsewhere

♦♦ The differential includes lymphoma (lymphoid markers+, cytokeratin−), basaloid squamous cell carcinoma (p63+, neuroendocrine marker−, and TTF-1−), and variants of adenoid cyst carcinoma (see below)

Microscopic

Large Cell Neuroendocrine Carcinoma (LCNC) Clinical

♦♦ Tumors exhibit finger-like papillary architecture. Invasion into the underlying stroma may or may not be present. The prognosis corresponds to the extent of invasion. The cytologic atypia exceeds that encountered in papillomas. Atypia is generally full-thickness and mitotic figures are readily apparent

Differential Diagnosis ♦♦ Squamous papillomas, with or without dysplasia, exhibit less cytologic atypia than papillary squamous cell carcinoma. Koilocytes, typical of papilloma, are not readily apparent in papillary squamous cell carcinoma

Molecular Findings ♦♦ HPV 6 and 16 are the subtypes most commonly associated with papillary squamous cell carcinoma

Lymphoepithelioma-Like Carcinoma Clinical ♦♦ This tumor exhibits histology similar to its nasopharygeal counterpart (see above) and behaves in a like manner with

♦♦ Most cases of laryngeal LCNC arise in the supraglottis. There is a strong association with smoking. Prognosis is poor with a mean survival of 36 months. Lymph node and systemic metastasis are typical

Microscopic ♦♦ Larger, polygonal tumor cells exhibit a nested and/or trabecular pattern of growth. Eosinophilic cytoplasm may appear granular. Nuclei are large, pleomorphic, and hyperchromatic with viable chromatin ♦♦ Mitotic figures are readily apparent and necrosis is common. Ultrastructurally, dense core neurosecretory granules are present

Immunohistochemical ♦♦ The diagnosis of LCNC is dependent upon immunohistochemical (or ultrastructural) evidence of neuroendocrine differentiation (i.e., synaptophysin and/or chromogranin positivity). Cytokeratin staining is positive as well

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Differential Diagnosis ♦♦ Paraganglioma can bear a superficial resemblance to LCNC but lack mitotic activity and necrosis. Furthermore, paraganglioma is cytokeratin negative and contains S-100 positive sustentacular cells

Adenoid Cystic Carcinoma Clinical ♦♦ Adenoid cystic carcinoma is the second most common malignant tumor of trachea after squamous cell carcinoma. These tumors have a slow but relentless course with poor prognosis

Microscopic ♦♦ They are histologically similar to those occurring elsewhere (see Chapter 23, Salivary Gland Tumors). Solid pattern and dedifferentiated variants must be distinguished from the basaloid variant of squamous cell carcinoma and small cell carcinoma

Chondrosarcoma Clinical ♦♦ Chondrosarcoma, the most common malignant adult mesenchymal tumor of the larynx, typically is centered upon the cricoid cartilage. With a mean size of 3.5 cm, the majority

are low grade (grade 1 or 2). Conservative resection is advocated for low grade tumors

Microscopic ♦♦ Lobules of well-differentiated cartilage exhibit increased cellularity and chondrocyte atypia (including nucleoli, binucleation, and pleomorphism) as seen in low grade chondrosarcoma occurring at other sites (i.e., long bones)

Differential Diagnosis ♦♦ The principal diagnostic consideration is chondroma. Distinction can be difficult as is the case for cartilaginous tumors occurring elsewhere. Some have advocated considering all symptomatic lesions as representing chondrosarcoma – nomenclature aside, surgeons must be informed that conserva­tive resections is the treatment of choice for low grade tumors.  Nonneoplastic anatomic cartilage should be rule out as biopsy of an occasional “mass” will retrieve such material. We urge corroborating the histologic findings with the clinical  and radiographic findings in all cartilaginous lesions of the larynx

Mesenchymal/Soft Tissue Tumors ♦♦ Isolated case reports describe a wide spectrum of benign and malignant mesenchymal neoplasms arising in the larynx (see the chapter on soft tissue) ♦♦ The most frequent malignant laryngeal neoplasm in children and adolescents is the embryonal variant of rhabdomyosarcoma

TNM CLASSIFICATIONS FOR THE LIP AND ORAL CAVITY (2010 REVISION) Rules for Classification

Definition of TNM

♦♦ The classification applies only to carcinomas. There should be histologic confirmation of the disease ♦♦ The following are the procedures for assessing T, N, and M categories

Primary Tumor (T)

T categories N categories M categories

Physical examination, laryngoscopy, and imaging Physical examination and imaging Physical examination and imaging

TX T0 Tis T1 T2 T3 T4a

T4b

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor 2 cm of less in greatest dimension Tumor more than 2 cm but not more than 4 cm in greatest dimension Tumor more than 4 cm in greatest dimension Moderately advanced local disease* (lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face, that is, chin or nose (oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone [mandible or maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face) Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery

*Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4

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Regional Lymph Nodes (N)

Distant Metastasis (M)

NX N0 N1

MX M0 M1

N2

N2a N2b N2c N3

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, 3  cm or less in greatest dimension Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6  cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension Metastasis in a lymph node more than 6  cm in greatest dimension

Distant metastasis cannot be assessed No distant metastasis Distant metastasis

TNM CLASSIFICATIONS FOR THE LARYNX (2010 REVISION) Definition of TNM Primary Tumor (T) TX T0 Tis

Glottis T1 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ

Supraglottis T1 T2

T3

T4a

T4b

Tumor limited to one subsite of supraglottis with normal vocal cord mobility Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, preepiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage Moderately advanced local disease Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

T1a T1b T2 T3

T4a

T4b

Tumor limited to the true vocal cords (may involve anterior or posterior commissure) with normal mobility Tumor limited to one true vocal cord Tumor involves both true vocal cords Tumor extends to supraglottis and/or subglottis and/or with impaired true vocal cord mobility Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space, and/or inner cortex of the thyroid cartilage Moderately advanced local disease Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscle, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

Subglottis T1 T2 T3 T4a

T4b

Tumor limited to the subglottis Tumor extends to vocal cords with normal or impaired mobility Tumor limited to larynx with vocal cord fixation Moderately advanced local disease Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

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Regional Lymph Nodes (N)

Distant Metastasis (M)

NX N0 N1

MX M0 M1

N2

N2a N2b N2c N3

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6  cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension Metastasis in a lymph node more than 6 cm in greatest dimension

Distant metastasis cannot be assessed No distant metastasis Distant metastasis

SUGGESTED READINGS Nasal Cavity, Paranasal Sinuses, and Nasopharynx Banks ER, Frierson HF Jr, Mills SE, Swanson PE, et  al. Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol 1992; 16:939–946. Barnes L. Schneiderian papillomas and nonsalivary glandular neoplasms of the head and neck. Mod Pathol 2002;15:279–297. Bourne TD, Bellizzi AM, Stelow EB, et al. p63 Expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract. Am J Clin Pathol 2008;130:213–218. Devaney K. Wenig BM. Abbondanzo SL. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol 1996;9: 658–663. Devaney KO, Travis WD, Hoffman G, et al. Interpretation of head and neck biopsies in Wegener’s granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 1990;14:555–564. Fletcher CD. Distinctive soft tissue tumors of the head and neck. Mod Pathol 2002;15:324–330. Friedman GC, Hartwick RW, Ro JY, et  al. Allergic fungal sinusitis. Report of three cases associated with dematiaceous fungi. Am J Clin Pathol 1991;96:368–372. Frierson HF Jr, Mills SE, Fechner RE, et al. Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithelium and distinct from olfactory neuroblastoma. Am J Surg Pathol 1986; 10:771–779. Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses a clinicopathologic study of 20 cases. Cancer 1984;53:2140–2154. Iezzoni JC, Mills SE. “Undifferentiated” small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 2005;124 Suppl:S110–121.

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Ohshima K, Suzumiya J, Shimazaki K, et al. Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage. Histopathology 1997;31:444–450. Ridolfi RL, Lieberman PH, Erlandson RA, et  al. Schneiderian papillomas: a clinicopathologic study of 30 cases. Am J Surg Pathol 1977;1:43–53. Seethala RR, Hunt JL, Baloch ZW, LiVolsi VA, et  al. Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature. Am J Surg Pathol 2007;31: 1683–1694. Thompson LD, Miettinen M, Wenig BM. Sinonasal-type hemangiopericytoma: a clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation. Am J Surg Pathol 2003;27: 737–749. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003;27: 594–611.

Larynx and Trachea Banks ER, Frierson HF Jr, Mills SE, et al. Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol 1992;16:939–946. Baumann JL, Cohen S, Evjen AN, et al. Human papillomavirus in early laryngeal carcinoma. Laryngoscope 2009;119:1531–1537. Cook JR, Hill DA, Humphrey PA, Pfeifer JD, et  al. Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association. Mod Pathol 2000;13: 914–918. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope 2008;118:1236–1247.

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Ferlito A, Devaney KO, Rinaldo A. Neuroendocrine neoplasms of the ­larynx: advances in identification, understanding, and management. Oral Oncol 2006;42:770–778.

Thompson LD, Wieneke JA, Miettinen M, et al. Spindle cell (sarcomatoid) carcinomas of the larynx: a clinicopathologic study of 187 cases. Am J Surg Pathol 2002;26:153–170.

Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol 2002;15: 264–278.

Wenig BM. Necrotizing sialometaplasia of the larynx. A report of two cases and a review of the literature. Am J Clin Pathol 1995;103:609–613.

Thompson LD, Gannon FH. Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases with a review of the literature. Am J Surg Pathol 2002;26:836–851.

Wiernik G, Millard PR, Haybittle JL. The predictive value of histological classification into degrees of differentiation of squamous cell carcinoma of the larynx and hypopharynx compared with the survival of patients. Histopathology 1991;19:411–417.

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25 Eye and Ocular Adnexae Jose M. Bonnin, md

contents

I. Basic Anatomy of the Eye...................25-3

II. Diseases that Affect Multiple Structures in the Eye..........................25-3 Glaucoma..........................................................25-3 Congenital Glaucoma.............................25-3 Acquired Glaucoma................................25-3 Retinopathy of Prematurity (Retrolental Fibroplasia).............................25-3 Persistent Hyperplastic Primary Vitreous.....25-4 Inflammations of the Eye.................................25-4 Acute Inflammation................................25-4 Chronic Nongranulomatous Inflammation......................................25-5 Chronic Granulomatous Inflammation......................................25-6 Diabetes.............................................................25-6 Coat Disease......................................................25-6 Massive Retinal Gliosis....................................25-7 Phthisis Bulbi....................................................25-7

III. Cornea...............................................25-7 Basic Anatomy of the Cornea..........................25-7 Corneal Edema and Bullous Keratopathy.....25-8 Stromal Scarring and Vascularization...........25-9 Failed Corneal Graft........................................25-9 Corneal Opacification: Facette, Nebula, Macula, and Leukoma................................25-9 Keratitis (Corneal Inflammations) and Corneal Ulcers....................................25-10 Syphilitic Keratitis................................25-10 Onchocerciasis......................................25-10 Peripheral Corneal Ulcers...................25-10 Central Corneal Ulcers........................25-11 Acanthamoeba Corneal Ulcer.............25-11

Complications of Corneal Ulcers........25-11 Corneal Degenerations and Dystrophies......25-12 Fuchs Dystrophy (Fuchs Endothelial Dystrophy, Cornea Guttata)...........25-12 Granular Dystrophy.............................25-12 Macular Dystrophy...............................25-12 Lattice Dystrophy.................................25-12 Lipid Degeneration...............................25-12 Keratoconus..........................................25-13

IV. Conjunctiva.....................................25-13 Limbal (Epibulbar) Dermoids.......................25-13 Complex Choristomas....................................25-13 Degenerations.................................................25-14 Pinguecula.............................................25-14 Pterygium..............................................25-14 Conjunctival Cysts.........................................25-15 Conjunctival Inclusion Cysts...............25-15 Ductal Cysts..........................................25-15 Conjunctival Inflammations..........................25-15 Acute Conjunctivitis.............................25-15 Superior Limbic Keratoconjunctivitis........................25-16 Chronic Follicular Conjunctivitis.......25-16 Chronic Papillary Conjunctivitis........25-16 Ligneous Conjunctivitis.......................25-16 Rhinosporidiosis...................................25-17 Sarcoidosis.............................................25-17

V. Tumors and Mass Lesions of the Conjunctiva...........................25-18

Conjunctival Papillomas................................25-18 Conjunctival Intraepithelial Carcinoma (Squamous Cell Carcinoma In Situ)........25-18 Invasive Squamous Cell Carcinoma.............25-18

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_25, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Melanotic Lesions of the Conjunctiva..........25-18 Congenital and Acquired Melanosis..........................................25-18 Nevi........................................................25-19 Malignant Melanoma...........................25-19 Lymphoid Lesions..........................................25-20

VI. Tumors of the Eye............................25-20 Malignant Melanoma.....................................25-20 Retinoblastoma...............................................25-21 Other Tumors of the Eye...............................25-23 Malignant Lymphoma..........................25-23 Fuchs Adenoma....................................25-23 Medulloepithelioma..............................25-24 Leiomyomas..........................................25-24 Vascular Tumors...................................25-24 Glial Tumors of the Retina (Astrocytoma)...................................25-24 Metastatic Tumors................................25-24

Dacryolithiasis................................................25-29 Tumors of the Lacrimal Sac..........................25-29 Tumors of the Lacrimal Glands....................25-29

IX. Orbit................................................25-30 Tumors and Mass Lesions in the Orbit........25-30 Inflammatory Pseudotumor of the Orbit.......................................25-30 Graves Disease (Thyroid Ophthalmopathy).............................25-31 Rhabdomyosarcoma of the Orbit.................25-32 Glioma of the Optic Nerve (Pilocytic Astrocytoma of the Optic Nerve).............25-32 Meningioma of the Optic Nerve....................25-32 Lymphoid Tumors..........................................25-33

X. TNM Classification of Carcinoma of the Conjunctiva (2010 Revision)................................25-33

VII. Eyelids..............................................25-25 XI. TNM Classification of Malignant Melanoma of the Conjunctiva Anatomical Components...............................25-25 (2010 Revision)................................25-34 Inflammations.................................................25-25 Chalazion...............................................25-25 Hordeolum.............................................25-25 Cystic Lesions of the Eyelid...........................25-26 Epidermoid Cysts.................................25-26 Dermoid Cysts.......................................25-26 Hydrocystomas (“Water Cysts”).........25-26 Amyloidosis.....................................................25-26 Tumors and Other Mass Lesions of the Eyelid...............................................25-27 Squamous Papilloma............................25-27 Xanthelasma..........................................25-27 Basal Cell Carcinoma...........................25-28 Squamous Cell Carcinoma..................25-28 Sebaceous Carcinoma..........................25-28

VIII. Lesions of the Lacrimal Drainage System and Lacrimal Glands............25-28 Dacryocystitis..................................................25-29

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XII. TNM Classification of Malignant Melanoma of the Uvea (2010 Revision)................................25-34 XIII. TNM Classification of Retinoblastoma (2010 Revision)......25-36 XIV. TNM Classification of Carcinoma of the Eyelid (2010 Revision)...........25-36 XV. TNM Classification of Carcinoma of the Lacrimal Gland (2010 Revision)................................25-37 XVI. TNM Classification of the Tumors of the Orbit (2010 revision).............25-37 XVII. Suggested Reading...........................25-37

Eye and Ocular Adnexae

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BASIC ANATOMY OF THE EYE ♦♦ Histopathological evaluation of ophthalmic lesions requires some basic knowledge of the normal anatomy and histology of the eye and its adnexae ♦♦ Ocular lesions may affect one or more structures in the eye ♦♦ The basic structure of the eye consists of concentric layers or coats and the transparent media −− Fibrous coat (a) Cornea (b) Sclera −− Uveal tract or vascular coat (a) Iris

(b) Ciliary body (c) Choroid −− Neural coat (a) Retina −− Transparent media (a) Cornea (b) Anterior and posterior chambers (c) Lens (d) Vitreous body −− Optic nerve

DISEASES THAT AFFECT MULTIPLE STRUCTURES IN THE EYE Glaucoma

Microscopic

♦♦ An optic neuropathy associated with excavation of the optic nerve disk and progressive visual loss due to loss of ganglion cells and optic nerve fibers in the inner layers of the retina ♦♦ Often, but not always, associated with elevated intraocular pressure ♦♦ Aqueous humor is produced in ciliary body processes, flows through the pupil into the anterior chamber and is largely resorbed in the trabecular meshwork in the angle of the anterior chamber

♦♦ Degeneration an atrophy of inner layers of retina, mainly ganglion cell layer and optic nerve fiber layer ♦♦ Optic nerve atrophy with excavation (“cupping”) of optic nerve head ♦♦ Corneal edema ♦♦ Rupture of corneal Descemet membrane and Haab striae ♦♦ Atrophy of iris and ciliary body

Congenital Glaucoma ♦♦ Etiology: malformations involving iris and angle of anterior chamber (see Table 25.1)

Clinical ♦♦ Elevated intraocular pressure ♦♦ Corneal edema ♦♦ Generalized enlargement of the eye (buphthalmos)

Table 25.1. Diseases Associated with Congenital Glaucoma Iris anomalies   Iridocorneal synechiae and other anomalies   Peter anomaly   Axenfeld anomaly   Rieger anomaly Phacomatosis   Neurofibromatosis   Sturge–Weber syndrome Rubella Marfan syndrome Persistent hyperplastic primary vitreous Retinopathy of prematurity Retinoblastoma Juvenile xanthogranuloma

Acquired Glaucoma Types ♦♦ Primary −− Open-angle glaucoma or simple −− Closed-angle glaucoma ♦♦ Secondary (see Table 25.2) (Fig. 25.1)

Microscopic ♦♦ Degeneration and atrophy of inner layers of retina, mainly ganglion cell layer and optic nerve fiber layer ♦♦ Optic nerve atrophy with excavation (“cupping”) of optic nerve head ♦♦ Corneal edema ♦♦ Atrophy and fibrosis of anterior uvea (iris and ciliary body) ♦♦ Histological changes associated with coexisting lesions (see Table 25.2)

Retinopathy of Prematurity (Retrolental Fibroplasia) Clinical ♦♦ Develops in premature infants after birth ♦♦ Usually received supplemental oxygen therapy in early postnatal period

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Table 25.2. Conditions Associated with Secondary Glaucoma Abnormalities of the native lens Lens dislocation Persistent flat anterior chamber (post eye trauma) Iridocorneal endothelial syndrome Anterior uveitis (iritis) Retinopathy of prematurity Persistent hyperplastic primary vitreous Iris neovascularization Cysts of ciliary body and iris Juvenile xanthogranuloma Intraocular neoplasias Hemorrhage in anterior chamber Hemolysis

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Loose fibrovascular tissue in vitreous cavity (Fig. 25.2) Persistence of hyaloid vessels Adipose tissue, muscle fibers, and islands of cartilage Elongation of ciliary processes Retinal dysplasia

Inflammations of the Eye ♦♦ As in any other organ, inflammations may be acute or chronic ♦♦ May affect one or more coat of the eye or the transparent media ♦♦ Viruses, bacteria, fungi, and parasites may affect the eye (Fig. 25.3) ♦♦ Infection occurs mainly by direct penetration of the infectious agent through a wound, traumatic, or surgical ♦♦ Agents may reach the eye by extension of infectious processes from adjacent structures (i.e., paranasal sinuses) or hematogenous dissemination

Acute Inflammation Endophthalmitis Clinical ♦♦ Inflammation of the vitreous and inner coats of the eye ♦♦ Etiology: bacteria, fungi, virus (herpes virus, cytomegalovirus, measles) ♦♦ Tumors with extensive necrosis (melanoma and retinoblastoma) may present as endophthalmitis

Microscopic ♦♦ Suppurative inflammation in anterior chamber and vitreous cavity (Fig. 25.4) ♦♦ Variable degrees of necrosis of uvea and retina Fig. 25.1. Glaucoma. Closed-angle glaucoma due to extensive iridocorneal synechiae and obliteration of angle of anterior chamber in a patient with previous cataract surgery. ♦♦ May present with “white pupil” or “leukocoria” ♦♦ Often bilateral

Microscopic ♦♦ Capillary proliferation in retina ♦♦ Hemorrhages and fibrosis ♦♦ Fibrous membranes with tractional detachment of the retina −− Fibrous mass behind the lens may simulate retinoblastoma

Persistent Hyperplastic Primary Vitreous Clinical ♦♦ ♦♦ ♦♦ ♦♦

Congenital anomaly present at birth Often associated with microphthalmia Usually unilateral May present with “white pupil” or “leukocoria”

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Fig. 25.2. Persistent hyperplastic primary vitreous. The vitreous cavity is occupied with a loose fibroconnective and adipose tissues and remnants of the hyaloid vessels. The vitreous contents are firmly adherent to the retina, which is detached and is dysplastic.

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Panophthalmitis Clinical ♦♦ Inflammation involving all coats of the eye, including the sclera −− Etiology is similar to endophthalmitis but viruses rarely affect the sclera

Microscopic ♦♦ Suppurative inflammation involving all chambers and coats of the eye ♦♦ Process may extend to adjacent orbital soft tissues (Fig. 25.5)

Chronic Nongranulomatous Inflammation Clinical ♦♦ Usually affects of uveal tract (uveitis) ♦♦ Etiology −− Infectious agents −− Noninfectious (a)  Physical and chemical injury (b)  Allergic ♦♦ Affects one or more uveal structures −− Iritis −− Cyclitis −− Iridocyclitis −− Choroiditis ♦♦ Uveitis may be associated with numerous syndromes −− Ankylosing spondylitis −− Reiter syndrome −− Inflammatory bowel disease −− Psoriasis

Fig. 25.3. Viral infection. (A) Marked inflammation of the ciliary body due to CMV uveitis and retinitis in an HIV positive patient. (B) CMV inclusions in necrotic retinal pigment epithelium.

Microscopic

Fig. 25.4. Acute suppurative endophthalmitis with inflammation and necrosis of all intraocular structure.

Fig. 25.5. Acute suppurative panophthalmitis. Purulent exudates extend beyond the cavities of the eye with almost necrosis of the sclera.

♦♦ Focal of diffuse small mononuclear cell infiltration ♦♦ Plasma cells may be the predominant elements in the infiltrate

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♦♦ Iridocorneal synechiae, iris-lens synechiae, and glaucoma may follow repeated episodes of inflammation in the iris ♦♦ In late stages of the disease, phthisis bulbi may develop

Chronic Granulomatous Inflammation Sympathetic Uveitis (Sympathetic Ophthalmia) Clinical ♦♦ Diffuse bilateral inflammation of the uveal tract following eye trauma or surgery ♦♦ Delayed hypersensitivity reaction to antigen released at the time of injury ♦♦ Develops 2 weeks to years after a penetrating or perforating trauma to the eye ♦♦ The contralateral eye (sympathizing eye) develops lesions similar to those present in the affected, previously injured eye (exciting eye) ♦♦ Uveal incarceration or prolapse into the wound is usually observed ♦♦ Initial presentation characterized by blurred vision, photophobia, and muton-fat keratic deposits

Microscopic ♦♦ Diffuse granulomatous inflammation involving iris, ciliary body, and choroid ♦♦ The infiltrate is made up predominantly of epithelioid cells and lymphocytes ♦♦ The lymphocytic infiltrate includes almost exclusively T lymphocytes ♦♦ In the choroid, the choriocapillary layer is usually spared ♦♦ Epithelioid cells and multinucleated giant cells may contain phagocytized pigment granules in their cytoplasm ♦♦ Nodules of epithelioid cells and pigment laden cells (Dalén– Fuchs nodules) in the subretinal space are characteristic (Fig. 25.6)

Phacoantigenic (Phacoimmune, Phacoanaphylactic) Endophthalmitis Clinical ♦♦ Rare severe granulomatous inflammation of the eye ♦♦ It is an immune complex disease with loss of immune tolerance ♦♦ Secondary to traumatic rupture of the lens capsule and release of lens proteins ♦♦ It may coexist with sympathetic ophthalmia

Microscopic ♦♦ Zonal granulomatous inflammation around lens with ruptured capsule ♦♦ First zone: Prominent polymorphonuclear cell infiltration ♦♦ Second zone: Layer of histiocytes and multinucleated giant cells ♦♦ Third zone: In the periphery, there is a layer of granulation tissue with lymphoplasmacytic infiltration

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Fig. 25.6. Sympathetic ophthalmia. Ill-defined granulomas with multinucleated giant cells and marked lymphoplasmacytic infiltration in choroid. Noted the large group of epithelioid cells and pigment epithelium in the subretinal space, the Dalén–Fuchs nodule, characteristic of sympathetic ophthalmia.

♦♦ Depending on the severity of the initial trauma, the uvea may also show nongranulomatous inflammation or sympathetic uveitis (ophthalmia)

Diabetes Clinical ♦♦ Major cause of blindness in the USA and other Western countries ♦♦ Women are more commonly affected ♦♦ Diabetes and its complications may involve −− All coats and transparent media in the eye −− Optic nerve and intracranial visual pathways −− Ocular adnexae −− Orbit

Microscopic ♦♦ Conjunctival microaneurysms ♦♦ Recurrent erosions and corneal ulcers (in patients with diabetic neuropathy) ♦♦ Neovascularization of the iris (rubeosis iridis) ♦♦ Cataracts ♦♦ Glaucoma ♦♦ Proliferative retinopathy with retinal detachments ♦♦ Retinal hemorrhages ♦♦ Ischemic optic neuropathy

Coat Disease Clinical ♦♦ Exudative retinal detachment ♦♦ Usually unilateral

Eye and Ocular Adnexae

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Fig. 25.7. (A) Massive gliosis of the retina in an eye enucleated several years after severe ocular trauma follow by phthisis bulbi. Note the focus of ossification. (B) Rosenthal fibers in densely reactive glial proliferation. ♦♦ Mainly affects males up to 18 years of age ♦♦ Clinically, it mimics retinoblastoma

Microscopic ♦♦ Telangiectatic dilatation of retinal vessels, microaneurysms and areas of ischemia ♦♦ Protein and lipid-rich transudate in outer retinal layers ♦♦ Subretinal exudates containing foamy macrophages and cholesterol crystals ♦♦ Retinal detachment

♦♦ Glial cells are elongated (pilocytic) and have long pale eosinophilic processes ♦♦ Rosenthal fibers and foci of calcification may occur within the mass (Fig. 25.7) ♦♦ Blood vessels are usually dilated and have thin walls ♦♦ Degenerative changes in intraocular tissue and foci of ossification may be observed ♦♦ Cells forming the mass are positive for glial fibrillary acidic protein (GFAP)

Phthisis Bulbi Clinical

Massive Retinal Gliosis Clinical ♦♦ Segmental or total replacement of neural retina by glial tissue ♦♦ Usually follows penetrating trauma to the eye ♦♦ Chronic inflammatory processes, congenital malformations and retinal vascular disorders may also develop massive retinal gliosis

Microscopic ♦♦ Large mass of glial cells that partially or totally fills the cavities of the eye

♦♦ End stage of many diffuse ocular diseases ♦♦ Usually submitted by the ophthalmologists with the diagnosis of “blind painful eye” ♦♦ Marked atrophy and shrinkage of eye ball

Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Marked shrinkage and disorganization of eye (Fig. 25.8) Corneal scarring with or without vascularization Thickened sclera Profound disorganization of intraocular tissues Foci of calcification and ossification are usually observed

CORNEA Basic Anatomy of the Cornea ♦♦ The normal cornea is 9–13 mm in diameter ♦♦ It is 0.8–0.9  mm thick in the center and 1.1  mm in the periphery ♦♦ The cornea has six anatomic layers

−− Anterior corneal epithelium, five layers of ­nonkeratinizing squamous cells −− Basement membrane of the anterior corneal epithelium −− Bowman membrane, thick layer of collagen fibrils

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Fig. 25.8. Phthisis bulbi. (A) Marked shrinkage of entire globe with disorganization and atrophy of old intraocular structures. Note the scarring of the cornea, the atrophy and gliosis of the retina and the extensive synechiae of the iris and ciliary body to the cornea. (B) Hyperplasia and metaplasia of the retinal pigment epithelium and foci of ossification. (C) Posterior aspect of the globe. Old retinal detachment with atrophy and gliosis of retina and reactive proliferation of the retinal pigment epithelium.

−− Stroma represents 90% of the entire thickness of the ­cornea. It is made up of multiple lamellae of collagen and fibroblasts (keratocytes) −− Descemet membrane, thick basement membrane of the corneal endothelium −− Corneal endothelium ♦♦ Blood vessels are not observed in the normal cornea ♦♦ There is a rich innervation (ophthalmic division of the trigeminal nerve) ♦♦ Mitoses are not observed in the anterior corneal epithelium except in the periphery (stem cell region). Cells are continuously replaced by sliding of cells from the periphery towards the center

Corneal Edema and Bullous Keratopathy Clinical ♦♦ Corneal edema and bullous keratopathy are major indications for corneal transplantation or stripping of the Descemet membrane ♦♦ Many clinical conditions are associated with corneal edema

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♦♦ It may occur sometime after intraocular surgery (i.e., cataract extraction) ♦♦ It is usually secondary to dysfunction of the corneal endothelium (“endothelial decompensation”) ♦♦ Edema may be bilateral but is often asymmetric ♦♦ Chronic corneal edema may result in the formation of bullae in the anterior corneal epithelium ♦♦ Rupture of the bullae is associated with severe pain and may lead to complications ♦♦ In late stages, spindle cells from the stroma may migrate into the subepithelial space and form a dense fibrous layer (“fibrous pannus”)

Microscopic ♦♦ Increased fluid in corneal stroma is difficult to document histologically because it causes separation of the lamellae (which is also a common artifact of histological processing) ♦♦ Edema of the anterior corneal epithelium is the most reliable diagnostic feature (Fig. 25.9A) ♦♦ The number of endothelial cells may be reduced

Eye and Ocular Adnexae

♦♦ Thickening and lamination of the Descemet membrane suggest dysfunction of the endothelial cells ♦♦ Wart-like protrusions on the posterior surface of the Descemet membrane (“guttae”) may develop. They are best demonstrated with the PAS stain ♦♦ Epithelial bullae and fibrous pannus are seen late in the course of the disease (Fig. 25.9B)

Stromal Scarring and Vascularization ♦♦ Scarring and vascularization of the corneal stroma are nonspecific ♦♦ They may occur as complication of trauma, inflammatory processes, ulcers, chemical burns, irradiation, and other conditions ♦♦ Scars may be focal or diffuse, depending on the cause of the injury ♦♦ The Bowman membrane and corneal stroma do not ­regenerate after an injury but are replaced by scar tissue (Fig. 25.10)

Failed Corneal Graft ♦♦ Corneal transplants or penetrating keratoplasty is usually performed without providing any immunosuppression ♦♦ Success rate is markedly diminished if the cornea is vascularized

Fig.  25.9. (A) Cornea. Edema in anterior corneal epithelium overlying a focus of posttraumatic stromal scarring. (B) Chronic corneal edema. Atrophy of anterior corneal epithelium and dense subepithelial fibrous pannus.

25-9

♦♦ Failed corneal grafts are usually secondary to endothelial damage

Microscopic ♦♦ Changes are similar to those seen in chronic corneal edema and bullous keratopathy (Fig. 25.11) ♦♦ A layer of fibrous tissue may develop on the posterior surface of the cornea (“retrocorneal fibrous plaque”). It usually starts in the area of the surgical wound ♦♦ Immune rejection of a corneal graft may occur. It causes marked vascular proliferation and inflammatory cell infiltration in the periphery of the corneal button

Corneal Opacification: Facette, Nebula, Macula, and Leukoma Facette ♦♦ Small foci of thickening of the anterior corneal epithelium filling superficial defects with loss of Bowman membrane and superficial corneal stroma ♦♦ The normal curvature of the anterior surface of the cornea is preserved

Fig. 25.10. Cornea. (A) Scar in anterior corneal stroma following penetrating injury. (B) Scarring and vascularization of anterior corneal stroma.

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25-10

Fig. 25.11. Failed corneal graft. Atrophy and partial disorganization of epithelial cells. The anterior corneal epithelium is partly detached from the underlying Bowman membrane. The inflammatory infiltration and vascularization of graft rejection are not observed.

Nebula ♦♦ Small delicate opacities in corneal stroma ♦♦ Histologically, they appear as small superficial scars

Macula ♦♦ Larger opacities due to more extensive scarring, usually deeper in the stroma

Leukoma ♦♦ Focus of scarring involving almost the entire thickness of the cornea stroma

Keratitis (Corneal Inflammations) and Corneal Ulcers ♦♦ Corneal erosions: limited damage to epithelium, best seen clinically after fluorescein staining ♦♦ Keratitis: more extensive epithelial damage with variable depths of stromal involvement. It is seen on macroscopic examination

Etiology ♦♦ ♦♦ ♦♦ ♦♦

Trauma Toxic Radiation induced Infectious −− Viral (a) Adenovirus (several types, mainly type 8) (b) Herpes simplex virus (c) Herpes zoster virus (d) Epstein–Barr virus −− Bacterial (a) Pyogenic bacteria (b) Syphilis

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(c) Trachoma (d) Lyme disease (e) Tuberculosis (f) Leprosy −− Parasitic (a) Protozoal (b) Leishmaniasis (c) Trypanosomiasis −− Nematodes (a) Onchocerciasis ♦♦ Other causes −− Sarcoidosis −− Lymphogranuloma venereum −− Atopic keratoconjunctivitis −− Lymphoproliferative disorders Hodgkin lymphoma) −− Rosacea −− Crohn disease

(mycosis

fungoides,

Syphilitic Keratitis ♦♦ Extensive stromal involvement ♦♦ Anterior uveitis present in early stages ♦♦ Congenital form −− Usually bilateral −− May be present at birth −− Cloudy cornea due to inflammation and vascularization of deep stroma −− It is part of the Hutchinson triad ♦♦ Acquired form −− Late manifestation – 10 years after primary infection −− Usually unilateral, sector shape lesion

Onchocerciasis ♦♦ Leading cause of blindness in the world; Africa, Central and South America (18 million children and young adults) ♦♦ Causes the River blindness ♦♦ Acute phase: nummular or snowflake corneal opacities ♦♦ Late phase: dense stromal scarring ♦♦ Microfilariae migrate through skin and subcutaneous tissue ♦♦ Small, black fly, Simulium sp. transmits parasite from human to human

Peripheral Corneal Ulcers Ring Ulcer and Ring Abscess ♦♦ Linear stromal ulcerated lesion that involves most of the entire circumference of the cornea −− Usually follows accidental or surgical trauma −− Starts at 1–2 mm from the limbus into the clear portion of the cornea

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Rim of clear cornea always remains Central cornea rapidly undergoes necrosis Panophthalmitis follows The eye is lost Usually infectious; collagen diseases may be the cause

Central Corneal Ulcers Etiology ♦♦ ♦♦ ♦♦ ♦♦

Viral Bacterial Mycotic Parasitic

Herpes Simplex Keratitis ♦♦ ♦♦ ♦♦ ♦♦

Most common cause of central corneal ulcer Initially involves the epithelium with dendritic pattern Patients with atopic dermatitis – susceptible to dissemination The virus spreads from ganglion cells along branches of the ophthalmic division of the trigeminal nerve

Bacterial Ulcers ♦♦ They are associated with severe inflammation of the corneal epithelium and stroma ♦♦ Cause purulent infiltrate

Etiology ♦♦ Organisms that may cause corneal ulcers −− Pneumococcus −− Streptococcus −− Pseudomonas −− Klebsiella −− Staphylococcus −− Other less virulent bacteria

Mycotic Ulcers ♦♦ Usually present with a “dry” main lesion and smaller satellite lesions ♦♦ Hypopyon (purulent exudates in anterior chamber) is common (Fig. 25.12) ♦♦ Fungus may be isolated by scraping margins and depth of ulcer ♦♦ Agents isolated from ulcers may be in mycelial form (i.e., Aspergillus) or yeasts (i.e., Candida) ♦♦ Generally, they are secondary to trauma and contamination with plant or animal matter

Acanthamoeba Corneal Ulcer ♦♦ Agent is a free living protozoon found in soil, fresh water, and human oral cavity ♦♦ Most cases occur in patients who wear contact lenses ♦♦ The lesion is usually a painful, central, or paracentral ulcer ♦♦ The inflammatory infiltrate predominates in the anterior and mid section of the stroma ♦♦ The process has a waxing and waning course

Fig. 25.12. (A) Corneal ulcer with suppurative inflammation in the anterior chamber (hypopyon) due to fungal infection (Fusarium sp.). (B) Fungal organism in the stroma (GMS stain).

♦♦ An associated scleral infection may occur ♦♦ The diagnosis is confirmed by identification of the cysts in H&E stained sections. Cyst walls stain with PAS, GMS, and Giemsa ♦♦ Trophozoites are better identified in cultures

Complications of Corneal Ulcers ♦♦ Vascularization of the corneal stroma ♦♦ Scarring of the stroma may be focal or extensive and may involve only part of the entire thickness of the cornea ♦♦ Descemetocele is a herniation of the Descemet membrane through a defect of the corneal stroma secondary of a deep penetrating ulcer ♦♦ Ectasia, partial or diffuse protrusion of a thin cornea secondary to the inflammatory process ♦♦ Staphyloma. Lesion is a corneal ectasia with a bluish color produced by the pigmented uveal tissue behind the cornea ♦♦ Xerosis. Dryness and secondary keratinization of the cornea is secondary to destruction of conjunctival goblet cells and lacrimal glands by the inflammatory process

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Corneal Degenerations and Dystrophies Fuchs Dystrophy (Fuchs Endothelial Dystrophy, Cornea Guttata) Clinical ♦♦ ♦♦ ♦♦ ♦♦

The most common corneal dystrophy Etiology: primary defect of corneal endothelium Usually develops in late adult life Patients present with chronic corneal edema and bullous keratopathy ♦♦ Defects on posterior surface of Descemet membrane are easily observed on slit lamp examination

Microscopic ♦♦ Thickened Descemet membrane, best demonstrated in PAS stained sections ♦♦ Descemet membrane may have a laminated appearance ♦♦ Numerous wart-like or mushroom-like protrusions on posterior surface of Descemet membrane (“guttae”) due to abnormal deposition of basement membrane material by dysfunctional corneal endothelium (Fig. 25.13) ♦♦ Number of endothelial cells is decreased ♦♦ Melanin pigment granules from the iris may be observed in the cytoplasm of endothelial cells ♦♦ Changes due to chronic corneal edema and bullous kerato­ pathy are usually observed

Granular Dystrophy Clinical ♦♦ One of the classical dystrophies of the corneal stroma ♦♦ It is a hereditary condition transmitted as an autosomal dominant trait ♦♦ Usually develops in older adults ♦♦ Presents as multiple superficial opacities in the stroma of the cornea ♦♦ Visual acuity is minimally impaired ♦♦ The lesion recurs after corneal transplantation

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic ♦♦ Multiple irregular deposits of a pale eosinophilic material in stroma ♦♦ Deposits stain bright red with the Masson trichrome and are negative with Congo red ♦♦ Ultrastructurally, the deposits appear as dense crystalloids, occasionally with vague periodicity

Macular Dystrophy Clinical ♦♦ Conditions is inherited as an autosomal recessive trait ♦♦ Gene has been identified in chromosome 16 (16q22) ♦♦ Leads to more severe visual impairment requiring corneal transplantation in the second of third decades of life ♦♦ Relatively uncommon in the USA ♦♦ It is a form of localized corneal mucopolysaccharidosis

Microscopic ♦♦ The cornea may be thinner than normally ♦♦ Multiple delicate granules are observed within the keratocytes and interlamellar spaces in the stroma ♦♦ Endothelial cells are also affected ♦♦ The granular material is PAS positive ♦♦ Staining with colloidal iron or Alcian blue for acid mucopolysaccharides confirm the diagnosis (Fig. 25.14)

Lattice Dystrophy Clinical ♦♦ It is a localized form of corneal amyloidosis ♦♦ There are several variants ♦♦ Variants differ in age of presentation, distribution of the lesion and transmission as autosomal dominant or recessive trait ♦♦ The lesion usually manifests before adolescence, progresses slowly and may require corneal transplantation by the fifth decade ♦♦ On clinical examination, the deposits of amyloid appear as irregularly branched lines crisscrossing the cornea

Microscopic ♦♦ Irregular, round, or oval deposits of amyloid in the corneal stroma ♦♦ Deposits also accumulate in the subepithelial and preDescemet regions of the stroma (Fig. 25.15) ♦♦ The material is eosinophilic and stains positively with Congo red and crystal violet, is fluorescent in thioflavin-T-stained sections and shows the characteristic features of amyloid when examined with polarization

Lipid Degeneration Fig.  25.13. Fuchs dystrophy. The thickened Descemet membrane is studded with wart-like protrusions (“guttate”) on its posterior surface. PAS stain.

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♦♦ Arcus senilis, is a deposition of lipids in the stroma of the peripheral, paralimbal cornea −− It is not necessarily associated with abnormalities in lipid metabolism

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♦♦ Primary lipid degeneration appears as an exaggeration of arcus senilis, with extensive lipid deposits toward the center of the cornea ♦♦ Secondary lipid degeneration −− Usually follows some form of corneal trauma, including surgical injury −− The lipid deposition occurs within a thick subepithelial fibrous pannus

Keratoconus Clinical ♦♦ Thinning and ectasia of central or paracentral cornea ♦♦ Appears in early in adolescence and progresses until the fifth decade ♦♦ It is bilateral in 90% of the cases ♦♦ Females are more often affected ♦♦ Clinically, if produces irregular astigmatism ♦♦ It may be associated with multiple systemic diseases ♦♦ Corneal opacities may develop due to stromal scarring ♦♦ Rupture of the Descemet membrane results is severe acute corneal edema (“acute hydrops”)

Microscopic

Fig. 25.14. Macular corneal dystrophy. (A) Granular deposits of abnormal mucopolysaccharides in extracellular spaces and keratocytes. (B) Mucopolysaccharide deposits in extracellular spaces, cytoplasm of keratocytes, and endothelial cells. Alcian blue stain.

♦♦ The central corneal stroma is markedly thinner than the periphery ♦♦ Ruptures of the Bowman membrane are common and are sometimes associated with superficial stromal scarring ♦♦ The anterior corneal epithelium overlying the cone may be atrophic ♦♦ If the Descemet membrane ruptures, the coiled edges of the membrane appear as well-defined lines on clinical examination (“Haab striae”) ♦♦ Following rupture of the Descemet membrane, the stroma becomes markedly edematous (“acute hydrops”) (Fig. 25.16) ♦♦ The defect is usually covered by a newly deposited thin Descemet membrane ♦♦ Prussian blue staining may show a ring of iron deposition around the cone (Fleischer ring)

CONJUNCTIVA Limbal (Epibulbar) Dermoids Clinical ♦♦ Congenital lesions occurring in the temporal limbus (corneal/ conjunctival interface) ♦♦ Elevated plaques of skin with or without subcutaneous fat ♦♦ Some epibulbar dermoids are cystic

Microscopic ♦♦ Island of skin with skin adnexae and adipose tissue (Fig. 25.17A)

♦♦ Surface epidermis may be replaced by corneal or conjunctival epithelium ♦♦ Similar lesions, without skin adnexae, are designated as dermolipomas or lipodermoids ♦♦ Goldenhar syndrome: limbal dermoids, preauricular skin tags, aural fistulas, and vertebral anomalies

Complex Choristomas ♦♦ Limbal dermoids containing heterologous tissues −− Cartilage

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Fig. 25.15. Lattice corneal dystrophy. (A) and (B) Deposits of amyloid in corneal stroma. (C) Amyloid deposits in stroma are Congo red positive. (D) Birefringent amyloid deposits examined with polarization microscopy.

Degenerations Pinguecula Clinical ♦♦ ♦♦ ♦♦ ♦♦ Fig. 25.16. Keratoconus. Extreme thinning of cornea led to rupture of Descemet membrane with massive edema of stroma (“acute hydrops”). The curled edges of the ruptured membrane are seen clinically as lines or striae crossing the cornea “Haab striae.” −− −− −− −− −−

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Lacrimal gland (Fig. 25.17B) Smooth or striate muscle fibers Teeth Bone (Fig. 25.17C) Nervous tissue

Focal elevation in bulbar conjunctival mucosa Involves area corresponding to the interpalpebral fissure Reactive proliferative response in conjunctival mucosa Due to environmental irritants, dust, winds, particulate and chemical air pollution, solar irradiation

Microscopic ♦♦ Atrophy or hyperplasia of surface epithelium ♦♦ Increased fibrovascular tissue in conjunctival stroma ♦♦ Elastotic degeneration (solar elastosis). It may be minimal in some cases

Pterygium ♦♦ Similar etiology to pinguecula ♦♦ Involves paralimbal conjunctiva and encroaches on the cornea ♦♦ The underlying Bowman membrane is absent

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Fig. 25.18. Wall of a conjunctival inclusion cysts with rupture and secondary inflammation. Note the goblet cells in the lining epithelium of the cyst. ♦♦ Squamous cell carcinoma and amelanotic melanoma of conjunctiva may mimic pterygia

Conjunctival Cysts Conjunctival Inclusion Cysts Clinical ♦♦ May be congenital ♦♦ Or secondary to postsurgical or posttraumatic implantation of conjunctival epithelium or epithelial inclusion in conjunctivitis

Microscopic ♦♦ Lining made up of conjunctival epithelium with goblet cells ♦♦ Contents may be mucinous, proteinaceous, or both (Fig. 25.18) ♦♦ Focal calcification occurs in some cases

Ductal Cysts Clinical ♦♦ Cystic lesions secondary to blockage of accessory lacrimal gland ducts

Microscopic ♦♦ Cyst lining is made up of a double layer ductal epithelium ♦♦ Lumen contains clear fluid Fig. 25.17. (A) Limbal dermoid. Island of skin and skin adnexae in limbal conjunctiva. (B) Heterologous tissues (ectopic lacrimal gland and cartilage) in complex choristoma of conjunctiva. (C) Osseous tissue in a complex choristoma of conjunctiva.

Conjunctival Inflammations Acute Conjunctivitis ♦♦ ♦♦ ♦♦ ♦♦

Rarely examined pathologically except in scrapings and smears Etiology: viruses, bacteria, fungi, and parasites Clinical presentation: redness and chemosis Exudates may be purulent

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Superior Limbic Keratoconjunctivitis ♦♦ Marked inflammation of palpebral conjunctiva of superior eyelid or upper bulbar conjunctiva ♦♦ Etiology is unknown ♦♦ Microscopically, there is keratinization of surface epithelium with dyskeratosis, acanthosis, and mixed inflammatory cell infiltration

Chronic Follicular Conjunctivitis ♦♦ Common pattern of chronic conjunctival inflammation ♦♦ Etiology −− Viruses (a) Herpes simplex (b) Adenovirus (c) Enterovirus (d) Newcastle virus −− Chlamydia (a) Trachoma; one of the most important causes of blindness worldwide −− Cosmetics −− Topical medications −− Environmental irritants ♦♦ Clinically, multiple gray-white rounded or oval elevations in conjunctival surface and marked congestion of conjunctival mucosa ♦♦ Microscopically, marked follicular lymphoid hyperplasia in substantia propria (Fig. 25.19A)

Chronic Papillary Conjunctivitis Clinical ♦♦ Common nonspecific reaction of conjunctiva in chronic inflammation ♦♦ Occurs mainly in palpebral conjunctiva ♦♦ Gives the conjunctiva a “cobblestone” appearance ♦♦ Appears in late stages of chronic conjunctivitis of various etiologies ♦♦ Often seen in vernal conjunctivitis, a form of recurrent atopic conjunctivitis

Microscopic ♦♦ Papillary hypertrophy of mucosa with deep infoldings of epithelium (Fig. 25.19B) ♦♦ Fibrovascular cores may contain a prominent mixed inflammatory infiltration ♦♦ The surface of the papillae may undergo squamous metaplasia ♦♦ Hyperplasia of goblet cells occurs in the “valleys” between papillae

Ligneous Conjunctivitis Clinical ♦♦ Rare form of chronic conjunctivitis ♦♦ Recurrent disease

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Fig. 25.19. (A) Chronic follicular conjunctivitis. Note the associated goblet cell hyperplasia on the left. (B) Papillary conjunctivitis with numerous inclusions of conjunctival epithelium. (C) Ligneous conjunctivitis. Granulation tissue and fibrinous material. Lesion bleeds easily when overlying pseudomembranes are removed.

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♦♦ Affects mainly young girls ♦♦ Characteristic pseudomembranes with woody consistency ♦♦ Removal of pseudomembranes causes bleeding and is rapidly replaced by another pseudomembrane

Microscopic ♦♦ Pseudomembranes containing inflammatory cells, cell debris, and fibrinous material ♦♦ Granulation tissue with mixed inflammatory cell infiltration (Fig. 25.19C) ♦♦ Variable degrees of fibrosis

Rhinosporidiosis ♦♦ Rhinosporidium seeberi may affect conjunctiva and nasal mucosae ♦♦ Rarely seen in the USA but it is common in India and other developing countries

Clinical ♦♦ Coarse, fleshy papillary lesions ♦♦ Numerous endosporulating and encapsulated organisms are seen in the lesion (Fig. 25.20) ♦♦ Recurrence is common after removal ♦♦ Large lesions may lead to scleral perforation

Sarcoidosis

Fig. 25.20. (A) and (B) Rhinosporidiosis of eyelid.

♦♦ Sarcoidosis may affect multiple structures in the eye including retina and optic nerve ♦♦ Conjunctival biopsies are sometimes obtained for diagnosis (Fig. 25.21) ♦♦ Approximately one-fifth of blind conjunctival biopsies show the classical sarcoid granulomas ♦♦ As in other sites, an infectious etiology should be ruled out

Fig. 25.21. Sarcoid granulomas in conjunctival mucosa. (A) Prominent lymphoid aggregates adjacent to cluster of noncaseating granulomas. (B) Coalescent noncaseating granulomas with multinucleated giant cells.

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TUMORS AND MASS LESIONS OF THE CONJUNCTIVA Conjunctival Papillomas Clinical ♦♦ ♦♦ ♦♦ ♦♦

Multiple papillary fronds on conjunctival surface Multiple lesions may occur in children Recurrence is common May be associated with human papillomavirus types 16 and 18

Microscopic ♦♦ Papillomatous processes of variable complexity ♦♦ Papillae are covered with conjunctival epithelium with a variable number of goblet cells (Fig. 25.22) ♦♦ Delicate fibrovascular cores may contain inflammatory cells

Conjunctival Intraepithelial Carcinoma (Squamous Cell Carcinoma In Situ) Clinical ♦♦ Plaque or slightly elevated lesions ♦♦ White or a pale pink color

Microscopic ♦♦ Thickened conjunctival epithelium ♦♦ Epithelial cell atypia with loss of polarity, nuclear hyperchromatism and increased number of mitoses (Fig. 25.23A) ♦♦ Keratinization may be observed in lesions with a white color ♦♦ Basement membrane is intact ♦♦ Marked inflammatory cell infiltration in superficial conjunctival stroma may be present

Invasive Squamous Cell Carcinoma ♦♦ Is observed less often than conjunctival intraepithelial neoplasia ♦♦ Generally invades locally (Figs. 25.23B, C) ♦♦ Early invasive lesions are clinically similar to noninvasive carcinoma ♦♦ Invasion of sclera and orbital soft tissues may occur if not treated ♦♦ Preauricular and submandibular lymph nodes may contain metastatic foci ♦♦ See TNM Classification section

Microscopic ♦♦ Similar features of squamous cell carcinomas of the skin

Melanotic Lesions of the Conjunctiva Congenital and Acquired Melanosis Congenital Melanosis Oculi ♦♦ Diffuse increased number of melanocytes in conjunctival substantia propria, episcleral and scleral tissue

Clinical

Fig.  25.22. (A) Conjunctival papilloma. (B) The presence of goblet cells in the nonkeratinized epithelium differentiate this lesion from squamous papillomas.

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♦♦ Broad patches of brown to light blue pigmentation ♦♦ Ota nevus −− Heavily pigmented melanocytes with diffuse infiltration of (a) Conjunctiva (b) Sclera (c) Episcleral soft tissues (d) Uvea (e) Eyelids (f) Facial skin

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♦♦ Diffuse pigmentation of conjunctiva that moves easily and is not adherent to sclera ♦♦ Variable degrees of melanocytic atypia ♦♦ Lesion is analogous to lentigo maligna of the skin ♦♦ Approximately 20% become malignant ♦♦ Enlarges slowly over a period of years

Secondary Acquired Melanosis Oculi ♦♦ Diffuse conjunctival pigmentation secondary to −− Radiation −− Pregnancy −− Addison disease −− Chemical and drug induced −− Chronic conjunctival lesions −− Trachoma −− Vernal conjunctivitis −− Keratomalacia

Nevi ♦♦ Common conjunctival lesions ♦♦ Types −− Junctional −− Compound −− Stromal of subepithelial, analogous to dermal nevi of the skin ♦♦ Architectural and cytological features similar to cutaneous nevi ♦♦ Often associated with numerous small conjunctival inclusion cysts (Fig. 25.24) ♦♦ Large number of cysts and lymphocytic infiltration may obscure nevus cell component ♦♦ Junctional component may occur in the wall of the inclusion cysts

Malignant Melanoma ♦♦ May arise from −− Preexisting nevi −− Primary acquired melanosis oculi −− Direct extension of intraocular melanoma −− De novo

Fig. 25.23. (A) High grade dysplasia in conjunctival epithelium. Extensive elastotic degeneration in underlying substantia propria. (B) and (C) Invasive keratinizing squamous cell carcinoma involving ciliary body and choroid. Primary tumor developed in the conjunctiva (not shown in picture).

Primary Acquired Melanosis Oculi ♦♦ Minimal to marked junctional melanocytic proliferation in basal layer of conjunctival epithelium

Fig.  25.24. Compound nevus of conjunctiva with numerous small conjunctival inclusion cysts.

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♦♦ Most frequently located in the limbal or paralimbal region ♦♦ It is usually locally invasive ♦♦ Clinically less aggressive than melanomas of the eyelid skin ♦♦ See TNM Classification section ♦♦ Microscopically, similar to malignant melanomas of the skin (Fig. 25.25)

Lymphoid Lesions ♦♦ Conjunctival lymphoid lesions include the entire spectrum, from benign lymphoid follicular hyperplasia to malignant lymphoma ♦♦ Lymphomas may be primary in the conjunctiva, direct extension from an orbital lymphoma or metastatic from a systemic lymphoma ♦♦ Clinically, “Salmon pink” patch in conjunctival mucosa ♦♦ Microscopically, similar to malignant lymphomas elsewhere ♦♦ Immunophenotyping is necessary for final classification of tumor type

Fig. 25.25. Malignant melanoma involving conjunctival stroma. Tumor developed in the conjunctival epithelium (main tumor mass not shown). ♦♦ If biopsy is not very small, part of the sample should be saved for flow cytometry

TUMORS OF THE EYE Malignant Melanoma Clinical ♦♦ Malignant melanocytic tumors of the uvea are the most frequent intraocular tumors in adults ♦♦ Malignant melanomas of the uvea may occur at any age but they are most frequent in older adults ♦♦ Tumors arising in the choroid are more frequent than those originating in the ciliary body or iris ♦♦ Iris tumors are diagnosed earlier and tend to be smaller ♦♦ Choroidal melanomas usually are identified after they produce significant visual disturbances because of retinal detachment or because the mass reaches the visual axis

Macroscopic ♦♦ Their color vary from light tan to heavily pigmented lesions ♦♦ Iris melanomas are usually small elevated masses ♦♦ Choroidal melanomas tend to be large nodules and are often associated with detachment of the retina and accumulation of serous fluid in the subretinal space ♦♦ Mushroom-shaped lesions are frequent (Fig. 25.26) ♦♦ Ciliary body tumors usually extend anteriorly and infiltrate the root of the iris. They may be seen in the angle through the transparent cornea (Fig. 25.27)

Microscopic ♦♦ There are three main cytological variants ♦♦ Spindle cell melanomas, with elongated cells, with moderately nuclear pleomorphism and distinct nucleoli

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♦♦ Epithelioid melanomas made up of large cells, with vesicular nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm ♦♦ Mixed cell melanomas contain a variable amount of both spindle and epithelioid cell components (Fig. 25.28) ♦♦ The degree of pigmentation in tumor cells is variable. In some lesion, the pigment is present mainly in numerous melanophages. Amelanotic lesions do occur ♦♦ Immunohistochemical features of the tumor cells is similar to cutaneous malignant melanomas ♦♦ The vascularity of the tumor may be prominent ♦♦ Necrosis may be present but it usually not extensive ♦♦ Some tumors show massive necrosis and hemorrhage at the time of the initial presentation

Tumor Extension ♦♦ Choroidal melanomas −− Optic nerve extensions may occur but they are less frequent than in retinoblastoma −− The tumor may invade scleral channels and extend to the orbit along perivascular spaces and nerves (Fig. 25.29) −− Anterior extension and rupture through the sclera or cornea is rare (Fig. 25.30) ♦♦ Ciliary body melanomas −− Usually grow anteriorly to involve the iris root, the angle of the anterior chamber, and the trabecular meshwork −− The tumor may also invade scleral channels ♦♦ Distant metastases usually occur in the liver, lung, bone, and skin

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♦♦ Morphological features with prognostic implications that should appear in the surgical pathology report −− Tumor size, large tumors have a poorer outcome −− Cell type: Epithelioid melanomas are associated with a lower survival rate than mixed and spindle cell tumors −− Location: Iris tumors have a better prognosis since they are diagnosed and treated earlier −− Extrascleral extension −− Necrosis −− Other features, such as neovascularization, lymphocytic infiltration, degree of pigmentation, deposition of reticulin fibers, and others, may be mentioned in the report but are not known to affect the patient outcome −− Classification (T categories) for ciliary body and chordoid uveal melanoma is based on thickness and diameter (see Table 25.6, listed with TNM Classifications)

Retinoblastoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Fig.  25.26. (A) Malignant melanoma of choroid extending into subretinal space through a defect of Bruch membrane. The mushrooming head of the tumor detaches the retina. (B) Malignant melanoma of choroid.

The most common intraocular tumor in children Most tumors are probably congenital The tumor may be sporadic or familial The retinoblastoma gene (Rb) has been identified in chromosome 13q14 ♦♦ Retinoblastomas may be bilateral, especially in familial cases ♦♦ “Trilateral” retinoblastomas: bilateral retinoblastomas and a morphologically identical pineoblastoma may occur ♦♦ A large number of intraocular diseases may mimic retino­ blastoma −− Retinal detachment −− Coat disease −− Glial tumors of the retina

Fig. 25.27. (A) Malignant melanoma of ciliary body with invasion of iris and angle of anterior chamber. (B) Malignant melanoma of ciliary body.

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Fig. 25.28. Malignant melanoma. (A) Spindle cell melanoma. (B) and (C) Epithelioid melanoma. (D) Heavily pigmented tumors require bleaching to evaluate cytological details.

−− Persistent hyperplastic primary vitreous −− Retrolental fibroplasia ♦♦ Clinical presentation −− Leukocoria (white papillary reflex) is the most frequent sign at presentation −− Strabismus may occur −− Proptosis due to orbital extension of the tumor is rare

Macroscopic ♦♦ Large masses partially or completely filling the vitreous cavity or subretinal space ♦♦ Necrosis and calcifications may be present ♦♦ Extensive retinal detachment ♦♦ The lens may be displaced forward

Microscopic ♦♦ Sheets and cords of small round cells with hyperchromatic nuclei and scanty cytoplasm

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♦♦ Small Flexner–Wintersteiner rosettes (with a central lumen) and Homer Wright rosettes (with a fibrillary center) are often encountered (Fig. 25.31) ♦♦ Fleurettes, small groups of abortive photoreceptors mimicking the petals of a flower, may occur in some tumors ♦♦ The tumor cells massively expand the retina and extend into the subretinal space (exophytic tumors), the vitreous cavity (endophytic tumors), or both ♦♦ Mitoses are numerous ♦♦ Necrosis is usually extensive with the viable component of the tumor remaining only around blood vessels ♦♦ A basophilic granular material may be deposited on the outer surface of blood vessels. They are debris from necrotic tumor cells ♦♦ Granular calcification tends to be prominent in areas of necrosis ♦♦ Extension into optic nerve, choroid, or beyond the vitreous base into the posterior or anterior chamber may occur

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Fig. 25.29. Malignant melanoma of choroid extending to orbital soft tissues through scleral channel. Fig.  25.31. Retinoblastoma. (A) Sheets of retinoblasts with numerous Flexner–Wintersteiner and Homer Wright rosettes. (B) Large areas of necrosis and calcification. ♦♦ Immunohistochemistry and electron microscopic are usually not needed for diagnosis ♦♦ See TNM Classification section

Other Tumors of the Eye Malignant Lymphoma

Fig. 25.30. Massive epithelioid malignant melanoma protruding onto the anterior surface of the eye through a corneal defect. (These findings have prognostic and therapeutic implications and should always be mentioned in the pathology report). (Fig. 25.32) ♦♦ Tumor cells in the anterior chamber may mimic a purulent exudate (pseudohypopyon)

♦♦ Intraocular lymphomas do not differ morphologically from their systemic counterparts (Fig. 25.33) ♦♦ Lymphomas involving the vitreous body are usually associated with a central nervous system lymphoma while lymphomas of the uvea are generally seen in patients with systemic lymphomas

Fuchs Adenoma ♦♦ Benign epithelial tumor of the ciliary body ♦♦ It rarely becomes clinically evident

Microscopic ♦♦ Interlacing cords of monomorphic cells with features similar to the nonpigment layer of the ciliary epithelium

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Fig. 25.33. (A) Vitreous opacification in a patient with intrao­ cular malignant lymphoma. (B) Lymphoma cells in vitrectomy specimen. ♦♦ A PAS positive material is usually associated with the cellular proliferation

Medulloepithelioma Leiomyomas Leiomyomas may occur in the ciliary body or iris (Fig. 25.34)

Vascular Tumors ♦♦ Hemangioma ♦♦ Hemangioblastoma

Fig. 25.32. Retinoblastoma. (A) Exophytic component of tumor extends to Bruch membrane, without involving choroid. (B) Massive tumor infiltration in choroid. (C) Tumor extension into optic nerve beyond the lamina cribrosa.

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Glial Tumors of the Retina (Astrocytoma) Metastatic Tumors ♦♦ Intraocular metastatic tumors usually involve the choroid ♦♦ Their distribution is similar to metastases to the central nervous system

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♦♦ Most frequent tumors that metastasize to the eye are breast (in females), lung (in males), gastrointestinal

tract, the genitourinary tract, and cutaneous malignant melanomas ♦♦ May mimic primary malignant melanomas of the eye

EYELIDS Anatomical Components ♦♦ Skin with delicate hair follicles and small skin adnexae ♦♦ Skeletal muscle fibers of the orbicularis oculi and tendinous fibers of levator ♦♦ Tarsus, a dense lamina of fibrous tissue that invests the meibomian glands, long branches sebaceous glands that are more numerous in the upper than the lower eyelids ♦♦ Palpebral conjunctiva ♦♦ Structures present in the eyelid margin −− Large hair follicles, the cilia or eyelashes −− Glands of Zeis, small sebaceous glands attached to the follicles of the cilia −− Glands of Moll, small apocrine sweat glands ♦♦ Other glands in the eyelids −− Glands of Wolfring: small accessory lacrimal glands that empty their secretion on the palpebral conjunctiva, just above the tarsus −− Glands of Krause: small accessory lacrimal glands in the fornix of the conjunctiva

Inflammations Chalazion Clinical ♦♦ Lipogranulomatous inflammation resulting from the release of lipids by the meibomian glands or the glands of Zeis ♦♦ Firm painless nodules in the eyelid ♦♦ Its rupture may lead to a rapidly enlarging pyogenic granuloma ♦♦ Sebaceous carcinoma may mimic chalazion clinically ♦♦ Recurrent chalazia should be examined histologically

Microscopic ♦♦ Early stages: small abscess centered around a meibomian gland or a gland of Zeis ♦♦ Granulomatous inflammation with multinucleated giant cell reaction and empty vacuoles of released lipid from the sebaceous glands (Fig. 25.35)

Hordeolum External Hordeolum or Stye Definition ♦♦ Acute suppurative inflammation of the superficial glands and hair follicles in the eyelids Fig. 25.34. (A) Leiomyoma of iris. Clinically, the lesion appears heavily pigmented. (B) Tumor stained for smooth musclespecific actin, and (C) desmin.

Clinical ♦♦ Superficial elevation of skin of eyelid with signs of acute inflammation

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Fig.  25.35. Chalazion. Lipogranulomatous inflammation of eyelid glands. Clinically recurrent chalazia should be examined histopathologically to rule out malignant processes such as sebaceous carcinoma. ♦♦ Usually is located at the eyelid margin or adjacent to it

Microscopic ♦♦ Polymorphonuclear cell infiltration involving a hair follicle and adjacent soft tissues and adnexal glands

Internal Hordeolum ♦♦ Acute suppurative inflammation of meibomian gland ♦♦ Diffuse, tender erythematous lesion affecting most of the eyelid

Cystic Lesions of the Eyelid Epidermoid Cysts Dermoid Cysts Hydrocystomas (“Water Cysts”)

Fig. 25.36. (A) Eccrine hydrocystoma of the eyelid. (B) Lining of eccrine hydrocystoma with double layer of cuboidal cells.

♦♦ Develop after occlusion of eccrine or apocrine sweat glands ♦♦ Hydrocystomas may be solitary or multiple

Apocrine Hydrocystoma ♦♦ Derived from the gland of Moll ♦♦ Usually occur in adults, near the eyelid margin (Fig. 25.36) ♦♦ The surface may have a vague bluish discoloration

Eccrine Hydrocystoma ♦♦ Similar appearance to apocrine hydrocystomas ♦♦ Microscopically, two layers of cuboidal cells, similar to those observed in the secretory portion of the gland of origin (Fig. 25.37)

Amyloidosis ♦♦ Primary amyloidosis −− In systemic amyloidosis, abnormal deposits may occur around blood vessels in the eyelids and conjunctiva but are of lesser clinical importance than the retinal, uveal, and orbital lesions

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Fig.  25.37. Apocrine hydrocystoma arising from the gland of Moll (apocrine sweat gland).

Eye and Ocular Adnexae

−− Localized nodular amyloidosis (a) Nodules of red-brown color and variable size may develop in the eyelids and conjunctiva (b) No other ocular structures are affected ♦♦ Secondary amyloidosis −− Multiple small nodules of amyloid deposition may occur in the eyelid of patients with chronic inflammatory disease such as osteomyelitis, rheumatoid arthritis, leprosy, and multiple myeloma −− Secondary localized amyloidosis may develop in patients with chronic inflammatory lesions in the conjunctiva and eyelid

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♦♦ Xanthelasma develops in patients with hypercholestero­ lemia but it is more common in persons with normal serum cholesterol

Microscopic ♦♦ Pale eosinophilic and amorphous deposits in the connective tissue and in blood vessel walls ♦♦ Deposits are positive when stained with Congo red, show fluorescence with thioflavin-T and display birefringence when examined with polarized light

Microscopic ♦♦ Finger-like projections of the dermis covered by normal epidermis (Fig. 25.38) ♦♦ Trauma may led to epidermal erosions and inflammatory cell infiltration

Tumors and Other Mass Lesions of the Eyelid ♦♦ Benign and malignant tumors of the eyelid skin do not differ from those occurring elsewhere in the skin and soft tissues (Figs. 25.39–25.41) (see Chapters 18 and 19)

Squamous Papilloma ♦♦ Lesions may be sessile or pedunculated ♦♦ They may occur anywhere in the skin of the eyelids

Xanthelasma ♦♦ Middle aged and elderly patients are usually affected

Fig. 25.38. Squamous papilloma of the eyelid skin.

Fig. 25.39. Dermal blue nevus in eyelid margin. Note the dilated glands of Moll. There is also atrophy of the meibomian gland and dilatation of its main duct.

Fig.  25.40. Plexiform neurofibroma of eyelid extending into orbit in a patient with neurofibromatosis I.

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Fig.  25.41. Orbital cavernous hemangioma. The fibrous septa separating the vessels may contain smooth muscle.

Fig. 25.42. Xanthelasma. Clusters of foamy, lipid-laden histiocytes that tend to aggregate around blood vessels.

♦♦ See Chapter 18

♦♦ It is more frequent in the upper eyelid. Occasionally they develop in the caruncle and in the eyebrow ♦♦ Typically, it affects elderly patients ♦♦ It is more frequent in women ♦♦ Treatments −− Early detection and treatment improves prognosis −− Wide local excision with clear margins, whenever feasible, is the treatment of choice ♦♦ Particular attention should be given to the presence or absence of pagetoid spread ♦♦ Orbital exenteration is often performed when there is extension into the orbit ♦♦ Radiation is reserved for advanced cases

Squamous Cell Carcinoma

Microscopic

Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Irregular elevated soft, yellow plaques Both eyelids may be affected The inner aspects of the eyelids are usually involved Bilateral and multiple lesions are not uncommon They may recur after excision

Microscopic ♦♦ Multiple clusters of xanthoma cells in the dermis (Fig. 25.42)

Basal Cell Carcinoma

♦♦ See Chapter 18

Sebaceous Carcinoma Clinical ♦♦ The large majority of sebaceous carcinomas develop in the eyelids ♦♦ In the eyelids, they are second in frequency to basal cell carcinomas ♦♦ Most tumors originate from the meibomian glands ♦♦ Clinically, sebaceous carcinomas may resemble chalazia and other eyelid lesions

♦♦ Lobular masses of neoplastic cells (Fig. 25.43) ♦♦ Cellular anaplasia may be extreme ♦♦ Cytoplasmic lipid vacuoles are observed in well and moderately differentiated tumors ♦♦ Mitoses are frequent ♦♦ Pagetoid spread along the epidermis and conjunctival epithelium is common and can be extensive, even in small tumors ♦♦ Foci of necrosis, sometimes with a comedo pattern, are often observed ♦♦ Direct extension into orbital soft tissues and metastases to lymph nodes, lung, liver, bone, and brain may occur ♦♦ See TNM Classification section

LESIONS OF THE LACRIMAL DRAINAGE SYSTEM AND LACRIMAL GLANDS ♦♦ The lacrimal fluid drains from the inner canthus into the nasal cavity through the canaliculi, lacrimal sac, and nasolacrimal duct ♦♦ Their epithelial lining varies

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−− Canaliculi, stratified squamous epithelium without keratinization −− Lacrimal sac, stratified squamous epithelium, numerous goblet cells and islands of respiratory epithelium

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Fig. 25.43. Sebaceous carcinoma arising in eyelid margin. (A) and (B) Tumor involves both skin and conjunctival surfaces. (C) Pagetoid spread of tumor cells into conjunctival epithelium. (D) Marked cytoplasmic vacuolation in tumor cells.

−− Nasolacrimal duct, respiratory epithelium similar to the one in the nasal cavity

Dacryocystitis ♦♦ Inflammation of the lacrimal sac ♦♦ May be acute or chronic ♦♦ Specimens obtained at dacryocystorhinostomy usually show a variable chronic lymphoplasmacytic infiltration

Dacryolithiasis ♦♦ Concretions with a vague laminated pattern and made up of proteinaceous material ♦♦ They may contain fungal structures ♦♦ Sulfur granules of Actinomyces sp. may also occlude the lacrimal drainage

Tumors of the Lacrimal Sac ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Squamous papilloma Inverted papilloma Oncocytoma (Fig. 25.44) Squamous cell carcinoma Adenocarcinoma Adenoid cystic carcinoma Malignant melanoma

Tumors of the Lacrimal Glands ♦♦ The main lacrimal gland is located in the superior temporal aspect of the orbit in a shallow depression of the frontal bone

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♦♦ The accessory lacrimal glands of Krause drain into the conjunctival sac at the level of the fornix ♦♦ The accessory lacrimal glands of Wolfring are in the posterior aspect of the eyelid and their ducts open on the palpebral conjunctiva, just above the tarsal plate ♦♦ All lacrimal glands are considered to be minor salivary glands ♦♦ They contain serous acini exclusively ♦♦ Tumors of the lacrimal glands are morphologically identical to tumors of the salivary glands (see Chapter 23) ♦♦ Tumors of the lacrimal glands show less variation than those in the salivary glands −− Pleomorphic adenoma is the most frequent benign tumor of the lacrimal gland −− Warthin tumor is extremely rare −− Oncocytoma ♦♦ Malignant tumors in the lacrimal gland are more frequent than in the major salivary glands −− Adenoid cystic carcinoma is the second most common lacrimal gland tumor alter pleomorphic adenoma −− Adenocarcinoma −− Carcinoma ex pleomorphic adenoma −− Mucoepidermoid carcinomas and acinic cell carcinomas are rare in the lacrimal glands ♦♦ Orbital malignancies often involve the lacrimal gland ♦♦ See TNM Classification section

Fig. 25.44. (A) and (B) Oncocytoma of the caruncle. This tumor may also occur in the lacrimal gland, lacrimal sac, and rarely in the eyelids.

ORBIT Tumors and Mass Lesions in the Orbit Inflammatory Pseudotumor of the Orbit Clinical ♦♦ Relatively common orbital disease ♦♦ Defined as any nonneoplastic mass occupying lesion with inflammatory features ♦♦ Generally affects adults but it can occur in children and the elderly ♦♦ Abrupt onset with diffuse or localized orbital pain ♦♦ Double vision (diplopia) ♦♦ Restriction of eye movements ♦♦ Swelling and reddening of the eye ♦♦ May be chronic or recurrent

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Diagnosis ♦♦ Usually not biopsied unless it becomes recurrent and to rule out other neoplastic and nonneoplastic known diseases ♦♦ Pathologically, the diagnosis is often made only after other known entities have been excluded (see “Differential Diagnosis”)

Microscopic ♦♦ Multiple variants: granulomatous, sclerosing, vasculitic, eosinophilic ♦♦ Fibrovascular tissue proliferation with an inflammatory infiltrate that includes polymorphonuclear leukocytes, lymphocytes, plasma cells, eosinophils, histiocytes, and sometimes multinucleated giant cells (Fig. 25.45) ♦♦ Lymphoid follicles with or without germinal centers

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Fig. 25.45. Idiopathic orbital inflammation. (A) Cross-section of posterior aspect of orbit. The lesion surrounds the extraocular muscle above the optic nerve. (B) The orbital fat contains islands of chronic inflammatory cells and variable degrees of fibrosis. (C) The inflammatory infiltrate may contain numerous eosinophils. (D) Prominent lymphocytic and plasma cell infiltration.

♦♦ The inflammatory process involves the soft tissue of the orbit as well as extraocular muscles and lacrimal gland

Differential diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Malignant lymphoma Graves disease Dacryoadenitis Sjögren syndrome Orbital cellulitis Sarcoidosis Wegener granulomatosis Orbital amyloidosis

Treatment ♦♦ Steroid therapy is usually given. The inflammation often recurs when treatment is discontinued ♦♦ Sclerosing variant responds poorly to steroids

♦♦ Radiation therapy and chemotherapy may be added for recurrent pseudotumors

Graves Disease (Thyroid Ophthalmopathy) Clinical ♦♦ Most common cause of unilateral or bilateral xophthalmos ♦♦ Visual loss due to optic nerve compression by swollen extraocular muscles ♦♦ Exposure keratopathy ♦♦ Coexist with signs of thyroid gland dysfunction ♦♦ Thyroid function test may be low, high, or normal ♦♦ Diagnosis is apparent in CT or MRI scans

Macroscopic ♦♦ Enlargement of extraocular muscles

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Microscopic ♦♦ Chronic lymphoplasmacytic infiltration in extraocular muscles ♦♦ Tendinous tissue and soft tissues of the orbit are spared ♦♦ Biopsy is rarely performed for diagnosis (Table 25.3)

Rhabdomyosarcoma of the Orbit Clinical ♦♦ Rhabdomyosarcoma is the most frequent malignant tumor of the orbit in children ♦♦ It is always in the differential diagnosis of pediatric orbital lesions ♦♦ The tumor affects boys more often than girls and usually occurs in the first decade of life ♦♦ Patients often present with a rapidly developing proptosis ♦♦ Prompt diagnosis and treatment are associated with improved survival

♦♦ Spindle cells and strap-like cells may be the predominant component ♦♦ Large rhabdomyoblasts with abundant eosinophilic cytoplasms are sometimes observed ♦♦ Cross-striations may be difficult to identified ♦♦ Some tumors have an abundant myxoid matrix ♦♦ Immunohistochemical staining for muscle markers and rarely electron microscopy are needed to confirm the diagnosis ♦♦ The alveolar type has the worst prognosis ♦♦ Molecular confirmation is important for treatment planning and prognosis

Glioma of the Optic Nerve (Pilocytic Astrocytoma of the Optic Nerve) Clinical

♦♦ They usually involve the superior orbit ♦♦ The tumor is usually soft, with a yellow or red-tan color

♦♦ It most often affects children before the age of ten ♦♦ The initial manifestations are usually strabismus, unilateral proptosis, and visual loss ♦♦ The patient may have signs of neurofibromatosis type I ♦♦ The tumor is readily diagnosed with CT or MRI scans

Microscopic

Macroscopic

Macroscopic

♦♦ Most pediatric orbital rhabdomyosarcomas are of the embryonal type

Table 25.3. Orbital Tumors Benign Cartilaginous and osseous tumors Dermoid cysts Fibrous dysplasia Granular cell tumor Hemangiomas Leiomyoma Lipoma Lymphangiomas Neurofibroma Reactive lymphoid hyperplasias Schwannoma Solitary fibrous tumor

Rare benign tumors Aneurysmal bone cysts Giant cell reparative granuloma Giant cell tumor Eosinophilic granuloma

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Malignant Hemangiopericytoma Langerhans cell histiocytosis Lymphoma Malignant fibrous histiocytoma Osteosarcoma Rhabdomyosarcoma Other soft tissue sarcomas Teratomas

Rare malignant tumors Alveolar soft part sarcoma Germ cell tumors Paraganglioma, primary Orbital carcinoid Primary orbital Melanoma Malignant rhabdoid tumor Primitive neuroectodermal tumor

♦♦ Resection is often accomplished without eye enucleation ♦♦ The lesion appears as a large fusiform enlargement of the optic nerve ♦♦ Tumor is usually contained within the optic nerve sheath ♦♦ The resection margin (the intracranial end, in tumors removed without eye enucleation) should be sampled for histological examination

Microscopic ♦♦ Elongated, “piloid” astrocytes invade the optic nerve along its fibers ♦♦ The cells are GFAP positive (Fig. 25.46) ♦♦ Rosenthal fibers, thick bright eosinophilic fibers, may be observed ♦♦ The tumor does not extend beyond the optic nerve sheath but it often invades the subarachnoid space (“subarachnoid gliomatosis”) ♦♦ The optic nerve meninges may show a remarkable hyperplasia of the meningothelial cells, which may be misinterpreted as “optic nerve meningioma” in superficial biopsies of the nerve

Meningioma of the Optic Nerve Clinical ♦♦ The tumor may affect patients of all ages ♦♦ Patients usually complain of visual loss ♦♦ Clinical examination reveals optic nerve atrophy and abnormal vascular patterns in the optic disk ♦♦ Lesions developing in children tend to behave more aggressively ♦♦ Primary orbital meningiomas and meningiomas extending into the orbit from the intracranial compartment may also occur

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Table 25.4. Most Frequent Metastatic Tumors to the Orbit Breast Lung Prostate Gastrointestinal tract Neuroblastoma Ewing sarcoma

Table 25.5. Direct Tumor Extension from Adjacent Structures to the Orbit Tumors of the skin of eyelids Tumors of the nasal cavity and paranasal sinuses Tumors of the eye Tumors of the lacrimal gland Tumors of the base of the skull Tumors of the meninges

♦♦ Atypical cells may occur but have no prognostic implications unless they are associated with other signs of malignancy

Lymphoid Tumors Clinical Fig.  25.46. Glioma of the optic nerve. (A) Hematoxylin and eosin. (B) Tumor stained for glial fibrillary acidic protein.

Microscopic ♦♦ Sheaths or nodules of proliferating cells with meningothelial, fibroblastic, or mixed patterns ♦♦ Cellular whorls and psammoma bodies may be numerous ♦♦ The vascular component of the tumor is sometimes very prominent and occasionally mimics a angiomatous lesion ♦♦ Mitoses are rare except in malignant tumors with aggressive biological behavior

♦♦ Benign and malignant lymphoid tumors of the orbit are relatively common ♦♦ Primary orbital lymphomas usually develop in older adults ♦♦ Clinically, they are usually become manifested with proptosis ♦♦ They are rarely associated with pain ♦♦ A salmon pink conjunctival mass may be the only manifestation of a large orbital tumor ♦♦ Most lymphomas involve the superior aspect of the orbit and the lacrimal gland is often involved ♦♦ Their diagnosis and treatment does not differ from lymphomas involving other organ systems (Tables 25.4 and 25.5) ♦♦ See TNM Classification section

TNM Classification of Carcinoma of the Conjunctiva (2010 Revision) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ −− T1: Tumor 5 mm or less in greatest dimension*

−− T2: Tumor more than 5 mm in greatest dimension, without invasion of adjacent structures −− T3: Tumor invades adjacent structures, excluding the orbit −− T4: Tumor invades the orbit with or without further extension

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−− T4a: Tumor invades orbital soft tissues, without bone invasion −− T4b: Tumor invades bone −− T4c: Tumor invades adjacent paranasal sinuses −− T4d: Tumor invades brain ♦♦ Regional Lymph Nodes (N) NX: Regional lymph nodes cannot be assessed

−− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis

*Tumors occur most commonly in the bulbar limbal conjunctiva **Adjacent structures include the cornea (3, 6, 9, or 12 o’clock hours), intraocular compartments, forniceal conjunctiva (lower and/or upper), palpebral conjunctiva (lower and/or upper), tarsal conjunctiva (lower and/or upper), lacrimal punctum and canaliculi (lower and/or upper), plica, caruncle, posterior eyelid lamella, anterior eyelid lamella, and/or eyelid margin (lower and/or upper)

TNM Classification of Malignant Melanoma of the Conjunctiva (2010 Revision) ♦♦ Primary Tumor (pT) −− pTX: Primary tumor cannot be assessed −− pT0: No evidence of primary tumor −− pT(is): Melanoma of the conjunctiva confined to the epithelium* −− pT1a: Melanoma of the bulbar conjunctiva not more than 0.5 mm in thickness with invasion of the substantia propria −− pT1b: Melanoma of the bulbar conjunctiva more than 0.5 mm but not more than 1.5 mm in thickness with invasion of the substantia propria −− pT2a: Melanoma of the palpebral, forniceal, or curuncular conjunctiva not more than 0.5 mm in thickness with invasion of the substantia propria

−− pT2b: Melanoma more than 0.5 mm but not greater than 1.5 mm in thickness with invasion of the substantia porpria −− pT3: Melanoma invades the eye, eyelid, nasolacrimal system, orbit, or sinuses −− pT4: Melanoma invades the central nervous system ♦♦ Regional Lymph Nodes (pN) −− pNX: Regional lymph nodes cannot be assessed −− pN0: No regional lymph node metastasis −− pNX: Regional lymph node metastasis present ♦♦ Distant Metastasis (pM) −− pM0: No distant metastasis −− pM1: Distant metastasis

*pT(is) melanoma in situ (includes the term primary acquired melanosis) with atypia replacing greater than 75% of the normal epithelial thickness, with cytologic features of epithelioid cells, including abundant cytoplasm, vesicular nucleoli, and/or presence of intraepithelial nests of atypical cells

TNM Classification of Malignant Melanoma of the Uvea (2010 Revision) ♦♦ Primary Tumor (T)* All Uveal Melanomas −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor Iris** −− T1: Tumor limited to the iris −− T1a: Tumor limited to the iris not more than 3 clock hours in size −− T1b: Tumor limited to the iris more than 3 clock hours in size

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−− T1c: Tumor limited to the iris with secondary glaucoma −− T2: Tumor confluent with or extending into the ciliary body and/or choroid −− T2a: Tumor confluent with or extending into ciliary body and/or choroids with secondary glaucoma −− T3: Tumor confluent with or extending into the ciliary body and/or choroid with scleral extension −− T3a: Tumor confluent with or extending into the ciliary body and/or choroid with scleral extension and secondary glaucoma

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−− T4: Tumor with extrascleral extension −− T4a: Tumor with extrascleral extension less than or equal to 5 mm in diameter −− T4a: Tumor with extrascleral extension more than 5 mm in diameter Ciliary Body and Choroid −− T1: Tumor size category 1 −− T1a: Tumor size category 1 without ciliary body involvement and extraocular extension −− T1b: Tumor size category 1 with ciliary body involvement −− T1c: Tumor size category 1 without ciliary body involvement but with extraocular extension less than or equal to 5 mm in diameter −− T1d: Tumor size category 1 with ciliary body involvement and extraocular extension less than or equal to 5 mm in diameter −− T2: Tumor size category 2 −− T2a: Tumor size category 2 without ciliary body involvement and extraocular extension −− T2b: Tumor size category 2 with ciliary body involvement −− T2c: Tumor size category 2 without ciliary body involvement but with extraocular extension less than or equal to 5 mm in diameter −− T2d: Tumor size category 2 with ciliary body involvement and extraocular extension less than or equal to 5 mm in diameter −− T3: Tumor size category 3 −− T3a: Tumor size category 3 without ciliary body involvement and extraocular extension −− T3b: Tumor size category 3 with ciliary body involvement

−− T3c: Tumor size category 3 without ciliary body involvement but with extraocular extension less than or equal to 5 mm in diameter −− T3d: Tumor size category 3 with ciliary body involvement and extraocular extension less than or equal to 5 mm in diameter −− T4: Tumor size category 4 −− T4a: Tumor size category 4 without ciliary body involvement and extraocular extension −− T4b: Tumor size category 4 with ciliary body involvement −− T4c: Tumor size category 4 without ciliary body involvement but with extraocular extension less than or equal to 5 mm in diameter −− T4d: Tumor size category 4 with ciliary body involvement and extraocular extension less than or equal to 5 mm in diameter −− T4e: Any tumor size category with extraocular extension more than 5 mm in diameter ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis −− M1a: Largest diameter of the largest metastasis 3 cm or less −− M1b: Largest diameter of the largest metastasis 3.1-8.0 cm −− M1c: Largest diameter of the largest metastasis 8 cm or more

*When histopathologic measurements are recorded after fixation, tumor diameter and thickness may be underestimated because of tissue shrinkage **Iris melanomas originate from, and are predominantly located in, this region of the uvea. If less than half of the tumor volume is located within the iris, the tumor may have originated in the ciliary body and consideration should be given to classifying it accordingly

Table 25.6 Classification (T categories) for ciliary body and choroid uveal melanoma based on thickness and diameter Thickness (mm)

> 15.0

 

 

 

 

4

4

4

12.1-15.0

 

 

 

3

3

4

4

9.1-12.0

 

3

3

3

3

3

4

6.1-9.0

2

2

2

2

3

3

4

3.1-6.0

1

1

1

2

2

3

4

£ 3.0

1

1

1

1

2

2

4

 

£ 3.0

3.1-6.0

6.1-9.0

9.1-12.0

12.1-15.0

15.1-18.0

> 18.0

Largest basal diameter (mm)

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TNM Classification of Retinoblastoma (2010 Revision) ♦♦ Primary Tumor (pT) −− pTX: Primary tumor cannot be assessed −− pT0: No evidence of primary tumor −− pT1: Tumor confined to the eye with no optic nerve or choroidal invasion −− pT2: Tumor with minimal optic nerve and/or choroidal invasion −− pT2a: Tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion −− pT2b: Tumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion −− pT3: Tumor with significant optic nerve and/or choroidal invasion −− pT3a: Tumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion −− pT3b: Tumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion −− pT4: Tumor invades optic nerve to resection line or exhibits extraocular extension elsewhere

−− pT4a: Tumor invades optic nerve to resection line but no extraocular extension identified −− pT4b: Tumor invades optic nerve to resection line and extraocular extension identified ♦♦ Regional Lymph Nodes (N) −− pNX: Regional lymph nodes cannot be assessed −− pN0: No regional lymph node involvement −− pN1: Regional lymph node involvement (preauricular, cervical) −− N2: Distant lymph node involvement ♦♦ Metastasis (M) −− pM0: No metastasis −− pM1: Metastasis to sites other than CNS −− pM1a: Single lesion −− pM1b: Multiple lesions −− pM1c: CNS metastasis −− pM1d: Discrete mass(es) without leptomeningeal and/or CSF involvement −− pM1e: Leptomeningeal and/or CSF involvement

TNM Classification of Carcinoma of the Eyelid (2010 Revision) ♦♦ Primary Tumor (T) −− −− −− −−

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor 5 mm or less in greatest dimension, no invading the tarsal plate or eyelid margin −− T2a: Tumor more than 5 mm, but not more than 10 mm in greatest dimension; or, any tumor that invades the tarsal plate or eyelid margin −− T2b: Tumor more than 10 mm, but not more than 20 mm in greatest dimension; or, involves full thickness eyelid −− T3a: Tumor more than 20 mm in greatest dimension; or, any tumor that invades adjacent ocular or orbital structures; any T with perineural invasion

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−− T4: Tumor is not resectable due to extensive invasion or ocular, orbital, craniofacial structures, or brain ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− cN0: No regional lymph node metastasis, based upon clinical evaluation or imaging −− pN0: No regional lymph node metastasis, based upon lymph node biopsy −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis

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TNM Classification of Carcinoma of the Lacrimal Gland (2010 revision)

♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor 2 cm or less in greatest dimension, with or without extraglandular extension into the orbital soft tissue −− T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension* −− T3: Tumor more than 4 cm in greatest dimension* −− T4: Tumor invades periosteum or orbital bone or adjacent structures −− T4a: Tumor invades periosteum

−− T4b: Tumor invades orbital bone −− T4c: Tumor invades adjacent structures (brain, sinus, pterygoid fossa, temporal fossa) ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: regional lymph node metastasis ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis

*As the maximum size of the lacrimal gland is 2 cm, T2 and greater tumors will usually extend into the orbital soft tissue

TNM Classification of the Tumors of the Orbit (2010 revision) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor 15 mm or less in greatest dimension −− T2: Tumor more than 15 mm in greatest dimension without invasion of globe or bony wall −− T3: Tumor of any size with invasion of orbital tissues and/ or bony wall −− T4: Tumor invasion of globe or periorbital structure, such as eyelids, temporal fossa, nasal cavity and paranasal sinuses, and/or central nervous system

♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis

SUGGESTED READING Apple DJ, Rabb MF. Ocular Pathology: Clinical Applications and Self Assessment, 5th edition. St Louis, CV Mosby, 1998.

Hurst EA, Harbour JW, Cornelius LA. Ocular melanoma: a review and the relationship to cutaneous melanoma. Arch Dermatol 2003;139:1067–1073.

Castillo BV Jr, Kaufman L. Pediatric tumors of the eye and orbit. Pediatr Clin North Am 2003;50:149–172.

Klintworth GK, Garner G (ed). Garner and Klintworth. Pathology of Ocular Disease, 3rd edition. New York, Informa Healthcare, 2008.

Davis JL. Diagnosis of intraocular lymphoma. Ocul Immonol Inflamm 2004;12:7–16.

Lucas DR. Greer Ocular Pathology, 4th edition. Boston, Blackwell Scientific, 1989.

Eagle RC. Eye Pathology. An Atlas and Basic Text. Philadelphia, WB Saunders, 1999.

Margo CD, Macroscopicniklaus HE. Ocular Histopathology. A Guide to Differential Diagnosis. Philadelphia, WB Saunders, 1991.

Harry J, Misson G. Clinical Ophthalmic Pathology: Principles of Diseases of the Eye and Associated Structures. Oxford, Elsevier Science, 2002.

Marigo FA, Finger PT. Anterior segment tumors: current concepts and innovations. Surv Ophthalmol 2003;48:569–593.

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McLean IW, Burnier MN, Zimmerman LE et al. Tumors of the Eye and Ocular Adnexa. Atlas of Tumor Pathology, 3rd Series, Vol 12. Washington, American Registry of Pathology, 1995. Ohtsuka K, Hashimoto M, Suzuki Y. A review of 244 orbital tumors in Japanese patients during a 21-year period: origins and locations. Jpn J Ophthalmol 2005;49:49–55. Poulaki V, Colby K. Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol 2008;23:9–17.

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Sassani JW. Ophthalmic Pathology with Clinical Correlations. Lippincott Williams & Wilkins, 1997. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors. An Atlas and Text. 2nd edition. Philadelphia, Lippincott Williams and Wilkins, 2007. Tsai T, O’Brien JM. Masquerade syndromes: malignancies mimicking inflammation in the eye. Int Ophthalmol Clin 2002;42:115–131. Yanoff M, Sassani JW. Ocular Pathology, 6th edition. Maryland Heights, Mosby Elsevier, 2009.

26 Mediastinum and Thymus Chung-Che (Jeff) Chang, md, phD, Munir Shahjahan, md, and Joseph F. Tomashefski, jr., md

Contents

I. Nonneoplastic Disorders...................26-2 Inflammatory/Infectious..................................26-2 Acute Mediastinitis................................26-2 Granulomatous Mediastinitis (Localized Fibrosing Mediastinitis).....................................26-2 Fibrosing Mediastinitis..........................26-2 Cystic Lesions...................................................26-4 Bronchogenic Cyst.................................26-4 Esophageal Cyst.....................................26-5 Gastroenteric Cyst.................................26-5 Pericardial Cyst (Coelomic Cyst)........26-5 Unilocular Thymic Cyst (Developmental Origin)....................26-6 Multilocular Thymic Cyst (Acquired [Reactive] Process)..........26-6 Nonneoplastic Lesions of Thymus..................26-7 Thymic Dysplasia...................................26-7 Thymic Aplasia.......................................26-7 True Thymic Hyperplasia.....................26-7 Lymphoid Hyperplasia (Thymic Follicular Hyperplasia).....................26-7 Lesions Mimicking Primary Mediastinal Neoplasms....................................................26-8 Substernal Thyroid (Mediastinal Goiter).........................26-8

Mediastinal Parathyroid Lesions..........26-8 Other Conditions..............................................26-9 Pneumomediastinum.............................26-9

II. Neoplasms.........................................26-9 Thymus..............................................................26-9 Histologic Features of Thymus.............26-9 Thymoma..............................................26-10 Thymic Carcinoma (Type C Thymoma by the Previous WHO Classification).......26-13 Thymic Carcinoid (Including Atypical Carcinoid).........................26-15 Thymic Stromal Tumors......................26-16 Neoplasms Not Limited to Thymus..............26-17 Neurogenic Tumors..............................26-17 Paraganglioma.....................................26-18 Germ Cell Tumors...............................26-18 Lymphoproliferative Disorders..........26-20 Mesenchymal Tumors (Other than Nerve Sheath Tumors)...........26-25 Metastatic Tumors...............................26-27

III. TNM Classification of Thymoma......26-28 IV. Suggested Reading...........................26-29

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_26, © Springer Science+Business Media, LLC 2002, 2006, 2011

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NONNEOPLASTIC DISORDERS Inflammatory/Infectious Acute Mediastinitis Clinical ♦♦ Acute mediastinitis is a life-threatening acute infection. Primary acute mediastinitis is rare; nearly all cases are the result of direct inoculation or spread from another compartment. The presenting clinical symptoms vary depending on the site of origin of infection. As mediastinitis evolves, patients experience chest pain, fever, and dysphagia ♦♦ The most common causes of acute mediastinitis are secondary to cardiac surgery, following esophageal perforation, spread from infections of the head and neck, and spread to the mediastinum from other sites such as lungs or meninges −− Cardiac surgery is complicated by mediastinitis ranging from 0.66 to 2.4% of surgical procedures. The infection localizes in the anterior mediastinum −− Esophageal perforation typically involves the posterior mediastinum. Boerhaave syndrome represents spontaneous rupture of the esophagus following bouts of vomiting. The most common cause of esophageal rupture is iatrogenic −− Descending necrotizing mediastinitis is secondary to head and neck infections which track through fascial planes from deep cervical infections originating in the oropharynx. Typically infections are due to mixed aerobic and anaerobic organisms, and locate in the superior or posterior mediastinum −− Direct extension from lung or pleural infections is an infrequent cause of mediastinitis

Macroscopic ♦♦ Acute mediastinitis is characterized by purulent exudate layered on mediastinal structures with or without abscess formation. Hemorrhagic necrosis is characteristic of mediastinitis due to inhalational anthrax. Air crepitance is the result of pneumomediastinum following esophageal rupture or pneumothorax

Microscopic ♦♦ Acute fibrinopurulent inflammation is the major histological pattern. Infectious agents are identified by appropriate stains for fungi and bacteria

Differential Diagnosis ♦♦ There are variable potential organisms, depending on the source of the infection and immune status of the patient. Microbiologic cultures and special stains for microorganisms are helpful in determining the causative agent

Granulomatous Mediastinitis (Localized Fibrosing Mediastinitis) Clinical ♦♦ Granulomatous mediastinitis is a localized process due to chronic mediastinal adenitis. Lymph nodes enlarge, become

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confluent, and the capsules thicken with fibrotic reaction in the immediate vicinity of the lymph nodes ♦♦ The most common cause of granulomatous mediastinitis is histoplasmosis, followed in frequency by tuberculosis ♦♦ Complications of this process include perforation and fistula formation, esophageal diverticula, or compression of a bronchus. Lymph nodes frequently calcify and may erode into the airways as broncholiths causing bronchial obstruction

Macroscopic ♦♦ The appearance is that of a large, calcified, and fibrocaseous mass of coalesced lymph nodes (mediastinal granuloma) (Fig. 26.1A)

Microscopic ♦♦ Lymph node architecture is partially or completely effaced by necrotizing granulomatous inflammation, fibrosis, and calcified caseonecrotic debris. The histological pattern is similar in both fungal and mycobacterial infections (Fig. 26.1B) ♦♦ Organisms may be visualized by acid fast stains for mycobacteria or Gomori methenamine silver for yeast forms of Histoplasma capsulatum (Fig. 26.1C)

Differential Diagnosis ♦♦ Mycobacterial versus fungal infection −− The histopathological features are similar as discussed above. Organisms may be demonstrated by acid fast or fungal stains ♦♦ Sarcoidosis −− In sarcoidosis mediastinal lymph nodes are enlarged by nonnecrotizing granulomas. Stains for microorganisms are negative, and granulomas are confined within the capsule of the lymph node ♦♦ Infected teratoma or bronchogenic cyst −− Necrosis may obscure typical identifying features of teratoma or bronchogenic cyst simulating the appearance of a fibrotic cavitated mass of lymph nodes ♦♦ Fibrosing mediastinitis −− Fibrosing mediastinitis (see below) is a more generalized process within the mediastinum, extending well beyond infected lymph nodes. Caseous necrosis is usually absent. The major histological feature is coarse, ropy, sparsely cellular collagen. Obstruction of major mediastinal structures such as the superior vena cava is commonly present

Fibrosing Mediastinitis Clinical ♦♦ Fibrosing mediastinitis is a form of chronic mediastinitis characterized by compressive and obstructive involvement of mediastinal structures. The presenting manifestation is often that of an asymptomatic mediastinal mass. There is a predominance of young adult females

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Fig. 26.1. (a) Mediastinal granuloma. Enlarged, matted lymph nodes replaced by fibrocaseous granulomas (scale = 1 cm). (b) Fibrocaseous, granuloma with central cavitation within lymph node. (c) Budding yeast-like organisms consistent with Histoplasma capsulatum (GMS stain).

♦♦ A variety of compression syndromes include −− Superior vena caval syndrome −− Tracheobronchial compression (hilar fibrosis) −− Pulmonary artery or venous obstruction ♦♦ Mediastinal fibrosis may be associated with collagen vascular disease, pseudotumor of orbit, Riedel struma, retroperitoneal fibrosis, and pulmonary hyalinizing granuloma. A rare association with elevated IgG4 levels has recently been described −− The etiology of fibrosing mediastinitis is unknown; however, a response to histoplasma infection is thought to be involved in many, if not most, cases

Microscopic

Macroscopic

♦♦ CD45, CD3, Vimentin, or Muscle actins are nonspecific markers of lymphocytes or mesenchymal cells in  early cellular lesions. There are few reactive cells in sclerotic lesions

♦♦ Macroscopically a firm, gray, ill-defined mass of fibrous tissue invades and compresses mediastinal structures

♦♦ Histologically fibrosing mediastinitis is characterized by dense paucicellular hyalinized collagenous tissue (ropy collagen) (Fig. 26.2), with scant lymphocytic and plasmacytic inflammation. Fibromyxoid granulation tissue may represent an early stage of the process. Rare granulomas, if  present, may suggest an infectious etiology ♦♦ Secondary effects seen in open lung biopsy include hyalinizing granulomas, or are the result of central pulmonary vein occlusion including pulmonary hemosiderosis, venous infarcts, and venous and arterial sclerosis which can simulate pulmonary veno-occlusive disease or pulmonary venous hypertension

Immunohistochemistry

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Fig.  26.2. Fibrosing Mediastinitis. Dense, ropy, collagenous fibrosis infiltrates adjacent lung tissue (right and upper).

Differential Diagnosis ♦♦ Nodular sclerosis Hodgkin disease; other lymphomas with sclerosis −− Reed–Sternberg cells in Hodgkin disease are positive for CD30 and CD15. Sclerosing lymphomas of the mediastinum are often of B-cell type (see section on lymphoproliferative diseases) ♦♦ Fungal/mycobacterial infection (granulomatous mediastinitis) −− Histoplasmosis is the most common cause of granulomatous mediastinitis, although mycobacteria are sometimes responsible. Histologically fibrocaseous granulomas form a localized mass (see granulomatous mediastinitis) ♦♦ Amyloidosis −− Amyloidosis is more amorphous than the ropey collagen of fibrosing mediastinitis. Stains for amyloid include Congo red with apple green birefringence on polarization, or metachromasia with crystal violet stain

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Progressive massive fibrosis (PMF) −− PMF refers to large conglomerate masses due to the inhalation of coal dust and/or silica. PMF usually resides within the lung parenchyma although lesions may extend to mediastinal structures. Coarse collagen may have a whorled appearance especially when silica exposure has occurred. Abundant black pigment and birefringent crystals consistent with silica and silicates appear throughout the lesion ♦♦ Desmoplastic mesothelioma (rare) −− Desmoplastic mesothelioma is a variant of sarcomatous mesothelioma in which coarse paucicellular collagen is a major histological feature. Mesothelioma may extend from the pleura or pericardium into the mediastinum. Pleomorphic sarcomatoid tumor cells which stain positively for keratin suggest the diagnosis of desmoplastic mesothelioma

Cystic Lesions Bronchogenic Cyst Clinical ♦♦ Bronchogenic cyst, the most common congenital cyst of the mediastinum, is derived from the embryonic foregut and occurs mainly in children and young adults. Symptoms occur when the cyst becomes infected or compresses bronchi. The usual location is middle mediastinum

Macroscopic ♦♦ The gross appearance is that of a smooth, thin-walled spherical, unilocular or multilocular, and clear or gelatinous fluidfilled cyst (Fig. 26.3A)

Microscopic ♦♦ Respiratory or squamous epithelium forms the inner lining which overlays a wall in which bronchial glands, smooth muscle, and cartilage may be present (Fig. 26.3B)

Fig. 26.3. (a) Bisected bronchogenic cyst showing inner trabeculations of cyst wall and mucoid content (scale = 1 cm). (b) Epithelial lining of bronchogenic cyst consists of ciliated respiratory epithelium.

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Immunohistochemistry

Differential Diagnosis

♦♦ The epithelium of bronchogenic cyst stains positively for CK7 and TTF1

♦♦ Bronchogenic cyst −− Cartilage is often present in the wall and there is no double muscular layer. Bronchogenic cysts may occur in the wall of the esophagus

Differential Diagnosis ♦♦ Esophageal cyst −− The esophageal cyst usually occurs on the right side. Histologically it is lined by squamous epithelium, and has a wall structure devoid of cartilage with a prominent double muscle layer ♦♦ Metastatic teratoma −− Metastatic testicular teratoma may occur in the mediastinum. The distinction from bronchogenic cyst includes better differentiated architecture in bronchogenic cyst with predominantly respiratory-type epithelium that is positive for CK7 and TTF1. Metastatic teratoma has mixed enteric and respiratory type epithelium and variably stains positively for CK20, CDX-2, CK7, and TTF1 respectively

Esophageal Cyst Clinical ♦♦ Esophageal duplication cyst is most frequently seen in infancy and early childhood. The cyst closely approximates the wall of the esophagus in the middle or posterior mediastinum. Symptoms occur due to compression of bronchopulmonary structures

Macroscopic ♦♦ The gross appearance is that of a smooth-walled spherical, unilocular fluid-filled cyst

Microscopic ♦♦ Histologically the inner lining consists of squamous and/or ciliated epithelium or columnar epithelium (Fig. 26.4a) ♦♦ Esophageal glands may be present, but cartilage is absent. The most definitive feature is a double layer of smooth muscle in the wall (Fig. 26.4b)

Gastroenteric Cyst Clinical ♦♦ Gastroenteric cyst is most frequently seen in infancy and early childhood. The cyst is usually located in the posterior mediastinum, and is frequently connected to the vertebral column. Symptoms occur due to compression of bronchopulmonary structures, or to nerve compression, peptic ulceration or perforation ♦♦ Gastroenteric cysts are often associated with malformations of thoracic vertebrae (neuroenteric cyst)

Macroscopic ♦♦ The gross appearance is that of a unilocular cyst attached to the vertebral column or within esophageal wall

Microscopic ♦♦ The inner lining is variable: gastric, duodenal, small intestinal, large intestinal, squamous, or respiratory epithelium (or mixed epithelium). There is usually a well-developed muscularis propria

Differential Diagnosis ♦♦ Gastroenteric cysts are differentiated from bronchogenic cysts by the absence of cartilage and the presence of columnar epithelium. The distinction from esophageal cyst is by location and the presence of gastric or intestinal epithelium

Pericardial Cyst (Coelomic Cyst) Clinical ♦♦ Pericardial cysts usually occur in adulthood and have a typical location in the cardiophrenic angles. Large cysts may cause hemodynamic compromise

Fig. 26.4. (a) Esophageal duplication cyst. Thick double-layered smooth muscle. Cyst wall devoid of cartilage. (b) Squamous epithelium lines surface of cyst.

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Fig. 26.5. (a) Pericardial (coelomic) cyst. (b) Cyst lined by flattened mesothelial cells. (c) Cyst lining cells show nuclear and cytoplasmic staining for calretinin.

Macroscopic

Macroscopic

♦♦ The gross appearance is that of a roughly spherical, unilocular, and thin-walled cyst filled with serous fluid (Fig.  26.5a). There is usually no communication with the pericardial sac

♦♦ The gross appearance is that of a unilocular cyst with a thin, translucent wall

Microscopic ♦♦ The inner lining is composed of a single layer of mesothelial cells overlying loose connective tissue (Fig. 26.5b)

Immunohistochemistry ♦♦ Lining mesothelial cells are strongly keratin and calretinin positive (Fig. 26.5c)

Differential Diagnosis ♦♦ See bronchogenic, esophageal, and gastroenteric cysts ♦♦ Thymic cyst −− Thymic cyst is located in the superior mediastinum, and there is thymic tissue in its wall

Unilocular Thymic Cyst (Developmental Origin) Clinical ♦♦ Unilocular thymic cyst is of developmental origin. It is a small cyst located more often in the lateral neck than in the (superior) mediastinum

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Microscopic ♦♦ The histological appearance shows flat, cuboidal, columnar, or (rarely) squamous epithelial lining of the inner cyst wall. Usually there is a lack of inflammation and thymic tissue is present in the cyst wall

Differential Diagnosis ♦♦ Pericardial cyst −− Pericardial cyst is located at the cardiophrenic angles and lacks thymic tissue in its wall

Multilocular Thymic Cyst (Acquired [Reactive] Process) Clinical ♦♦ Multilocular thymic cyst is regarded as an acquired, reactive lesion that clinically presents most frequently as an asymptomatic large tumor-like mass in the anterosuperior mediastinum ♦♦ It is usually an incidental finding on chest x-ray

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♦♦ It is frequently associated with thymic neoplasms, most notably Hodgkin disease and seminoma ♦♦ Multilocular thymic cyst may arise in setting of HIV infection

Macroscopic ♦♦ The macroscopic appearance is that of a multiloculated cyst with thick fibrous septa forming compartments that contain cloudy to blood-tinged fluid ♦♦ Large cysts may be densely adherent to adjacent mediastinal structures, simulating a neoplasm

Microscopic ♦♦ The lining epithelium of the cysts is usually squamous; however, flat cuboidal or ciliated columnar cells may occur either as a single layer or as a stratified epithelial lining ♦♦ Acute and chronic inflammation with fibrovascular proliferation, necrosis, hemorrhage, cholesterol granulomas, and reactive lymphoid hyperplasia are also common ♦♦ Thymic tissue is present in the cyst wall

Differential Diagnosis ♦♦ Cystic thymoma −− As opposed to multilocular thymic cyst, cystic thymoma maintains features of thymoma with nodular proliferation of thymic epithelial cells in addition to prominent cystic changes −− Cystic teratoma (see germ cell tumors below) ♦♦ Cystic lymphangioma −− Prominent ectatic lymphatic channels are the hallmark of cystic lymphangioma −− Nodular sclerosis Hodgkin disease and large cell lymphoma with cystic changes (see lymphoproliferative disorders below) −− Seminoma (germinoma) with cystic changes (see germ cell tumors below) ♦♦ Thymic carcinoma −− Thymic carcinoma can be distinguished from multilocular thymic cyst by its malignant cytology showing invasive growth

Nonneoplastic Lesions of Thymus Thymic Dysplasia Clinical ♦♦ Thymic dysplasia is a condition present at birth, thought to represent failure or arrest in thymic development ♦♦ Thymic dysplasia is associated with various immunodeficiency syndromes, including: usual X-linked or autosomal recessive form of severe combined immunodeficiency, ataxia telangiectasia, and related chromosomal instability syndromes; Nezelof syndrome; and incomplete form of DiGeorge syndrome (thymus is usually located ectopically in DiGeorge syndrome)

Macroscopic ♦♦ The thymus is of very small size (<5 g)

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Microscopic ♦♦ The histological features include primitive-appearing epithelium without segregation into cortical and medullary regions ♦♦ Absence of Hassall corpuscles ♦♦ Almost total absence of lymphocytes ♦♦ Small-sized vessels

Differential Diagnosis ♦♦ The major differential diagnosis of thymic dysplasia is acute thymic involution, often seen at autopsy. The discriminating features of acute thymic involution are −− Acute thymic involution results from stress and superimposed infections −− There is marked lymphocytic depletion with preservation of lobular architecture and of Hassall corpuscles −− Vessels are disproportionately large compared to size of lobules −− Inflammatory cells (particularly plasma cells) are scattered within interlobular and perilobular tissue

Thymic Aplasia Clinical ♦♦ Thymic aplasia refers to the complete absence of the thymus ♦♦ Thymic aplasia is present from birth and is most notably associated with the complete form of DiGeorge syndrome

Macroscopic and Microscopic ♦♦ There is complete absence of thymus gland, accompanied by parathyroid developmental failures in DiGeorge Syndrome

True Thymic Hyperplasia Clinical ♦♦ True thymic hyperplasia refers to enlargement of the thymus gland (by weight and volume) beyond upper limit of normal for age ♦♦ Seen mainly in children, the clinical significance of true thymic hyperplasia is unknown. It may represent an immunologic rebound phenomenon (e.g., post cessation of chemotherapy) or a sequela of other therapeutic manipulation

Macroscopic ♦♦ Enlarged thymus gland by weight and volume

Microscopic ♦♦ Microscopically the thymic architecture is normal

Differential Diagnosis ♦♦ Thymoma −− True thymic hyperplasia is discerned from thymoma by the preservation of thymic architecture in hyperplasia

Lymphoid Hyperplasia (Thymic Follicular Hyperplasia) Clinical ♦♦ Lymphoid hyperplasia refers to the increased presence of  lymphoid follicles within the thymus gland. Lymphoid

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Fig. 26.6. Thymic lymphoid hyperplasia. Prominent lymphoid follicles are present in thymus gland. Note adjacent Hassall corpuscle (arrow).

hyperplasia is associated with myasthenia gravis (in majority of cases), systemic lupus erythematosus, ­rheumatoid arthritis, scleroderma, allergic vasculitis, thyrotoxicosis and other autoimmune diseases

Macroscopic ♦♦ The thymus gland is usually of normal size and weight for age

Microscopic ♦♦ There are an increased number of lymphoid follicles with prominent germinal centers (Fig. 26.6)

Differential Diagnosis ♦♦ Thymoma −− There is preservation of thymic architecture in lymphoid hyperplasia ♦♦ Reactive lymph node hyperplasia or lymphoproliferative lesions −− Reactive germinal centers with preserved thymic architecture distinguish thymic lymphoid hyperplasia from reactive lymph nodes and from lymphoproliferative disorders involving the thymus

Lesions Mimicking Primary Mediastinal Neoplasms Substernal Thyroid (Mediastinal Goiter) Clinical ♦♦ Substernal goiter refers to enlarged thyroid due to nodular hyperplasia located in the superior mediastinum. Mediastinal goiter is usually connected to a cervical goiter and receives its blood supply from cervical arteries ♦♦ The main presentation is an asymptomatic neck mass. Tracheal compression with associated dyspnea is the major complication in about 25% of cases ♦♦ Radioactive iodine scanning is positive in over 50% of cases

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Fig.  26.7. Large substernal goiter arising from the lower pole of the left lobe of the thyroid gland (scale = 1 cm).

♦♦ Associated thyroid malignancy ranges from 2 to 20% ♦♦ Substernal goiter can usually be excised via a neck incision

Macroscopic ♦♦ Features of adenomatous goiter frequently extend from the inferior pole of the thyroid in the neck (Fig. 26.7) (see Chapter 20)

Microscopic ♦♦ The histopathology is that of typical nodular thyroid hyperplasia as seen in cervical adenomatous goiter (see Chapter 20)

Differential Diagnosis ♦♦ Other mediastinal thyroid lesions such as adenoma or carcinoma are much less frequent

Mediastinal Parathyroid Lesions Clinical ♦♦ Parathyroid lesions arise from ectopic parathyroid tissue in the superior mediastinum ♦♦ Clinically parathyroid adenomas and hyperplasia are associated with hyperparathyroidism and hypercalcemia ♦♦ Mediastinal parathyroid lesions may assume a larger size than cervical lesions

Macroscopic ♦♦ The macroscopic appearance is that of an enlarged parathyroid gland. Parathyroid cysts are rare

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Microscopic ♦♦ The features of parathyroid adenoma or hyperplasia are similar to cervical lesions (Chapter 20) ♦♦ Parathyroid cyst is a simple cyst with parathyroid tissue in its wall

Differential Diagnosis ♦♦ The major differential considerations in the mediastinum are paraganglioma or thymic carcinoid tumor −− Neither of these lesions is associated with hypercalcemia −− Histologically chief cells and/or water clear cells indicate parathyroid lesions. Sustentacular cells are seen in paragangliomas

Other Conditions Pneumomediastinum Clinical ♦♦ Pneumomediastinum refers to air within the fascial planes of the mediastinum, often in association with pulmonary interstitial emphysema, pneumopericardium, pneumothorax, and subcutaneous emphysema ♦♦ The major causes of pneumomediastinum are mechanical ventilation (barotrauma), esophageal perforation, acute mediastinitis, and increased intrathoracic pressure (e.g., straining, Valsalva maneuver) ♦♦ Chest x-ray and CT scan show mediastinal air outlining the aorta, esophagus, and left heart border

Macroscopic ♦♦ Grossly, air bubbles and crepitance in mediastinal tissue are seen at autopsy ♦♦ Associated tension pneumothorax is often also seen in patients receiving mechanical ventilation

Fig. 26.8. Pneumomediastinum. Empty-appearing cystic spaces displace mediastinal fat and fibrovascular tissue (Elastic van Gieson).

Microscopic ♦♦ The microscopic appearance is that of widened, empty interstitial spaces in the mediastinal fat (Fig. 26.8) ♦♦ Associated interstitial pulmonary emphysema shows similar widened spaces which track along broncho-vascular bundles within the lung

Differential Diagnosis ♦♦ The major histological differential diagnosis is lymphangiectasia −− Lymphangiectasia has the same distribution as interstitial air dissection −− Look for endothelial lining in lymphangiectasia vs. acute hemorrhage and empty spaces in air dissection

NEOPLASMS Thymus Histologic Features of Thymus ♦♦ The thymus is a lobulated and encapsulated organ and is subdivided into cortex and medulla ♦♦ The different cell types of the thymus include epithelial cells, lymphocytes (traditionally known as thymocytes), and other (minor) cell types ♦♦ Epithelial cells are endodermally derived cells. They modulate the differentiation of T lymphocytes and are  Keratin andHLA-DR positive. The different subtypes of epithelial cells include cortical cells that are medium to large, round, or polygonal with clear nuclei and conspicuous nucleoli; and

medullary cells with spindle nuclei and epithelium forming Hassall corpuscles ♦♦ Lymphocytes (traditionally known as thymocytes) are bonemarrow derived cells. The different subtypes include: (a) cortical thymocytes which are immature T-cells (immunophenotyping: cytoplasmic CD3+/surface CD3−, CD1a+, terminal deoxynucleotidyl transferase (TdT) +, and double negative for CD4/8 or coexpressing CD4/8); and (b) medullary thymocytes which are mature T lymphocytes (immunophenotyping: surface CD3+, either CD4+ or CD8+) ♦♦ Other (minor) cell types of the thymus are interdigitating reticulum cells, Langerhans cells, mast cells, eosinophils (especially in neonates), and mesenchymal stromal cells

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Thymoma ♦♦ Thymomas are tumors of the thymic epithelium that are cytologically bland and demonstrate the presence of associated cortical-type T-cells (cortical thymocytes) ♦♦ Major subtypes −− Circumscribed (usually benign) thymoma, or invasive thymoma −− Histologic classification −− WHO classification, see Table 26.1 ♦♦ Lattes–Bernatz (L-B) −− Predominantly spindle cell −− Predominantly lymphoid −− Predominantly mixed −− Predominantly epithelial −− Invasive (malignant) thymoma: any of above histologic subtypes with evidence of invasion

Clinical ♦♦ Thymomas are mainly seen in adults. They are usually located in the anterosuperior mediastinum. On chest x-ray, CT, and MRI a thymoma appears as a lobulated mediastinal mass. Thymomas can be seen in association with certain diseases −− Myasthenia gravis (almost exclusively associated with nonmedullary thymoma or type B thymoma by WHO classification) −− Hypogammaglobulinemia (mainly associated with medullary thymoma [type A thymoma by WHO classification]) −− Erythroid hyperplasia (mainly associated with medullary thymoma)

Treatment ♦♦ Surgery alone can be the treatment for an entirely encapsulated (benign) thymoma; however, there is a 2–10% recurrence rate. Surgery with radiation is used for invasive thymomas and chemotherapy is used for metastatic disease

Prognosis ♦♦ The degree of tumor invasion (stage of disease) is the best prognostic factor. WHO histologic subtype may be an inde-

Essentials of Anatomic Pathology, 3rd Ed.

pendent prognostic factor, particularly in Stage I and II thymomas, among which WHO type A, AB, and B1 thymomas form a low-risk group. The proportion of invasive tumors increases by type – from A to AB, B1, B2, and B3. Myasthenia gravis has no prognostic significance (see TNM Classification section)

Macroscopic ♦♦ Circumscribed thymomas are usually 2–20  cm in size. They are predominantly solid, yellowish gray, lobulated by connective tissue septa, and encapsulated (Fig. 26.9a). Cystic degeneration may be seen in larger tumors. Invasive thymomas are histologically similar to circumscribed thymomas, but, in addition, infiltrate surrounding structures

Microscopic ♦♦ In general (applies to all histologic subtypes) thymomas show cellular lobules separated by fibrous septa (Fig.  26.9B, c). The fibrous capsule is complete in circumscribed thymomas and incomplete with capsular invasion in invasive thymomas (Fig.  26.9d). Varying proportion of lymphocytes and neoplastic epithelial cells are seen. Perivascular spaces containing lymphocytes, proteinaceous fluid, red blood cells, foamy macrophages, or fibrous tissue are also seen (Fig.  26.9e). Occasional gland or pseudogland structures or Hassall corpuscle-like structures can be present ♦♦ Histologic subtypes ♦♦ Type A, WHO classification (predominantly spindle cells [L-B]) (Fig. 26.10A, b) −− Predominantly spindle-shaped epithelial cells are present with few mature lymphocytes. This type of thymoma can show variable patterns including storiform, hemangiopericytoma-like, rosette-like (without central lumen), and glandular formation. Perivascular spaces are uncommon. Capsular invasion is rare ♦♦ Type AB, WHO classification −− Mixture of type A thymoma and predominantly lymphoid rich type B thymoma pattern. Perivascular spaces are occasionally seen. Capsular invasion is rare

Table 26.1. The Definitions of the WHO Classification Categories of Thymic Epithelial Tumors Type A: A tumor composed of homogeneous population of neoplastic epithelial cells having spindle/oval shape, lacking nuclear atypia, and accompanied by few or no nonneoplastic lymphocytes. Type AB: A tumor in which foci having the features of type A thymoma are admixed with foci rich in lymphocytes; the segregation of the two patterns can be sharp or indistinct. Type B1: A tumor which resembles the normal functional thymus in that it combines large expanses having an appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla. Type B2: A tumor in which the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes; foci of squamous metaplasia and perivascular spaces are common. Type B3: A tumor predominantly composed of epithelial cells having a round or polygonal shape and exhibiting mild atypia, admixed with a minor component of lymphocytes; foci of squamous metaplasia and perivascular spaces are common. Thymic carcinoma: Previously known as “type C thymoma,” thymic carcinomas are primary epithelial tumors of the thymus that show overt cytologic features of malignancy. Morphologically, they look like carcinomas of other organs.

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Fig. 26.9. (a) Circumscribed thymoma (mixed type). Note lobules of tumor separated by bands of connective tissue and central scar. (b) Thymoma, general features. Cellular lobules separated by fibrous septa. (c) Thymoma, general features. Note intact capsule. (d) General features. Invasive thymoma. The thymoma breaks through the capsule and invades the lung parenchyma. (e) Thymoma, general features. Perivascular spaces (serum lakes) containing lymphocytes, proteinaceous fluid, red blood cells, and foamy macrophages.

♦♦ Type B1, WHO classification (less than 33% epithelial cells, predominantly lymphoid [L-B]) (Fig. 26.11a) −− Closely resembles the normal thymus. Well-formed lobules are seen with intervening sclerotic septa. Scattered large polygonal epithelial cells in diffuse, small, and

round lymphocytic background (CD1a+, coexpress CD4/8) are present. Sparse foci of medullary differentiation containing tingible body macrophages are seen (“starry sky” pattern). Perivascular spaces are often present. Capsular invasion is rare

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Fig. 26.10. (a) Thymoma, predominantly spindle cell (Type A [WHO]). (b) Thymoma, predominantly spindle cell, higher magnification (Type A [WHO]).

Fig. 26.11. (a) Thymoma, predominantly lymphoid (Type B1 [WHO]). (b) Thymoma, predominantly mixed (Type B2 [WHO]). (c) Thymoma, predominantly epithelial (Type B3 [WHO]). ♦♦ Type B2, WHO classification −− Sheets of polygonal epithelial cells (large nuclei and prominent nucleoli) are intermixed with lymphocytes (Fig. 26.11b). Lobulation is often seen. There is minimal

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medullary differentiation. Capsular invasion may be present ♦♦ Type B3, WHO classification (predominantly epithelial [L-B]) (Fig. 26.11c)

Mediastinum and Thymus

−− Sheets of polygonal epidermoid cells with irregular “raisinoid” nuclei, inconspicuous nucleoli and eosinophilic to clear cytoplasm are seen. In other cases, cells may show large vesicular, hyperchromatic granular nuclei, and conspicuous nucleoli. Slight to moderate cellular atypia may be present and mitotic figures (up to 10/10 HPF) can be seen. They usually show an invasive growth and are considered to be a variant of cortical thymoma −− Invasive (malignant) thymomas are defined as thymomas with any of the above histologic subtypes with evidence of invasion (Fig. 26.9d)

Electron Microscopy ♦♦ Neoplastic epithelial cells show branching tonofilaments, complete desmosomes, elongated cell processes, and basal lamina

Immunohistochemistry (see Table 26.2) ♦♦ Neoplastic epithelial cells are keratin positive and epithelial membrane antigen (EMA) positive. The nonneoplastic lymphocytes include the medullary mature lymphocytes with features of medullary thymocytes (CD1a−, either CD4+ or CD8+) and nonmedullary with immature lymphocytes showing features of cortical thymocyte (TdT+, CD1a+, coexpress both CD4 and CD8) ♦♦ Recent studies have shown a possible role of anti-x-linked inhibitor of apoptosis protein (XIAP) in differentiating thymic hyperplasia from thymoma, especially in small biopsy specimens. XIAP expression is positive in majority of the thymoma cases and was negative in all thymic hyperplasia cases except only one. Additionally, CD205 and Foxn1 have been described to be expressed in the majority cases of thymoma

Differential Diagnosis ♦♦ Thymic carcinoma −− Cytologically malignant with high mitotic rate, atypical mitoses, invasive growth, sclerosis in center of tumor, and coagulative necrosis. CEA and B72.3 are positive in thymic carcinoma, but negative in thymoma. Infiltrating lymphocytes are mature lymphocytes and negative for CD1a (very useful criteria in needle biopsy). Usually thymic carcinomas are not associated with myasthenia gravis ♦♦ Carcinoid −− Unencapsulated; monomorphous cell population with true rosettes, ribbons, or festoons are seen. These tumors show positive staining for neuroendocrine markers. Some are associated with Cushing syndrome ♦♦ Thymic Hodgkin lymphoma −− There is extensive fibrosis with rounded (as opposed to angulated) lobules. Prominent cysts can be seen. Reed– Sternberg cells or lacunar cells (CD15+, CD30+) and mixed inflammatory cells are also seen ♦♦ Precursor B or T lymphoblastic lymphoma (LBL) −− Diffuse growth or thin, separated lobules with numerous mitoses in lymphoid cells. They are positive for T-cell receptor or immunoglobulin chain gene rearrangement

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♦♦ Primary mediastinal (thymic) large B-cell lymphoma ­(diffuse large B-cell lymphoma [DLBCL] with sclerosis) −− Diffuse growth pattern with variable fibrosis with occasional compartmentalization. Residual cystic thymus can be seen. Lymphocytes have vesicular nuclei, prominent nucleoli, and variable cytoplasm. B-cell markers (CD20) are positive ♦♦ Thymic seminoma −− Subdivided by fine fibrous trabeculae into variable-sized compartments. Placental-like alkaline phosphatase (PLAP) positive and keratin negative ♦♦ Localized lymphoid hyperplasia (vs. thymoma, predominantly lymphoid subtype) −− Retention of normal cortical and medullary structure and presence of lymphoid follicles with germinal centers is seen ♦♦ Fibrous histiocytoma and hemangiopericytoma (vs. predominantly epithelial or predominantly spindle-cell ­thymoma with storiform and hemangiopericytoma-like growth pattern) −− Keratin negative ♦♦ Spindle epithelial tumor with thymus-like elements (SETTLE) −− Seen at young age with occurrence in thyroid gland. Mucous glands are frequently present. Lymphocytes are absent

Thymic Carcinoma (Type C Thymoma by the Previous WHO Classification) Clinical ♦♦ Tumors of thymic epithelium that are cytologically malignant and not associated with cortical-type immature T-cells ♦♦ Thymic carcinomas are rarely associated with myasthenia gravis or other thymoma-related paraneoplastic syndromes. Patients are usually asymptomatic or have nonspecific symptoms found by routine chest x-ray. Occasionally they may present with superior vena cava syndrome. The usual metastatic sites are lymph nodes (mediastinal, cervical, and axillary), bone, lung, liver, and brain. Treatment is surgery and radiation with or without chemotherapy. Prognosis depends on the histologic subtype. Nonkeratinizing carcinomas (including lymphoepithelioma-like tumors), sarcomatoid carcinoma, clear cell carcinoma, and undifferentiated (anaplastic) carcinoma (Fig.  26.12a, b) are very aggressive. Squamous cell carcinomas (SCC) are of intermediate category and mucoepidermoid and basaloid carcinomas are relatively indolent

Macroscopic ♦♦ Thymic carcinomas show a homogeneous, yellow to gray cut surface with hemorrhage, necrosis, and infiltrating borders

Microscopic ♦♦ Morphologically these tumors are similar to carcinoma in other organ systems. Cytologic features of malignancy are present and display none of the characteristic features of thymoma. They lack cortical-type T lymphocytes

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Thymic carcinoma

+ − − −

−

− − − −

−

EMA LCA (CD45) CD1a TdT CD5

CD15 CD30

PLAP CEA B72.3 PAX-5a

Neuroendocrine marker

−

− − − −

−

− + + except medullary +

−

−

− +/− +/− −

−

+ − − −

+

− (+ in small cell undifferentiated Ca)

− +/− +/− −

−

+ − − +

+

− +/− +/− − +

−

−

+/− − − −

+/−

− − − −

−

− + − +

−

−

+ − − −

− embryonal Ca CD30+/−

+ except seminoma − − − − − − − − (+ in background T-cells) + (in R-S cells and variants) − − − Week in R-S cellsb −

−

HL

−

−

− − − +

−

− − − − −

− + − −

− − + + + (− in B-LL)

−

Primary mediastinal (thymic) LBCL LL

HL Hodgkin lymphoma, LL lymphoblastic lymphoma, B-LL B-cell LL, LBCL large B-cell lymphoma, RS Reed–Sternberg, + positive in majority of cases, − negative in majority of cases, +/− variable % of cases positive a PAX5 may be expressed in small cell carcinoma b Characteristically weaker staining in R-S cells compared to background reactive B-cells

+

Keratin

Neoplastic Neoplastic epithelial Nonneoplastic Metastatic epithelial Nonneoplastic Thymic Germ cell cells lymphoid cells carcinoid cells lymphoid cells carcinoma tumor

Thymoma

Table 26.2. Immunohistochemistry Stain Profile of Mediastinal Tumors

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Fig.  26.12. Thymic carcinoma, undifferentiated (nonkeratinizing type) (a, b). Note infiltrative malignant cells with prominent nucleoli and mitotic figures. −− Subtypes (a) Common * Keratinizing or nonkeratinizing SCC * Lymphoepithelioma-like carcinoma (1) Epstein-Barr virus associated (some cases) (b) Rare * Mucoepidermoid carcinoma * Adenosquamous carcinoma * Basaloid carcinoma * Papillary adenocarcinoma * Adenocarcinoma * Small cell undifferentiated carcinoma * Large cell undifferentiated (anaplastic) carcinoma * Sarcomatoid carcinoma, spindle-cell carcinoma, and carcinosarcoma * Clear cell carcinoma * Undifferentiated carcinoma (Fig. 26.12a, b) * Hepatoid carcinoma * Rhabdoid carcinoma

Immunohistochemistry ♦♦ Neoplastic epithelial cells are positive for keratin, EMA, CEA, B72.3, and infrequently Leu-7 (CD57). Thymic carcinoma cells are usually CD5 positive (CD5 usually negative in carcinomas other than thymic primary). Infiltrating lymphocytes are CD1a negative ♦♦ Recent studies have reported that Foxn1 is a sensitive and specific marker for thymic carcinoma, and appears to be superior to CD5 and CD117 for the diagnosis of thymic carcinoma. Similarly, CD205 (DEC205) has been reported to be expressed in thymic carcinoma but its sensitivity is lower than CD5 and CD117

Differential Diagnosis ♦♦ Thymoma (see above thymoma) ♦♦ Carcinoma metastatic to or invading anterior mediastinum (particularly carcinoma of lung) and malignant mesothelioma ♦♦ Thymic squamous carcinoma often exhibits lobulated growth pattern, central sclerosis, and abrupt keratinization simulating Hassall corpuscles. Other subtypes of thymic carcinoma can-

not be differentiated based solely on histology (thymic carcinoma is a diagnosis of exclusion – in presence of malignant epithelial tumor located in thymic region in absence of known primary). CD5 positivity for tumor cells supports diagnosis of primary thymic carcinoma ♦♦ Germ cell tumors −− PLAP+, human chorionic gonadotropin (HCG) (see section on germ cell tumors) ♦♦ Primary mediastinal (thymic) large B-cell lymphoma (diffuse large cell lymphoma with sclerosis) (New WHO) −− Leukocyte common antigen (LCA) +, CD20 (B-cell marker) +, keratin −, EMA − ♦♦ Carcinoma with thymus-like elements (CASTLE) −− Tumor of thyroid gland or soft tissues of neck of middleaged adult. Histologically identical to thymic lymphoepithelioma-like carcinoma with better prognosis and more indolent course −− Thymic epithelial tumor with features borderline between thymoma and thymic carcinoma −− Also referred to as atypical thymoma, these tumors are rare thymic epithelial tumors with more cytomorphological or architectural atypia than the typical thymoma but lacks the obvious features of thymic carcinoma. These tumors probably represent a gray zone between thymoma and thymic carcinoma. Histologically, some of these tumors can demonstrate lobulation and perivascular spaces characteristic of thymomas with significant cellular atypia, whereas in other cases there is absence of lobulation and perivascular spaces of typical thymoma but the degree of cellular atypia is less than that of thymic carcinoma

Thymic Carcinoid (Including Atypical Carcinoid) Clinical ♦♦ Thymic carcinoids are commonly seen in adults. Radiologically nonfunctional carcinoids are large, radiopaque, noncystic

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anterior mediastinal masses with/without fine calcification. Functional carcinoids (associated with Cushing syndrome) are usually of small size and detected by CT scan ♦♦ There have been no reported cases of carcinoid syndrome. Functional tumors have more aggressive course, invade locally, and metastasize infrequently. Occasionally they are associated with multiple endocrine neoplasia syndrome (MEN) types 1 or 2a or carcinoid tumors of other sites, such as bronchus and ileum. Thymic carcinoids are usually cured by excision. Atypical carcinoids have increased metastatic potential and worse prognosis

Macroscopic ♦♦ Thymic carcinoids are solid, well-circumscribed, but not encapsulated (Fig. 26.13a). They appear as a lobulated, yellow-tan, or hemorrhagic mass

Microscopic ♦♦ Typical carcinoid shows rosette-like glands with central lumina, ribbon, and festoon formation (Fig. 26.13b). They have uniform nuclei with low mitotic rate. Marked vascularization is usually seen. On the other hand, atypical carcinoids (majority of tumors) show nuclear pleomorphism with increased mitotic rate and necrosis

Electron Microscopic ♦♦ Dense core neuroendocrine granules

Immunohistochemistry ♦♦ Keratin +, neuron-specific enolase +, chromogranin +, adrenocorticotropic hormone (ACTH) + (for cases associated with Cushing syndrome) ♦♦ Foxn1 and CD205 (DEC205) are both negative in thymic neuroendocrine carcinoma

Differential Diagnosis ♦♦ Small cell undifferentiated carcinoma (vs. atypical carcinoid) shows high mitotic rate, small nuclear size, with homogenous chromatin pattern

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Epithelial cell predominant thymoma with rosette-like structures will show rosette-like structures frequently associated with lymphocytes. These are negative for neuroendocrine markers

Thymic Stromal Tumors Thymolipoma Clinical ♦♦ Seen in young adults (mean age = 20–30 years) with a male to female ratio of 2.3:l. They present as a benign, large, and asymptomatic mass (>500 g) of anterior mediastinum. They are associated with myasthenia gravis, aplastic anemia, and Graves disease. These tumors radiographically resemble cardiomegaly or pulmonary sequestration

Macroscopic ♦♦ These are encapsulated tumors and they can be very large in size. They have the appearance of a lipoma with focal presence of whitish solid areas

Microscopic ♦♦ There is an admixture in various proportions of mature adipose tissue and unremarkable thymic tissue being in excess of that normally expected for age (Fig. 26.14)

Differential Diagnosis ♦♦ Lipoma −− Lacks thymic component ♦♦ Lymphoid hyperplasia −− They are smaller size with less adipose tissue and prominent germinal centers ♦♦ Thymic stromal sarcomas −− These are rare, low grade malignant mesenchymal tumors arising from thymic stroma. Well-differentiated liposarcoma is the predominant component in these tumors (“thymoliposarcoma”)

Fig.  26.13. (a) Thymic carcinoid tumor. The hemorrhagic appearance denotes prominent tumor vascularity (scale = 1  cm). (b) Typical carcinoid tumor. Note uniform appearance of cells in a neuroendocrine nesting pattern.

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Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapter 22 ♦♦ Mediastinal neurofibroma is often enclosed by a complete fibrous capsule

Malignant Peripheral Nerve Sheath Tumor Clinical

Fig. 26.14. Thymolipoma. Thymic tissue is separated by lobules of mature adipose tissue.

Neoplasms Not Limited to Thymus Neurogenic Tumors ♦♦ Neurogenic tumors account for approximately 19% of primary mediastinal masses; the majority occur in the posterior mediastinum. Neurogenic tumors may be of either sympathetic nervous system origin (neuroblastoma, ganglioneuroblastoma) or peripheral nerve sheath origin (neurilemmoma, neurofibroma)

Peripheral Nerve Sheath Tumors Schwannoma (Neurilemmoma) Clinical ♦♦ Schwannoma is the most common neurogenic tumor of the mediastinum, typically occurring in young adults ♦♦ It is usually asymptomatic, occasionally presenting as a “dumbbell” tumor with extension through intervertebral foramen causing nerve root and spinal cord compression

Radiology ♦♦ Schwannoma is seen radiographically as a well-circumscribed posterior mediastinal mass, usually single ♦♦ Multiple tumors are associated with von Recklinghausen disease ♦♦ Schwannomas usually have a good prognosis; recurrence is rare

Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapter 22 ♦♦ Mediastinal schwannomas frequently attain large size and are associated with degenerative changes including sclerosis, fatty degeneration, hemorrhage, and cyst formation

Neurofibroma Clinical ♦♦ The clinical presentation of neurofibroma is similar to that of schwannoma. Neurofibroma is second to schwannoma in frequency

♦♦ Malignant peripheral nerve sheath tumor (MPNST) occurs in the age range of 20–50 years. It is rare in the mediastinum (<10% of thoracic neurogenic tumors). The prognosis of MPNST is poor, and characterized by local invasion, recurrence, and metastasis ♦♦ MPNST is associated with von Recklinghausen disease and prior radiation

Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapter 22

Tumors of Sympathetic Nervous System Neuroblastoma Clinical ♦♦ Neuroblastoma is the most common mediastinal neurogenic neoplasm in children, particularly <1 year of age. It is usually symptomatic ♦♦ Direct extension may lead to esophageal or spinal nerve root compression, or erosion of contiguous vertebral bones. Some patients may develop a paraneoplastic neurologic syndrome known as opsoclonus myoclonus (“dancing feet and dancing eyes”). Failure to thrive is common. Elevated level of catecholamine metabolites in urine or blood may be helpful in establishing the clinical diagnosis ♦♦ More than half of patients present with metastasis at the time of diagnosis. Frequent sites of metastasis include brain, liver, bone, or regional lymph nodes

Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapter 20

Ganglioneuroblastoma Clinical ♦♦ Ganglioneuroblastoma usually occurs in older infants and children. It tends to be less aggressive than neuroblastoma

Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapter 20

Ganglioneuroma Clinical ♦♦ Occurs in older children and young adults ♦♦ Usually asymptomatic, occasionally with spinal nerve root compression ♦♦ Usually good prognosis

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Essentials of Anatomic Pathology, 3rd Ed.

Macroscopic, Microscopic, and Differential Diagnosis ♦♦ See Chapters 20 and 22

Paraganglioma Clinical ♦♦ There are two major clinical presentations of mediastinal paragangliomas based on the location of the tumor −− Paragangliomas of the anterosuperior mediastinum (a) Associated with aorticopulmonary paraganglia (b) Average age = 49 years (c) Slight predilection for women (d) 3% of cases synthesize catecholamines −− Paragangliomas of the posterior mediastinum (a) Associated with the aortico-sympathetic ganglia in a paravertebral location (b) Average age = 29 years (c) Men dominant (d) 50% of cases synthesize catecholamines (e) Secretory paragangliomas produce clinical symptoms similar to those of pheochromocytoma −− Approximately 50% of cases of mediastinal paraganglioma are associated with significant morbidity or mortality due to infiltrative growth and unresectability due to close association with great vessels. This rate of aggressive behavior is higher than that seen with paragangliomas of other locations (a) There are no well-defined histological criteria which separate benign from malignant paragangliomas (b) A high mitotic rate correlates with clinical malignant behavior −− Carney triad (a) The Carney triad includes functional paragangliomas, pulmonary chondromas, and gastrointestinal malignant stromal tumors (b) The syndrome is most common in young women

Macroscopic ♦♦ Paragangliomas are typically solitary and tan to red-brown on cross section. Hemorrhage is common. Larger tumors undergo fibrosis or cyst formation

Microscopic (Fig. 26.15) ♦♦ The characteristic microscopic organoid pattern consists of cell nests (Zellballen) of cuboidal cells ♦♦ Nuclear pleomorphism may be considerable with nuclear pseudoinclusions ♦♦ Mitotic figures are scarce ♦♦ Sustentacular cells are seen at the periphery of tumor nests ♦♦ There is a highly vascularized fibrous stroma ♦♦ Stromal hemorrhage or fibrosis may be prominent

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Fig. 26.15. Paraganglioma. Uniform neuroendocrine cells in a zelballen pattern.

Electron Microscopic ♦♦ The dominant chief cells contain abundant cytoplasmic dense core neurosecretory granules (120–250  nm in diameter). Each granule is round and regular in shape with a clear halo ♦♦ Junctions are a constant feature but true desmosomes are not typically seen

Immunohistochemistry ♦♦ Positivity for peptide hormones including neuron specific enolase, synaptophysin, chromogranin, somatostatin, neurofilament, and other peptide hormones ♦♦ Keratin is negative ♦♦ Sustentacular cells are positive for S-100 protein

Differential Diagnosis ♦♦ Carcinoid tumors are usually keratin positive and lack sustentacular cells (some carcinoid tumors, however, do have S-100 positive sustentacular cells). The Zellballen pattern is usually less pronounced in carcinoid tumor

Germ Cell Tumors General Features ♦♦ Account for approximately 20% of mediastinal tumors and cysts ♦♦ Germ cell tumors tend to be located in the anterior and superior mediastinum ♦♦ They are intimately associated with the thymus ♦♦ Except for mature cystic teratoma, mediastinal germ cell tumors almost exclusively occur in males ♦♦ There is an association between germ cell tumors and Klinefelter syndrome ♦♦ There is also an association with hematologic neoplasia (e.g., leukemia, anaplastic large cell [Ki-1] lymphoma) ♦♦ Symptoms of germ cell tumors are due to compression. Some tumors are detected incidentally as an asymptomatic mass

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♦♦ Isolated mediastinal metastasis from a testicular or retroperitoneal germ cell tumor must always be excluded but is a rare occurrence

Immature Teratoma Clinical

Teratomas Mature Cystic Teratoma Clinical

♦♦ Immature teratoma of the mediastinum is a rare variant ♦♦ Like mature cystic teratoma, immature teratoma has a benign clinical course

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Most common mediastinal germ cell tumor Affects adolescents and young adults There is an equal sex distribution Mature cystic teratoma is often asymptomatic Rarely mature cystic teratoma may erode a bronchus, followed by expectoration of tumor content ♦♦ Surgical excision is curative

Macroscopic ♦♦ Grossly, mature cystic teratoma appears as a cystic, wellcircumscribed mass with fibrous encapsulation; it may contain fat, oily liquid, and hair

Microscopic ♦♦ The histological picture is similar to gonadal teratoma (see Chapter 32) (Fig. 26.16) ♦♦ Pancreatic and gastric tissue is more common than in gonadal teratomas ♦♦ Frequently there is a prominent inflammatory reaction with xanthogranulomatous features on the periphery of the neoplasm

Differential Diagnosis ♦♦ Metastatic teratoma of gonadal origin ♦♦ Immature teratoma −− Embryonic tissue components ♦♦ Teratoma with additional malignant components −− Mixed germ cell or nongerm cell malignant components

Macroscopic ♦♦ Macroscopically immature teratoma is typically a large, solid mass which is adherent to mediastinal structures, similar to mature cystic teratoma ♦♦ The cut surface is variegated

Microscopic ♦♦ Contains immature epithelial, mesenchymal, or neural elements, with or without elements of mature teratoma ♦♦ Embryonal carcinoma is not present

Differential Diagnosis ♦♦ See mature teratoma (above)

Teratoma with Additional Malignant Components Clinical ♦♦ This variant has an aggressive course with invasion of adjacent structures

Macroscopic ♦♦ Grossly the lesion appears solid with areas of hemorrhage and necrosis

Microscopic ♦♦ Microscopically one sees mature or immature teratoma with components of other germ cell tumors (mixed germ cell tumor) −− Teratocarcinoma refers to the combination of embryonal carcinoma and teratoma. ♦♦ Teratoma with malignant nongerm cell components (carcinoma, sarcoma). This microscopic pattern is associated with a very poor prognosis and lack of response to germ cell type chemotherapy protocols.

Seminoma (Germinoma) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Males predominant, exceedingly rare in females Occurs in the second to fourth decades Responsive to radiation therapy (up to 100% 5-year survival) Serum HCG may be positive

Macroscopic ♦♦ Solid, lobulated, and homogeneous mass

Microscopic Fig. 26.16. Mature cystic teratoma of thymus. Note teratomatous elements alternating with thymic tissue (right). A keratinous cyst with adjacent sebaceous glands is a major component of the neoplasm.

♦♦ Similar to testicular seminoma, but with a greater tendency toward anaplastic features (see Chapter 39) ♦♦ Lymphoid and granulomatous component may be prominent

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Immunohistochemistry ♦♦ Immuno positivity for PLAP, OCT4, CD117, and CD57 ♦♦ Dot-like positivity for CAM 5.2 in minority of cells

Cytogenetics ♦♦ 80% of mediastinal germ cell tumors of all histological types show gain of 12p [i(12p)], detectable by FISH

Differential Diagnosis ♦♦ Lymphoepithelioma-like carcinoma of thymus −− Immunopositivity for EMA and cytokeratin; Negative for PLAP ♦♦ Diffuse large cell lymphoma −− Immunopositivity for leukocytic common antigen ♦♦ Hodgkin disease −− Reed–Sternberg cells are present, positive for CD15 and CD30 −− Negative for PLAP

Embryonal Carcinoma Clinical ♦♦ Embryonal carcinoma is a rare, highly malignant mediastinal tumor ♦♦ Embryonal carcinoma almost exclusively affects males

Macroscopic ♦♦ Grossly embryonal carcinoma appears as a large, solid, hemorrhagic, and necrotic mass

Microscopic ♦♦ Poorly differentiated, with necrosis (identical to gonadal embryonal carcinoma) ♦♦ Usually mixed with other germ cell tumor components (mixed germ cell tumor)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ It is associated with high levels of serum alpha fetoprotein ♦♦ Yolk sac tumor may be associated with hematologic neoplasia ♦♦ There is a poor prognosis for pure mediastinal yolk sac tumor

Macroscopic ♦♦ Large, necrotic, and invasive mass

Microscopic ♦♦ Mediastinal yolk sac tumor is histologically similar to gonadal yolk sac tumor, but may have prominent spindle cell or hepatoid features ♦♦ Yolk sac tumor is usually mixed with teratoma or other germ cell tumor elements (i.e., mixed germ cell tumor)

Differential Diagnosis ♦♦ Embryonal carcinoma −− Absence of Schiller–Duval bodies or a reticular growth pattern −− Embryonal carcinoma is immunopositive for CD30

Choriocarcinoma Clinical ♦♦ Choriocarcinoma affects males in their third decade ♦♦ In evaluating a possible mediastinal choriocarcinoma it is important to exclude metastasis from an occult testicular primary choriocarcinoma. Testicular choriocarcinoma may regress in the testis as metastases develop ♦♦ Serum HCG is usually elevated ♦♦ Gynecomastia is a common symptom ♦♦ Mediastinal choriocarcinoma has a poor prognosis

Macroscopic

Immunohistochemistry

♦♦ Choriocarcinoma appears grossly as a necrotic, hemorrhagic mass.

♦♦ Embryonal carcinoma is immunoreactive for keratin, CD30, PLAP, and CD57

Microscopic

Differential Diagnosis

Differential Diagnosis

♦♦ Undifferentiated carcinoma (e.g., thymic carcinoma) of mediastinum −− Occurrence in a young male should raise concern of possible embryonal carcinoma −− Undifferentiated carcinoma is immunopositive for keratin, but negative for CD30 and PLAP ♦♦ Metastatic adenocarcinoma −− Adenocarcinoma is negative for PLAP and CD30 ♦♦ Yolk sac tumor −− Histologically yolk sac tumor includes the presence of Schiller–Duval bodies and a reticular pattern

Yolk Sac Tumor Clinical ♦♦ Yolk sac tumor affects males in the third and fourth decades

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♦♦ Identical to gonadal choriocarcinoma (see Chapter 39) ♦♦ Metastatic choriocarcinoma from a gonadal primary must always be excluded for mediastinal choriocarcinomas. Testicular choriocarcinomas may regress as metastases develop ♦♦ Mixed germ cell tumor includes other components in addition to choriocarcinoma ♦♦ Anaplastic carcinoma −− Immunoreactive for keratin, negative for HCG (however, some large cell carcinomas of lung are immunoreactive for HCG)

Lymphoproliferative Disorders General ♦♦ Lymphoproliferative disorders can occur in all mediastinal compartments. Malignant lymphomas are the most ­common primary neoplasms of the middle portion of ­mediastinum.

Mediastinum and Thymus

Lymphoma may be a primary mediastinal process or a manifestation of disseminated disease (see Chapter 15)

Hodgkin Lymphoma Clinical ♦♦ Hodgkin disease involves the thymus and/or lymph nodes. Hodgkin disease is usually seen in young adults  with a female predominance. Patients may present with local pressure symptoms (dyspnea, cough or chest pain) or an incidental finding on chest x-ray. Mediastinal Hodgkin disease is nearly always nodular sclerosis type and frequently also involves the cervical lymph nodes

Macroscopic ♦♦ These are well-circumscribed tumors with a thick capsule. They can mimic a thymoma. They are composed of single or multiple hard nodules with a lobulated pattern. Occasionally they can be cystic (within thymus)

Microscopic ♦♦ Cellular nodules surrounded by fibrous bands are seen (Fig.  26.17a). They are composed of a polymorphic cell

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population with diagnostic lacunar cells (Fig. 26.17b), and Reed–Sternberg (R-S) cells with a mixed inflammatory background

Immunohistochemistry ♦♦ R-S cells and lacunar cells are CD15+ (Fig.  26.17c) and CD30+ (Fig. 26.17d)

Differential Diagnosis ♦♦ Thymoma (see thymoma above) ♦♦ Thymic cysts (see thymic cyst above)

Primary Mediastinal (Thymic) Large B-Cell Lymphoma Clinical ♦♦ Large B-cell lymphoma presents as a mass in the thymus with or without lymph node involvement. It is usually seen in young adult females (<35 years old). Patients present with superior vena cava syndrome. On radiology a large mass in the anterior mediastinum is seen. The mass frequently invades adjacent structures such as large vessels,

Fig. 26.17. Hodgkin disease. (a) Cellular nodules surrounded by fibrous bands. (b) Polymorphic cell population with diagnostic lacunar cells. (c) CD15 stain. (d) CD30 stain. Note targetoid staining pattern in large neoplastic cells in (c) and (d).

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pericardium, pleura, lung, and chest wall. These tumors frequently recur (usually involving kidney) after initial good response to chemotherapy and radiotherapy

Macroscopic ♦♦ These are large tumors (>10 cm) with grossly invasive features and show extension into pericardium, pleura, lung, ­sternum, and chest wall. They are firm with lobulation and foci of necrosis

Microscopic ♦♦ These tumors have lobules separated by wide fibrous bands (Fig. 26.18a). Neoplastic lymphocytes with large, vesicular, and irregularly shaped nuclei (indented, kidney-shaped, and polylobated) and abundant pale to basophilic cytoplasm (Fig. 26.18b) are also present. Frequent mitotic figures are seen. There is entrapment of intrathymic and perithymic fat. Invasion of blood vessel wall, pleura, or lung is seen. Sometimes abundant reactive histiocytic cells are also present

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Surface immunoglobulins are often negative; when positive, are of IgG or IgA type, in contrast to other large cell lymphomas of nodal origin (IgM or D type) ♦♦ Positive for heavy chain and light chain gene rearrangements ♦♦ Immunophenotype and genotype suggesting a germinal center or post germinal center B-cell origin

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Malignant thymoma: keratin + Germinoma: PLAP+ Hodgkin disease: CD15+, CD30+ Metastatic undifferentiated carcinoma: keratin + Metastatic amelanotic melanoma: S-100 protein +, HMB 45+ Other systemic lymphomas

Immunophenotyping and Genotyping

B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classic Hodgkin Lymphoma Clinical

♦♦ Majority with B-cell phenotype (CD19+, CD20+ (Fig. 26.18c), CD5−, CD21−, CD10+/−, Bcl-6+/−, MUM1+/−)

♦♦ These are B-cell lymphomas that show clinical, morphological, and/or immunophenotypic features of both DLBCL and

Fig. 26.18. Primary mediastinal (thymic) large B-cell lymphoma. (a) Lobules separated by wide fibrous bands. (b) Neoplastic lymphocytes with large, vesicular, and irregularly shaped nuclei (indented, kidney-shaped, polylobated) and abundant pale to basophilic cytoplasm. (c) CD20 stain.

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classic Hodgkin lymphoma (HL). They are usually seen in young males (between ages 20 and 40), but may be seen in younger or older individuals. In about 20% or fewer cases, Epstein-Barr viral sequences have been identified. These tumors most commonly present as a large anterior mediastinal mass with or without supraclavicular lymph node involvement. Patients may present with ­superior vena caval syndrome. These lymphomas have an aggressive clinical course and relatively poorer prognosis compared to either primary mediastinal B-cell lymphoma or classic HL

Microscopic

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shaped, doughnut-shaped, and Reed–Sternberg-like cells. The hallmark anaplastic cells are typically seen in clusters near blood vessels. Although the hallmark cells are large, smaller cells with similar cytologic features can be seen. The tumor cells can grow within lymph node sinuses and are often mistaken for metastatic carcinoma. ALK+ ALCL cases in children without leukemic involvement have the best overall prognosis and ALK negative cases in older individuals have a poorer prognosis

Immunophenotyping

♦♦ Sheets of pleomorphic cells within a diffusely fibrotic stroma are seen. There is variation in the cytomorphological characteristics in different areas of the tumor with some areas showing features of classic HL and other areas showing features of DLBCL. Mild inflammatory infiltrate can be seen. Necrosis is frequent

♦♦ Neoplastic cells are usually CD30+ (membranous and Golgi staining), ALK+, EMA+, CD45+, and one or more T-cell antigens (CD2, CD5, and CD4) positive. Most cases show positivity for TIA1, granzyme B, and/or perforin. CD3 is negative in more than 75% of cases and CD8 is also usually negative. B-cell antigens, CD15, and EBV antigens are usually negative

Immunophenotyping

Differential Diagnosis

♦♦ Neoplastic cells are CD45+, CD30+, and frequently CD15+. CD20 and CD79a are usually positive. Surface or cytoplasmic Ig is absent. PAX-5, OCT-2, and BOB-1 are usually positive. Variably positive for bcl-6 but negative for CD10. Anaplastic lymphoma kinase (ALK) is usually negative

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Differential Diagnosis

Precursor B or T Lymphoblastic Lymphoma Clinical

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Classic Hodgkin lymphoma of B-cell type Classic Hodgkin lymphoma of T-cell type T-cell rich B-cell lymphoma Primary mediastinal DLBCL ALK-negative anaplastic large cell lymphoma

Anaplastic Large Cell Lymphoma Clinical ♦♦ Anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma that usually presents with nodal disease, anaplastic cytologic features, CD30 positivity, and ALK positivity. However, ALK negative ALCL cases are also seen. Approximately 3% of adult lymphomas and 10–20% of childhood lymphomas are ALK+ ALCL. There is a bimodal age distribution with ALK+ ALCL most frequently seen in patients in their first three decades of life. ALCL occurs more commonly in males. Both lymph nodes and extranodal sites such as lung, liver, bone, skin, and soft tissue are frequently involved. Most patients present with peripheral or abdominal lymphadenopathy with frequent involvement of extranodal sites. Frequency of bone marrow involvement is 10–17% on morphologic assessment but can increase to 36% with CD30 immunostaining. Mediastinal presentation of ALCL is less frequent than seen in Hodgkin lymphoma

Microscopic ♦♦ Total or partial obliteration of lymph node architecture with diffuse infiltration of large cells with pleomorphic nuclei containing one or more nucleoli and variable number of ­anaplastic cells including multinucleated forms, horseshoe-

CD30+ B-cell lymphoma with anaplastic features DLBCL with immunoblastic or plasmablastic features Classic Hodgkin lymphoma Metastatic carcinoma or melanoma Histiocytic sarcoma

♦♦ LBLs have a predilection for the thymic region. Children and adolescents present with acute respiratory distress due to a large mediastinal mass. There is a male predominance. Bone marrow, lymph node, central nervous system, and gonads are also usually involved

Macroscopic ♦♦ These are solid, soft, and nonencapsulated masses

Microscopic ♦♦ There is a diffuse and infiltrative pattern of atypical lymphocytic growth involving thymic parenchyma. The neoplastic lymphocytes are medium-sized with very fine chromatin ­pattern with frequent nuclear convolutions (Fig. 26.19a). Numerous mitotic figures and necrotic cells are seen. A starry sky pattern similar to that seen in Burkitt lymphoma is seen. The neoplastic lymphocytes extend into perithymic fat and blood vessels

Immunophenotyping and Genotyping ♦♦ T-cells (80% of cases) −− Immunophenotyping similar to cortical thymocytes (TdT+ [Fig.  26.19b], CD1a+, coexpression of CD4/ CD8). There usually is positive T-cell receptor gene rearrangement ♦♦ B-cells (20% of cases) −− TdT and B-cell marker (CD19, PAX5) are positive. Usually, positive immunoglobulin heavy chain and light chain gene rearrangement is also detected

Differential Diagnosis ♦♦ Thymoma, predominantly lymphoid

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Fig. 26.19. Lymphoblastic lymphoma. (a) Neoplastic lymphocytes with medium-sized, very fine chromatin pattern with frequent nuclear convolutions. Frequent mitotic figures are present. (b) TdT stain. Note the nuclear stain pattern. −− Residual thymic lobules and Hassall corpuscles in LBL can mimic thymomas. Lymphocytes are not atypical in thymoma. Other features of thymoma such as perivascular spaces are present. True thymomas are rare in children ♦♦ Other lymphomas

Low Grade B-Cell Lymphoma of MALT Type Clinical ♦♦ These tumors are localized at diagnosis. They have an indolent clinical course and are usually cured by excision. Some are associated with Sjogren syndrome

Macroscopic ♦♦ They are encapsulated large masses (9–12 cm) with a pale, tan, homogenous cut surface studded with fluid-filled cysts

Microscopic

Macroscopic ♦♦ These tumors show a greenish hue on cut surface

Microscopic ♦♦ Blastic lesions are composed of predominantly myeloblasts. Immature lesions are composed of myeloblasts and promyelocytes. Differentiated lesions are composed of promyelocytes and cells at later stages of maturation

Immunophenotyping and Enzyme Histochemical Stains ♦♦ CD43+, myeloperoxidase +, lysozyme +, chloracetate esterase +

Differential Diagnosis ♦♦ Large cell lymphoma, LBL, and small noncleaved cell lymphoma: see above lymphoproliferative disorders and Chapter 15 ♦♦ Undifferentiated carcinomas are keratin +

♦♦ Normal architecture of the thymus is obscured by lymphoid infiltrate, in which Hassall corpuscles are seen. Lymphoid infiltrate consists of reactive type of follicles and diffuse growth of predominantly “centrocyte-like lymphocytes” (monocytoid B-cells), with abundant, clear, faintly granular cytoplasm, and sharp cell borders, admixed with scattered large transformed lymphocytes and scattered plasma cells. Scattered cysts are lined by attenuated epithelium or Hassall corpuscles are infiltrated by neoplastic lymphocytes.

Extramedullary Plasmacytoma Clinical

Immunophenotyping

♦♦ See Chapter 15

♦♦ CD20+, CD22+, CD5−, CD10−

Granulocytic Sarcoma (Myeloblastoma, Chloroma) Clinical ♦♦ Granulocytic sarcoma may occur de novo, as a manifestation of acute myeloid leukemias at presentation or relapse, or as a manifestation of blastic transformation of a myeloproliferative disorder such as chronic myeloid leukemia. These are most common in pediatric patients. They rarely present in the mediastinum

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♦♦ Extramedullary plasmacytomas rarely involve the mediastinum (they more commonly occur in the head and neck region, primarily in mucosa-associated sites)

Macroscopic, Microscopic, and Differential Diagnosis Castleman Disease (Angiofollicular Lymphoid Hyperplasia) Localized Form: Hyaline-Vascular Type (90% of Cases) Clinical ♦♦ Castleman disease is asymptomatic and seen more commonly in children and adults of middle age. Castleman disease commonly involves the anterosuperior mediastinal lymph nodes. It is rarely centered in the thymus

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Fig. 26.20. Castleman disease (angiofollicular lymphoid hyperplasia), hyaline-vascular type. (a) Abnormal follicles with atrophic germinal centers and expanded mantle zones and striking interfollicular vasculature. (b) One or more small blood vessels entering from perifollicular tissue into follicles.

Macroscopic ♦♦ Castleman disease presents as a single encapsulated mass with a solid, homogenous, gray nodular and sometimes hemorrhagic appearance

Microscopic ♦♦ The tumors show abnormal follicles and striking interfollicular vasculature (Fig. 26.20a). Follicles with expanded mantle zones with atrophic germinal centers are seen. One or more small blood vessels are seen entering from perifollicular tissue into follicles (Fig.  26.20b) and the vessels have hyalinized and thickened walls. More than one small germinal center within a single follicle may be seen

Localized Form: Plasma Cell Type Clinical ♦♦ The clinical features are similar to the hyaline vascular type, but also include systemic manifestations. Patients may have anemia, polyclonal gammopathy, elevated ESR, bone marrow plasmacytosis, and thrombocytosis. The systemic manifestations disappear following excision of the mass

Macroscopic ♦♦ The localized plasma cell type presents as several discrete matted nodes or a mass with adjacent smaller nodes

Microscopic ♦♦ The nodal architecture is relatively well-preserved. The interfollicular areas are densely infiltrated by polyclonal plasma cells (Fig. 26.21a). The central region of the follicle shows abundance of dendritic reticulum cells

Multicentric Form: Plasma Cell Type Clinical ♦♦ The multicentric form usually occurs in older patients. This is frequently associated with HHV-8 infection in HIV infected patients. This is a peripheral nodal disease. These

tumors have a more aggressive clinical course with ­development of malignancies such as Kaposi sarcoma or ­lymphomas. Some are associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, ­monoclonal gammopathy, and skin changes)

Microscopic ♦♦ The plasma cell form is the dominant cell type and the plasma cells frequently are lambda light chain restricted. Plasma cells around the mantle zone have a blastic morphology (Fig. 26.21b)

Differential Diagnosis ♦♦ For hyaline-vascular type −− Other lymphomas including mantle cell lymphoma, follicle center lymphoma, and angioimmunoblastic T-cell lymphoma ♦♦ For plasma cell type −− Lymphadenopathy in patients with rheumatoid arthritis (a) Clinical correlation −− Lymphadenopathy in patients with syphilis (a) Nonnecrotizing (sarcoidal) or necrotizing granulomas are seen (b) Spirochetes may be found −− Lymphoplasmacytic lymphoma ♦♦ For both types −− Lymphadenopathy in patients with HIV infections

Mesenchymal Tumors (Other than Nerve Sheath Tumors) ♦♦ Mesenchymal tumors account for <2% of primary tumors of the mediastinum ♦♦ Many types of mesenchymal tumor have been described ♦♦ Most mesenchymal tumors have similar clinical findings, including mediastinal mass and/or compressive symptoms

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Fig. 26.21. Castleman disease (angiofollicular lymphoid hyperplasia), plasma cell type. (a) Interfollicular areas are densely infiltrated by polyclonal plasma cells (localized form). (b) Some plasma cells with blastic (prominent nucleoli) morphology.

Benign (Low Grade) Mesenchymal Tumors Lipoma Clinical ♦♦ Usually located in anterior compartment ♦♦ Tends to be bulky with extension to bilateral pleural cavities ♦♦ Lipoma can cause respiratory embarrassment

Differential Diagnosis ♦♦ Thymolipoma −− In thymolipoma there is the presence of thymic tissue in addition to mature adipose tissue ♦♦ Lipomatosis −− Refers to a diffuse accumulation of adipose tissue seen in association with obesity, Cushing syndrome, and steroid therapy −− Associated with “sabre-sheath” tracheal deformity ♦♦ Other benign adipose tissue tumors and low grade lipo­ sarcoma (see Chapter 22)

Lymphangioma Clinical ♦♦ Lymphangiomas occur most frequently in the anterosuperior mediastinum. ♦♦ Lymphangiomas usually occur in children, often there is a cervical component (i.e., cystic hygroma)

Macroscopic ♦♦ The gross appearance of lymphangioma is that of a circumscribed mass with large, cystic, and smooth-walled spaces

Microscopic ♦♦ The histologic appearance of lymphangioma includes endothelial-lined lymphatic channels accompanied by a lymphocytic infiltrate

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Differential Diagnosis ♦♦ Hemangioma −− In hemangioma the cystic spaces are blood-filled ♦♦ Lymphangioleiomyomatosis (LAM) −− Prominent smooth muscle component (immunoreactive for HMB 45) −− LAM is infiltrative and occurs almost exclusively in females

Hemangioma Macroscopic ♦♦ Poor circumscription, large cystic spaces filled with blood

Microscopic ♦♦ Cavernous hemangioma is more common in adults. Histologically dilated blood-filled spaces are separated by thin fibrous trabeculae −− Thrombosis, calcification, and cholesterol granulomas are commonly present ♦♦ Cellular hemangiomas are more commonly seen in children.

Differential Diagnosis ♦♦ Lymphangioma (see above) ♦♦ Other vascular tumors include hemangiopericytoma, epithelioid hemangioendothelioma, and angiosarcoma (see Chapter 22)

Solitary Fibrous Tumor Clinical ♦♦ Solitary fibrous tumor of the mediastinum is analogous to solitary fibrous tumor of the pleura. Solitary fibrous tumor of the mediastinum accounts for approximately 15% of all solitary fibrous tumors. Some tumors may extend from the mediastinal pleura; however, most solitary fibrous tumors probably originate from mediastinal fibrous stroma

Mediastinum and Thymus

♦♦ Solitary fibrous tumor of the mediastinum tends to be locally infiltrative and may run an aggressive course. There is a higher rate of sarcomatous transformation than in solitary fibrous tumors of the pleura ♦♦ Some mediastinal solitary fibrous tumors are associated with hyperglycemia, like their pleural counterparts

Macroscopic ♦♦ Solitary fibrous tumor tends to be large, tan, firm, and wellcircumscribed

Microscopic ♦♦ Solitary fibrous tumor is histologically represented by a variable combination of bland-appearing short spindle cells and fibrous stroma with thick collagen bundles

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♦♦ Some liposarcomas may include a heavy lymphoid infiltrate mimicking lymphoma

Differential Diagnosis ♦♦ Lipoma: −− In lipoma lipoblasts are absent ♦♦ Thymic liposarcoma or thymolipoma −− Remnants of thymus gland are present in association with lipomatous neoplasm

Synovial Sarcoma Clinical

♦♦ Solitary fibrous tumors are immunoreactive for CD34 and bcl-2, and are negative for cytokeratin

♦♦ Synovial sarcoma is rare in the mediastinum where it tends to occur in the superior and middle compartments ♦♦ Synovial sarcoma is usually a tumor of adults. Symptoms include pain, dyspnea, and superior vena cava syndrome ♦♦ Most cases follow a highly aggressive course

Differential Diagnosis

Macroscopic and Microscopic

♦♦ Thymoma (hemangiopericytoma-like) is immunoreactive for cytokeratin and negative for CD34 ♦♦ Synovial sarcoma features malignant spindle cells which are immunoreactive (focally) for cytokeratin and bcl-2 and negative for CD34 ♦♦ Sarcomatous mesothelioma features malignant appearing spindle cells which are immunoreactive for keratin and negative for CD34 ♦♦ Fibromatosis shows poor circumscription, and is immunohistochemically negative for CD34 and bcl-2 ♦♦ Spindle-cell liposarcoma lacks the dense collagen of solitary fibrous tumor. Spindle-cell liposarcoma is immunoreactive for CD34 and may weakly express bcl-2 and S-100 ♦♦ Leiomyomas are immunoreactive for smooth muscle markers (smooth muscle actin and desmin) and are negative for CD34 and bcl-2 ♦♦ Nerve sheath tumors are immunoreactive for bcl-2 and S-100, but are negative for CD34

♦♦ Similar to soft tissue counterpart (see Chapter 22)

Immunohistochemistry

Malignant Mesenchymal Tumors Liposarcoma Clinical ♦♦ Most common malignant mesenchymal tumor of the mediastinum; may be associated with liposarcoma at other body sites ♦♦ Liposarcoma usually occurs in adults, is rare in children ♦♦ Some liposarcomas may be cured by surgical excision, however recurrence rate is high

Microscopic ♦♦ The histological appearance of mediastinal liposarcoma is similar to that in other soft tissue locations. Well differentiated liposarcoma is the most common form (60% of cases) including lipoma-like and spindle-cell liposarcoma. Myxoid liposarcoma (28%) and pleomorphic liposarcoma (12%) may also occur

Immunohistochemistry ♦♦ Synovial sarcoma is focally reactive for cytokeratin, bcl-2, and variably reactive for CD99

Cytogenetics ♦♦ Synovial sarcoma is characterized by the t (X;18) translocation

Differential Diagnosis ♦♦ Other spindle-cell sarcomas (see diagnosis for solitary fibrous tumor)

above

differential

Rhabdomyosarcoma Clinical ♦♦ Rhabdomyosarcoma occurs in adults or children, usually as a component of germ cell tumors or sarcomatoid thymic carcinoma. Rhabdomyosarcoma follows a highly aggressive course

Macroscopic and Microscopic ♦♦ Similar to soft tissue counterparts (see Chapter 22)

Metastatic Tumors Small Cell Undifferentiated Carcinoma of Lung Clinical ♦♦ Frequently presents with mediastinal widening due to lymph node metastases that overshadows lung involvement

Differential Diagnosis ♦♦ Thymic small cell undifferentiated carcinoma −− Absence of recognizable lung primary, more solid mass (as opposed to lymph node involvement), and lobulated appearance −− Primary small cell carcinoma of lung is usually TTF1 positive. Primary thymic small cell carcinoma is often TTF1 negative

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Lymphoma −− Tends to show less cell cohesion and a coarse chromatin pattern −− Lymphomas are immunoreactive for LCA and negative for cytokeratin and neuroendocrine markers

Metastases from Distal (Nonthoracic) Sites Clinical ♦♦ Distinguishing metastatic from primary mediastinal tumors is especially problematic for: metastatic germ cell tumors, melanoma, and prostatic carcinoma ♦♦ Clinical data and radiographic imaging may suggest an extrathoracic primary site

Macroscopic ♦♦ Lymph node involvement often predominates in metastatic lesions with lesser degree of extranodal soft tissue spread

Differential Diagnosis ♦♦ In the consideration of thymic carcinoma and primary germ cell tumors, metastases from an extramediastinal source must always be excluded ♦♦ In distinguishing thymic carcinoma from histologically similar tumors of the lung or head and neck, thymic carcinoma tends to have a lobulated appearance and may express CD5 (approximately 50% of cases), CD70 (50%), or CD117 (40–100%). These markers are usually negative in metastatic tumors of lung or head and neck origin Direct extension of tumors from esophagus, chest wall, vertebrae, pleura, lung, and trachea (Fig. 26.22)

Fig. 26.22. Mediastinal structures are encased by direct extension from a nonsmall cell lung cancer. Tumor replaces lymph node (LN), invades and compresses SVC (arrows), and surrounds aortic arch (AO) and pulmonary arteries (PA).

TNM Classification of Thymoma ♦♦ Primary Tumor (T) −− T1: M  acroscopically completely encapsulated and microscopically no capsular invasion −− T2: M  acroscopic adhesion or invasion into surrounding fatty tissue or mediastinal pleura, or microscopic invasion into capsule −− T3: I nvasion into neighboring organs, such as pericardium, great vessels, and lung −− T4: Pleural or pericardial dissemination ♦♦ Regional Lymph Node (N) −− N0: No lymph node metastasis −− N1: Metastasis to anterior mediastinal lymph nodes −− N2: Metastasis to intrathoracic lymph nodes other than anterior mediastinal lymph nodes −− N3: Metastasis to extrathoracic lymph nodes

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♦♦ Distant metastasis (M) −− M0: No distal metastasis −− M1: Distal metastasis ♦♦ Clinical Staging −− Stage I: C  ompletely encapsulated without microscopic capsular invasion (benign thymoma) −− Stage II: M  acroscopic invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule −− Stage III: M  acroscopic invasion into neighboring organs (i.e., pericardium, great vessels, or lung) −− Stage IVa: Diffuse pleural or pericardial involvement −− Stage IVb: Distal metastasis

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Pericardial

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Inflammation/Fibrosing Mediastinitis Berry DF, Buccigriossi D, Peabody J, et al. Pulmonary vascular occlusion and fibrosing mediastinitis. Chest 1986;89:296–301. Crotty TB, Colby TV, Gay PC, et al. Desmoplastic malignant mesothelioma masquerading as sclerosing mediastinitis: a diagnostic dilemma. Hum Pathol 1992;23:79–82. Dines DE, Payne WS, Bernatz PW, et  al. Mediastinal granuloma and fibrosing mediastinitis. Chest 1979;75:320–324. Flieder DB, Suster S, Moran CA. Idiopathic fibroinflammatory (fibrosing/ sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity. Mod Pathol 1999;12:257–264.

Nonneoplastic Lesions of Thymus Berry CL, Thompson EN. Clinico-pathological study of thymic dysplasia. Arch Dis Child 1968;43:579–584. Gow KW, Kobrynski L, Abramowsky C, Lloyd D. Massive benign thymic hyperplasia in a six-month-old girl: case report. Am Surg 2003;69:717–719. Levine GD, Rosai J. Thymic hyperplasia and neoplasia: review of current concepts. Hum Pathol 1978;9:495–515. Parrens M, Dubus P, Danjoux M, et al. Mucosa-associated lymphoid tissue of the thymus – hyperplasia vs lymphoma. Am J Clin Pathol 2002;117:51–56. Van Baarlen J, Schuurman H-J, Huber J. Acute thymus involution in infancy and childhood: reliable marker for duration of acute illness. Hum Pathol 1988;19:1155–1160.

Lesions Mimicking Mediastinal Tumors

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Pneumomediastinum Bejvan SM, Godwin JW. Pneumomediastinum: old signs and new signs. AJR 1996;166:1041–1048. Wright CD. Non-neoplastic disorders of mediastinum. In: Fishman AP, ed. Pulmonary Diseases and Disorders. 3rd ed. New York: McGraw-Hill; 1998:1485–1498.

Thymoma Addis BJ, den Bakker MA. Classifying thymomas. Histopathology 2008;52:759–766. Chalabreysse L, Roy P, Cordier JF, Loire R, Gamondes JP, ThivoletBejui F. Correlation of the WHO schema for the classification of thymic epithelial neoplasms with prognosis: a retrospective study of 90 tumors. Am J Surg Pathol 2002;26:1605–1611. Chen G, Marx A, Wen-Hu C, Yong J, Puppe B, Stroebel P, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420–429.

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Thymic Carcinoid Tumor

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Thymic Stromal Tumors

Tomaszek S, Wigle DA, Keshavjee S, Fischer S. Thymomas: review of current clinical practice. Ann Thorac Surg 2009;87:1973–1980. Wu M, Sun K, Gil J, Gan L, Burstein DE. Immunohistochemical detection of p63 and XIAP in thymic hyperplasia and thymomas. Am J Clin Pathol 2009;131:689–693.

Moran CA, Rosado-de-christenson M, Suster S. Thymolipoma: clinicopathologic review of 33 cases. Mod Pathol 1995;8:741–744. Havlicek F, Rosai J. Sarcoma of thymic stroma with features of liposarcoma. Am J Clin Pathol 1984;82:217–224.

Neurogenic Tumors Thymic Carcinoma Berezowski K, Grimes MM, Gal A, et al. CD5 immunoreactivity of epithelial cells in thymic carcinoma and CASTLE using paraffin-embedded tissue. Am J Clin Pathol 1996;106:483–486. Brown JG, Familiari U, Papotti M, Rosai J. Thymic basaloid carcinoma: a clinicopathologic study of 12 cases. With a general discussion of basaloid carcinoma and its relationship with adenoid cystic carcinoma. Am J Surg Pathol 2009;33:1113–1124. Dorfman DM, Shahsafaei A, Chan JK. Thymic carcinomas, but not thymomas and carcinomas of other sites, show CD5 immunoreactivity. Am J Surg Pathol 1997;21:936–940. Hasserjian RP, Klimstra DS, Rosai J. Carcinoma of thymus with clear cell features: report of eight cases and review of literature. Am J Surg Pathol 1995;19:835–841. Kornstein MJ, Rosai J. CD5 labeling of thymic carcinomas and other nonlymphoid neoplasms. Am J Clin Pathol 1998;109:722–726.

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Ackerman LV, Taylor FH. Neurogenous tumors within thorax. A clinical pathologic evaluation of forty-eight cases. Cancer 1951;4:669–691. Akwari OE, Payne WS, Onofrio BM, et al. Dumbbell neurogenic tumors of mediastinum: diagnosis and management. Mayo Clin Proc 1978;53: 353–358. Carachi R, Campbell PE, Kent M. Thoracic neural crest tumors. A clinical review. Cancer 1983;51:949–954. Oberman HA, Abell MR. Neurogenous neoplasms of mediastinum. Cancer 1960;13:882–898.

Paragangliomas Odze R, Begin LR. Malignant paraganglioma of posterior mediastinum case report and review of literature. Cancer 1990;65:564–569. Olson JL, Salyer WR. Mediastinal paragangliomas (aortic body tumor) report of four cases and review of literature. Cancer 1978;41:2405–2412.

Mediastinum and Thymus

Mediastinum Germ Cell Tumors den Bakker MA, Oosterhuis JW. Tumours and tumour-like conditions of the thymus other than thymoma; a practical approach. Histopathology 2009;54:69–89. de Ment SH. Association between mediastinal germ cell tumors and hematologic malignancies: update. Hum Pathol 1990;21:699–703. Kazur ME, Cobleigh MA, Greco FA, et al. Endodermal sinus tumor of mediastinum. Cancer 1982;50:766–774. Moran CA, Suster S. Mediastinal seminomas with prominent cystic changes. A clinicopathologic study of 10 cases. Am J Surg Pathol 1995;19:1047–1053. Moran CA, Suster S. Primary germ cell tumors of the mediastinum: I. Analysis of 322 cases with special emphasis on teratomatous lesions and a proposal for histopathologic classification and clinical staging. Cancer 1997;80:681–690. Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediastinum. III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum – a clinicopathologic and immunohistochemical study of 64 cases. Cancer 1997;80:699–707. Moran CA, Suster S, Przygodzki RM, Koss MN. Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas – a clinicopathologic and immunohistochemical study of 120 cases. Cancer 1997;80:691–698. Sung M-T, MacLennan GT, Lopez-Beltran A, Zhang S, Montironi R, Cheng L. Primary mediastinal seminoma: a comprehensive assessment integrated with histology, immunohistochemistry, and fluorescence in situ hybridization for chromosome 12p abnormalities in 23 cases. Am J Surg Pathol 2008;21:146–155. Suster S, Moran CA, Dominguez-Malagon H, Quevedo-Blanco P. Germ cell tumors of the mediastinum and testis: a comparative immunohistochemical study of 120 cases. Hum Pathol 1998;29:737–742.

Mediastinum Lymphoproliferative and Myeloproliferative Disorders Davis RE, Dorfman RF, Warnke RA. Primary large-cell lymphoma of thymus: a diffuse B-cell neoplasm presenting as primary mediastinal lymphoma. Hum Pathol 1990;21:1262–1268. de Leval L, Ferry JA, Falini B, Shipp M, Harris NL. Expression of bcl-6 and CD10 in primary mediastinal large B-cell lymphoma: evidence for derivation from germinal center B cells? Am J Surg Pathol 2001;25:1277–1282. Isaacson PG, Chan JK, Tang C, et  al. Low grade B-cell lymphoma of mucosa-associated lymphoid tissue arising in the thymus. A thymic lymphoma mimicking myoepithelial sialadenitis. Am J Surg Pathol 1990;14:342–351. Keller AR, Hochholzer L, Castleman B. Hyaline–vascular and plasma – cell types of giant lymph node hyperplasia of mediastinum and other locations. Cancer 1972;29:670–683.

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Kubonishi I, Ohtsuki Y, Machida K-I, et al. Granulocytic sarcoma presenting as mediastinal tumor. Report of case and cytological and cytochemical studies of tumor cells in vivo and in vitro. Am J Clin Pathol 1984;82:730–734. Lamarre L, Jacobson JO, Aisenberg AC, et al. Primary large cell lymphoma of mediastinum. A histologic and immunophenotypic study of 29 cases. Am J Surg Pathol 1989;13:730–739. Perrone T, Frizzera G, Rosai J. Mediastinal diffuse large–cell lymphomas with sclerosis. A clinicopathologic study of 60 cases. Am J Surg Pathol 1986;10:176–191. Sander CA, Jaffe ES, Gebhardt FC, et  al. Mediastinal lymphoblastic lymphoma with immature B-cell immunophenotype. Am J Surg Pathol 1992;16:300–305. Suster S, Moran CA. Pleomorphic large cell lymphomas of mediastinum. Am J Surg Pathol. 1996;20:224–232. Pileri SA, Gaidano G, Zinzani PL, Falini B, Gaulard P, Zucca E, et al. Primary mediastinal B-cell lymphoma: high frequency of BCL-6 mutations and consistent expression of the transcription factors OCT-2, BOB.1, and PU.1 in the absence of immunoglobulins. Am J Pathol 2003;162:243–253. Swerdlow SH, Campo E, Harris NL, et al (eds). WHO classification of tumours of haematopoietic and lymphoid tissues. WHO classification of tumours. IARC Press, Lyon, 2008.

Mediastinum Mesenchymal Tumors Brown LR, Reiman HM, Rosenow EC III, et  al. Intrathoracic lymphangioma. Mayo Clin Proc 1986;61:882–892. Cheng LSL, Tse GMK, Li WWL, Lee TW, Yim APC. Mediastinal synovial sarcoma: a case report and literature review. Can Respir J 2003;10:393–395. Hanau CA, Miettinen M. Solitary fibrous tumor: histological and immunohistochemical spectrum of benign and malignant variants presenting at different sites. Hum Pathol 1995;26:440–449. Hoffman OA, Gillespie DJ, Aughenbaugh GL, et al. Primary mediastinal neoplasms (other than thymoma). Mayo Clin Proc 1993;68:880–891. Klimstra DS, Moran CA, Perino G, et al. Liposarcoma of anterior mediastinum and thymus. A clinicopathologic study of 28 cases. Am J Surg Pathol 1995;19:782–791. Moran CA, Suster S, Perino G, et al. Malignant smooth muscle tumors presenting as mediastinal soft tissue mass. A clinicopathologic study of 10 cases. Cancer 1994;74:2251–2260. Suster S, Moran CA, Koss MN. Epithelioid hemangioendothelioma of anterior mediastinum: clinicopathologic, immunohistochemical and ultrastructural analysis of 12 cases. Am J Surg Pathol 1994;18: 871–881. Witkin GB, Miettinen M, Rosai J. Biphasic tumor of mediastinum with features of synovial sarcoma. A report of four cases. Am J Surg Pathol 1989;13:490–499. Witkin GB, Rosai J. Solitary fibrous tumor of the mediastinum. A report of 14 cases. Am J Surg Pathol 1989;13:547–557.

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27 Cardiovascular Pathology Eric A. Pfeifer, md

Contents

I. Pathology of Heart.............................27-2 Congenital Heart Disease................................27-2 Aortic Stenosis........................................27-2 Atrial Septal Defect (ASD).....................27-2 Coarctation of Aorta..............................27-2 Patent Ductal Artery (Patent Ductus Arteriosis, PDA)....................27-2 Pulmonary Stenosis................................27-2 Tetralogy of Fallot...................................27-2 Transposition of Great Arteries............27-2 Ventricular Septal Defect (VSD)...........27-2 Acquired Diseases of the Myocardium...........27-3 Ischemic Heart Disease..........................27-3 Cardiomyopathy (Heart Muscle Disease of Unclear Cause).................27-3 Hypertensive Heart Disease...................27-5 Infiltrative Myocardial Diseases............27-5 Myocarditis..............................................27-5 Anthracycline Cardiotoxicity................27-6 Angiokeratoma Corporis Diffusum Universale...........................................27-6 Diseases of the Pericardium............................27-6 Pericardial Effusion and Hemopericardium..............................27-6 Pericarditis..............................................27-6 Diseases of the Valves and Endocardium.......27-7 Acute and Chronic Rheumatic Heart Disease......................................27-7 Aortic Valve Stenosis..............................27-7 Aortic Valve Insufficiency......................27-8 Carcinoid Heart Disease (CHD)............27-8 Endocarditis: Infectious.........................27-8

Endocarditis: Noninfectious..................27-8 Mitral Regurgitation..............................27-8 Mitral Stenosis........................................27-8 Prosthetic Valves.....................................27-9 Cardiac Neoplasms...........................................27-9 Benign Tumors........................................27-9 Malignant Tumors................................27-11

II. Pathology of Blood Vessels...............27-12 Arteriosclerosis...............................................27-12 Atherosclerosis......................................27-12 Hypertensive Vascular Disease............27-12 Fibromuscular Dysplasia...............................27-13 Myxoid Medial Degeneration (Cystic Medial Necrosis) of Aorta............27-13 Aneurysms......................................................27-13 Atherosclerotic Aneurysm of the Abdominal Aorta.............................27-13 Berry Aneurysm of Cerebral Arteries.............................................27-14 Infectious (Mycotic) Aneurysms.........27-14 Syphilitic Aneurysms............................27-14 Dissection........................................................27-14 Vasculitis.........................................................27-14 Infectious Vasculitis..............................27-15 Noninfectious Vasculitis (Mediumto Large-Sized Vessels)....................27-15 Noninfectious Vasculitis (Smallto Medium-Sized Vessels)................27-15

III. Suggested Reading...........................27-17

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_27, © Springer Science+Business Media, LLC 2002, 2006, 2011

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PATHOLOGY OF HEART Congenital Heart Disease ♦♦ General Information −− 0.6–0.8% of live births −− No identifiable cause in most cases −− Approximately 5% associated with chromosomal abnormality −− First trimester rubella infection can lead to patent ductal artery, pulmonary stenosis −− Down syndrome associated with septal defects (atrial and ventricular), defects of atrioventricular valves −− Turner syndrome associated with coarctation of aorta −− Drugs, such as alcohol and thalidomide, can also lead to congenital heart abnormalities

Aortic Stenosis ♦♦ Approximately 6% of congenital heart abnormalities ♦♦ May assume valvular and subvalvular forms ♦♦ Most common cause is bicuspid aortic valve, with typical clinical presentation of valve failure in early middle age

Atrial Septal Defect (ASD) ♦♦ Comprises approximately 10% of congenital abnormalities ♦♦ Ostium secundum (OS) defect is much more common than ostium primum (OP) defect −− Diagnosis was usually made clinically in both cases ♦♦ Often not detected in childhood but presents in adult ♦♦ Results in increased pulmonary blood flow, systolic ejection murmur, widely split second heart sound, eventual right ventricular hypertrophy ♦♦ Most important complication is pulmonary hypertension; others include right heart failure, paradoxical embolization ♦♦ OP ASD presents in childhood, associated with mitral valve defects and mitral incompetence

Coarctation of Aorta ♦♦ Approximately 7% of congenital heart abnormalities ♦♦ Coarctation located usually just distal to ductus arteriosus (adult type), but may occur just proximal to this structure in infantile type ♦♦ More common in males ♦♦ Common in Turner syndrome ♦♦ Approximately 60% will die (frequently of aortic rupture) by age 40 if not corrected ♦♦ 50% of cases associated with other congenital heart defects

Patent Ductal Artery (Patent Ductus Arteriosis, PDA) ♦♦ Manifestations depend on the size of communication between aorta and pulmonary artery ♦♦ Indomethacin induces closure by inhibiting prostaglandin E (PGE) synthesis

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♦♦ Small PDA results in small left-to-right shunt, with “machinery” murmur ♦♦ Very mild symptoms in patients with small PDA ♦♦ Large PDA results in large shunt, with pulmonary hypertension, eventuating in shunt reversal with cyanosis

Pulmonary Stenosis ♦♦ Approximately 7% of congenital heart abnormalities ♦♦ Caused usually by valve cusp fusion ♦♦ In case of pulmonary atresia, right ventricle will behypoplastic

Tetralogy of Fallot ♦♦ ♦♦ ♦♦ ♦♦

Most common cyanotic congenital anomaly Presents at birth with severe cyanosis Poor prognosis if not corrected surgically Four classic anatomical findings −− Ventricular septal defect (VSD) −− Dextroposed aorta that overrides right ventricular outflow tract, and leads to (a) Pulmonary stenosis, which leads to (b) Right ventricular hypertrophy

Transposition of Great Arteries ♦♦ Approximately 4% of congenital heart defects ♦♦ Cyanosis at birth ♦♦ Child does not survive without some interatrial communication (PDA, VSD) ♦♦ Can be corrected surgically ♦♦ Grossly, aorta arises from morphologic right ventricle and is situated anterior and to the right of pulmonary artery (normal is situated posterior and to the right of pulmonary artery)

Ventricular Septal Defect (VSD) ♦♦ Most common cardiac defect seen in children ♦♦ Classified according to the size of the defect, e.g., large, small (<5 mm) ♦♦ Mostly occurs in membranous portion of interventricular septum ♦♦ May predispose to infective endocarditis

Small VSD ♦♦ Infrequent, minor symptoms usually ♦♦ Systolic murmur with mild shunt ♦♦ May close spontaneously as the patient gets older

Large VSD ♦♦ More serious than small VSDs ♦♦ Large left-to-right shunts producing −− Volume overload −− Biventricular hypertrophy −− Pulmonary hypertension

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−− Eventual reversal of shunt with cyanosis (Eisenmenger syndrome)

Acquired Diseases of the Myocardium Ischemic Heart Disease Clinical ♦♦ Most often due to coronary artery atherosclerosis ♦♦ Sometimes with demonstrable complications (plaque rupture, thrombosis, etc.) in the acute setting ♦♦ May manifest as angina pectoris, myocardial infarct (MI), congestive heart failure, arrhythmias, and sudden death ♦♦ Complications include −− Arrhythmia −− Congestive heart failure −− Hypotension −− Post-MI ventricular and/or papillary muscle dysfunction rupture −− Extension of infarct −− Pericarditis −− Microbial colonization −− Mural thrombosis/embolism −− Ventricular aneurysm/rupture

Macroscopic ♦♦ Myocardial necrosis in an acute MI may appear grossly as myocardial mottling or even as hemorrhagic-appearing areas (Fig. 27.1) ♦♦ May be either transmural, patchy, or subendocardial ♦♦ Usually no grossly detectable changes in first 6–12 h ♦♦ After 18–24  h, there may be either myocardial pallor or a red-blue discoloration ♦♦ The infarcted zone begins to appear yellow as polymorphonuclear neutrophils move in (2–3 days) ♦♦ By 7–8 weeks, cicatrization may be complete ♦♦ “Old” ischemic heart disease may manifest as an old MI, interstitial myocardial fibrosis, chamber dilation, and compensatory hypertrophy (Fig. 27.2)

Fig. 27.1. Macroscopic view of autopsy heart showing dark red discoloration of an acute MI in the left ventricle.

Microscopic ♦♦ Acute myocardial ischemia, with eosinophilic change in myocytes, contraction bands, myocytolysis, and inflammatory response (see Table 27.1, Figs. 27.3 and 27.4) ♦♦ Old myocardial ischemia (as interstitial fibrosis [Fig.  27.5], vacuolar change in cardiac myocytes) ♦♦ Compensatory myocyte hypertrophy

Cardiomyopathy (Heart Muscle Disease of Unclear Cause) Idiopathic Hypertrophic Cardiomyopathy Clinical ♦♦ 50% familial (autosomal dominant), myosin ♦♦ Heavy chain defect

Fig. 27.2. Macroscopic view of autopsy heart showing old myocardial ischemia, now interstitial fibrosis (white areas) of left ventricle.

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Table 27.1. Sequence of Certain Microscopic Changes in Acute Myocardial Ischemia (Approximate) Time after event

Histopathologic findings

1 day

Eosinophilic necrosis, edema, interstitial hemorrhage, contaction band change, nuclear pyknosis, beginning neutrophil infiltration

2–3 days

Marked neutrophil infiltrate, loss of nuclei, and striations

3 days to 1 week

Beginning macrophage infiltration, with phagocytosis and early fibroblastic response

10 days

Extensive phagocytosis, granulation tissue formation

2 months

Cicatrization

Fig. 27.5. Interstitial fibrosis. ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

HLA linkage to chromosome 6 Symptoms of left ventricular outflow obstruction Associated with sudden death during exercise Treated by beta adrenergic blockage, septal Myotomy or myomectomy

Macroscopic ♦♦ Asymmetric septal hypertrophy ♦♦ Mitral valve thickening and enlarged left atrium

Microscopic ♦♦ Nonspecific myofiber disarray, hypertrophy, patchy interstitial fibrosis

Differential Diagnosis ♦♦ Hypertensive or valvular (especially aortic) heart disease, which may show concentric left ventricular hypertrophy Fig. 27.3. Acute myocardial contraction band necrosis.

Idiopathic Dilated Cardiomyopathy ♦♦ Often severe four-chamber dilation grossly ♦♦ Biopsy may show nonspecific hypertrophy, interstitial fibrosis ♦♦ The differential diagnosis includes ruling out ischemia and other causes

Arrhythmogenic Right Ventricular Cardiomyopathy (Arrhythmogenic Right Ventricular Dysplasia [ARVD]) (Fig. 27.6)

Fig. 27.4. Acute myocardial infarction.

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♦♦ Associated with asymptomatic, arrhythmias, and sudden death ♦♦ Can be familial ♦♦ Gross infiltration of right ventricular free wall by fat and/or fibrous tissue, with dilation and wall thinning ♦♦ Left ventricle may also be involved ♦♦ Myocyte loss, with presence of admixed myocytes, adipose, and/or fibrous tissue ♦♦ Myocarditis may be present

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Fig. 27.6. Biopsy of patient with arrhythmogenic right ventricular cardiomyopathy.

Fig. 27.7. Amyloidosis: Congo red staining showed apple green interstitial and vascular amyloid deposits.

♦♦ The differential diagnosis includes normal fat infiltration of right ventricle, especially in obese persons

Glycogen Storage Diseases

Hypertensive Heart Disease ♦♦ Secondary to longstanding systemic hypertension ♦♦ Grossly, concentric left ventricular hypertrophy ♦♦ Must exclude the possible contribution of valvular disease, etc., to the hypertrophy

Infiltrative Myocardial Diseases Amyloidosis Clinical ♦♦ Depending upon the type and degree of involvement, it may be asymptomatic or present with congestive heart failure, arrhythmias, valve disease, ischemic disease, and sudden death ♦♦ Amyloid in heart, which may be deposited in most types of amyloidosis, may be further characterized by identifying protein subclass, using immunohistochemical techniques ♦♦ In senile systemic amyloidosis with cardiac involvement, amyloid is composed of transthyretin ♦♦ Atrial amyloid can be composed of atrial natriuretic factor, a naturally occurring material produced in the atrium

Macroscopic ♦♦ Extensive deposits may lead to pale, firm, and rubbery myocardium ♦♦ Valvular deposits may appear waxy and shiny

Microscopic ♦♦ Amorphous, extracellular, pink material on hematoxylin and eosin (H&E) stained section ♦♦ Deposits can be interstitial and/or intravascular, and may cause vessel stenosis ♦♦ By definition, deposits are Congo red positive, with apple green birefringence with polarized light (Fig. 27.7) ♦♦ Electron microscopy is also definitive, but rarely necessary

♦♦ Excess sequestration of various glycogen storage products leads to heart failure

Hemochromatosis/Hemosiderosis ♦♦ Systemic iron deposition with organ damage (usually in hemochromatosis) ♦♦ Iron stain to demonstrate reticuloendothelial iron in hemosiderosis, parenchymal iron in hemochromatosis

Myocarditis ♦♦ “Dallas criteria”: leukocytic infiltrate (usually lymphocytic) with myocyte degeneration/necrosis

Clinical ♦♦ Associated with viral infections (most often coxsackievirus B), bacterial, fungal, parasitic, collagen-vascular disease, drug reaction, and radiation ♦♦ Complications include congestive heart failure, conduction defects, arrhythmias, and sudden death

Macroscopic ♦♦ Range from normal to biventricular dilation/hypertrophy with pale “flabby” myocardium or fibrosis

Microscopic ♦♦ In most cases, a T-cell lymphocytic infiltrate admixed with histiocytes (Fig.  27.8), occasionally with eosinophils, and necessarily with myocyte destruction ♦♦ Giant cells are seen in giant cell or Fiedler myocarditis (idiopathic), as well as sarcoidosis ♦♦ Distinction between these two entities may be difficult

Variant: Giant Cell Myocarditis ♦♦ Occurs in young and middle-aged adults ♦♦ Presents with arrhythmias, conduction defects, cardiac failure, and sudden death (50%)

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♦♦ Etiology unknown, may be due to lipid peroxidation of ­myofiber membrane ♦♦ Earliest changes include myocyte vacuolization secondary to sarcotubular system dilation ♦♦ “Adria” cells: myocyte with loss of cross striation and homogenous basophilic staining ♦♦ EM findings include cytoplasmic vacuolization, sarcotubular system dilation, and lysis of myofibrils ♦♦ Grading (0–3) is based on the percentage of cells affected in ten plastic-embedded blocks of tissue

Angiokeratoma Corporis Diffusum Universale

Fig. 27.8. Acute myocarditis.

♦♦ X-linked recessive inheritance ♦♦ Deficiency of lysosomal alpha galactosidase leading to ceramide trihexoside ♦♦ Accumulation ♦♦ Skin, cornea, kidney, and heart affected ♦♦ Microscopically, myocyte vacuolization seen ♦♦ Intralysosomal concentric or parallel lamellae by electron microscopy

Diseases of the Pericardium Pericardial Effusion and Hemopericardium Clinical ♦♦ Accumulation of fluid (serous, chylous, serosanguinous) and/or pure blood in pericardial sac, respectively ♦♦ If volume is rapidly increasing, cardiac tamponade may result

Macroscopic Fig. 27.9. Giant cell myocarditis.

♦♦ Rapidly progressive and fatal; heart transplantation may be indicated ♦♦ Associated with thymoma, lupus, and thyrotoxicosis

Microscopic ♦♦ Lymphohistiocytic infiltration and geographic myocyte necrosis (Fig. 27.9) ♦♦ Lacks discrete granulomas or epithelioid histiocytes ♦♦ Giant cells are of both macrophage and myocyte origin

Differential Diagnosis ♦♦ Cardiac sarcoidosis −− Myocardial necrosis associated with discrete nonnecrotizing epithelioid granulomata

Anthracycline Cardiotoxicity ♦♦ Includes cases associated with doxorubicin (adriamycin) and daunorubicin

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♦♦ Excess fluid/blood in sac (>50 mL or so) ♦♦ Fibrinous exudate in fibrinous pericarditis (see below) ♦♦ Hemopericardium usually due to ruptured myocardial infarction, trauma, and aortic rupture ♦♦ Serosanguinous exudate most often due to malignancy, but infection and renal failure (uremic pericarditis) need to be considered

Pericarditis Acute Pericarditis Clinical ♦♦ Fever, friction rub, heart failure, pain

Macroscopic ♦♦ Serous exudate: usually noninfectious ♦♦ Fibrinous: acute MI, post-MI (Dressler syndrome), uremia, radiation, trauma, lupus, and rheumatic fever ♦♦ Purulent: usually due to infections, but consider malignant effusion ♦♦ Hemorrhagic: usually due to malignancy in pericardium, also tuberculosis (TB) in other countries

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Aortic Valve Stenosis Clinical

Fig. 27.10. Chronic fibrosing pericarditis.

♦♦ Caseous (rare!): TB until proven otherwise, infrequently fungi

Chronic Pericarditis ♦♦ Healed phase of acute pericarditis ♦♦ May result in constrictive pericarditis ♦♦ Fibrosis, sometimes residual collections of lymphocytes (Fig. 27.10)

Diseases of the Valves and Endocardium Acute and Chronic Rheumatic Heart Disease ♦♦ Included here, although it can affect valves as well as myocardium and/or pericardium, because long-term effects in survivors are predominantly valvular

Clinical ♦♦ Recurrent acute febrile disease of children following streptococcal pharyngitis (group A Streptococcus) ♦♦ Etiology is due to an autoimmune mechanism ♦♦ Most common cause of mitral stenosis

Gross ♦♦ Stereotypically, mitral valve thickening, chordal fusion

Microscopic ♦♦ Subendocardial/perivascular areas of fibrinoid necrosis in acute form ♦♦ Later, lymphocytic then macrophage infiltrates that may become granulomatous ♦♦ These are called Aschoff bodies, and they may contain characteristic “caterpillar cell” ♦♦ Small valvular vegetations may be present ♦♦ In chronic form, one may see (especially mitral) valvular fibrosis and thickening, calcification, with thickened and shortened chordae (see “Mitral Stenosis,” below)

♦♦ Most common cause of left ventricular outflow obstruction ♦♦ Patients may develop concentric left ventricular hypertrophy, pulmonary hypertension, infective endocarditis, and systemic embolization ♦♦ Associated with sudden death ♦♦ Most commonly a consequence of congenital bicuspid aortic valve (in persons younger than 70), and degenerative fibrosis and calcification (senile-type) in persons older than 70 ♦♦ Other etiologies of aortic valve stenosis include congenital unicuspid valve, postinflammatory (rheumatic) state, which occurs usually in association with mitral valve involvement ♦♦ A small percentage of cases may preclude definitive assessment

Congenital Bicuspid Aortic Valves ♦♦ Rarely stenotic at birth ♦♦ Tend to develop fibrosis and calcification with increasing age, resulting in stenosis ♦♦ Prevalence of stenosis is proportional with age ♦♦ Gross cusps are oriented either anterior–posterior, or right–left ♦♦ A raphe may be seen in either right or anterior cusp, depending on the orientation ♦♦ Calcification and fibrosis may be severe

Degenerative Fibrosis and Calcification (Senile-Type) ♦♦ Occurs in three-cusped aortic valves ♦♦ Usually affects patients older than 60 years ♦♦ Gross calcification and fibrosis of valve cusps, with calcific deposits that may fill sinuses of Valsalva ♦♦ Senile-type calcification and fibrosis may be associated with fusion of one or more comissures, making the distinction from congenital bicuspid valve difficult ♦♦ Helpful features are summarized in Table 27.2

Table 27.2. Helpful Distinguishing Features of Congenital and Bicuspid Aortic Valves Acquired commisural fusion

Congenital bicuspid valve

Intercommisural distances are nearly equal in three cusps

Intercommisural distance of each fused cusp is smaller than the unfused cusp

Cephalad height of raphe is equal to the height of unfused commissures

Cephalad height of raphe is lower than the height of unfused commissures

Raphe is wide and extends to the cusp margin

Raphe is narrow and does not extend to the cusp margin

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Aortic Valve Insufficiency ♦♦ May result from a lesion of valvular cusps or dilation of aortic root itself ♦♦ Cusp lesions may include postinflammatory, rheumatic changes, infectious endocarditis, congenital bicuspid valve, and others

Carcinoid Heart Disease (CHD) Clinical ♦♦ Occurs in setting of metastatic carcinoid tumor, in patients with the carcinoid syndrome ♦♦ Left-sided lesions are associated with carcinoid tumors in the lung ♦♦ The valvular lesions may cause pulmonary stenosis, tricuspid regurgitation, but rarely pure tricuspid stenosis

Macroscopic ♦♦ White endocardial or valvular plaques, usually of right atrium and/or ventricle

Microscopic ♦♦ Smooth muscle proliferation in proteoglycan-rich matrix

Differential Diagnosis ♦♦ Endocardial fibroelastosis, which unlike CHD, occurs in infants and children (typically not adults)

Endocarditis: Infectious (Fig. 27.11) ♦♦ Usually due to hematogenously transmitted infections of bacteria, but fungi are also sometimes seen; rarely viral ♦♦ Most commonly Staphylococci and Streptococci (viridans, bovis, and faecalis), which are less virulent than Staphylococcus aureus ♦♦ Complications include −− Valve insufficiency (or stenosis less commonly) −− Thrombosis and septic systemic embolization

Essentials of Anatomic Pathology, 3rd Ed.

−− Grossly friable vegetations on the side of direct flow, often near the free edge (composed of thrombus material and bacteria or fungi, etc.) −− Endothelial injury −− Abscess formation −− Valve destruction −− Acute myocarditis ♦♦ IV drug use may lead to infectious endocarditis, usually of right-sided valves

Endocarditis: Noninfectious Nonbacterial Thrombotic Endocarditis (Marantic Endocarditis) ♦♦ Occurs in setting of cancer (especially mucinous adenocarcinoma) or other systemic wasting illness ♦♦ May embolize ♦♦ Grossly, small or large fibrin masses ♦♦ Without organisms, present at the lines of closure on the aortic or mitral valves ♦♦ Microscopically, fibrin and entrapped red blood cells; no inflammation

Libman–Sacks Disease (Verrucous Endocarditis) ♦♦ Seen in systemic lupus erythematosus (SLE) ♦♦ Multiple small leaflet vegetations, usually on nonflow side (ventricular surface) of mitral and/or tricuspid valves ♦♦ Microscopically, fibrin intermixed with cellular debris and scattered inflammatory cells

Mitral Regurgitation Floppy Mitral Valve/Mitral Valve Prolapse Clinical ♦♦ Most common cause of mitral regurgitation in one series ♦♦ Risk of developing severe regurgitation due to the floppy valve increasing in its size with age, especially over 50 ♦♦ Complications include ruptured chordae, infective endocarditis, thromboembolism, arrhythmias, and sudden death

Gross and Microscopic ♦♦ Excess valve cusp material, which is thick and hooded, with thickening or thinning of chordae ♦♦ Loose myxoid connective tissue expanding spongiosa layer, which may extend into the chordae

Mitral Regurgitation: Other Causes ♦♦ Papillary muscle dysfunction ♦♦ Infective endocarditis ♦♦ Chronic rheumatic valvular disease

Mitral Stenosis Clinical Fig. 27.11. Acute bacterial endocarditis, gram staining.

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♦♦ Most common cause is rheumatic fever ♦♦ More common in women

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♦♦ Latent period of several years followed by progressive ­stenosis, leading to conditions, such as pulmonary hypertension, left atrial thrombosis, systemic thromboembolism, and infective endocarditis

Macroscopic ♦♦ Pronounced fibrosis along valvular-free edges and lines of closure, and fusion of posterior leaflet scallops, fused and shortened chordae tendineae ♦♦ New subendocardial blood vessel formation on valves themselves may be seen

Microscopic ♦♦ Fibrosis, thick-walled blood vessels, calcification, lymphocytes, and sometime myxomatous change

Prosthetic Valves ♦♦ Complications include −− Mechanical fatigue of components −− Failure of the valve −− Thrombosis and thromboembolism −− Infection (most commonly Staphylococcus) −− Perivalvular leaks in suture area ♦♦ In general, the porcine valves tend to last longer than the ones made of manmade materials

Cardiac Neoplasms Benign Tumors Myxoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Sporadic (usually middle-aged women) and familial types Comprise approximately 50% of primary tumors of heart Heart failure, secondary to valvular or chamber interference Constitutional symptoms (fever, malaise, and weight loss) due to interleukin-6 production ♦♦ Associated with thromboembolism ♦♦ May occur in younger patients with recurrence and extracardiac lesions (myxoma syndrome) ♦♦ Extracardiac lesions −− Myxoma of other organs −− Breast myxoid fibroadenoma −− Sertoli cell tumor of testis −− Endocrine anomalies (adrenal cortical hyperplasia, pituitary adenoma with acromegaly) −− Skin lesions (blue nevi, lentiginosis, psammomatous melanocytic schwannoma)

Macroscopic ♦♦ Most commonly left atrial (approximately 75%) and right atrial mass ♦♦ Located in fossa ovalis in atrial septum ♦♦ Attached to endocardium without deeper infiltration

Fig. 27.12. Atrial myxoma.

Microscopic (Fig. 27.12) ♦♦ Myxoma cells (abundant eosinophilic cytoplasm with indistinct cell borders, ovoid nuclei, nucleoli variably present) forming trabeculae, syncytia, and rings in a myxoid and/or fibrous matrix ♦♦ Hemosiderin is present in hemosiderophages and sometimes myxoma cells ♦♦ Prominent vascularity ♦♦ Inflammation, extramedullary hematopoiesis may be present ♦♦ May show well-developed mucin-producing glands (glandular myxoma), which may be confused with metastatic adenocarcinoma ♦♦ Immunohistochemically, positive staining has been reported for Factor VIII, vimentin, actin, desmin, smooth muscle myosin, alpha-1 antitrypsin, and alpha-1 antichymotrypsin ♦♦ Glandular areas may be positive for CEA, EMA, and keratin

Differential Diagnosis ♦♦ Myxoid sarcoma, myxoid hemangioma −− Both of the above lack myxoma cells and fine capillary vasculature ♦♦ Mural (organized) thrombus −− May be indistinguishable with myxoma ♦♦ Papillary fibroelastoma −− No predilection for left atrium −− Usually located on a valve cusp −− Avascular papillary frond and laminated elastic fibers −− Myxoid areas often located toward the peripheral of the lesion ♦♦ Fibroma −− Prominent elastic fibers with frequent calcifications

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Papillary Fibroelastoma Clinical

Microscopic

♦♦ Asymptomatic, incidental finding at surgery or autopsy ♦♦ May represent organized thrombi (similar to Lambl excrescence) ♦♦ May give rise to thromboemboli, rarely obstruction of a coronary ostium, with sudden death

Macroscopic ♦♦ Small, papillary structure usually occurs on the surface of valves, commonly the aortic valve ♦♦ May also occur on other endocardial locations

Microscopic (Fig. 27.13) ♦♦ Papillary formation with a paucicellular core covered by hyperplastic endocardial cells

hyalinized

Differential Diagnosis ♦♦ Lambl excrescences −− Occur along the line of closure and free cuspal edge of valves −− Small and less gelatinous

Fibroma Clinical ♦♦ Occurs in children, often <1 year old and may present with congestive heart failure ♦♦ No sex predilection ♦♦ Probably represents hamartomatous lesions ♦♦ May be part of nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Macroscopic ♦♦ Usually single, well-circumscribed, “fibroid”-like tumors of myocardium ♦♦ Located in the ventricular septum ♦♦ No hemorrhage or necrosis

♦♦ Fibrocytes, collagen, elastic tissue, and sometimes calcifi­ cation and bone formation ♦♦ No necrosis, cellular pleomorphism, or prominent inflam­ matory infiltrate

Differential Diagnosis ♦♦ Old infarcts −− Usually contracted areas of fibrous tissue, and nonexpansile masses ♦♦ Inflammatory pseudotumors −− Prominent inflammation with plasma cells ♦♦ Papillary fibroelastoma −− Avascular papillary fronds with endothelial lining ♦♦ Fibrosarcoma −− Frequent mitotic figures −− Usually occurs in adults, but in other age groups as well (cellular fibromas occur exclusively in early childhood) ♦♦ Organized mural thrombi and cicatrized myxomas −− Oriented endocardially, unlike intramural location of fibroma ♦♦ Solitary fibrous tumor of the pericardium −− Pericardial location

Rhabdomyoma Clinical ♦♦ Seen mostly during the first decade of life; many are congenital ♦♦ No sex predilection ♦♦ Associated with tuberous sclerosis and congenital heart disease ♦♦ Probably of myocyte origin

Macroscopic ♦♦ Single or multiple, firm, white, well-circumscribed nodules ♦♦ The most common locations are the left ventricle and ventricular septum

Microscopic (Fig. 27.14) ♦♦ “Spider cells,” with radial cytoplasmic extensions ♦♦ Immunohistochemical positivity for myoglobin, actin, desmin, vimentin, and sometimes HMB 45

Lipomatous Hypertrophy of the Interatrial Septum Clinical ♦♦ May represent acquired processes related to metabolic disturbance ♦♦ Often associated with obesity, advanced age, and cardiomegaly ♦♦ May cause arrhythmia with sudden death

Microscopic Fig. 27.13. Papillary fibroelastoma.

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♦♦ Infiltrative, numerous vacuolated adipocytes with ­interspersed hypertrophic myocytes

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♦♦ Patients may have hypertension and elevated urine ­catecholamine levels

Macroscopic ♦♦ Most commonly a tumor of left atrium

Microscopic (See Also Chapter 20) ♦♦ Other benign tumors −− Granular cell tumor, hemangioma, lymphangioma, lipoma, angiolipoma, schwannoma, ganglioneuroma, teratoma, ectopic thyroid, and ectopic thyroid tissue

Malignant Tumors

Fig. 27.14. Cardiac rhabdomyoma.

Differential Diagnosis ♦♦ Liposarcoma −− Lipoblast and mitotic figures ♦♦ Lipoma −− Epicardial location

Cystic Tumor of the Atrioventricular Node Clinical ♦♦ ♦♦ ♦♦ ♦♦

Usually occurs in young adults with female predilection May cause complete heart block due to its location Believed to be a developmental abnormality May be associated with other congenital anomalies

Macroscopic ♦♦ Cyst-like lesion in the inferior interatrial septum in the region of AV node

Microscopic

♦♦ In general, primary cardiac sarcomas are very rare ♦♦ Some may defy classification with present day diagnostic techniques ♦♦ Metastatic tumors to heart are much more common

Angiosarcoma Clinical ♦♦ Probably most common primary malignant cardiac neoplasm ♦♦ Congestive heart failure, arrhythmias, and chamber obstruction

Macroscopic ♦♦ Large, hemorrhagic, invasive tumor; most frequently of right atrium and pericardium

Microscopic ♦♦ Malignant mesenchymal neoplasm, showing endothelial differentiation ♦♦ Most are poorly differentiated ♦♦ Immunohistochemistry for Factor VIII, CD34, CD31 is positive ♦♦ Electron microscopy shows Weibel–Palade bodies

Differential Diagnosis ♦♦ Papillary endothelial hyperplasia of hemangioma −− Lack mitotic figures or cytologic atypia

♦♦ Ductules, cysts, and solid nests of epithelioid cells ♦♦ Positive for cytokeratin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), and B72.3 ♦♦ Negative for Factor VIII ♦♦ Electron microscopy shows desmosomes and microvilli (lesion once thought of as a type of mesothelioma)

Lymphoma Clinical

Differential Diagnosis

Microscopic

♦♦ Bronchogenic and mesothelial cyst −− Usually occur on the epicardial surface −− These tend to be larger lesions ♦♦ Teratoma −− Presence of neural and other ectodermal components

Paraganglioma (Extraadrenal Pheochromocytoma) Clinical ♦♦ Young adults

♦♦ Primary tumors are rare ♦♦ Secondary involvement by advance lymphoma or leukemia is much more common ♦♦ Usually diffuse large cell type

Neoplasms Metastatic to Heart Clinical ♦♦ Far more common than primary cardiac tumors ♦♦ Most result from a primary tumor which is in thoracic cavity (e.g., extension from a contiguous carcinoma of lung)

Microscopic ♦♦ Depends on the tumor type and includes malignant melanoma, carcinomas of kidney, lung, breast, choriocarcinomas, rhabdomyosarcoma, and others

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Other Malignant Tumors of the Heart

A Note About Staging

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦ Presently there is no uniform, agreed upon staging scheme for primary malignant tumors of the heart ♦♦ The TNM scheme may be useful, but regional lymph node metastases in most primary malignant tumors of the heart is rare ♦♦ Primary sarcomas of the heart can be regarded as “deep” tumors in attempting to stage the disease

Leiomyosarcoma Rhabdomyosarcoma Malignant fibrous histiocytoma Osteosarcoma Fibrosarcoma Liposarcoma Synovial sarcoma Malignant peripheral nerve tumor Rhabdoid tumor

PATHOLOGY OF BLOOD VESSELS Arteriosclerosis ♦♦ Means literally “hardening of arteries” ♦♦ Encompasses several entities, such as atherosclerosis, arteriolosclerosis (see under hypertensive vascular disease, below), and Mönckeberg medial calcificsclerosis

Atherosclerosis Clinical ♦♦ Accounts for more deaths in the West than any other disease ♦♦ Predominantly ischemic consequences of narrowed vessels, e.g., myocardial infarction, stroke, gangrene of extremities, etc ♦♦ Aortic aneurysms are another important consequence

Gross ♦♦ Affects predominantly elastic and large and small muscular arteries ♦♦ Lesions (atheroma) consist of a raised intimal plaque, with a lipid core of mostly cholesterol and cholesterol esters, and a fibrous cap ♦♦ The fatty streak, seen usually in children, thought to be precursor lesion ♦♦ In smaller vessels, atherosclerosis results in stenosis ♦♦ In larger vessels, lesion results in focal destruction and weakening of wall, with potential to aneurysm formation, thrombosis, and thromboembolism ♦♦ Abdominal aorta is affected more severely than thoracic

Microscopic ♦♦ Fibrous cap, containing smooth muscle cells and collagen, lipid core with cholesterol clefts, and lipid-laden macrophages ♦♦ Dystrophic calcification, plaque rupture (Fig  27.15), intraplaque hemorrhage, and luminal thrombosis

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Fig. 27.15. Ruptured atherosclerotic plaque in a coronary artery.

Hypertensive Vascular Disease Hyaline Arteriosclerosis Clinical ♦♦ Most severe in hypertensive subjects, but also seen in normotensive elderly persons ♦♦ Vascular narrowing leads to ischemic end-organ damage ♦♦ Most notably in kidneys (nephrosclerosis)

Microscopic ♦♦ Hyaline (pink, glassy) thickening of arteriole walls, concomitant with lumen narrowing

Hyperplastic Arteriolosclerosis Clinical ♦♦ Seen in more severe and acute hypertension, such as “malignant hypertension,” when diastolic pressures can exceed 110 mmHg

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Microscopic ♦♦ “Onion-skinning” of arteriole walls by smooth muscle cells forming concentric layers that thicken and narrow the vessel ♦♦ Basement membrane reduplicated ♦♦ Often accompanied by fibrinoid necrosis of vascular wall

Mönckeberg Medial Calcific Sclerosis Clinical ♦♦ Minor clinical significance, as this lesion rarely, if at all, ­produces vascular narrowing ♦♦ Occurs typically in individuals older than 50 ♦♦ May be seen radiographically ♦♦ May coexist in same vessel with atherosclerosis ♦♦ The cause is unknown

Macroscopic ♦♦ Usually affects femoral, tibial, radial, ulnar arteries, and ­vascular supply to genitalia ♦♦ Also seen frequently in arteries of thyroid gland

Microscopic ♦♦ Annular calcifications in media of medium to small muscular arteries ♦♦ Occasionally with bone and bone marrow formation lesion locally

Fibromuscular Dysplasia Clinical ♦♦ Seen most often in young women (35 years old) ♦♦ May be found in virtually any artery of the body ♦♦ Pathological end-effect is the same as in any other form of arterial stenosis ♦♦ Ischemia, related to degree of blockage ♦♦ Complications include aneurysm, emboli, and sudden death ♦♦ Uncommon cause of renal artery stenosis ♦♦ More common in right renal artery with distal two-thirds of artery involved ♦♦ Etiology unknown ♦♦ Has a characteristic gross and radiographic appearance ♦♦ Manifests as a solitary narrowing or as a grouped series

Gross and Microscopic (Fig 27.16) ♦♦ Arterial wall thickening and consequent lumen narrowing ♦♦ Due to nonatheromatous and noninflammatory fibrous or fibrous and smooth muscle hyperplasia, which can be present in intima, media (the most common location), or adventitia

Myxoid Medial Degeneration (Cystic Medial Necrosis) of Aorta Clinical ♦♦ Cause unknown ♦♦ Develops with age

Fig. 27.16. Fibromuscular dysplasia. ♦♦ Important complication of Marfan syndrome ♦♦ Despite its name, it is not associated with necrosis or cyst formation

Microscopic ♦♦ Disintegration of elastic fibers (seen best with elastic stain) with “cystic” spaces containing mucopolysaccharide (appears myxoid on H&E section) ♦♦ Leads to weakening of aortic wall with potential for aneurysm formation and dissection ♦♦ Similar process can be seen in pulmonary artery and represents usually a normal, age-related change of little, if any clinical consequence

Aneurysms ♦♦ ♦♦ ♦♦ ♦♦

Abnormal dilation of part of vascular wall Caused by an acquired or congenital weakness of media May assume certain shapes such as saccular, and fusiform May predispose to dissection

Atherosclerotic Aneurysm of the Abdominal Aorta Clinical ♦♦ Mostly occurs in patients older than 50 ♦♦ Most frequently seen in aneurysms (along with those of common iliac arteries) ♦♦ May present as palpable abdominal mass and/or radiographic finding ♦♦ Most patients are men, and half of them are hypertensive ♦♦ Larger (>6  cm) are prone to rupture, with fatal internal hemorrhage ♦♦ Encroachment on renal, mesenteric, celiac, and/or iliac arteries may lead to ischemia of those respective distributions ♦♦ Atherosclerotic aneurysm of thoracic aorta is much less common

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Macroscopic

Macroscopic

♦♦ Mostly occur between renal artery ostia and iliac aortic bifurcation ♦♦ Usually fusiform ♦♦ May possess mural thrombus/thrombi

♦♦ “Tree-barking” of thoracic aorta, with aneurysm formation

Microscopic ♦♦ Atherosclerosis with destruction of media, wall thinning ♦♦ Chronic inflammation

Berry Aneurysm of Cerebral Arteries Clinical ♦♦ Associated with autosomal dominant (adult) polycystic ­kidney disease ♦♦ Clinically undetected aneurysms are found in as many as 25% of persons older than 55 years ♦♦ May present with focal neurologic deficits, headache, to fatal subarachnoid hemorrhage from a rupture

Macroscopic ♦♦ More than 90% are seen at various branch points in circle of Willis ♦♦ Multiple aneurysms are seen in approximately 20% ♦♦ Most commonly seen at the junctions of anterior communicating with anterior cerebral arteries, trifurcation of middle cerebral arteries, and arterial branches of internal carotid artery (internal carotid complex)

Microscopic ♦♦ A discontinuity (thought to be congenital) of internal elastic membrane at branch point ♦♦ May see eventual destruction of this membrane with wall thinning and a thin adventitial coat ♦♦ Mural thrombus may be present

Infectious (Mycotic) Aneurysms Clinical ♦♦ A complication of septicemia, and/or endocarditis with embolization of infectious material ♦♦ Occur in aorta, cerebral, mesenteric, splenic arteries, and elsewhere ♦♦ May also occur next to a nidus of tuberculosis or bacterial abscess ♦♦ Abscesses tend to rupture and hemorrhage

Microscopic ♦♦ Infectious destruction of vessel wall, with pattern of inflammation depending on type of organism, which can be bacterial, mycobacterial, and fungal

Syphilitic Aneurysms Clinical ♦♦ Rare in USA

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Microscopic ♦♦ Vasitis vasorum (endarteritis/periarteritis of vasa vasorum with plasma cells, lymphocytes, and macrophages) ♦♦ Necrosis and scarring of media and elastic fiber disintegration ♦♦ Not prone to dissection, unlike atherosclerotic aneurysm

Dissection ♦♦ Entrance of blood into the vessel wall with extension along certain length of that vessel ♦♦ Mistakenly called a dissecting “aneurysm,” when it is really a hematoma

Clinical ♦♦ Typically sudden severe chest and/or back pain (in case of aortic dissection) ♦♦ May also see hypotension, shock, loss of arterial pulse, cardiac tamponade, and ischemic effects of encroachment upon vessel lumens ♦♦ Occurs three times more frequently in men ♦♦ Most common in sixth and seventh decades of life ♦♦ History of hypertension in common

Macroscopic ♦♦ Most often affects aorta and/or its major branches ♦♦ Classified as DeBakey I (ascending aorta), II (ascending and descending aorta), and III (descending only) ♦♦ Also Stanford type A (ascending only or ascending plus descending) and type B (descending only) ♦♦ Aorta shows an intimal tear, typically a few centimeters above the aortic ring ♦♦ Dissecting hematoma in media may extend into and compromise coronaries, carotids, renal, mesenteric, and/or iliac arteries ♦♦ Dissection may penetrate back into original aortic lumen, creating a “double-barrel” aorta ♦♦ Dissection into ascending aorta with adventitial tear may give rise to hemopericardium, hemomediastinum, ­hemothorax, and retroperitoneal hemorrhage ♦♦ Other risk factors for ascending thoracic aorta dissection −− Hypertension −− Myxoid medial degeneration −− Bicuspid aortic valve ♦♦ Other risk factors for abdominal aortic aneurysm −− Atherosclerosis −− Hypertension

Vasculitis ♦♦ Classification of vasculitis based on the size of involved vessel(s) is practical ♦♦ Specific cause can be identified in only a minority of cases

Cardiovascular Pathology

♦♦ Can be divided into infectious and noninfectious groups, with the latter much more extensive ♦♦ There is a correlation between the type of antineutrophil cytoplasmic autoantibodies (ANCA) and the specific vasculitis syndrome ♦♦ cANCA (antiproteinase 3) often seen in −− Active Wegener disease −− Microscopic polyarteritis −− Churg–Strauss syndrome (allergic granulomatosis and angiitis) ♦♦ pANCA (antimyeloperoxidase) often seen in −− Polyarteritis nodosa −− Primary glomerular disease (idiopathic crescentic glomerulonephritis) −− Kawasaki disease

Infectious Vasculitis ♦♦ Causes are bacterial (including syphilitic, with characteristic involvement of proximal aorta with vasitis vasorum and gross “tree-barking,” with aortic root dilation and clinical insufficiency), rickettsial (Rocky Mountain spotted fever), mycotic, tuberculous (typically small vessels), and viral (herpes, CMV)

Noninfectious Vasculitis (Mediumto Large-Sized Vessels) Giant Cell Arteritis/Aortitis (See Also Temporal Arteritis, Below) Clinical and Macroscopic ♦♦ Most commonly seen in adults ♦♦ May be seen associated with rheumatoid arthritis, ankylosing spondylitis, scleroderma, and temporal arteritis ♦♦ Aortic insufficiency, aneurysms, and dissection

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Fig. 27.17. Giant cell arteritis.

Takayasu Disease Clinical ♦♦ Occurs mostly in young Asian women ♦♦ Decreased/absent pulses in upper extremities ♦♦ Neurologic/ocular symptoms, renovascular hypertension

Macroscopic ♦♦ Involvement of aorta, aortic arch branches, pulmonary arteries, and occasionally coronary arteries

Microscopic ♦♦ Chronic granulomatous vasculitis (may or may not have giant cells) ♦♦ Fibrosis of arterial wall in later stages

♦♦ Chronic inflammation (multinucleated giant cells in giant cell aortitis, see “Temporal Arteritis”, below), with focal medial destruction (Fig 27.17)

Noninfectious Vasculitis (Smallto Medium-Sized Vessels) Churg–Strauss Syndrome Clinical

Kawasaki Disease (Mucocutaneous Lymph Node Syndrome) Clinical

♦♦ Probably a type of polyarteritis nodosa (see below) ♦♦ Triad of asthma, blood eosinophilia, and eosinophilic vasculitis (pulmonary, systemic, and/or isolated organ involvement)

♦♦ Occurs usually in infants (also named infantile polyarteritis nodosa) ♦♦ Fever, exanthema, conjunctivitis, reddened tongue, lips, oropharynx, and cervical lymphadenopathy ♦♦ Sudden death from coronary involvement ♦♦ Due to necrotizing vasculitis leading to coronary artery aneurysm with rupture ♦♦ Leading cause of acquired heart disease in child

Microscopic

Microscopic

Macroscopic and Microscopic ♦♦ Necrotizing polyarteritis (cardiac and elsewhere), arterial aneurysms ♦♦ Recent and/or healed myocardial infarction

♦♦ Vasculitis with eosinophilic infiltrate ♦♦ Necrotizing granuloma ♦♦ Both arteries and veins are involved

Polyarteritis Nodosa (PAN) (Fig. 27.18) Clinical ♦♦ Ischemic, multiorgan system involvement ♦♦ Associated with history of hepatitis B infection ♦♦ Fever, hypersensitivity, and eosinophilia (see “Churg–Strauss,” above) ♦♦ Treated with steroids and cyclophosphamide

also

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

into vascular wall with neutrophil disintegration) of systemic arterioles, capillaries, and venules Lesions of the same histologic age Smaller vessels (skin, lung, and kidney) are involved than polyarteritis nodosa (PAN) Muscular and large arteries spared Usually without demonstrable immune complex deposition Skin-limited form called cutaneous leukocytoclastic vasculitis may be seen

Differential Diagnosis ♦♦ Polyarteritis nodosa −− Lesions of various age with skip lesions

Fig. 27.18. Acute necrotizing vasculitis in polyarteritis nodosa (PAN).

Temporal Arteritis (Giant Cell Arteritis) Clinical ♦♦ Predominant in women, usually greater than 50 years ♦♦ Elevated sedimentation rate

Macroscopic

Macroscopic

♦♦ Visible/palpable nodular arterial thickenings, typically at branch points ♦♦ Involves predominantly renal and visceral muscular arteries and arterioles ♦♦ Pulmonary vessels spared

Microscopic

Microscopic ♦♦ Segmental necrotizing vasculitis of small- to medium-sized arteries ♦♦ Coexistent healing/healed lesions and segments of normal vessel (skip lesions) ♦♦ Medial destruction with interruption of elastic laminae

Differential Diagnosis ♦♦ Churg–Strauss syndrome −− Asthma, peripheral eosinophilia and pulmonary involvement −− Both artery and vein involved −− Microscopically, necrotizing granuloma and eosinophils are seen

Microscopic Polyarteritis Clinical ♦♦ Depends on the severity of end-organ involvement ♦♦ Hemoptysis, hematuria/proteinuria (necrotizing glomerulonephritis), bowel pain/enterorrhagia, muscle pain and weakness, and/or palpable skin purpura may be seen ♦♦ Not hypertensive (in contrast to PAN) ♦♦ Immune reaction against an antigenic challenge (drugs, microorganisms, etc.) can be postulated in many cases

♦♦ Involvement of aorta, aortic arch branches, pulmonary arteries, and occasionally coronary arteries ♦♦ Chronic granulomatous vasculitis (may or may not have giant cells) ♦♦ Fibrosis of arterial wall in later stages ♦♦ Destruction of elastica ♦♦ Biopsy should include generous length (some say 2 cm) of superficial temporal artery, as lesion may be missed due to its segmental nature

Thromboangiitis Obliterans (Buerger Disease) Clinical ♦♦ Predominant in young men less than 40 years old ♦♦ Associated strongly with use of tobacco

Macroscopic ♦♦ Segmental stenosis of small- to medium-sized arteries and veins of extremities, sometimes mesenteric vessels, rarely elsewhere ♦♦ Extremital ischemia

Microscopic ♦♦ Early stage shows arterial/venous thrombosis with inflammation ♦♦ Affecting the entire wall of vessel, sometimes with multinucleated giant cells in thrombus itself ♦♦ Later stages may be difficult to distinguish from organizing the thrombus of other etiology or atherosclerosis

Microscopic

Wegener Granulomatosis Clinical

♦♦ Vasculitis with fibrinoid necrosis of media and/or leukocytoclastic vasculitis (infiltration of ­polymorphonuclear ­neutrophils

♦♦ Peaks in fifth decade, with pneumonitis, upper airway inflammation and ulceration, and renal dysfunction (80%)

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♦♦ cANCA detected in over 90% of patients who exhibit active disease ♦♦ Most patients die if untreated ♦♦ Responds well to immunosuppressive and cytotoxic medication

♦♦ Renal involvement may manifest as necrotizing and/or crescentic glomerulonephritis ♦♦ Vascular and/or glomerular immune complexes may be seen in some patients

Differential Diagnosis

Microscopic ♦♦ Necrotizing vasculitis of small- to medium-sized arteries and veins, with granulomatous features ♦♦ Pulmonary involvement leads to cavity formation and characteristic geographic necrosis

♦♦ Mycosis, tuberculosis, and lymphomatoid granulomatosis

Other ♦♦ Vasculitis may be associated with connective tissue disease (e.g., SLE and rheumatoid arthritis), malignancy (lymphomas and others), cryoglobulinemia, and Henoch–Schonlein purpura

SUGGESTED READING Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol 1987;18:619–624.

Maron BJ. Hypertrophic cardiomyopathy. Lancet 1997;350:127–1333.

Aretz HT, Colvin RB. Endomyocardial biopsies: an early warning system for chronic transplant arteriopathy. JAMA 1997;278:1169–1175.

Mukhtyar C, Brogan P, Luqmani R. Cardiovascular involvement in primary systemic vasculitis. Best Pract Res Clin Rheumatol 2009;23: 419–428..

Baker PB. Pathology of Cardiac Valves ASCP/CAP 1994 Fall Meeting and Exhibits: Washington, DC, October 27, 1994. Brown CA, O’Connell JB. Myocarditis and idiopathic dilated cardiomyopathy. Am J Med 1995;99:309–314.

Pardo-Mindan FJ, Lozano MD, Contreras-Mejuto F, et al. Pathology of heart transplant through endomyocardial biopsy. Semin Diagn Pathol 1992;9:238–248.

Burke AP, Virmani R. Cardiac rhabdomyoma: a clinicopathologic study. Mod Pathol 1991;4:70–74.

Rivera RJ, Vicenty S. Cardiac manifestations of amyloid disease. Bol Asoc Med P R 2008;100:60–70.

Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer 1992;69:387–395.

Rodríguez-Calvo MS, Brion M, Allegue C, et al. Molecular genetics of sudden cardiac death. Forensic Sci Int 2008;182:1–12.

Burke, AP, Litovsky S, Virmani R. Lipomatous hypertrophy of the atrial septum presenting as a right atrial mass. Am J Surg Pathol 1996;20:678–685.

Rodríguez JE, McCudden CR, Willis MS. Familial hypertrophic cardiomyopathy: basic concepts and future molecular diagnostics. Clin Biochem 2009;42:755–765.

Dare AJ, Tazelaar HD, Edwards WD, Mullany CJ. Evaluations of surgically excised mitral valves: revised recommendations based on changing operative procedure in the 1990s. Hum Pathol 1993;24:1286–1294. Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990;65:1456–1459. Kottke-Marchant K, Ratliff BB. Endomyocardial biopsy: pathologic findings in cardiac transplantation recipients. Pathol Annu 1990;25:211–244. Luthringer DJ, Virmani R, Weiss SW, et al. A distinctive cardiovascular lesion resembling histiocytoid (epithelioid) hemangioma. Am J Surg Pathol 1990;14:993–1000.

Shoen FG. Surgical pathology of removed natural and prosthetic heart valves. Hum Pathol 1987;18:558–567. Waller BF. Etiology of clinically isolated, severe, chronic, pure mitral regurgitation: Analysis of 97 patients over 30 years of age having mitral valve replacement. Am Heart J 1982;104:276–288. Waller BF. Pathology of the cardiomyopathy. J Am Soc Echo 1988;1:4–l9. Winters GL. The pathology of heart allograft rejection. Arch Pathol Lab Med 1991;15:266–272.

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28 Lung and Pleura Carol F. Farver, md and Andrea V. Arrossi, md

Contents

I. Nonneoplastic Diseases of the Lung........................................28-3

Congenital Anomalies and Pediatric Lesions..........................................................28-3 Pulmonary Sequestration-Two Subtypes..............................................28-3 Bronchogenic Cysts................................28-3 Congenital Pulmonary Airway Malformation.....................................28-3 Diffuse Pulmonary Lymphangiomatosis...........................28-4 Bronchopulmonary Dysplasia (BPD).................................28-4 Infantile (Congenital) Lobar Emphysema........................................28-5 Pediatric Interstitial Lung Disease........28-5 Airways and Obstructive Diseases..................28-5 Emphysema.............................................28-5 Large Airway Disease.............................28-6 Small Airway Disease.............................28-8 Interstitial Diseases..........................................28-8 Acute Lung Injury..................................28-8 Idiopathic Interstitial Pneumonias.....28-10 Pneumoconioses....................................28-15 Vascular Conditions.......................................28-17 Vasculitides............................................28-17 Pulmonary Hypertension.....................28-19 Infections.........................................................28-20 Viral.......................................................28-20 Bacteria..................................................28-21 Mycobacterial Infections......................28-22

Mycoplasma Pneumoniae....................28-24 Fungal....................................................28-24 Protozoan...............................................28-26 Lung Transplantation....................................28-27 Histologic Grading of Pulmonary Allograft Rejection..........................28-27

II. Neoplastic Diseases of the Lung......................................28-28 Benign Tumors................................................28-28 Benign Epithelial Tumors....................28-28 Benign Mesenchymal Tumors.............28-29 Preinvasive Lesions........................................28-30 Squamous Dysplasia/Carcinoma In Situ................................................28-30 Atypical Adenomatous Hyperplasia......................................28-30 Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia......................................28-31 Malignant Tumors..........................................28-31 Tumors of Salivary Gland Type..........28-31 Epithelial Tumors.................................28-33 Neuroendocrine Tumors......................28-35 Mesenchymal Tumors....................................28-37 Fibrous and Fibrohistiocytic Tumors..............................................28-37 Vascular Tumors and Related Conditions.........................................28-39 Neurogenic Tumors..............................28-41 Cartilaginous Tumors...........................28-41

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_28, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Pleuropulmonary Blastoma of Childhood.....................................28-41 Lymphoproliferative Lesions of the Lung.......................................28-41 Tumors of Uncertain Histogenesis......................................28-44 Masses and Tumor-Like Lesions..............................................28-45

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III. Tumors of the Pleura........................28-47 Malignant Mesothelioma...............................28-47 Localized Fibrous Tumor..............................28-48

IV. TNM Classification of Cancer (2010 Revision)................................28-49 V. Suggested Reading...........................28-50

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NONNEOPLASTIC DISEASES OF THE LUNG

Congenital Anomalies and Pediatric Lesions Pulmonary Sequestration-Two Subtypes Intralobar Clinical ♦♦ 90% lower lobes; 55% on left; M:F = 1.1:1 ♦♦ 50% over 20 years; usually presents with recurrent infections

Macroscopic (Fig. 28.1) ♦♦ Firm, cystic area within lobe ♦♦ Systemic arterial supply from muscular artery from thoracic aorta or below the diaphragm ♦♦ Venous return via normal pulmonary veins ♦♦ No communication with normal tracheobronchial tree ♦♦ Invested by normal visceral pleura

♦♦ Older patients: shows chronic obstructive pneumonia; ­honeycomb changes are common changes

Extralobar Clinical ♦♦ 60% are found in children <1 year; 90% on left side; M:F = 4:1 ♦♦ Frequently found with repair of diaphragmatic defect ♦♦ 60% have other congenital anomalies such as diaphragmatic hernia, pectus excavatum (funnel chest)

Macroscopic ♦♦ Spongy, pyramidal mass outside of normal pleura; invested by own pleura ♦♦ Systemic anomalous arterial supply; venous drainage through systemic or portal systems

Microscopic

Microscopic

♦♦ Young patients: may be normal

♦♦ May appear normal; may resemble congenital pulmonary airway malformation (CPAM)

Bronchogenic Cysts Clinical ♦♦ Supernumerary lung buds from foregut; commonly found in subcarinal or middle mediastinum location ♦♦ Usually incidental findings on chest imaging

Macroscopic ♦♦ Usually unilocular cysts with smooth margins; no communication with tracheobronchial tree

Microscopic (Fig. 28.2) ♦♦ Respiratory epithelium with smooth muscle, cartilage, and submucosal glands ♦♦ Squamous metaplasia, purulent exudate, chronic inflammation, and fibrosis if infected

Differential Diagnosis ♦♦ Lung abscess −− Frequent bronchial communication ♦♦ Enteric cysts −− Lined by gastric epithelium ♦♦ Esophageal cysts −− Squamous epithelium −− Wall contains double layer of smooth muscle and no cartilage

Congenital Pulmonary Airway Malformation Clinical Fig.  28.1. Intralobar sequestration. Lower segment of lobe shows endstage changes with marked, fibrosis, and remodeled airways.

♦♦ Stillborn with anasarca and newborn with acute respiratory distress ♦♦ Most communicate with tracheobronchial tree

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Fig. 28.2. Bronchogenic cyst. Cyst lining contains normal ciliated respiratory epithelium submucosal glands (lower left) and hyaline cartilage, features seen in normal bronchials.

Macroscopic ♦♦ Five types of lesions −− Type 0 - malformation of proximal tracheobronchial tree; acinar dysplasia or dysgenesis −− Type 1 - one or more large cysts; cured with surgical removal −− May progress to bronchioloalveolar carcinoma in older children/adults −− Type 2 - multiple, even cysts; poor prognosis −− Type 3 - spongy tissue; no cysts; large bulky lesion with mediastinal shift; poor prognosis −− Type 4 - large thin-walled cystic lesions usually in periphery of lobe

Microscopic (Fig. 28.3) ♦♦ Type 0 - bronchial-like structure with respiratory epithelium, smooth muscle, and cartilaginous plates ♦♦ Type 1 - pseudostratified, primitive epithelium; cartilagenous islands; may progress to bronchioloalveolar carcinoma (BAC) ♦♦ Type 2 - ciliated cuboidal or columnar epithelium ♦♦ Type 3 - randomly distributed bronchial-like structures with ciliated cuboidal epithelium ♦♦ Type 4 - thinned type I and type II alveolar lining cells

Differential Diagnosis ♦♦ Extralobar sequestration −− Located outside the pleura −− Have a separate arterial blood supply

Diffuse Pulmonary Lymphangiomatosis Clinical ♦♦ Occurs in young children; presents with wheezing and dyspnea; slowly progressive

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Fig. 28.3. Type I congenital cystic adenomatoid malformation. Pseudostratified respiratory-like epithelium and, in some areas, are more cuboidal epithelium line the cyst spaces There are mixed inflammatory cells within the interstitium.

Macroscopic ♦♦ Firm, lobulated lung

Microscopic ♦♦ Proliferation of dilated, endothelial-lined spaces; may have smooth muscle in walls

Differential Diagnosis ♦♦ Lymphangioleiomyomatosis −− Occurs only in women of reproductive years −− Smooth muscle is HMB 45+ ♦♦ Lymphangiectasia −− Dilated channels but not increased number

Bronchopulmonary Dysplasia (BPD) Clinical ♦♦ Early BPD has features of respiratory distress syndrome (RDS) with hypoxemia and the need for assisted ventilation for at least 28 days ♦♦ Established BPD causes chronic respiratory disease, with significant wheezing reactions and may have an associated pulmonary hypertension

Macroscopic ♦♦ Early BPD in nonsurfactant-treated infants resembles RDS with firm, congested, and heavy lungs ♦♦ Late BPD has pleural dobblestoning caused by underlying parenchymal areas that alternate between overdistension and fibrosis (Fig. 28.4A)

Microscopic ♦♦ Early BPD has hyaline membranes with necrotizing bronchiolitis, atelectasis, interstitial edema ♦♦ Late BPD has lobules which alternate between interstitial fibrosis and distension. Lobules with distension have

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Fig. 28.4. Bronchopulmonary dysplasia (A and B). Late BPD shows a cobblestoning gross appearance (A) due to underlying alternating areas of overdistension and fibrosis (B).

constrictive bronchiolitis as a sequela of the necrotizing bronchiolitis from the early BPD (Fig. 28.4B)

Differential Diagnosis

Pediatric Interstitial Lung Disease Clinical ♦♦ Interstitial lung disease presenting in the pediatric popular (<18 years of age)

♦♦ Early BPD is similar to DAD ♦♦ Late BPD has features of emphysema, interstitial fibrosis, and constrictive bronchiolitis

Macroscopic

Infantile (Congenital) Lobar Emphysema Clinical

Microscopic

♦♦ Most frequent lung malformation ♦♦ Lobar overinflation within the first six months of life; presents with respiratory distress ♦♦ M:F = 1.8:1

Differential Diagnosis

Macroscopic ♦♦ Lung is overinflated ♦♦ Most commonly found in left upper lobe

Microscopic ♦♦ Alveolar ducts and alveoli are distended (classic form) ♦♦ Absolute increase in the number of alveoli (hyperplastic form)

Differential Diagnosis ♦♦ Congenital pulmonary airway malformation, type IV ♦♦ Congenital lobar inflation −− Normal number of alveoli

♦♦ Varies depending upon interstitial disease involvement; consolidation, fibrosis, and hemorrhage ♦♦ All of adult forms of interstitial lung disease: DIP, NSIP UIP, PAP, HP and includes chronic pneumonitis of infancy; DIP is the most common form ♦♦ Varies with the entity

Airways and Obstructive Diseases Emphysema Clinical ♦♦ Pink puffer ♦♦ Four major types found in four different clinical settings −− Centrilobular (proximal acinar) (a) Smokers; upper lobes most affected −− Panacinar (panlobular) (a) Alpha-1-protease inhibitor deficiency (ZZ); lower lobes most affected (b) Can be seen in talc IV drug abuse and in Ritalin use

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−− Localized (distal acinar) (a) May contribute to spontaneous pneumothoraces and bullae formation in tall, asthenic male adolescent −− Paracicatricial (irregular) emphysema (a) Most common type; around area of fibrosis

Macroscopic ♦♦ May manifest as bullae-alveolar spaces >1  cm or blebsrepresenting airspaces made by dissection of loose ­connective tissue

Microscopic (Fig. 28.5A–C) ♦♦ Alveolar wall destruction distal to terminal bronchioles; ♦♦ No fibrosis ♦♦ Four major types −− Centrilobular (proximal acinar): proximal part of acini −− Panacinar: acini are uniformly involved −− Localized: peripheral acinar involved −− Paracicatricial emphysema: emphysema adjacent to fibrosis

Differential Diagnosis ♦♦ Congenital lobar overinflation −− No destruction of alveoli ♦♦ Honeycomb lung −− Fibrosis with metasplastic columnar epithelium

Large Airway Disease Bronchiectasis Clinical ♦♦ Causes include: postinflammatory, postobstructive; seen in setting of cystic fibrosis, ciliary disorders, immunologic deficiencies, and idiopathic ♦♦ Recurrent pneumonias with productive cough; hemoptysis; recurrent fevers −− Cystic fibrosis

Macroscopic (Fig. 28.6A) ♦♦ Diffuse or localized enlarged, fibrotic cartilaginous airways; dilated airways extend to pleural surface; commonly filled with mucopurulent material

Microscopic (Fig. 28.6B) ♦♦ Ectatic, dilated airways; chronically inflamed wall; follicular bronchitis may be present. Acute and organizing pneumonia is common

Fig. 28.5. Emphysema (A and B: centrilobular; C: panacinar). Upper lobe tissue destruction with bulla formation is characteristic of centrilobular emphysema (A). In this form, alveolar walls area destroyed in the area surrounding the bronchovascular area at the proximal and center of the respiratory lobule (B). In panacinar emphysema, tissue destruction results in a more even loss of alveolar walls throughout the lobule (C).

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Differential Diagnosis ♦♦ Mucinous tumors of the airways −− Malignant epithelium

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Chronic Bronchitis Clinical ♦♦ “Blue bloater” ♦♦ Most common etiology is cigarette smoking

Macroscopic ♦♦ Excessive mucous secretion within airways

Microscopic ♦♦ Goblet cell hyperplasia, thickened basement membrane, submucosal gland hyperplasia, smooth muscle hypertrophy ♦♦ Reid index: thickness of mucous gland layer/thickness of bronchial wall (normal <0.4)

Asthma Clinical ♦♦ Nonproductive cough and wheezing; atopic, nonatopic, exercise, and occupational types ♦♦ Affects 5% of all children; 65% of asthmatics have symptoms before age 5 ♦♦ M:F = 2:1

Macroscopic ♦♦ Mucous plugging of airways; overdistention with abundant air trapping ♦♦ May see saccular bronchiectasis, especially upper lobe

Microscopic ♦♦ Thickened basement membranes; mucous plugs; goblet cell hyperplasia ♦♦ Submucosal gland hypertrophy; may show eosinophilic infiltrate ♦♦ Smooth muscle hypertrophy ♦♦ Curshmann spirals, Charcot–Leyden crystals, Creola bodies ♦♦ Chronic bronchitis −− Histology very similar to asthma, except found only in smokers

Bronchocentric Granulomatosis Clinical ♦♦ 50% of patients have asthma; also may have allergic bronchopulmonary aspergillosis ♦♦ High serum IgE; type I and III hypersensitivity reaction

Microscopic Fig.  28.6. Bronchiectasis (A and B). Diffuse airway enlargement, fibrosis, and remodeling occurs in this lung with cystic fibrosis (A). The airways are irreversible distended and surrounding by a lymphoplasmacytic infiltrate. The overlying respiratory epithelium many times shows a metaplastic squamous epithelium (B).

♦♦ Bronchocentric granulomatous inflammation

Differential Diagnosis ♦♦ Wegener granulomatosis −− Necrotizing vasculitis −− c-ANCA+

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Small Airway Disease Respiratory Bronchiolitis (Smoker’s) Clinical

Microscopic

♦♦ Incidental findings in smokers

Interstitial Diseases Acute Lung Injury Diffuse Alveolar Damage/Acute Interstitial Pneumonia Clinical

Microscopic (Fig. 28.7) ♦♦ Pigmented macrophages within terminal bronchioles and surrounding alveoli ♦♦ Mild chronic inflammation, fibrosis

Follicular Bronchiolitis Clinical ♦♦ Rare usually associated with collagen vascular diseases, including Sjogren disease and rheumatoid arthritis, and with immunodeficiencies

Microscopic (Fig. 28.8) ♦♦ Marked chronic inflammatory infiltrate surrounding bronchioles; germinal centers are frequent; acute inflammatory cells within lumen can be seen

♦♦ Dense peribronchiolar infiltrate with characteristic foamy macrophages within the walls of the small bronchioles

♦♦ Pathologic correlate of adult respiratory distress syndrome; acute onset of dyspnea, diffuse pulmonary infiltrates, and rapid respiratory failure ♦♦ Causes include pulmonary edema, septic shock, oxygen toxicity, drugs (including chemotherapeutics), radiation, and trauma ♦♦ Idiopathic variant is known as acute interstitial pneumonia (AIP) – Hamman-Rich syndrome

Constrictive (Obliterative) Bronchiolitis Clinical ♦♦ Complication of lung or bone marrow transplantation; drug toxicity; connective tissue disease and idiopathic disease

Microscopic (Fig. 28.9) ♦♦ Bronchiolar and peribronchiolar fibrosis with narrowing and eventual obliteration of the lumen; may be preceded by a lymphocytic bronchiolitis

Diffuse Panbronchiolitis Clinical ♦♦ Seen almost exclusively in Japan; association with HLA BW54 −− Etiology unknown; erythromycin offers some benefit

Fig. 28.7. Respiratory bronchiolitis. Pigmented macrophages accumulate around a small airway with chronic remodeling changes consisting of increased smooth muscle and mild fibrosis.

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Fig. 28.8. Follicular bronchiolitis. A marked chronic inflammatory infiltrate with germinal centers curround small airways.

Fig. 28.9. Constrictive (oblierative) bronchiolitis. Collagenoustype fibrosis narrows and eventually obliterates the lumen of the small airways.

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Fig.  28.11. Cryptogenic organizing pneumonia (COP)/ Brochiolitis obliterans organizing pneumonia (BOOP). Organizng fibrosis in the form of fibroblastic proliferation are present within the bronchiolar and alveolar airspaces. The adjacent alveolar walls are relatively unremarkable. ♦♦ Process is patchy around bronchioles ♦♦ Hyaline membranes are not seen ♦♦ Organization is intraluminal

Cryptogenic Organizing Pneumonia (COP)/ Bronchiolitis Obliterans Organizing Pneumonia (BOOP) Clinical Fig. 28.10. Acute and organizing diffuse alveolar damage (A and B). Hyaline membranes for in the alveolar spaces (A) and are eventually organized into and widen the interstitium (B).

Macroscopic ♦♦ “Respirator lung”-dense, red/gray diffuse consolidation

Microscopic (Fig. 28.10A, B) ♦♦ Temporally uniform injury ♦♦ Two phases: acute and organizing −− Acute: interstitial edema, type I pneumocyte sloughing, and hyaline membranes −− Organizing: proliferating type II pneumocytes and interstitial fibroblasts with focal airspace organization −− Bronchiolar epithelial necrosis, reepithelialization and organization within airways (a) Acute and organizing thrombi within vessels are common

Differential Diagnosis Organizing pneumonia including cryptogenic organizing pneumonia (COP)/bronchiolitis obliterans organizing pneumonia (BOOP) ♦♦ More subacute clinical course

♦♦ Causes include collagen vascular disease, toxic inhalants, postinfectious, bronchial obstruction, and idiopathic ♦♦ Subacute onset of cough, dyspnea, and fever; multiple patchy airspace opacities, usually bilateral, on chest x-ray ♦♦ Treated with steroids; excellent prognosis

Microscopic (Fig. 28.11) ♦♦ Temporally uniform injury ♦♦ Patchy, immature fibroblastic proliferations within bronchiolar lumina and peribronchiolar airspaces; usually sharply demarcated with adjacent normal parenchyma ♦♦ Foamy macrophages are commonly found in airspaces ­surrounding fibrosis ♦♦ Interstitial chronic inflammation and type II pneumocyte hyperplasia in area of fibrosis

Differential Diagnosis ♦♦ Diffuse alveolar damage/acute interstitial pneumonia −− More acute clinical course −− More diffuse process, involving both bronchioles and alveoli −− Organizing fibrosis is interstitial ♦♦ Usual interstitial pneumonia −− Temporally heterogenous injury

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−− Interstitial fibrosis is predominantly subpleural and paraseptal with scattered fibroblastic foci −− Collagen deposition honeycomb foci can be found

Idiopathic Interstitial Pneumonias Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD) Clinical ♦♦ Smoker’s disease ♦♦ Dyspnea, cough, mild restrictive defects ♦♦ Chest x-ray usually normal; may present as interstitial infiltrates

Microscopic ♦♦ Finely granular pigmented macrophages accumulate within lumens of distal bronchioles and surrounding alveoli ♦♦ Mild chronic inflammation and fibrosis

Differential Diagnosis ♦♦ Desquamative interstitial pneumonia −− Mild interstitial fibrosis ♦♦ Pulmonary Langerhans cell histiocytosis (PLCH) −− Characteristic nodules with Langerhans cells (S-100 ­protein+, CD1a+) −− Peribronchiolar-based Langerhans cells

Desquamative Interstitial Pneumonitis (DIP) Clinical ♦♦ Usually middle-aged adults, 90% are smokers; insidious onset of dyspnea ♦♦ Chest x-ray: bilateral, lower lobe, ground-glass opacities ♦♦ Favorable response to corticosteroids ♦♦ Mean survival = 12 years

Microscopic (Fig. 28.12) ♦♦ Striking pigmented macrophages within alveolar spaces; type 2 pneumocyte hyperplasia with subtle interstitial fibrosis ♦♦ Diffuse process; temporally uniform

Differential Diagnosis ♦♦ DIP-like reaction of UIP −− Temporally heterogeneous pattern of injury ♦♦ Pulmonary Langerhans cell histiocytosis (PLCH) −− Patchy distribution; predominantly bronchiolar −− Tightly packed macrophages (Langerhans cells) −− Can be found in patients <40 years old ♦♦ Respiratory bronchiolitis −− No interstitial fibrosis −− Less macrophage accumulation and more airway centered

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Fig.  28.12. Desquamative interstitial pneumonitis. Abundant pigmented macrophages fill the alveolar spaces. Reactive type 2 pneumocytes line the alveolar walls.

Usual Interstitial Pneumonitis Clinical ♦♦ Insidious onset of dyspnea with chronic, progressive downhill course ♦♦ Most patients are over 60 years of age; collagen vascular diseases are commonly present ♦♦ 60% of patients die; mean survival 3 years

Macroscopic (Fig. 28.13A) ♦♦ Honeycomb changes most advanced at bases and periphery

Microscopic (Fig. 28.13B, C) ♦♦ Temporally heterogenous pattern of injury; “variegated” low power appearance; fibrosis worse in subpleural and para­ septal regions ♦♦ Infiltrate is chronic with plasma cells; germinal centers commonly seen in rheumatoid arthritis ♦♦ Most fibrosis is dense collagen; intervening fibromyxoid foci are seen; large, ectatic airspaces with mucin pooling usually found in more advanced areas; areas of normal lung present centrally in lobule ♦♦ Smooth muscle hypertrophy and DIP-like reaction around bronchioles are common ♦♦ Vascular changes of intimal fibroplasia and medial hypertrophy are common

Differential Diagnosis ♦♦ DIP −− Macrophage accumulation is diffuse −− Injury is temporally uniform ♦♦ COP/BOOP −− Injury is temporally uniform −− Clinical course is subacute −− Fibroblastic foci are more pronounced −− Areas of dense collagen deposition are absent

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Fig. 28.13. Usual interstitial pneumonia with honeycomb changes (A and B) and fibroblastic foci (C). Honeycomb airspaces filled with mucous are present in the base of the lobe (A). The chronic inflammation and fibrosis in this pattern of injury has a variegated low power appearance (B) with characteristic fibroblastic foci intervening between the normal and the fibrotic areas of the lung (C). ♦♦ Nonspecific interstitial pneumonia/fibrosis (NSIP) −− Injury is temporally uniform

Nonspecific Interstitial Pneumonia/Fibrosis Clinical ♦♦ Dyspnea and cough over several months; bilaterial ­interstitial infiltrates on chest x-ray ♦♦ Middle-aged adults; underlying connective tissue disease is common; idiopathic ♦♦ Usually steroid responsive with good prognosis

Microscopic (Fig. 28.14) ♦♦ Two types −− Cellular (a) Interstitial chronic inflammation with lymphocytes and plasma cells (b) Preserved lung architecture −− Fibrosing (a) Patchy or diffuse temporally uniform interstitial fibrosis

Differential Diagnosis ♦♦ Usual interstitial pneumonia −− Injury is temporally heterogenous with fibroblastic foci −− Collagen deposition and honeycomb changes are seen

Fig. 28.14. Nonspecific interstitial pneumonia. A chronic, lymphocytic infiltrate is present in the alveolar walls and the overall lung architecture is preserved in this cellular type of NSIP.

Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis) Clinical ♦♦ Insidious onset of dyspnea with dry cough, fatigue, and malaise

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Fig.  28.15. Extrinsic allergic alveolitis/hypersensitivity pneumonitis. A prominent cellular bronchiolitis along with an interstitial pneumonitis are major components. ♦♦ Exposure source not identified in 2/3 cases diagnosed by pathology; diffuse interstitial infiltrates on chest x-ray ♦♦ Corticosteroids help after exposure has been eliminated

Microscopic (Fig. 28.15) Triad of features: interstitial pneumonitis; chronic bronchiolitis with areas of organizing pneumonia and ill-formed, nonecrotizing granulomas, or giant cells in parenchyma

Differential Diagnosis ♦♦ Usual interstitial pneumonia −− Injury is temporally heterogenous −− Granulomas usually not seen ♦♦ Sarcoidosis −− Interstitial pneumonis, if present, is very mild −− Granulomas are well-formed in lymphatic distribution ♦♦ Lymphoid interstitial pneumonia −− Pathology is more diffusely distributed −− Does not have areas of organizing pneumonia

Eosinophilic Pneumonia Clinical ♦♦ Four clinical categories −− Simple: Loeffler syndrome; mild; self-limiting −− Tropical: found in tropics due to filarial infestation −− Acute: acute, febrile illness with respiratory failure; unknown etiology −− Chronic: subacute illness; blood eosinophilia; F > M; patchy, peripheral infiltrate (photographic negative of pulmonary edema); etiologic agents:drugs, fungal, parasites, inhalants, and idiopathic

Microscopic (Fig. 28.16) ♦♦ Filling of alveolar spaces with eosinophils and variable number of macrophages

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Fig.  28.16. Eosinophilic pneumonia. There are abundance eosinophils with scattered alveolar macrophages that fill the alveolar spaces. ♦♦ Eosinophilic abscesses and necrosis of cellular infiltrate; organizing pneumonia is common ♦♦ Features of DAD have been seen in acute form; mild, nonnecrotizing vasculitis of small arterioles and venules common

Differential Diagnosis ♦♦ Churg–Strauss syndrome −− Necrotizing granulomatous vasculitis is present ♦♦ Pulmonary Langerhans cell histiocytosis (PLCH) −− Infiltrate is interstitial and usually peribronchiolar −− Seen only in smokers ♦♦ Desquamative Interstitial Pneumonitis −− Eosinophilic abscesses and necrosis of infiltrate rarely seen

Pulmonary Langerhans Cell Histiocytosis Clinical ♦♦ Occurs almost exclusively in smokers; M:F = 4:1; symptoms may be minimal; fourth decade ♦♦ Chest x-ray: multiple, bilateral nodules 0.5–1.0 cm in upper lung lobes with cystic lesions

Microscopic (Fig. 28.17A, B) ♦♦ Discrete, nodular/stellate lesions; bronchiolocentric ♦♦ Langerhans cell: convoluted (kidney-bean) nuclei

Immunohistochemistry ♦♦ S-100+, CDla+, HLR-DR+

Electron Microscopy ♦♦ Birbeck granule (“tennis racket” morphology)

Differential Diagnosis ♦♦ DIP −− Interstitial lesion ♦♦ Respiratory bronchiolitis-associated interstitial lung disease −− Does not destroy bronchiole

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Fig. 28.18. Sarcoidosis. Predominantly nonnecrotizing granulomas with giant cells follow the subpleural and interlobular septa in a lymphatic type distribution. Fig. 28.17. Pulmonary histiocytosis-X (eosinophilic granuloma) (A and B). The cellular phase of this disease shows prominent bronchiolocentric inflammation that has a somewhat stellate shape (A); histiocytes with a kidney-bean type appearance are present (B). −− Minimal fibrosis −− No Langerhans cells

Sarcoidosis Clinical ♦♦ Most common in young, African-American female (20–35 years) ♦♦ Deficient T-cell response (cutaneous T-cell anergy and decreased helper T-cells) ♦♦ Associations: functional hypoparathyroidism; hypercalciuria ± hypercalcemia; erythema nodosum; uveitis ♦♦ Kveim test: granulomatous reaction following injection of human spleen extract ♦♦ Serum ACE (angiotensin converting enzyme) ♦♦ Radiologic stage −− Stage 0: normal chest x-ray −− Stage 1: hilar/mediastinal adenopathy

−− Stage 2: hilar/mediastinal adenopathy + interstitial pulmonary infiltrate −− Stage 3: interstitial pulmonary infiltrate only −− Stage 4: endstage fibrosis with honeycombing

Microscopic (Fig. 28.18) ♦♦ Interstitial noncaseating granulomas distributed in lymphatic and bronchovascular pathways; vascular and pleural involvment common

Differential Diagnosis ♦♦ Chronic berylliosis −− Elevated beryllium levels on tissue quantitation −− Clinical history of beryllium exposure ♦♦ Extrinsic allergic alveolitis −− Ill-formed granulomas; interstitial distribution −− Accompanying interstitial pneumonia

Pulmonary Alveolar Proteinosis Clinical ♦♦ Etiologies: dusts, drug, immunodeficiency, leukemia, kaolin ♦♦ Bronchoalveolar lavage: treatment of choice ♦♦ Idiopathic or associated with infection

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♦♦ Anti-GM-CSF circulating antibody found in idiopathic variant

♦♦ Hemosiderin-laden macrophages accumulate in the alveoli, especially in subpleura

Microscopic (Fig. 28.19)

Immunohistochemistry

♦♦ Accumulation of granular eosinophilic material in alveoli; PAS (+) material

♦♦ HMB 45+

Electron Microscopy ♦♦ Lamellar body

Differential Diagnosis ♦♦ Pulmonary edema −− Interstitial/septal edema ♦♦ Mycobacterial, nocardial, or Pneumocystis pneumonia −− + Special stains or microbiologic cultures

Lymphangioleiomyomatosis Clinical ♦♦ Occurs exclusively in women of reproductive years ♦♦ Progressive dyspnea, chylous pleural effusions, recurrent pneumothoraces ♦♦ Chest x-ray: enlarged lungs; can show cystic or “honeycomb” changes ♦♦ Found in patients with tuberous sclerosis

Differential Diagnosis ♦♦ Benign metastasizing leiomyoma −− Discrete nodules, some contain entrapped pulmonary epithelium ♦♦ UIP with honeycomb changes −− Small lungs, lower lobe predominant −− Chronic inflammatory changes and fibrosis −− Older age group; men and women

Antibasement Membrane Antibody Disease-[ABMA] (Goodpasture Syndrome) Clinical ♦♦ M:F = 9:1; bimodal distribution of presentation (peaks at 30 and 60 years) ♦♦ Smokers; DRw15, DQw6

Macroscopic (Fig. 28.20A) ♦♦ Randomly distributed cystic airspaces with thin walls

Microscopic (Fig. 28.20B) ♦♦ Haphazard proliferation of smooth muscle in lymphatics, blood vessels, bronchioles, and alveolar septa

Fig.  28.19. Pulmonary alveolar proteinosis. An eosinophilic material fillws the alveolar spaces; the alveolar walls are essentially unremarkable.

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Fig.  28.20. Lymphangioleiomyomatosis (A and B). Brown/red cysts are characteristic of the gross appearance (A). Spindle-shaped cells infiltrate predominantly around veins and bronchioles (B).

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♦♦ Cytotoxic, antibody-mediated, immune reaction; antibodies to type IV collagen in serum cross react to both kidney and lung ♦♦ Hemoptysis, anemia, azotemia, and diffuse lung infiltrates

Microscopic ♦♦ Extensive intra-alveolar hemorrhage; nonspecific type 2 pneumocyte hyperplasia ♦♦ Small vessel vasculitis may be present ♦♦ Iron encrustration of elastic fibers within interstitium and vessels may be present ♦♦ Mild interstitial fibrosis can be seen

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Differential Diagnosis ♦♦ ABMA Disease −− Linear immunofluorescence pattern (IgG) −− Kidney involvement

Pneumoconioses A nonneoplastic reaction of the lungs to inhaled mineral or organic dust.

Silicosis Clinical

♦♦ Linear staining of glomerular and pulmonary basement membranes for IgG

♦♦ Reaction in lung to inhaled crystalline silica: stonecutting, quarry work, or sandblasting ♦♦ 0.5–2 mm fibers: most fibrogenic ♦♦ Predisposed towards tuberculosis (TB)

Differential Diagnosis

Macroscopic

♦♦ Other causes of small vessel vasculitis −− Absence of ABMA in tissue by immunofluorescence ♦♦ Idiopathic pulmonary hemosiderosis −− Child and adolescent −− Immunofluorescent linear pattern is absent −− No acute hemorrhage

♦♦ Firm, discrete, rounded lesions with variable amounts of black pigment ♦♦ Nodules in lymphatic distribution: around bronchovascular bundles, in subpleural and interseptal areas

Immunofluorescence

Idiopathic Pulmonary Hemosiderosis Clinical ♦♦ Exclusively in children <16 years; M:F = 1:1 ♦♦ Hemoptysis, chest infiltrates; iron deficiency anemia

Microscopic (Fig. 28.21) ♦♦ Intra-alveolar hemorrhage without capillaritis; alveolar wall thickening and type II pneumocyte hyperplasia

Fig. 28.21. Idiopathic pulmonary hemosiderosis. Hemosiderinladen macrophages are abundant adjacent to mildly thickened alveolar septae with type 2 pneumocytes.

Microscopic (Fig. 28.22) ♦♦ Discrete foci of concentric layers of hyalinized collagen; dust-filled histiocytes are abundant; birefringent particles usually present ♦♦ When necrosis is present, consider complicating infection by mycobacterial tuberculosis

Differential Diagnosis ♦♦ Inactive mycobacterial or fungal infections −− Giant cells and palisading histiocytes are usually seen ♦♦ Hyalinizing pulmonary granuloma −− Collagen bundles are disorganized −− Birefringent material is unusual

Fig.  28.22. Silicotic nodule. Multiple hyalinized nodules are adjacent to bronchioles.

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Asbestos-Related Reactions Clinical ♦♦ Reactions of the lung to asbestos with accompanying cations, (i.e., iron, calcium, magnesium, sodium); serpentine, and amphibole are the most common types ♦♦ Fibrosis occurs 15–20 years after exposure and can progress after exposure stops

Macroscopic ♦♦ Firm, fibrotic lungs with areas of honeycomb change

Microscopic (Fig. 28.23) ♦♦ Marked interstitial fibrosis with minimal inflammatory infiltrate; UIP-like reactions common ♦♦ Presence of asbestos bodies, fibrosis, and exposure history are needed for definitive diagnosis ♦♦ Hyalinizing pleural plaques, pleural fibrosis, and rounded atelectasis can also be seen

Fig.  28.23. Asbestos-related reactions – ferruginous body. Asbestos fiber within the core surrounded by a proteinaceous iron-containing coat takes on a dumbbell shape.

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Differential Diagnosis ♦♦ Usual interstitial pneumonia −− Temporally heterogenous −− Lack of asbestos bodies

Coal Worker’s Pneumoconiosis (CWP) Clinical ♦♦ Simple: single nodule, <2 cm ♦♦ Complicated: >2 cm, including progressive massive fibrosis ♦♦ Caplan syndrome: rheumatoid nodule with CWP (progressive massive fibrosis)

Macroscopic (Fig. 28.24A) ♦♦ Dense fibrosis and anthracosis, predominantly upper and middle lobes

Fig. 28.24. Progressive massive fibrosis/coal worker’s pneumoconiosis (A and B). Black/tan mass involves majority of the upper lobe (A); hyalinized nodule adjacent to the airway with emphysema (B).

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Microscopic ♦♦ Nonnecrotizing granulomas in a lymphatic distribution

Differential Diagnosis ♦♦ Sarcoidosis −− No history of beryllium exposure ♦♦ Infections (mycobacterial or fungal) −− Necrotizing granulomas −− More airway distribution

Fig. 28.25. Hard metal pneumoconiosis giant cell pneumonita. Peribronchiolar infiltrate with macrophages and scattered giant cells and prominent smooth muscle are seen in small airways.

Microscopic (Fig. 28.24B) ♦♦ Hyalinized nodule with anthracotic pigment in lung and lymph nodes ♦♦ Macules adjacent to bronchioles; may have centrilobular emphysema

Hard Metal Pneumoconiosis Clinical ♦♦ Exposure to tungsten carbide and cobalt, usually in grinding, drilling, cutting, or sharpening ♦♦ Dyspnea with restrictive pulmonary function tests

Microscopic (Fig. 28.25) ♦♦ Giant cell interstitial pneumonitis with interstitial fibrosis, peribronchiolar giant cells, and DIP-like reaction ♦♦ Giant cells are multinucleated and commonly engulf other inflammatory cells

Differential Diagnosis ♦♦ Viral bronchiolitis/pneumonitis −− No history of tungsten carbide/cobalt exposure −− Viral inclusions and viral cultures positive ♦♦ Hypersensitivity pneumonitis −− Increased interstitial and peribronchiolar inflammatory infiltrate −− Nonnecrotizing granulomas

Berylliosis Clinical ♦♦ Acute: massive exposures produce acute respiratory distress syndrome-like pictures ♦♦ Chronic: progressive dyspnea and cough with imaging studies similar to sarcoidosis; may progress to interstitial fibrosis

Macroscopic ♦♦ Nodules (up to 2 cm) with associated emphysema

Vascular Conditions Vasculitides (Also See Chapter 22) Wegener Granulomatosis Clinical ♦♦ Triad: upper airway, lower airway (lung) and kidney; saddle nose; rarely lung only (so called “limited”) ♦♦ 40% of patients in remission are c-ANCA (+) (antiproteinase 3); 90% of patients with active disease are c-ANCA (+) ♦♦ Chest x-ray: multiple well-demarcated peripheral nodules, lower lobes; rarely as a solitary pulmonary lobule

Microscopic (Fig. 28.26a, b) ♦♦ Triad: parenchymal (basophilic) necrosis, vasculitis, granulomatous inflammation ♦♦ Variants: eosinophil rich, bronchiolocentric, solitary, capillaritis, and diffuse pulmonary hemorrhage ♦♦ Parenchymal necrosis may be in form of microabscesses or geographic necrosis ♦♦ Vasculitis may affect arteries, veins, or capillaries

Differential Diagnosis (Table 28.1) ♦♦ Lymphomatoid granulomatosis −− Atypical cytology ♦♦ Granulomatous infections −− Well-formed, nonnecrotizing granulomas −− Eosinophilic necrosis

Churg–Strauss Syndrome (Allergic Angiitis Granulomatosis) Clincial ♦♦ Asthma, eosinophilia, systemic vasculitis, mono- or poly­ neuropathy ♦♦ Nonfixed lung infiltrate, paranasal sinus abnormalities; p-ANCA (+)

Microscopic ♦♦ Eosinophilic infiltrates, granulomatous inflammation, and necrotizing vasculitis

Differential Diagnosis (Table 28.1) ♦♦ Chronic eosinophilic pneumonia −− Nongranulomatous

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Necrotizing Sarcoid Granulomatosis (NSG) Clinical ♦♦ F:M = 2.2:1; variable age presentation; cough, chest pain, weight loss, fever ♦♦ No systemic vasculitis ♦♦ Chest x-ray: bilateral lung nodules, usually lower lobe; hilar adenopathy is present in <10% of cases

Microscopic ♦♦ Lymphoplasmacytic or granulomatous vasculitis; parenchymal necrosis without necrotizing vasculitis; numerous caseating sarcoid-like granulomas

Differential Diagnosis (Table 28.1) ♦♦ Wegener granulomatosis −− No sarcoidal granulomas ♦♦ Infection −− Vasculitis not prominent component −− (+) organismal stains ♦♦ Churg–Strauss syndrome (allergic angiitis granulomatosis) −− No hilar adenopathy −− History of asthma −− Peripheral eosinophilia

Necrotizing Capillaritis Clinical Fig. 28.26. Wegener granulomatosis. (A) Geographic necrosis; (B) collagenous necrosis. A large area of basophilic necrosis (A) is lined by histiocytes and scattered giant cells (B).

Associated conditions: collagen vascular disease, especially systemic lupus erythematosus; Wegener granulomatosis; Henoch– Schonlein purpura, cryoglobulinemia, Behcet disease, drug reactions (sulfonamides), and Goodpasture disease.

Microscopic (Fig. 28.27)

♦♦ Allergic bronchopulmonary aspergillosis −− Bronchocentric ♦♦ Drug-induced vasculitis ♦♦ Polyarteritis nodosa −− Rarely involves the lung ♦♦ Wegener granulomatosis −− Geographic necrosis

♦♦ Focal necrosis of alveolar septa with neutrophilic infiltration, capillary fibrin thrombi, and interstitial hemorrhage/ hemosiderosis ♦♦ Often associated with foci of DAD

Differential Diagnosis ♦♦ Acute hemorrhagic bronchopneumonia −− Neutrophils predominate in alveolar space

Table 28.1. Differential Diagnosis of Granulomatous Lesions NSG Sarcoidal granuloma Vasculitis Necrosis Hilar adenopathy Cavitation Asthma/peripheral eosinophilia

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++ ++ ++ +/− + −

Wegener − ++ ++ − ++ −

Infection

Churg–Strauss syndrome

++ +/− ++ ++ + −

+ ++ ++ − ++ +

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Fig.  28.27. Necrotizing capillaritis. A neutrophilic infiltrate involves the alveolar septae capillaries.

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Fig. 28.28. Pulmonary hypertension – plexogenic arteriopathy. A plexogenic lesion contains a remodeled artery wall with abnormal vascular spaces lined by myofibroblasts.

Pulmonary Hypertension Pulmonary Arterial Hypertension Clinical ♦♦ Idiopathic pulmonary hypertension −− F:M 1.7:1 ♦♦ Familial (FPAH) −− Germ-line mutations in BMPR2 (chromosome 2q31–32) ♦♦ Associated with −− Collagen vascular disease −− Congenital cardiac shunts −− Portal hypertension −− HIV infection −− Drugs and toxins (a) Aminorex fumarate

Microscopic (Fig. 28.28) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Grade 1: muscularization of pulmonary arteries Grade 2: cellular intimal proliferation Grade 3: intimal concentric laminar fibrosis Grade 4: plexiform lesions Grade 5: plexiform and angiomatoid lesions Grade 6: necrotizing arteritis (may actually preceed grades 4 and 5 developmentally)

Pulmonary Veno-Occlusive Disease Clinical ♦♦ Rare form of pulmonary hypertension; 1/3 occur in children ♦♦ Causes: drug toxicity, especially chemotherapeutics, viral infections

Microscopic (Fig. 28.29) ♦♦ Congestive changes with hemosiderin-laden macrophages ♦♦ Pulmonary hypertensive changes

Fig. 28.29. Pulmonary veno-occulsive disease (PVOD). A vein containing prominent intimal fibrosis and recanalization (colander lesion) is characteristically found in this disease. ♦♦ Intimal fibrosis and thrombosis of veins; recanalization is common

Pulmonary Capillary Hemangiomatosis Clinical ♦♦ Rare cause of pulmonary hypertension; most patients between 20 and 40 years

Microscopic ♦♦ Abnormal proliferation of capillary-like vessels in alveolar septa; patchy hemosiderin ♦♦ May have secondary venous changes with intimal fibrosis

Pulmonary Hypertension Due to Chronic Thrombotic and/or Embolic Disease Clinical ♦♦ Sudden shortness of breath with pleuritic pain

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Macroscopic (Fig. 28.30) ♦♦ Hemorrhagic wedge-shaped peripheral lesions

Microscopic (Fig. 28.31) ♦♦ Eccentric intimal fibrosis; collander lesions common; widespread small vessel thrombi ♦♦ Plexigenic lesions are rarely found (probably represents plexogenic arteriopathy with superimposed thrombi) ♦♦ Ischemic necrosis and surrounding areas of organization and hemosiderin pigment

Differential Diagnosis ♦♦ Necrotizing pneumonia

Infections (Also See Chapter 6) Viral Cytomegalovirus Clinical

Fig.  28.30. Thrombotic arteriopathy. An eccentric pattern of intimal fibroplasia is seen in this form of pulmonary hypertensive disease.

♦♦ Found almost exclusively in immunocompromised patients

Microscopic (Fig. 28.32) ♦♦ Diffuse interstitial pneumonitis and nodular (miliary) pneumonia ♦♦ Cytopathic changes: cytomegaly (2–3 times normal cell); ampholic/basophilic nuclear inclusions; basophilic cytoplasmic inclusions; ♦♦ Inclusions found in pneumocytes, histiocytes, and endothelial cells; PAS (+); Grocott(+)

Differential Diagnosis ♦♦ Herpes viral pneumonia −− Necrotizing pneumonia −− Cowdry type A nuclear inclusions ♦♦ Adenoviral pneumonia −− No cytoplasmic inclusions −− Smudge cells (nuclear inclusions)

Fig. 28.31. Pulmonary infarction. A wedge-shaped hemorrhagic­ area represents a recent, hemorrhagic infarction of the lung.

Herpes Simplex Virus Clinical ♦♦ Bloodborne or airborne dissemination; immunocompromised patient, inhalation injuries, and chronic obstructive pulmonary disease patient ♦♦ Laryngotracheobronchitis, bronchopneumonia

Microscopic ♦♦ Miliary foci of necrosis ♦♦ Cytopathic changes: may be difficult to find in lung; mild nucleomegaly (1.25–1.5 times normal cell); dispersion of nuclear chromatin; condensation of nuclear chromatin on nuclear membrane ♦♦ Cowdry type A inclusions: intranuclear viral particles that coalesce ♦♦ Multinucleation may be absent in lung ♦♦ Epithelial cells mainly affected

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Fig. 28.32. Cytomegalovirus (CMV) inclusion in alveolar macrophage. Both nuclear and cytoplasmic inclusions can be seen in this enlarged alveolar macrophage infected by CMV.

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Differential Diagnosis ♦♦ Cytomegalovirus pneunomia −− Affects both epithelial and mesenchymal cells −− Cytoplasmic inclusions

Measles Virus Clinical ♦♦ Immunocompromised patient

Microscopic ♦♦ Diffuse alveolar damage and acute necrotizing bronchopneumonia; multinucleated cells (5–20 nuclei/cell); intranuclear and intracytoplasmic inclusions present (Feulgen−) ♦♦ Warthin–Finkeldey cell with lymphoid hyperplasia: CD4 + T-cells

Differential Diagnosis

Fig. 28.33. Adenovirus infection. Dark, intranuclear inclusions are found in the “smudge” cells.

♦♦ Giant cell interstitial pneumonitis/hard metal pneumoconiosis −− Acute lung injury usually not present −− Giant cells with 2–5 nuclei

Adenovirus Clinical ♦♦ Generally found in children; can cause fulminent pneumonia in immunosuppressed

Microscopic (Fig. 28.33) ♦♦ Destruction of bronchioles with sloughing; ♦♦ Cytopathic changes: smudge-Feulgen + round eosinophilic intranuclear inclusions

Electron Microscopy ♦♦ Lattice-like hexagonal viral particle

Respiratory Syncytial virus Clinical ♦♦ Usually seen in babies and young children; diagnosis usually made by serologies

Microscopic ♦♦ Cellular, lymphocytic bronchiolitis with intraluminal neutrophils ♦♦ Metaplastic bronchial epithelium; can show multinucleation ♦♦ Cytopathic effect: small, inconspicuous eosinophilic cytoplasmic inclusions in bronchiolar cells

Epstein–Barr Virus Clinical ♦♦ Biopsy rarely performed for diagnosis; 10% of patients with mononucleosis show clinical symptoms of respiratory infection

Microscopic ♦♦ Perivascular (especially perivenular) chronic inflammation with plasmacytoid and/or immunoblastic features, cellular bronchiolitis, and interstitial infiltrates

Fig. 28.34. Hantavirus pulmonary syndrome. Fluid-filled alveolar spaces and interstitial edema are present.

Hantavirus Pulmonary Syndrome Clinical ♦♦ Young, healthy adults; rapidly fatal; progressive pulmonary edema and hemorrhage ♦♦ Host: deer mice ♦♦ Diagnosis usually made by culture or serologies; biopsy rarely done for diagnosis

Microscopic (Fig. 28.34) ♦♦ Pulmonary edema and pleural effusions; early DAD

Bacteria Legionnaires Disease Clinical ♦♦ First recognized in large outbreak in American Legion convention in Philadelphia

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Fig. 28.36. Actinomyces. Gram-positive sulfur granules are seen in this Splendore-Hoeppli reaction. ♦♦ Silver stain is best for diagnosis: fine, filamentous organisms – may be very difficult to find ♦♦ Weakly acid-fast (Fite stain) and gram-positive

Actinomycosis Clinical Fig.  28.35. Legionnaires disease. A prominent intra-alveolar exudate with degenerating inflammatory cells (A) is present; the organisms, pleomorphic gram-negative bacilli, are highlighted by Dieterle stain (B).

♦♦ Acute pneumonic process with high fever, cough, chill, and chest pain; gastrointestinal symptoms are prominent; renal failure is common ♦♦ Renal and bone marrow transplant patients at high risk

Microscopic (Fig. 28.35A, B) ♦♦ Acute bronchopneumonia with characteristic intra-alveolar exudate of neutrophils, macrophages, and karyorrhectic debris

Special Studies ♦♦ Small, pleomorphic gram-negative bacillus; cultured in modified Mueller-Hinton agar ♦♦ Dieterle silver stain best for visualizing organism; fluorescent studies of smears and scrapes are most sensitive for diagnosis

Nocardiosis Clinical ♦♦ Localized abscess or miliary bilateral infection (common) in immunocompromised host

Microscopic ♦♦ Mixture of acute and chronic inflammation with micro­ abscess formation

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♦♦ Aspiration of oral or tonsillar organisms; patients with poor dentition or repeated tonsillitis

Microscopic (Fig. 28.36) ♦♦ Abscess in lung or mediastinum; sulfur granules found with palisading eosinophilic proteinaceous halo – SplendoreHoeppli reaction

Malakoplakia Clinical ♦♦ Nodular lesions in immunocompromised patients, particular HIV-infected individuals; Rhodococcus equi is common ­etiologic agent

Microscopic ♦♦ Chronic infiltrate with plasma cells and lymphocytes with sheets of histiocytes containing abundant Michaelis– Gutmann bodies

Mycobacterial Infections Tuberculosis Clinical ♦♦ High risk factors include elderly, immigrants, lower socio­ economic groups, aboriginal races, HIV infection, silicosis, diabetes mellitus, hemodialysis, gastrectomy, nutritional deficiency, intravenous drug abuse, and organ transplantation ♦♦ Clinical classification −− Primary TB: exogenous first infection; usually self-limiting −− Progressive TB: inadequate acquired immunity (infants or elderly); progression of original infection; <10% of patients

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Fig. 28.38. Mycobacterium avium complex (MAI) in an AIDS patient, Abundant acid-fast bacilli are present within alveolar macrophages.

♦♦ Postprimary TB −− Apical lesion (due to higher oxygen tension); miliary spread can occur

Microscopic (Fig. 28.37B) ♦♦ Primary/postprimary TB −− Necrotizing granulomatous inflammation, airway-based; nonnecrotizing granulomas commonly present away from main mass ♦♦ Progressive TB −− Necrotizing granulomatous inflammation with cavitation and spread throughout lung; pleura commonly involved

Nontuberculous Mycobacteria ♦♦ Most common are Mycobacterium avium complex (Mycobacterium intracellulare and M. avium) and Mycobacterium kansasii

Clinical

Fig.  28.37. Mycobacterial tuberculosis. A cavitating apical lesion (A) and necrotizing granulomas (B) are seen.

−− Postprimary TB (reactivation; secondary): endogenous reactivation

Macroscopic (Fig. 28.37A) ♦♦ Primary TB −− Ghon focus: single subpleural nodule, above or below interlobar fissure and enlarged caseous lymph nodes ♦♦ Progressive TB −− Cavitation and progression of initial or reactivation nodule; consolidation or miliary spread can occur

♦♦ Opportunistic infections in HIV-infected patients ♦♦ Other risk factors COPD, bronchiectasis, pneumoconioses ♦♦ Also found in patients without underlying lung disease ­(nonsmoking women)

Macroscopic ♦♦ Can cause upper lobe cavitary lesion ♦♦ Noncavitating form may be associated with local bronchi­ ectasis

Microscopic ♦♦ Necrotizing granulomatous inflammation most common with nonnecrotizing granulomas present ♦♦ Organizing pneumonia and nonnecrotizing granulomas can be seen

Special Studies ♦♦ Ziehl–Neelsen stain for acid-fast organisms (Fig. 28.38) ♦♦ Auroamine-rhodamine more sensitive

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Differential Diagnosis

(b) Chronic necrotizing aspergillosis:

♦♦ Wegener granulomatosis (Table 28.1) −− No sarcoidal-like granulomas −− Basophilic necrosis ♦♦ Necrotizing fungal infections −− Results of special stains and microbiologic cultures

* Usually single, upper lobe lesion, subacute clinical course * Chronic, granulomatous inflammation; eosinophils are prominent; hyphae should be readily ­apparent; no vascular invasion (c) Fulminant invasive aspergillosis

Mycoplasma Pneumoniae Clinical ♦♦ Community-acquired pneumonia; dry cough with subacute course

Microscopic ♦♦ Cellular bronchiolitis with acute and chronic inflammation; plasma cells may be abundant ♦♦ Metaplastic bronchiolar epithelium without cilia; organism destroys cilia

Special Studies ♦♦ Complement fixation tests used for diagnosis; fourfold titer increase is diagnostic of infection ♦♦ Stains on Giemsa stain; DNA probe is best way to find organisms in tissue

* Immunocompromised host; vascular invasion and infarction

Differential Diagnosis ♦♦ Mucormycosis −− Nonseptate, larger, right angle branching −− Culture needed to distinguish, especially if Asp. is treated ♦♦ Alternaria −− Golden brown club-shaped macroconidia with longitudinal and transverse septation; bullous swelling near septation in hyphae

Mucormycosis (Phycomycosis) Clinical ♦♦ Immunocompromised host: uncontrolled diabetes, burn injury, and renal failure

Fungal Aspergillosis (Fig. 28.39)

Microscopic (Fig. 28.40)

♦♦ Aspergillus: thick-walled hyphae, septated, and 45° branching; oxalic acid/calcium oxalate crystals seen in Asperillus niger ♦♦ Four different pathologic patterns −− Allergic bronchopulmonary aspergillosis (ABPA)

Differential Diagnosis

(a) Seen exclusively in asthmatics (b) Mucoid impaction, bronchocentric granulomatosis, and eosinophilic pneumonia −− Aspergilloma (a) Fungus ball growing in preexisitng cavity, e.g. bulla

Fig. 28.39. Aspergillus fungal hyphae. A silver stain highlights the septated hyphae with acute angle branching.

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♦♦ Nonseptate hyphae 10–25  mm wide; irregular right angle branching; pleomorphic, collapsing walls; necrotizing bronchopneumonia with infarction ♦♦ Aspergillosis −− Septate, right angle branching

Candidiasis Clinical ♦♦ Immunocompromised hosts, burns, trauma, catheters, and gastrointestinal surgery

Fig.  28.40. Mucormycosis. Nonseptate hyphae with a ribbonlike morphology are present within infarcted lung tissue.

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Fig. 28.41. Histoplasmosis. Necrotizing granulomas are present over the majority of airways (A) and usually show abundant central necrosis (B). Present within the area of necrosis are budding yeast forms of Histoplasma capsulatum (C).

Microscopic ♦♦ Yeast forms 2–6  mm; mycelial pseudohyphae forms are common ♦♦ Acute bronchopneumonia and emboli to other organs, especially kidney

Histoplasmosis Clinical ♦♦ Can be seen in normal host; commonly found in Mississippi and Ohio River Valley; bird and bat feces

Microscopic (Fig. 28.41A–C) ♦♦ Necrotizing granulomas, similar to Mycobacterium tuberculosis; yeast forms (2–5 mm), usually degenerating forms are seen; budding is unusual but seen

Coccidioidomycosis Clinical (Fig. 28.42) ♦♦ Can be seen in normal host; southwest U.S., dry arid climate (San Joaquin Valley Fever); inhaled arthrospores develop into spherules ♦♦ Coccidioides immitis usual organism; complement fixation tests positive in 90% patients

Microscopic ♦♦ Necrotizing granulomas, resembling M. tuberculosis

Fig. 28.42. Coccidioides immitis. A silver stain highlights large spherules containing endospores that spill out into infected lung tissue.

Special Studies ♦♦ Spherules (20–200 mm) with endospores – PAS+, GMS+

Sporotrichosis Clinical ♦♦ Male, alcoholic; infects preexisting lung disease (emphysema); Sporothrix schenckii usually organism; found in straw, moss, timber, and plants

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Fig. 28.43. Blastomycosis. Loosely formed necrotizing granuloma (A) are characteristic of this infection; a silver stain highlights the broad-based budding of Blastomyces dermatitides (B).

Microscopic ♦♦ Single, necrotizing lesion; significant hilar adenopathy

Blastomycosis Clinical ♦♦ Can be seen in normal host; Blastomyces dermatitidis, soil growing fungus; ♦♦ North America around Mississippi and Ohio rivers and Southeast (Georgia)

Microscopic (Fig. 28.43A, B) ♦♦ Necrotizing granulomas with central microabscess multi­ nucleated giant cells; yeast forms: broad-based budding ♦♦ Bronchial lesions are common; bronchial stenosis common

Cryptococcosis Clinical ♦♦ Can be seen in normal host, most symptomatic cases are in immunocompromised hosts; predilection for CNS ♦♦ Cryptococcus neoformans most common organism; source: pigeons

Microscopic (Fig. 28.44) ♦♦ Granulomatous lesions with acute inflammation; pleomorphic yeast forms (2–10 mm); single bud

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Fig.  28.44. Cryptococcus neoformans. A PAS stain highlights the presence of a capsule and budding commonly found in this yeast.

Special Studies ♦♦ Silver+; mucicarmine+ capsule

Protozoan Pneumocystis jirovecii Pneumonia Clinical ♦♦ Immunocompromised host, especially AIDS; insidious onset; bilateral infiltrates

Microscopic (Fig. 28.45) ♦♦ Frothy, eosinophilic intra-alveolar exudate with faint blue dots ♦♦ Mild chronic interstitial pneumonitis ♦♦ Unusual reactions include granulomatous inflammation, ­diffuse alveolar damage, alveolar proteinosis, calcifications, and tissue invasion

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Fig.  28.46. Minimal acute vascular rejection of pulmonary allograft. A scattering of mononuclear cells surrounds a small vessel and are difficult to distinguish from low power.

Toxoplasma gondii Pneumonia Clinical ♦♦ Immunocompromised host, especially AIDS and neonate; cats are carriers ♦♦ Infection of humans is via cat feces or raw meat

Microscopic Fig. 28.45. Pneumocystis jiroveci pneumonia (PCP). A “frothy” intra-alveolar exudative is present with prominent type 2 pneumocytes (A). Pneumocystis jiroveci organisms are highlighted by a silver stain (B).

Special Studies ♦♦ Cyst (5–8 mm) is best seen on methenamine silver stain ♦♦ Trophozoite (1–2 mm) best seen on Giemsa stain

Differential Diagnosis ♦♦ Pulmonary alveolar proteinosis −− Negative methenamine silver stain (a) Minimal interstitial reaction (b) PAS+

Dirofilarial (Dog Heart Worm) Granulomas Clinical ♦♦ Dirofilaria immitis, dog heart worm; adult worm resides in right ventricle/pulmonary artery of dogs; microfilariae in dog blood transmitted to human via mosquito bites ♦♦ Asymptomatic coin lesion on chest x-ray

Microscopic ♦♦ Pathologic triad: spherical infarct, eosinophilic pneumonia, and endarteritis ♦♦ Dirofilarial parasite is present within branch of pulmonary artery within center of infarct ♦♦ 100–200 mm; thick cuticle with longitudinal ridges

♦♦ Necrotizing nodules with central coagulative necrosis ♦♦ Tachyzoites are present within necrosis ♦♦ DAD can be seen

Special Studies ♦♦ Giemsa stains tachyzoites ♦♦ Immunohistochemical studies helpful for identification of cysts

Paragonimiasis (Lung Fluke) Clinical ♦♦ Endemic in South America, Africa, India, Southeast Asia; in immigrants in North America ♦♦ “Endemic hemoptysis;” pleural and blood eosinophilia; benign clinical course

Microscopic ♦♦ Adult flukes in human lung: red/brown and fleshy;0.8–1.4 cm in length ♦♦ Chronic abscess formation; upper lobes > lower lobes

Special Studies ♦♦ Ziehl–Neelsen stains eggshells

Lung Transplantation (Also See Chapter 5) Histologic Grading of Pulmonary Allograft Rejection Acute Vascular Rejection (Fig. 28.46) ♦♦ Perivascular and interstitial mononuclear cell infiltrates −− Grade A0: normal pulmonary parenchyma

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−− Grade A1: infrequent perivascular mononuclear infiltrates not obvious at low magnification −− Grade A2: frequent perivascular mononuclear infiltrates surrounding venules and arterioles readily recognizable at low magnification −− Grade A3: readily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, usually associated with endothelialitis; interstitial mononuclear cell infiltrates −− Grade A4: diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells and prominent alveolar pneumocyte damage usually associated with inflammatory cell debris

Airway Inflammation-Lymophocytic Bronchitis/ Bronchiolitis ♦♦ ♦♦ ♦♦ ♦♦

Grade B0: none Grade B1R: low grade Grade B2R: high grade Grade BX: ungradeable

♦♦ Grade C1: present

Chronic Vascular Rejection-Accelerated Graft Sclerosis ♦♦ Fibrointimal thickening of arteries and veins of uncertain clinical significance

Antibody-Mediated Rejection (AMR) Clinical ♦♦ Progressive respiratory failure, pulmonary edema, and opacification of allograft

Microscopic ♦♦ Diffuse alveolar damage ♦♦ Pulmonary hemorrhage with capillaritis

Special Studies ♦♦ Deposition of IgG and complement (C3d and C4d) in the alveolar septa

Differential Diagnosis

Chronic Airway Rejection/Bronchiolitis Obliterans ♦♦ Grade C0: None

♦♦ Ischemia-reperfusion injury with acute lung injury −− No vasculitis or capillaritis is seen −− Negative lymphocyte cross-match

NEOPLASTIC DISEASES OF THE LUNG Benign Tumors Benign Epithelial Tumors Squamous Papillomas and Papillomatosis Clinical

Papillary Adenoma of Type 2 Cells Clinical

♦♦ Upper airway-solitary; adult smoker ♦♦ Lower airway-multiple; papillomatosis: children and young adults

♦♦ Circumscribed lesion of branching, papillary fronds lined by cytologically bland columnar cells; no mitoses, necrosis; intranuclear inclusions common

Macroscopic (Fig. 28.47A) ♦♦ Multiple lobulated escrescences in bronchioles; distal bronchiectasis common

Microscopic (Figure 28.47B) ♦♦ Fibrovascular core with cytologically bland nonkeratinizing squamous epithelium; koilocytotic changes are common; mucous-secreting, transitional or intermediate cells are sometimes interspersed

Differential Diagnosis ♦♦ Well-differentiated squamous cell carcinoma/verrucous carcinoma −− Lack of maturation −− Marked cytologic atypia −− Invasion into adjacent tissue −− Increased dyskeratosis and hyperkeratosis

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♦♦ Asymptomatic, coin lesion

Microscopic

Differential Diagnosis ♦♦ Metastatic papillary carcinoma −− Rule out primary ovarian, thyroid, kidney, colon, breast ♦♦ Sclerosing hemangiomas −− More diversity of pathology with solid areas and bloodfilled spaces ♦♦ Papillary adenocarcinoma −− Cytologic atypia, necrosis and mitoses

Alveolar Adenoma Clinical ♦♦ Solitary nodule in women

Microscopic ♦♦ Multicystic, well-circumscribed with ectatic spaces filled with eosinophilic material; flat lining cells;interstitium contains collagenous matrix with myofibroblasts

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♦♦ Adenocarcinomas −− Cytologic atypia, necrosis, mitoses, lack of large cystic spaces

Mucinous Cystadenoma Clinical ♦♦ Nodule in adult smokers ♦♦ Usually asymptomatic

Macroscopic ♦♦ Mucus-filled cysts

Microscopic ♦♦ Cystic spaces lined by benign, mucus-secreting epithelium; no invasion into adjacent tissue; borderline lesions show increased cytologic atypia

Differential Diagnosis ♦♦ Well-differentiated adenocarcinoma and mucinous bronchioloalveolar carcinomas −− No fibrous cyst wall ♦♦ Mucinous cystadenocarcinoma −− Invasive growth into surrounding lung

Benign Mesenchymal Tumors Hamartoma Clinical Fig. 28.47. Squamous papillomatosis. A tan-lobulated mass is present in the trachea (A) and microscopically shows cytologically bland squamous epithelium with some superficial keratinization (B).

Differential Diagnosis ♦♦ Lymphangioma −− Endothelial-lined spaces; cytokeratin−

Mucous Gland Adenoma Clinical ♦♦ Occurs in both children and adults; more common in women ♦♦ Large airway obstruction/irritation

Macroscopic

♦♦ Two locations: central endobronchial; parenchymal ♦♦ Central type causes symptoms −− Cough −− Obstructive pneumonia

Macroscopic (Fig. 28.48A) ♦♦ Well-circumscribed white, bulging nodules of cartilaginous consistency ♦♦ Calcium or bone may be present

Microscopic (Fig. 28.48B) ♦♦ Usually composed predominantly of cartilage; fat, smooth muscle, and fibromyxoid tissue can be seen ♦♦ Surrounded by clefts of benign ciliated or nonciliated epithelium, probably entrapped metaplastic epithelium ♦♦ Punctate calcifications can be seen

♦♦ Polypoid, endobronchial lesions in lobar or segmental bronchi ♦♦ Solid and cystic gelatinous surfaces

Cytogenetics

Microscopic

Differential Diagnosis

♦♦ Cystic, mucous-filled glands with cytologically bland, mucus-secreting epithelium; oncocytic metaplasia can be seen

Differential Diagnosis ♦♦ Low grade mucoepidermoid carcinoma −− Intermediate cells

♦♦ 6p21 rearrangement activates high mobility group gene (HMGI-Y) ♦♦ Bronchial chondromas as seen in young women with Carney triad: pulmonary chondromas, gastric epithelioid tumors, and extra-adrenal paragangliomas −− Are usually connected to airway cartilage ♦♦ Benign metastazing leiomyoma −− Fat, cartilage other fibromyxoid elements are not seen

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♦♦ Intrapulmonary solitary fibrous tumor −− Stromal cells are CD34+

Mesenchymal Cystic Hamartoma Clinical

Lipoma Clinical

♦♦ Lung cysts causing hemoptysis, pneumothoraces, and pleuritic chest pain ♦♦ Can be seen in children

♦♦ Usually arise in central bronchi; lead to obstruction, wheezing, bronchiectasis ♦♦ Large variant completely enveloping bronchus can be sequelae of chronic bronchiectasis

Macroscopic ♦♦ More frequent in left main bronchus than on right side ♦♦ Smooth-walled polyps projecting into lumen

Microscopic ♦♦ Mature adipose tissue; can have giant cells

Differential Diagnosis ♦♦ Hamartoma −− Other mesenchymal elements present

Macroscopic ♦♦ Small cysts with connections to bronchioles

Microscopic ♦♦ Normal respiratory or cuboidal epithelium; underlying primitive mesenchymal cells ♦♦ Hypertrophic arteries within mesenchyme

Differential Diagnosis ♦♦ Sequestration of the lung ♦♦ Congenital cystic adenomatoid malformation ♦♦ Cystic bronchiectasis −− None of the above contain primitive mesenchymal cells beneath epithelium ♦♦ Metastasis −− Primary sarcoma (many of the reported cases have been metastases from uterine neoplasms)

Preinvasive Lesions Squamous Dysplasia/Carcinoma In Situ Microscopic ♦♦ Dysplasia: cytologic atypia, nuclear enlargement in lower, middle, and upper third of mucosa (grades: mild, moderate, and severe); superficial surface maturation ♦♦ Carcinoma in situ: entire mucosal involvment by dysplasia; no invasion below basement membrane

Atypical Adenomatous Hyperplasia Microscopic (Fig. 28.49) ♦♦ Mild/moderate atypical in cuboidal cells lining alveolar walls

Fig. 28.48. Hamartoma. A well-circumscribed white nodule (A) extrudes from the underlying lung parenchyma and contains cartilage, adipose tissue, and benign entrapped respiratory epithelium (B).

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Fig. 28.49. Atypical adenomatous hyperplasia. A cuboidal epithelium contains hyperchromatic cells with cytologic atypia.

Lung and Pleura

♦♦ May be precursor to adenocarcinoma ♦♦ Difficult to separate from nonmucinous variant of bronchioloalveolar carcinoma ♦♦ Focal lesions, often £5 mm; atypical cuboidal/low columnar epithelium; mitoses rare

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Increased number of neuroendocrine cells Multiple airways involved Tumorlets are common and may obliterate airways Carcinoid tumors may be seen

Differential Diagnosis ♦♦ Neuroendocrine cell hyperplasia and tumorlet formation seen in the setting of other chronic lungs

Malignant Tumors Tumors of Salivary Gland Type Mucoepidermoid Carcinoma Clinical ♦♦ Half are in patients less than 30 years; symptoms of large airway obstruction/irritation

Macroscopic (Fig. 28.50A) ♦♦ Tan/pink endobronchial nodule, most common in main or lobar bronchi

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♦♦ Mucoid surface with underlying cystic areas; can ulcerate on surface

Microscopic (Fig. 28.50B) ♦♦ Mucin-secreting, squamous, and intermediate cells ♦♦ Low grade: mitoses, nuclear pleomorphism, and necrosis are absent ♦♦ High grade: mitoses (>4/10HPF), nuclear pleomorphism, and necrosis are present

Differential Diagnosis ♦♦ Bronchial mucous gland adenoma −− No intermediate or squamous cells ♦♦ Adenosquamous cell carcinomas −− Peripheral lesions with adjacent in situ changes −− Common to have keratinization −− Intermediate cells are absent

Adenoid Cystic Carcinoma Clinical ♦♦ Most common salivary gland type tumor of the lower respiratory tract ♦♦ Lower trachea, mainstem bronchi, or lobar bronchi ♦♦ Large airway obstruction/irritation ♦♦ Recurrence is common

Macroscopic ♦♦ Tan/gray tumors intrude bronchial wall with sessile or annular lesions; can spread submucosally along bronchial wall and diffusely involve adjacent airways

Fig. 28.50. Mucoepidermoid carcinoma. A tan polypoid endobronchial nodule is present in a proximal bronchus (A); microscopic features include both squamous and mucin-producing cells and more solid areas of intermediate cells (B).

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Microscopic (Fig. 28.51A–C)

Differential Diagnosis

♦♦ Small cells with hyperchromatic nuclei in cribriform, cylindromatous, trabecular, or glandular architecture; commonly infiltrates through airway cartilage; spaces contain alcian blue + basal lamina-type material; perineural invasion common

♦♦ Pleomorphic adenoma −− No cribriform or cylindromatous areas ♦♦ Mucoepidermoid carcinoma −− Smooth, well-circumscribed mass −− Squamous and intermediate cells

Fig.  28.51. Adenoid cystic carcinoma. A tan/white tumor mass thickens a bronchial wall (A); well-formed glands (B) with hyperchromatic cells and prominent basal lamina material are characteristic (C).

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♦♦ Adenocarcinomas of the lung −− Cytologic atypia, mitoses, necrosis

Epithelial Tumors Squamous Cell Carcinoma Clinical ♦♦ 2/3 are central; more commonly found in men; second most common bronchogenic carcinoma; strong association with smoking ♦♦ Hypercalcemia due to parathormone-related protein secretion by tumor

Macroscopic (Fig. 28.52A) ♦♦ Vary from small to large, obstructive lesions; commonly cavitate ♦♦ Usually found in segmental or subsegmental bronchi

Microscopic (Fig. 28.52B) ♦♦ Characterized by the presence of cytokeratin differentiation with keratinization and intercellular bridges by light microscopy ♦♦ Graded according to degree of squamous differentiation ♦♦ Spindle cells, osteoclastic-type and tumor giant cells, and clear cell changes can be seen ♦♦ Histologic variants include papillary, clear cell, small cell, basaloid

Differential Diagnosis ♦♦ Squamous metaplasia −− Minimal cytologic atypia; maturation; lack of stromal invasion ♦♦ Adenosquamous carcinoma and mucoepidermoid carcinoma −− Glandular component ♦♦ Small cell carcinoma −− Lack nucleoli, increased nuclear molding, and crush artifact −− Less cytoplasm; increased N/C ratio −− No squamous differentiation

Adenocarcinoma Clinical ♦♦ Most common form of bronchogenic carcinoma; most common lung cancer in women ♦♦ Hypertrophic pulmonary osteoarthropathy ♦♦ Smoking history is more variable than in other bronchogenic carcinomas

Macroscopic (Fig. 28.53A) ♦♦ More commonly peripheral ♦♦ Desmoplasia can be prominent (but true “scar carcinomas” also occur)

Microscopic (Fig. 28.53B) ♦♦ Four major histologic subtypes −− Acinar −− Papillary

Fig. 28.52. Squamous cell carcinoma. A proximal, obstructing, cavitating tumor is present in a proximal airway (A). Malignant squamous cells and prominent keratinization is present (B).

−− Bronchioloalveolar (Fig. 28.54) (a) No invasion into underlying stroma (b) Aerogenous spread with microsatellite lesions is common −− Solid ♦♦ Most commonly a mixed type with multiple histologic subtypes ♦♦ Clear change is common ♦♦ Uncommon variants −− Fetal adenocarcinoma −− Mucinous (colloid) adenocarcinoma

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Fig.  28.54. Bronchioloalveolar adenocarcinoma. Malignant mucinous glandular epithelium crawls along the alveolar wall without invasion into the underlying lung tissue.

Molecular ♦♦ Epidermal growth factor receptor (EGFR) and K-ras mutations

Differential Diagnosis

Fig.  28.53. Adenocarcinoma. A peripheral tan/white tumor mass arises adjacent to the pleural surface (A). Histologically, in this acinar variant, the tumor contains malignant glands with marked atypical epithelium (B).

−− Signet-ring cell adenocarcinoma −− Clear cell adenocarcinoma

Immunohistochemistry ♦♦ ♦♦ ♦♦ ♦♦

Thyroid transcription factor -1 (TTF-1): >80%+ Neuron specific enolase: 50% (+); Leu 7: 33%+ Chromogranin/synaptophysin: 10–20%+ Cytokeratin 7+ and cytokeratin 20+/−

Electron Microscopy ♦♦ Microvilli with glycocalx and rootlets

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♦♦ Organizing diffuse alveolar damage with treatment-related cytologic atypia −− History of treatment (chemotherapy/radiation therapy) −− Diffuse pattern on imaging studies −− Heterogeneity of cell types ♦♦ Metastatic adenocarcinoma from kidney, gastrointestinal tract, and breast −− Clinical history −− Mucin and cytokeratin 7− in renal cell carcinoma −− Cytokeratin 7− in colorectal adenocarcinomas ♦♦ Reactive type 2 pneumocyte hyperplasia and other reactive bronchiolar inflammatory lesions −− Cilia present −− Lesions limited to bronchioles ♦♦ Atypical adenomatous hyperplasia −− Less than or equal to 7 mm

Adenosquamous Carcinoma Clinical ♦♦ < 4.0% of lung carcinomas ♦♦ Strong association with smoking

Microscopic ♦♦ Contains well-defined squamous cell carcinoma and adenocarcinoma ♦♦ Each component must comprise at least 10% of tumor

Differential Diagnosis ♦♦ Adenocarcinoma with metaplastic squamous changes −− Squamous metaplasia has benign features

Lung and Pleura

♦♦ Squamous cell carcinoma with entrapped bronchial epithelium −− Entrapped glandular epithelium is benign ♦♦ High grade mucoepidermoid carcinoma −− Contains areas of low grade mucoepidermoid carcinoma −− Glandular component is usually goblet cell

Large Cell Undifferentiated Carcinoma Clinical ♦♦ 10–20% of lung carcinomas; strongly associated with smoking

Macroscopic ♦♦ Central or peripheral; typically large with pleural invasion ♦♦ Rarely occult

Microscopic (Fig. 28.55) ♦♦ Sheets and nests growth pattern with extensive necrosis; large nuclei with prominent nucleoli; lack definitive evidence of squamous or glandular differentiation ♦♦ Can have giant cell, clear cell, or spindle cell changes ♦♦ Variants include large cell neuroendocrine carcinoma (see neuroendocrine tumors), basaloid, lymphoepithelioma-like, and clear cell

Electron Microscopy ♦♦ 80% show glandular differentiation; 10% show squamous differentiation

Differential Diagnosis ♦♦ Melanoma −− (-) cytokeratin by immunohistochemical studies ♦♦ Large cell lymphoma (including anaplastic type) −− Nuclei tend to be smaller with more irregular nuclear membranes −− (-) cytokeratin and + for CD45 (leucocyte common antigen) by immunohistochemical studies

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Sarcomatoid Carcinomas ♦♦ Carcinomas associated with sarcoma or sarcoma-like elements ♦♦ Term for tumors with continuum of epithelial and mesenchymal differentiation ♦♦ Includes −− Pleomorphic carcinoma (a) Adenocarcinoma, squamous cell carcinoma with spindle cells and/or giant cells −− Spindle cell carcinoma (monophasic and biphasic) (a) Only spindle cells present −− Giant cell carcinoma (a) Large cell carcinoma with only giant cells – very rare −− Carcinosarcoma (a) Carcinoma with malignant heterologous elements; epithelial element is commonly squamous cell carcinoma; osteosarcoma, chondrosarcoma, and rhabdomyosarcoma are commonly part of sarcomatous −− Pulmonary blastoma (a) Biphasic tumor containing a primitive epithelial component and a primitive mesenchymal stroma −− Well-differentiated fetal adenocarcinoma

Clinical ♦♦ 90% of patients are 50–90 years ♦♦ Strong association with smoking; may be peripheral or central

Macroscopic ♦♦ Solitary and well-circumscribed

Microscopic ♦♦ Biphasic–sarcomatous and carcinomatous component ♦♦ Epithelium is commonly squamous cell carcinoma ♦♦ Osteosarcoma, chondrosarcoma, and rhabdomyosarcoma are commonly part of sarcomatous element ♦♦ Carcinoma may be scant

Immunohistochemistry ♦♦ Cytokeratin of spindle cell elements can be negative

Differential Diagnosis ♦♦ Sarcomas

Neuroendocrine Tumors Carcinoid Tumorlet Clinical ♦♦ Incidental microscopic finding ♦♦ Most common in adults; rarely in children

Microscopic (Fig. 28.56) Fig. 28.55. Large cell undifferentiated carcinoma. Pleomorphic cells show undifferentiated architecture with no squamous or glandular features.

♦♦ Neuroendocrine cells embedded in fibrotic stroma ♦♦ £0.5 cm ♦♦ Usually adjacent to bronchiole

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Fig. 28.56. Carcinoid tumorlet. Neuroendocrine cells are present in a small airway with fibrosis.

Differential Diagnosis ♦♦ Carcinoid tumor −− >0.5 cm ♦♦ Neuroendocrine cell hyperplasia −− Increased neuroendocrine cells within bronchiolar epithelium ♦♦ Bronchiolar metaplasia −− No evidence of neuroendocrine differentiation

Typical and Atypical Carcinoid Clinical ♦♦ ♦♦ ♦♦ ♦♦

May present with postobstructive changes Most common in adults; can occur in children Paraneoplastic syndromes can occur Can occur in patients with multiple endocrine neoplasia (MEN-1) (see Chapter 13)

Macroscopic (Fig. 28.57A) ♦♦ Central and peripheral: central lesions have large, endobronchial component with postobstructive changes distally ♦♦ Peripheral lesions are usually subpleural ♦♦ Tan/yellow mass; danger of bleeding on biopsy

Microscopic (Fig. 28.57B) ♦♦ Neuroendocrine cells with organoid, trabecular, insular, palisading ribbon, rosette-like architecture ♦♦ Round to oval nuclei with finely granular chromatin and inconspicuous nucleoli ♦♦ Stromal changes include bone, cartilage, dense fibrosis, and amyloid ♦♦ Atypical carcinoids have 2–10 mitoses/10 HPF, foci of necrosis ♦♦ Spindle cell variant is more common in peripheral lesions

Differential Diagnosis ♦♦ Spindle cell lesions (metastatic sarcoma, spindle cell carcinoma) −− No neuroendocrine differentiation

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Fig. 28.57. Typical carcinoid. A central, tan polypoid lesion is present in a proximal airway (A). Bland epithelial cells with finely granular chromatin are seen (B). ♦♦ Metastatic carcinoma of breast and prostate −− History of primary −− Multiple lesions

Small Cell Carcinoma Clinical ♦♦ 20–25% of all lung cancer; strong association with smoking ♦♦ Inappropriate antidiuretic hormone (ADH), Cushing and Eaton–Lambert syndrome ♦♦ Central tumors with early metastases ♦♦ Responsive to chemotherapy

Macroscopic ♦♦ 70% of cases present as perihilar mass ♦♦ Extensive lymph node metastases are common ♦♦ Typically peribronchial; endobronchial lesions are uncommon

Microscopic (Fig. 28.58) ♦♦ Round to fusiform nuclei; nuclear molding; faint or absent nucleoli; scant cytoplasm ♦♦ Extensive necrosis ♦♦ Combined small cell carcinoma variant ♦♦ Small cell carcinoma with a component of nonsmall cell carcinoma (at least 10%)

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Fig.  28.58. Small cell carcinoma. Fusiform nuclei with ­prominent nuclear molding and abundant mitoses are present.

Immunohistochemistry ♦♦ Can show chromogranin+, synaptophysin+, and Leu 7+; however, 25% of cases negative for neuroendocrine markers

Cytogenetics ♦♦ 3p deletions

Differential Diagnosis ♦♦ Nonsmall cell carcinoma, including large cell neuroendocrine carcinoma −− Larger nuclei −− Prominent nucleoli −− Lower nuclear/cytoplasmic ratio −− Lack of nuclear molding

Large Cell Neuroendocrine Carcinoma Clinical ♦♦ Strong association with smoking; average age = 64 years

Macroscopic ♦♦ Can extensively replace lung; central or peripheral; can be multinodular

Microscopic (Fig. 28.59) ♦♦ Organoid, palisading, trabecular patterns ♦♦ Large, polygonal nuclei and low nuclear/cytoplasmic ratio; frequent nucleoli ♦♦ High mitotic rate (>10 mitoses/10 HPF); necrosis can be prominent

Immunohistochemistry ♦♦ Chromogranin: 80%+; Leu 7: 40%+; synaptophysin: 40%+; bombesin: 40%+; CEA: 100%+; cytokeratin: 100%+ −− Neuroendocrine differentiation should be confirmed by immunohistochemistry or electron microscopy

Differential Diagnosis ♦♦ Small cell carcinoma −− Smaller nuclei

Fig. 28.59. Large cell neuroendocrine carcinoma. An organoid architecture with prominent geographic necrosis is seen. −− No nucleoli −− Increased nuclear/cytoplasmic ratio ♦♦ Atypical carcinoid −− 2–10 mitoses/10 HPF −− Single cell necrosis or focal central necrosis ♦♦ Large cell undifferentiated carcinoma −− No evidence of neuroendocrine differentiation by light microscopy or immunohistochemical or ultrastructural analysis

Unusual Tumors with Neuroendocrine Differentiation ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Paraganglioma Primitive neuroectodermal tumor Neuroendocrine carcinoma with rhabdoid phenotype Amphicrine neoplasms Neuroendrocrine carcinoma with anemone features Pulmonary blastoma with neuroendocrine differentiation

Mesenchymal Tumors Fibrous and Fibrohistiocytic Tumors Inflammatory Pseudotumor Clinical ♦♦ 60% occur under the age of 40; represents the majority of benign tumors in children ♦♦ Usually an asymptomatic mass

Macroscopic ♦♦ Solitary, round, well-circumscribed but unencapsulated mass; can penetrate pleura or extend into adjacent mediastinal structures ♦♦ Calcification and foci of necrosis can be seen; xanthoma cells can cause yellow color

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Microscopic (Fig. 28.60A, B) ♦♦ Circumscribed, with pushing border of organizing pneumonia ♦♦ Mixture of plasma cells, lymphocytes, macrophages with fibroblasts, and connective tissue ♦♦ Fibrohistiocytic subtype −− Myofibroblasts and fibroblasts predominate and can show pinwheel or storiform architecture −− Touton giant cells and xanthoma cells can be seen ♦♦ Plasma cell granuloma subtype −− Abundant plasma cells and lymphocytes −− Fibroblasts and collagen −− Mild nuclear atypia can be seen −− Lymphoid follicles can occur

Differential Diagnosis ♦♦ Malignant fibrous histiocytoma −− Increased cytologic atypia, cellularity, and necrosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Pleomorphic (spindle cell) carcinoma −− Foci of epithelial differentiation −− Reactivity for cytokeratin ♦♦ Pulmonary hyalinizing granuloma −− Usually multiple −− Distinctive, hyalinizing lamellar collagen ♦♦ Inflammatory fibrosarcoma −− Increased spindle cell atypia −− Increased cellularity ♦♦ Sclerosing hemangioma −− Interstitial collections of round, polygonal, or uniform cells −− + Epithelial membrane antigen

Inflammatory Myofibroblastic Tumor (IMT) Clinical ♦♦ Incidential nodule found in asymptomatic patient ♦♦ Most common in adolescent and children

Macroscopic ♦♦ Usually solitary well-demarcated mass, central, or peripheral ♦♦ Gray and white; may have hemorrhage or focal necrosis

Microscopic ♦♦ Spindle cells with inflammatory cells, especially plasma cells ♦♦ Variable mitotic activity

Immunohistochemistry ♦♦ Anaplastic lymphoma kinase (ALK)+ ♦♦ Spindle cells are immunopositive for actin, calponin; desmin+ in 50% of cases

Differential Diagnosis ♦♦ Inflammatory sarcomatoid carcinoma ♦♦ Malignant fibrous histiocytoma −− Increased cytologic atypia, cellularity, and necrosis −− Mitotic rate >3/50 HPF ♦♦ Solitary fibrous tumor −− CD34+

Malignant Fibrous Histiocytoma Clinical ♦♦ Older presentation: 60–70-year-old; primary is rare, always consider metastatic lesion ♦♦ Preoperative diagnosis is difficult due to negative cytologic specimens

Macroscopic Fig. 28.60. Inflammatory pseudotumor. A prominent myofibroblasts and fibroblasts are present with scattered giant cells in the fibrohistiocytic variant (A). The plasma cell granuloma variant contains abundant plasma cells within a collagen stroma (B).

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♦♦ Usually solitary mass (2–10 cm); peripheral location; rarely intrabronchial

Microscopic ♦♦ Spindle cells, pleomorphic giant cells, and histiocyte-like cells are present

Lung and Pleura

♦♦ Storiform, fascicular, or pleomorphic architecture ♦♦ Inflammatory cells can be a significant component

Differential Diagnosis ♦♦ Pleomorphic carcinoma with spindle cells −− Evidence of epithelial (squamous or glandular) differentiation −− + For carcinoembryonic antigen ♦♦ Inflammatory pseudotumor-fibrohistiocytic type −− Lack cytologic atypia −− <3 mitoses/50 HPF −− No significant necrosis

Smooth Muscle Tumors Leiomyosarcoma Clinical ♦♦ Rare; consider possibility of metastatic lesion, especially from uterus ♦♦ Symptomatic presentation: cough, hemoptysis

Macroscopic ♦♦ Large, circumscribed masses, most are parenchymal ♦♦ Propensity for hilar region

Microscopic ♦♦ Malignant spindle cells ♦♦ Smooth muscle actin+

Differential Diagnosis ♦♦ Leiomyoma −− <5 mitoses/50 HPF −− No cytologic atypic −− No significant necrosis ♦♦ Benign metastazing leiomyoma −− Multiple nodules −− Well-differentiated smooth muscle without mitoses/ necrosis/cytologic atypia ♦♦ Lymphangioleiomyomatosis −− Seen exclusively in women −− Multifocal, benign smooth muscle and cyst-like spaces

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Differential Diagnosis ♦♦ Metastatic rhabdomyosarcoma ♦♦ Carcinosarcoma −− Malignant epithelial component ♦♦ Pleuropulmonary blastoma −− 90% are found in children <10 years of age −− May have focal malignant primitive epithelial component

Vascular Tumors and Related Conditions Vascular Malformations (Fig. 28.61) ♦♦ Usually diagnosed radiographically; similar to those at other sites ♦♦ Multiple: Osler–Weber–Rendu

Epithelioid Hemangioendothelioma Clinical ♦♦ Mutliple nodules in young women (M:F = 1:4) ♦♦ Has been seen in children; over half patients are <40 years ♦♦ Concomitant multifocal disease can be seen in bone, soft ­tissue, and liver

Macroscopic ♦♦ Discrete, firm white nodules (1–2  mm); may resemble cartilage

Microscopic (Fig. 28.62A, B) ♦♦ Circumscribed, pale eosinophilic nodules; stroma may resemble cartilage or amyloid ♦♦ Cells are cytologically bland with round nuclei and nucleoli; intracytoplasmic vacuoles are present; endothelial differentiation is present

Immunohistochemistry ♦♦ Factor VIII+, CD34+, and CD31+

Skeletal Muscle Tumors Rhabdomyosarcomas Clinical ♦♦ Seen in both adults and children

Macroscopic ♦♦ Large, solid masses; may involve more than one lobe

Microscopic ♦♦ Cross striations are present; cells may be small, pleomorphic, or straplike ♦♦ Immunoreactive for desmin

Fig. 28.61. Arteriovenous malformation. Ectatic vascular spaces are surrounded by normal lung.

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−− Marked cytologic atypia −− Predominantly intravascular

Kaposi Sarcoma Clinical ♦♦ Rare initial site of involvment; 25% of disseminated disease affects the lung ♦♦ Hemoptysis

Macroscopic ♦♦ Hemorrhagic bronchial plaques or nodules present in a lymphatic distribution

Microscopic ♦♦ Spindle cells with intercellular spaces containing red blood cells ♦♦ Hemosiderin and plasma cells

Immunohistochemistry ♦♦ Spindle cells are CD34+ and CD31+

Differential Diagnosis ♦♦ Angiosarcoma −− Increased cytologic atypia −− Not usually found in immunocompromised patients ♦♦ Benign granulation tissue −− Lack red blood cells within spaces ♦♦ Bacillary angiomatosis −− Bacteria identified by special stains

Fig. 28.62. Epithelioid hemangioendothelioma. An eosinophilic matrix is present (A) and cells are cytologically bland with intracytoplasmic lumina formation (B).

Angiosarcoma Clinical ♦♦ Hemoptysis

Macroscopic ♦♦ Multiple, hemorrhagic nodules

Electon Microscopy

Microscopic

♦♦ Weibel-Palade bodies

♦♦ Atypical endothelial cells forming vascular spaces ♦♦ Intra-arterial or periarterial involvement is common ♦♦ Epithelioid variant

Differential Diagnosis ♦♦ Adenocarcinoma −− Mucin+ cytoplasmic vacuoles −− Cytokeratin+ ♦♦ Metastatic chondrosarcoma −− No endothelial differentiation −− S-100 protein+ ♦♦ Amyloid nodules −− Acellular −− Congo red+ ♦♦ Hamartoma −− Usually solitary −− Entrapped epithelium is cytokeratin+ ♦♦ Angiosarcoma

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Differential Diagnosis ♦♦ Kaposi sarcoma −− Lack cytologic atypia ♦♦ Metastatic sarcoma −− Primary lesion (e.g., heart or pulmonary artery) ♦♦ Primary/metastatic carcinoma −− Cytokeratin differentiation

Other Vascular Tumors ♦♦ Pulmonary artery and vein sarcomas (Fig. 28.63) −− Polypoid mass involving pulmonary vessels −− 80% involve pulmonary trunk ♦♦ Hemangiopericytomas

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−− Type I: >80% 5 year survival −− Type II and III: 40% 5 year survival

Macroscopic ♦♦ Type I: unilocular cyst ♦♦ Type II: solid and cystic ♦♦ Type III: tan/white solid

Microscopic (Fig. 28.64) ♦♦ Type I: cyst lined by benign ciliated columnar epithelium with underlying primitive small cells that can include rhabdomyoblasts ♦♦ May contain anaplastic sarcomatous elements such as embtyonal rhabdomyosarcoma, fibrosarcoma, chondrosarcoma, and anaplastic undifferentiated sarcoma ♦♦ Type II and III: mixture of sarcomatous and blastematous elements Fig. 28.63. Pulmonary artery sarcoma. Undifferentiated spindle and epithelioid cells with areas of prominent necrosis in a polypoid mass in the pulmonary artery. −− 10% of all primary hemangiopericytomas occur in lung −− Poor prognosis associated with >5  cm and increased mitotic rate

Neurogenic Tumors All neurogenic tumors are rare as primary lung tumors. Though the following can be found as primary lesions in the lung, the possibility of metastatic disease should be excluded first ♦♦ Malignant nerve sheath tumor ♦♦ Malignant psammomatous melanotic schwannoma ♦♦ Neuroblastoma and ganglioneuroblastoma ♦♦ Meningioma ♦♦ Neurilemmoma ♦♦ Neuroma and ganglioneuroma

Cartilaginous Tumors

Differential Diagnosis ♦♦ Pulmonary blastoma −− Adult −− Smoking history ♦♦ Congenital cystic adenomatoid malformation −− No malignant mesenchyme

Lymphoproliferative Lesions of the Lung Benign/Hyperplastic Lesions Nodular Lymphoid Hyperplasia Clinical ♦♦ Adults 30–80 years; most are asymptomatic ♦♦ Can be associated with autoimmune diseases such Sjogren syndrome, lupus erythematosus ♦♦ May have polyclonal hypergammaglobulinemia

Macroscopic ♦♦ Most are solitary masses; can present as multinodular lesions or infiltrate ♦♦ Rarely >5 cm

♦♦ All are rare lesions in the lung. Consider metastatic disease before primary lung lesions ♦♦ Chondroma −− Bronchial variant seen in Carney triad ♦♦ Chondroblastoma ♦♦ Chondrosarcoma

Microscopic

Pleuropulmonary Blastoma of Childhood Clinical

Differential Diagnosis

♦♦ Three types: I–III ♦♦ Found in children −− Type I: <1 year of age −− Type II: <3 years of age −− Type III: <4 years of age ♦♦ Survival depends upon type

♦♦ Heterogeneous inflammatory infiltrate; germinal centers are commonly seen ♦♦ Necrosis is rare; organizing pneumonia common ♦♦ Low grade B-cell lymphomas of mucosa associated lymphoid tissue (MALT) −− Should be monoclonal by immunohistochemistry −− Heavy chain rearrangements on molecular studies −− Lymphoepithelial lesions −− Granulomatous inflammation and amyloid can be seen −− Airway and vascular invasion

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Diffuse Lymphoid Hyperplasia/Lymphocytic Interstitial Pneumonitis Clinical ♦♦ Symptoms of interstitial disease: cough and dyspnea ♦♦ Can be seen in children and adults ♦♦ Associated with many conditions including: congenital or acquired immunodeficiency syndromes, autoimmune diseases (e.g. Sjogren), drug-induced lung disease

Macroscopic ♦♦ Firm, consolidated lung

Microscopic ♦♦ Dense, diffuse lymphoplasmocytic infiltrates in alveolar walls (LIP) ♦♦ Germinal centers around airways (follicular bronchiolitis) ♦♦ Granulomas and giant cells can be seen

Differential Diagnosis ♦♦ Diffuse low grade lymphoma −− Monomorphous population −− Lymphatic distribution −− Airway, vascular, and pleural invasion ♦♦ Extrinsic allergic alveolitis −− Areas of organization −− Prominent bronchiolitis

Lymphomas (Also See Chapter 15) Low Grade Lymphoma of the Mucosa Associated Lymphoid Tissue (MALT) Clinical ♦♦ Adults: 60 years; 1/2 are symptomatic ♦♦ 20% have monoclonal protein in serum ♦♦ Chest x-ray shows localized infiltrate or solitary lesion in 50%

Macroscopic ♦♦ Fleshy, nonnecrotizing mass; infiltrative growth pattern

Microscopic (Fig. 28.65A, B)

Fig. 28.64. Pleuropulmonary blastoma. A characteristic multicystic lesion with compact small cell proliferation beneath respiratory epithelium (A). Solid areas contain blastematous and sarcomatous foci (B) and foci of rhabdomyosarcoma are common (C).

♦♦ Dense, lymphoid infiltrate in lymphatic distribution; population may be monotonous ♦♦ Germinal centers are commonly seen; lymphoepithelial lesions can be seen ♦♦ Large mass lesions may be present ♦♦ Airway, vascular, and pleural invasion is common

Immunohistochemistry ♦♦ Light chain restriction can usually, but not always, be seen by immunohistochemistry

Molecular Studies ♦♦ Clonal B-cell rearrangements are usually seen by molecular studies

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♦♦ Immunodeficiency is a risk factor ♦♦ Poor prognosis

Macroscopic ♦♦ Nodular consolidation; nodules may have central necrosis

Microscopic ♦♦ Nodules or diffuse infiltrates of lymphoid cells ♦♦ Central necrosis and cavitation can be seen in larger nodules; prominent vascular invasion (angiocentric pattern) ♦♦ Cell population may be heterogeneous; graded according to degree of cytologic atypia and number of EBV+ cells −− Grade 1: benign lymphocytic vasculitis with < 5 EBV+ cells −− Grade 2: lymphomatoid granulomatosis, necrosis with 5–20 EBV+ cells −− Grade 3: angiocentric lymphoma with numerous EBV+ cells

Immunohistochemistry ♦♦ Most cells are + for T-cell markers (CD4, CD8); some are T-cell rich B-cell lymphomas ♦♦ Large atypical cells (+) CD20 and EBV in situ

Molecular Studies ♦♦ Either immunoglobulin rearrangements (B-cell) or T-cell receptor rearrangements (T-cell)

Differential Diagnosis Fig.  28.65. Marginal zone lymphoma of the BALT type. Prominent lymphoid aggregates are present throughout, usually with a lymphatic distribution (A). A monotonus population of lymphocytes with centrocyte cytoplasmic clearing is seen (B).

Differential Diagnosis ♦♦ Nodular lymphoid hyperplasia −− Heterogeneous and polyclonal population −− Solitary nodule ♦♦ Diffuse lymphoid hyperplasia −− Heterogeneous and polyclonal population −− No bronchial, vascular, or pleural invasion ♦♦ Secondary pulmonary involvement by chronic lymphocytic leukemia −− Peripheral white blood cell count consistent with CLL

Angiocentric Immunoproliferative Lesions/ Angiocentric Lymphomas/Lymphomatoid Granulomatosis/Polymorphic Reticulosis Clinical ♦♦ Average age: 40–50 years.; most present with multiple lung nodules ♦♦ Skin and CNS involvement is frequent

♦♦ Necrotizing granulomatous infections −− Well-formed granulomas ♦♦ Wegener granulomatosis −− Giant cells and neutrophilic microabscesses ♦♦ Low grade lymphomas of MALT −− Little necrosis −− Predominantly lymphatic distribution, not angiocentric ♦♦ Hodgkin disease −− Classic Reed-Sternberg cells (a) Classic background of lymphocytes and eosinophils ♦♦ Large cell lymphoma −− Distinction from high grade AIL/LYG may be arbitrary

Posttransplant Lymphoproliferative Disorder Clinical ♦♦ Found in patients who have undergone organ transplantation ♦♦ Associated with EBV infection

Macroscopic ♦♦ Single or multiple nodules or infiltrates

Microscopic ♦♦ Varied appearance: small cell to large cell; can be polymorphous ♦♦ Necrosis and vascular invasion can be seen

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Differential Diagnosis

Differential Diagnosis

♦♦ AIL/LYG −− Not restricted to immunosuppressed patients

♦♦ Bronchioloalveolar carcinoma −− No distinct cell population within stalk −− Cytologic atypia ♦♦ Adenocarcinoma, papillary type −− Marked cytologic atypia −− High mitotic rate

Other Lymphoproliferative Lesions Intravascular Lymphomatosis (Angiotropic Lymphoma) ♦♦ Aggressive, high grade lymphoma with tumor cells proliferating within small vessels −− Skin and CNS involvement are most common but pulmonary involvement is seen

Hodgkin Disease ♦♦ Usually involves lung by direct extension from mediastinum −− Primary lung involvement is rare −− Multiple nodules are common −− Histologic features of HD elsewhere

Benign Clear Cell (Sugar) Tumor Clinical ♦♦ Incidental mass on chest x-ray; asymptomatic

Macroscopic ♦♦ Small, red/tan masses; shell out from surrounding lung

Microscopic

♦♦ Female predominance (80% found in women); asymptomatic

♦♦ Circumscribed mass with round cells with abundant eosinophilic cytoplasm ♦♦ Extracellular amorphous eosinophilic material ♦♦ May contain fine granular pigment; abundant PAS+ materialglycogen ♦♦ Thin-walled blood vessels without a muscular coat

Macroscopic

Immunohistochemistry

♦♦ Gray/red circumscribed mass; 1/2 are in lower lobes

♦♦ HMB 45+ ♦♦ Cytokeratin−

Tumors of Uncertain Histogenesis Sclerosing Hemangioma Clinical

Microscopic (Fig. 28.66) ♦♦ Solid, papillary sclerotic, and hemorrhagic type; round, uniform epithelioid cells ♦♦ Mast cells may be numerous ♦♦ Papillae lined by cuboidal cells with eosinophilic cytoplasm and cytoplasmic inclusions

Immunohistochemistry ♦♦ Surface epithelial cells+ for: EMA, CK 7, and TTF-1 ♦♦ Stormal cells+ for: EMA and TTF-1; − for CK 7

Differential Diagnosis ♦♦ Primary lung cancer with clear cell change −− HMB 45− −− Glycogen not prominent −− Cytologic atypia ♦♦ Renal cell carcinoma −− CEA− −− Multiple, thick-walled vessels

Minute Pulmonary Meningothelial-Like Lesion (Minute Pulmonary Chemodectoma) Clinical ♦♦ Incidental microscopic findings; female predominance

Microscopic (Fig. 28.67) ♦♦ Spindle or oval-shaped cell; perivenule location ♦♦ Zellballen pattern

Histochemistry ♦♦ Do not stain with argyrophil or argentaffin stains

Differential Diagnosis Fig. 28.66. Sclerosing hemangioma. Cuboidal cells are seen lining solid and papillary areas.

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♦♦ Carcinoid tumorlets −− Associated with bronchioles −− Stain for neuroendocrine markers

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Fig.  28.67. Pulmonary meningothelial-like lesion (chemodectoma). Spindle cells form a “Zellballen” pattern.

♦♦ Angiomatoid lesions of pulmonary hypertension −− Associated with arteries/arterioles −− CD34+ and CD31+

Granular Cell Tumor (Granular Cell Myoblastoma) Clinical ♦♦ Schwann cell lineage ♦♦ Usually solitary mass of trachea or bronchus; can be multicentric ♦♦ Also found in skin, breast, esophagus, and rectum; respiratory tract may be metastatic lesion ♦♦ Primary lung lesions may metastasize

Macroscopic (Fig. 28.68A) ♦♦ Sessile or polypoid lesions with smooth surfaces; grow in walls of airways

Microscopic (Fig. 28.68B) ♦♦ Large, granular foamy cells; some areas may have fusiform cells ♦♦ No mitoses

Immunohistochemistry

Fig. 28.68. Granular cell tumor. A tan/pink sessile mass is present in the bronchi (A). Bland granular-type epithelioid cells with foamy cytoplasm are present (B).

♦♦ Associated diseases include multiple myeloma, lymphoid interstitial pneumonitis, low grade lymphomas, and Sjogren syndrome

Macroscopic

Electron Microscopy

♦♦ Five types: nodular, diffuse, tracheobronchial ♦♦ Waxy, hard irregular nodules

♦♦ Osmophilic inclusions

Microscopic (Fig. 28.69)

Differential Diagnosis

♦♦ Amorphous, eosinophilic material in vessels, airway or as nodules ♦♦ Congo red shows apple green birefringence

♦♦ S-100 protein+

♦♦ Oncocytic carcinoid −− Positive neuroendocrine immunohistochemistry

Masses and Tumor-Like Lesions Pulmonary Amyloidosis Clinical ♦♦ Patients have monoclonal proteins in serum or urine

alveolar-septal,

senile,

Differential Diagnosis ♦♦ Kappa light chain disease −− Congo red stain not birefringent ♦♦ Pulmonary hyalinizing granuloma −− Congo red stain−

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Fig. 28.70. Pulmonary hyalinizing granuloma. Thick bundles of collagen in storiform arrays are present. ♦♦ Hyalinized infectious granulomas −− Collagen arranged in parallel around center

Tracheobronchopathia Osteoplastica Clinical ♦♦ Middle-aged or elderly men with hoarseness, stridor, hemoptysis; possible relationship to tracheal amyloidosis

Macroscopic Fig.  28.69. Amyloidosis. Amorphous eosinophilic material is present surrounding vessels and within alveolar septae (A). A congo red stain reveals amyloid (B).

Pulmonary Hyalinizing Granuloma Clinical ♦♦ Asymptomatic; adults ♦♦ 60% have serologic evidence of autoimmunity

Macroscopic ♦♦ Bilateral nodules; white/gray-“cotton balls”

Microscopic (Fig. 28.70) ♦♦ Lamellar collagen in storiform or whorled array – “donuts”; mild lymphoplasmacytic infiltrate

Differential Diagnosis ♦♦ Sclerosed plasma cell granulomas −− Usually solitary −− More intense inflammatory infiltrate ♦♦ Nodular amyloidosis −− Congo red stains for apple green birefringence

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♦♦ Hard, yellow–white papilla-like formations on cartilaginous portion of trachea or bronchi

Microscopic ♦♦ Nodules of bone and cartilage in submucosa

Benign Metastasizing Leiomyoma Clinical ♦♦ Multiple nodules; invariably in women

Macroscopic ♦♦ Gray/white lobulated parenchyma

mass;

shells

out

from

lung

Microscopic ♦♦ Well-differentiated smooth muscle; may have type 2 epithelial inclusions ♦♦ £ 5 mitoses/50 HPF

Differential Diagnosis ♦♦ Hamartoma −− Bronchial epithelium ♦♦ Metastatic leiomyosarcoma −− >5 mitoses/50 HPF −− Primary sarcoma −− Usually multiple lesions

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Tumors of the Pleura Malignant Mesothelioma Clinical ♦♦ Asbestos is the most important cause of malignant mesothelioma; M > F ♦♦ Crocidolite and amosite more carcinogenic than asbestos chrysotile

Macroscopic (Fig. 28.71A) ♦♦ Tumor obliterates pleural space and encases lung

Microscopic (Fig. 28.71B, C) ♦♦ Three main pathologic types −− Epithelial (a) Most common (b) Subtypes: tubulopapillary, epithelioid are most common

−− Sarcomatoid −− Biphasic

Histochemistry and Immunohistochemistry ♦♦ See Table 28.2

Molecular Features ♦♦ Wilms tumor 1 (WT-1) overexpression

Differential Diagnosis ♦♦ Epithelial type: metastatic adenocarcinoma ♦♦ Sarcomatoid type: sarcoma −− Sarcomas are cytokeratin− ♦♦ Desmoplastic: hyalinized pleural plaque −− Increased cellularity and cytologic atypia in desmoplastic mesothelioma

Fig. 28.71. Malignant mesothelioma. The tan/white tumor infiltrates the pleura and compresses the underlying lung parenchyma (A). An epithelioid variant (B) and sarcomatoid variant (C) can be seen.

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Table 28.2. Diagnosis of Mesothelioma Versus Adenocarcinomaa Mesothelioma Histochemical studies Periodic and Schiff with diastase digestion Mucicarmine Alcian blue or colloidal iron Alcian blue or colloidal iron with hyaluronidase digestion Immunohistochemical studies Carcinoembryonic antigen Leu M1 (CD15) Calretinin1 WT Ber EP4 B72.3 TTF-1 Ultrastructural study

a

Adenocarcinoma

(−) (−) (+) (−)

(+):40–50% (+):50% (+) (+)

(−) (−) (+) (+) (−) (−) (−) Lung, branching villi, length/diameter £10:1 Perinuclear intermediate filaments

(+) (+) (−) (−) (+) (+) (+) Small microvilli Well developed rootlets

Though there are exceptions, (+) and (−) signs signify usual results.

Localized Fibrous Tumor Clinical ♦♦ Most are incidental masses ♦♦ Hypoglycemia due to insulin-like growth factor

Macroscopic (Fig. 28.72A) ♦♦ Usually pedunculated and arising from pleura; can be intrapulmonary ♦♦ Whorled and fibrous-appearing

Microscopic (Fig. 28.72B) ♦♦ Spindle cells with short fascicles or haphazard ♦♦ Pericytoma-like vasculature ♦♦ Varying amount of collagen; cytologic atypia and necrosis are absent ♦♦ Malignant features: >4 mitoses/10 HPF; >10 cm; necrosis

Fig. 28.72. Solitary fibrous tumor of the pleura. A large, tumor mass arises from the visceral pleura surface and extends into the pleural space (A). The tumor cells are spindled with a storiform architecture and can have intervening strands of collagen (B).

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TNM Classification of Cancer (2010 Revision) Lung ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ −− T1: Tumor £3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the labor bronchus* (i.e., not in the main bronchus) −− T1a: Tumor 2 cm or less in greatest dimension −− T1b: Tumor more than 2 cm but 3 cm or less in greatest dimension −− T2: Tumor more than 3 cm but 7 cm or less or tumor with any of the following features (T2 tumors with these features are classified T2a if 5 cm or less); involves main bronchus, 2 cm or more distal to the carina; invades visceral pleura (PL1 or PL2); associated with atelactasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung −− T2a: Tumor more than 3 cm but 5 cm or less in greatest dimension −− T2b: Tumor more than 5 cm but 7 cm or less in greatest dimension −− T3: Tumor more than 7 cm or that directly invades any of the following: parietal pleura (PL3), chest wall (including superior suleus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium:, or tumor in the main bronchus <2 cm distal to the carina, but without involvement of the carina: or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe −− T4: Tumor of any size that invades any of the following mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina: or with ­satellite tumor nodule(s) within a different ipsilateral lobe ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes involved by direct extension of primary tumor −− N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) −− N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) ♦♦ Distant Metastasis (M) −− M0: No distant metastasis

−− M1: Distant metastasis present −− M1a: Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion −− M1b: Distant metastasis

Pleura IMIG Staging System for Diffuse Malignant Pleural Mesothelioma ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor limited to the ipsilateral parietal pleura, with or without mediastinal pleura and with or without diaphragmatic pleura involvement −− T1a: No involvement of the visceral pleural −− T1b: Tumor involves the visceral pleura −− T2: Tumor involves any of the ipsilateral pleural surfaces (pariental, mediastinal, diaphragmatic, and visceral pleura) with at least one of the following Involvement of diaphragmatic muscle Extension of tumor from visceral pleura into the underlying pulmonary parenchyma −− T3: Locally advanced but potentially resectable tumor involves any of the ipsilateral pleural surfaces, with at least one of the following Involvement of the endothoracic fascia Extension into mediastinal fat Solitary, completely resectable focus of tumor extending into the soft tissues of the chest wall Nontransmural involvement of the pericardium −− T4: Locally advanced technically unresectable tumor involves any of the ipsilateral pleural surfaces, with at least one of the following Diffuse extension or multifocal masses of tumor in the chest wall, with or without associated rib destruction Direct transdiaphragmatic extension of tumor to the peritoneum Direct extension of the tumor to mediastinal organ(s) Direct extension to the contralateral pleura Direct extension of tumor into the spine Tumor extending through to the internal ­surface of the pericardium with or without a pericardial effusion or tumor involving the myocardium ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastases

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−− N1: Metastases in the ipsilateral bronchopulmonary and/ or hilar lymph nodes(s) −− N2: Metastases in the subcarinal lymph node(s)/or the ipsilateral mediastinal lymph node(s) including the ipsilateral internal mammary and peridiaphragmatic nodes

−− N3: Metastases in the contralateral mediastinal, contralateral internal mammary, or ipsilateral or contralateral supraclavicular lymph node(s) ♦♦ Distant Metastasis (M) −− M0: No distant metastases −− M1: Distant metastases

SUGGESTED READING Nonneoplastic Lesions American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277–304. Farver CF. Sarcoidosis. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and Hammar’s Pulmonary Pathology, 3rd ed. New York: Spirnger; 2008:668–964. Katzenstein A-LA. Acute lung injury patterns: diffuse alveolar damangge and bronchiolitis-obliterans-organizing pneumonia. In: Katzenstein AL, ed. Katzenstein and Askin’s Surgical Pathology of Non-neoplastic Lung Disease, 4th ed. Philadelphia: W.B. Saunders; 2006:17–44. Katzenstein A-LA, Fiorelli R. Non-specific interstitial pneumonia/fibrosis. Histologic patterns and clinical significance. Am J Surg Pathol 1994;18:136. Langston C. New concepts in the pathology of congenital lung malformations. Semin Pediatr Surg 2003;12:17–37 Myers JL, Colby TV. Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 1993;14:611. Presneill JJ, Makata K, Inoue Y, Seymour JF. Pulmonary alveolar proteinosis. Clin Chest Med 2004;25:593–613 Rich S, ed. Primary pulmonary hypertension. Executive summary from the world symposium, World Health Organization; September 6–10, 1998. Evian, France. www.whoint/ncd/cvd/pph.html. Ryu JH, Myers JL, Capizzi SA, Douglas WW, Vassaillo R, Decker PA. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005;127:178–184. Saubolle MA. Fungal pneumonias. Semin Respir Infect 2000;15:162–177. Stewart S, Fishbein MC, Snell GI, Berry GH, Boehler A, Burke MM, Glanville A, Gould FK, Magro C, Marboe CC, McNeil KD, Reed EF, Reinsmoen NL, Scott JP, Studer SM, Tazelaar HD, WAllwork JL, Westall G, Zamora MR, Zeevi A, Yousem SA. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 2007;26: 1229–1242. Stocker JT. Congenital and developmental diseases. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and Hammar’s Pulmonary Pathology, 3rd ed. New York: Springer; 2008:132–175.

Travis WD, Colby TC, Koss MN, Rosado-de-Christenson ML, Muller NL, King TEJ. Non-neoplastic disorders of the lower respiratory tract, 1st ed. Washington DC: The American Registry of Pathology; 2002 Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am J Surg Pathol 2000;24:19–33. Visscher DW, Myers JL. Bronchiolitis: The pathologist’s perspective. Proc Am Thorac Soc 2006;3:41–47. Yi ES, Colby TV. Wegener’s granulomatosis. Semin Diagn Pathol 2001; 18:34–46. Zaki SR, Paddock CD. Viral infections of the lung. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and Hammar’s Pulmonary Pathology, 3rd ed. New York: Spirnger; 2008:426–475.

Neoplastic Lesions: Common Lung Neoplasms Colby TV, Koss, MN, Travis WD. Atlas of tumor pathology, tumors of the lower respiratory tract, 3rd Series, Fascicle 13; 1995. Green FL, Page DL, Fleming ID, et al. AJCC Cancer Staging handbook, 6th ed. New York: Springer-Verlag; 2002. Jaffe ES, Lipford EH Jr, Margolick JB, et al. Lymphomatoid granulomatosis and angiocentric lymphoma: a spectrum of post-thymic T-cell proliferations. Semin Respir Med 1993;10:167–172. Kempson RL, Association of Directors of Anatomic and Surgical Pathology. Standardization of the surgical pathology report. Am J Surg Pathol 1992;16:84–86. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;11:1710–1717 Sattler M, Salgia R. Molecular and cellular biology of small cell lung cancer. Semin Oncol 2003;30:57–71. Sridhar KS, Bounassi MJ, Raub W Jr, Richman SP. Clinical features of adenosquamous lung carcinoma in 127 patients. Am Rev Respir Dis 1990;142:19–23. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (WHO Classification of Tumours). Lyon: IARC Press; 2004.

Tomashefski JF. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990;11:593–619.

Travis W, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol 1991;15:529–553.

Travis WE, Borok Z, Roum JH, et al. Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 1993;17:971.

Yousem SA, Taylor SR. Typical and atypical carcinoid tumors of lung: a clinicopathologic and DNA analysis of 20 tumors. Mod Pathol 1990;3:502-507.

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Uncommon Lung Neoplasms Fishback N, Travis W, Moran C, Guinee DG, McCarthy W, Koss MN. Pleomorphic (spindle/giant cell) carcinoma of the lung: a clinicopathologic study of 78 cases. Cancer 1994;73:2936–2945. Gaffey MJ, Mills SE, Askin FB, et al. Clear cell tumor of the lung. A clinicopathologic, immunohistochemical, and ultrastructural study of eight cases. Am J Surg Pathol 1990;14:248–259. Stocker JT, Husain AN, Dehner LP. Pediatric tumors. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and Hammar’s Pulmonary Pathology, 3rd ed. New York: Spirnger; 2008:542–557.

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Wick MR, Ritter JH, Humphrery PA. Sarcomatoid carcinomas of the lung. Am J Clin Pathol 1997;108:40–53. Yousem SA, Wick MR, Randhawa P, Manivel JC. Pulmonary blastoma. An immunohistochemical analysis with comparison with fetal lung in its pseudoglandular stage. Am J Clin Pathol 1990;93: 167–175.

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29 Breast Mohiedean Ghofrani, md and Fattaneh A. Tavassoli, md

Contents

I. Nonneoplastic Diseases of the Breast......................................29-3

Fibrocystic Changes.........................................29-3 Microcalcifications...........................................29-3 Mucocele-Like Lesion......................................29-4 Juvenile Hypertrophy......................................29-4 Gynecomastia...................................................29-4 Metaplastic Changes........................................29-5 Apocrine Metaplasia..............................29-5 Clear Cell Metaplasia............................29-5 Squamous Metaplasia............................29-5 Mucinous Metaplasia.............................29-5 Lactational Change (Lactational Metaplasia)..................................................29-5 Adenosis............................................................29-5 Sclerosing Adenosis................................29-5 Microglandular Adenosis......................29-6 Complex Sclerosing Lesion/Radial Scar........29-8 Duct Ectasia (Periductal Mastitis)..................29-8 Collagenous Spherulosis..................................29-8 Mastitis..............................................................29-9 Acute Mastitis/Periareolar Abscess......29-9 Granulomatous Mastitis........................29-9 Silicone Reaction....................................29-9 Lymphocytic Mastitis (Diabetic Mastopathy, Fibrous Mastopathy).........................................29-9 Amyloidosis.....................................................29-10 Fat Necrosis.....................................................29-10

II. Benign Neoplasms...........................29-11 Benign Epithelial Neoplasms........................29-11 Adenomas and Variants......................29-11

Benign Mesenchymal Tumors.......................29-12 Fibromatosis.........................................29-12 Myofibroblastoma................................29-13 Granular Cell Tumor...........................29-13 Neurilemmoma (Schwannoma)..........29-14 Lipoma..................................................29-14

III. Intraepithelial Proliferations............29-14 Summary of Cytologic Characteristics........29-14 Features of Ductal Proliferations........29-14 Features of Lobular Proliferations.....29-14 Ductal Intraepithelial Neoplasia...................29-14 Low Risk DIN (Usual Ductal Hyperplasia)....................................29-15 DIN 1a (Flat DIN 1, Flat Epithelial Atypia)..............................................29-15 DIN 1b (£2 mm; Atypical Ductal Hyperplasia)....................................29-15 DIN 1c (>2 mm; Ductal Carcinoma In Situ, Low Grade)........................29-16 DIN 2 (Ductal Carcinoma In Situ, Intermediate Grade).......................29-17 DIN 3 (Ductal Carcinoma In Situ, High Grade).....................................29-17 Cytologic Variants of DIN (DCIS)................29-17 Papillary DIN (DCIS)..........................29-17 Apocrine DIN (DCIS)..........................29-17 Clear Cell DIN (DCIS)........................29-18 Signet-Ring DIN (DCIS)......................29-18 Secretory DIN (DCIS)..........................29-18 Spindle Cell DIN (DCIS).....................29-18 Lobular Intraepithelial Neoplasia................29-19 Microinvasive Breast Carcinoma..................29-20

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_29, © Springer Science+Business Media, LLC 2002, 2006, 2011

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IV. Infiltrating Carcinoma......................29-20 VI. Biphasic Tumors...............................29-33 Reporting of Infiltrating Breast Carcinoma.................................................29-20 Grading of Invasive Carcinomas..................29-20 Axillary Lymph Node Status.........................29-21 Molecular Genetics of Breast Cancer............................................29-21 Infiltrating Ductal Carcinoma, NOS............29-22 Variants of Infiltrating Ductal Carcinoma.................................................29-23 Tubular Carcinoma..............................29-23 Mucinous (Colloid) Carcinoma..........29-24 Medullary Carcinoma.........................29-24 Apocrine Carcinoma............................29-25 Histiocytoid Carcinoma.......................29-25 Lipid-Rich Carcinoma.........................29-25 Secretory Carcinoma...........................29-26 Clear Cell Carcinoma..........................29-26 Carcinoma with Osteoclast-Like Giant Cells.......................................29-26 Tubulolobular Carcinoma...................29-27 Pleomorphic Carcinoma......................29-27 Inflammatory Carcinoma....................29-27 Invasive Micropapillary Carcinoma...29-28 Metaplastic Carcinomas................................29-28 Squamous Cell Carcinoma..................29-29 Adenocarcinoma with Squamous Differentiation.................................29-29 Adenocarcinoma with Spindle Cell Metaplasia................................29-29 Carcinoma with Chondroid and/or Osseous Metaplasia.........................29-29 Adenoid Cystic Carcinoma...........................29-30 Infiltrating Lobular Carcinoma....................29-30 Carcinoma of the Male Breast......................29-31

V. Papillary Lesions..............................29-31 Intraductal Papilloma....................................29-32 Intraductal Papillomatosis............................29-32 Atypical Papilloma.........................................29-32 Papillary DIN (DCIS)....................................29-33 Invasion Associated with Papillary DIN (DCIS)................................................29-33

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Fibroadenoma.................................................29-33 Phyllodes Tumor.............................................29-34 Periductal Stromal Sarcoma.........................29-35

VII. Nipple Lesions.................................29-36 Paget Disease..................................................29-36 Nipple Duct Adenoma (Erosive Adenosis)......29-36 Syringomatous Adenoma..............................29-37 Skin Adnexal Tumors....................................29-37

VIII. Myoepithelial Lesions......................29-37 Myoepitheliosis...............................................29-37 Adenomyoepithelioma...................................29-37 Malignant Myoepithelioma (Myoepithelial Carcinoma)......................29-38 Carcinoma Arising in Adenomyoepithelioma..............................29-39

IX. Vascular and Vascular-Like Lesions.............................................29-39 Pseudoangiomatous Hyperplasia..................29-39 Vasculitis.........................................................29-39 Microscopic Hemangioma.............................29-39 Palpable Hemangioma...................................29-39 Atypical Vascular Lesion...............................29-40 Angiomatosis..................................................29-40 Hemangiopericytoma.....................................29-40 Angiosarcoma.................................................29-40

X. Lymphoid Lesions.............................29-41 Lymphoma......................................................29-41 Plasmacytoma.................................................29-41 Granulocytic Sarcoma...................................29-42 Sinus Histiocytosis with Massive Lymphadenopathy (Rosai–Dorfman Disease).......................................................29-42

XI. Metastases to the Breast..................29-42 XII. Tnm Classification of Carcinoma of the Breast (2010 Revision)...........29-42 XIII. Suggested Reading...........................29-44

Breast

29-3

NONNEOPLASTIC DISEASES OF THE BREAST Fibrocystic Changes Clinical ♦♦ Occurs in women 20–50 years of age ♦♦ May show clinical stages: swelling/tenderness, multiple nodules, larger cysts ♦♦ Involutes after menopause unless patient is on hormone replacement therapy ♦♦ Alteration of estrogen/progesterone ratio may be the cause ♦♦ Viewed as aberration of normal involution and development ♦♦ No significant increase of cancer risk

Macroscopic ♦♦ Variably dense fibrous tissue with clear or blue-domed cysts 1 mm to 2 cm in size

−− Pleomorphic, linear, and branching patterns are associated with high grade DIN; granular, amorphous, or rod shaped calcifications with lower grades ♦♦ Calcium phosphate −− Most common form (90%) −− Easily visible on hematoxylin and eosin (H&E) −− Present in benign and malignant lesions ♦♦ Calcium oxalate −− May be difficult to see on H&E −− Requires polarized light −− Usually associated with benign lesions (particularly in ducts with apocrine metaplasia) ♦♦ Liesegang rings −− Laminated inclusions containing calcium, iron, silicone, and sulfur

Microscopic ♦♦ Fibrosis, cyst formation, atrophy of acini, variable chronic inflammatory infiltrate, and microcalcifications (Fig. 29.1) ♦♦ Type 1 cysts are typically lined by metaplastic apocrine cells, type 2 cysts by flattened epithelium ♦♦ May have some epithelial hyperplasia in the spectrum of ductal intraepithelial neoplasia (low risk ductal intraepithelial neoplasia (DIN) – see discussion later)

Differential Diagnosis ♦♦ Lymphocytic mastitis −− Dense lymphocytic infiltrate around lobules and vessels with or without atypical stromal cells

Microcalcifications ♦♦ May be associated with benign or malignant changes ♦♦ Different patterns seen radiologically can be classified in the American College of Radiologists Breast Imaging Reporting and Data System (BI-RADS) as typically benign, intermediate concern, or higher probability of malignancy, but no pattern pathognomonic ♦♦ Within benign breast disease −− Large, smooth and diffuse calcifications generally associated with benign lesions −− Popcorn, milk of calcium, and teacup calcifications are a few benign patterns ♦♦ Within malignant breast disease −− Malignant calcifications generally show clustering and linear branching −− Microcalcifications present in almost all comedocarcinomas and about half of cribriform (low grade) types −− Accordingly, mammographic estimation of the extent of DIN is better for higher grade lesions

Fig. 29.1. Fibrocystic change. (A) Cystically dilated ducts and (B) apocrine metaplasia are characteristic.

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Mucocele-Like Lesion Clinical ♦♦ Uncommon lesion with no distinctive clinical pattern; microscopic diagnosis

Microscopic ♦♦ Single or multiloculated cyst with extravasated mucin ♦♦ Epithelium may be in detached strips; occasionally papillary fragments ♦♦ Epithelium is cytologically benign ♦♦ Myoepithelial cells either adherent to the detached epithelial strips or the cyst wall ♦♦ Cysts have fibrous wall with mild chronic inflammation

Differential Diagnosis ♦♦ Mucin producing DIN 1–3 −− Atypical cells in the form of arcades, cribriform, or micropapillary formations ♦♦ Mucinous carcinoma −− Larger cells with more cytologic atypia; more frequently papillary; cell clusters in lakes of mucin ♦♦ Intraductal papillary carcinoma with mucin production ♦♦ Infiltrating ductal carcinoma with mucin production

Juvenile Hypertrophy Clinical ♦♦ Excessive and persistent enlargement of one or both breasts in young girls ♦♦ Age 11–14 years ♦♦ Usually coincides with menarche, but may precede it

Macroscopic ♦♦ Appears identical to surrounding breast tissue

Essentials of Anatomic Pathology, 3rd Ed.

Gynecomastia ♦♦ Gynecomastia is unique to the male breast ♦♦ Other breast lesions/neoplasms may be found in male patients less commonly than in female patients ♦♦ Lesions generally felt to be more common in male patients include myofibroblastoma (see mesenchymal lesions)

Clinical ♦♦ Unilateral or bilateral (equal or unequal) breast enlargement ♦♦ Most frequent in adolescents and elderly men ♦♦ Etiology is either endogenous hormonal imbalance (puberty, senescence, hypogonadism, liver failure) or exogenous (drugs, chemotherapy)

Prognostic Significance ♦♦ Usually physiologic if in teens/elderly ♦♦ Otherwise requires evaluation of medical status/drug history ♦♦ Not a premalignant condition

Macroscopic ♦♦ Rubbery gray/white tissue, variable, well-defined

Microscopic ♦♦ Florid type −− Increased ducts with florid epithelial proliferation, cellular periductal stroma (often myxedematous), and adipose tissue ♦♦ Fibrous type −− Dilated ducts, mild/moderate epithelial proliferation, hypocellular fibrous stroma, and no adipose tissue (Fig. 29.2) ♦♦ Hyperplasia is “gynecomastoid”: angulated epithelial tufts with smallest cells at apex ♦♦ Myoepithelial layer preserved ♦♦ Apocrine and squamous metaplasia may occur

Microscopic ♦♦ Proliferation of epithelium and stroma ♦♦ Proliferation of normal lobules and ductal structures ♦♦ May have occasional proliferation of ductules similar to gynecomastia ♦♦ Densely collagenous stroma is common ♦♦ Stroma may show pseudoangiomatous hyperplasia

Differential Diagnosis ♦♦ Fibroadenoma −− Better circumscribed grossly (shells out), often loosely cellular stroma with an intracanalicular or pericanalicular growth pattern microscopically in contrast to the generally dense collagenous stroma of juvenile hypertrophy (JH) ♦♦ Normal breast tissue −− Clinical history may be necessary to distinguish juvenile hypertrophy from normal breast tissue

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Fig.  29.2. Gynecomastia. Ductules with a cuff of myxedematous stroma proliferate in a dense collagenous stroma.

Breast

♦♦ Lobules are identified in 6% of cases ♦♦ Atypical intraductal hyperplasia is occasionally found

Differential Diagnosis ♦♦ Not a difficult diagnosis when you know that the sample is from a male patient

Metaplastic Changes ♦♦ Replacement of one cell type (mostly epithelium) with another mature cell type

Apocrine Metaplasia ♦♦ Cells with granular eosinophilic or foamy cytoplasm, round nuclei, and usually prominent nucleoli (Fig. 29.1B) ♦♦ Sometimes shows decapitation secretion or coarse hyaline granules ♦♦ Frequently occurs in fibrocystic change ♦♦ Papillary morphology common in cysts; papillae with fibrovascular cores

Differential Diagnosis ♦♦ Apocrine hyperplasia −− Diagnosed when there is more than the normal one or two cell thickness ♦♦ Atypical apocrine metaplasia or hyperplasia −− Nuclei show a threefold variation in size ♦♦ Apocrine DIN (DCIS) −− Atypia with luminal necrosis

Clear Cell Metaplasia ♦♦ Cytoplasm clear or vacuolated, rather than granular and eosinophilic (Fig. 29.3) ♦♦ May show PAS positive globules in cytoplasm ♦♦ No association with clear cell carcinoma

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Squamous Metaplasia ♦♦ Associated with the following −− Infarcted papilloma: may follow fine needle aspiration −− Phyllodes tumor −− Syringomatous adenoma −− Ducts associated with periareolar abscess −− May focally line a biopsy cavity

Mucinous Metaplasia ♦♦ ♦♦ ♦♦ ♦♦

Relatively uncommon Typically affects normal isolated lobule May occur focally in papillomas No known preneoplastic potential

Lactational Change (Lactational Metaplasia) Clinical ♦♦ Usually reproductive-age women with recent history of pregnancy ♦♦ Rarely in postmenopausal women, possibly drug-related (digitalis, neuroleptics); male patients on stilbestrol ♦♦ May present as a mass during pregnancy or at postpartum examination

Macroscopic ♦♦ Sharply circumscribed if involving a preexisting tubular adenoma (=lactating adenoma), usually <5 cm ♦♦ Soft texture

Microscopic ♦♦ Lobules expanded with diminished stroma; no epithelial proliferation ♦♦ Secretory pattern −− Eosinophilic material in lumen; cells with vacuolated cytoplasm ♦♦ Regressive pattern −− Less secretion; dilated acini with hobnail hyperchromatic nuclei

Differential Diagnosis ♦♦ May be mistaken for malignancy on fine needle aspirate (FNA): look for history, foamy background to smear, and myoepithelial cells

Adenosis ♦♦ Lobular expansion with increased ductules and acini but no epithelial proliferation (Fig. 29.4) ♦♦ Various types: sclerosing, microglandular, blunt duct, adenomyoepithelial, tubular, secretory, and apocrine Fig. 29.3. Clear cell metaplasia. The cells in the lobule on the right side of the image show cytoplasmic clearing in contrast to the granular eosinophilic cytoplasm on the left.

Sclerosing Adenosis Clinical ♦♦ Relatively common, often bilateral, lesion

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Fig. 29.5. Sclerosing adenosis retains a lobulated configuration; microcalcification may be abundant. ♦♦ May be associated with increased risk of carcinoma, especially in presence of atypia

Macroscopic ♦♦ Cannot be distinguished grossly from fibrocystic change

Microscopic ♦♦ Low power retention of lobulocentric configuration is key to diagnosis (Fig. 29.5) ♦♦ Fibrosis may distort or obliterate lumens and make myoepithelial cells prominent

Immunohistochemistry ♦♦ Smooth muscle actin (SMA) will stain myoepithelial cells, which are preserved in sclerosing adenosis

Differential Diagnosis ♦♦ Atypical apocrine adenosis −− Shows involvement of lobules by atypical cells with apocrine features ♦♦ Invasive carcinoma −− No myoepithelial cell layer and no lobulocentric pattern

Microglandular Adenosis Clinical ♦♦ A rare lesion, presenting as a palpable mass; most common among women in their fourth and fifth decades ♦♦ Usually 3–4 cm in size Fig. 29.4. Nodular adenosis. (A) Some cases of adenosis may present as a distinct nodule. (B) On higher magnification there is lobular expansion with increased ductules and acini but no epithelial proliferation. (C) Calponin highlights preservation of the myoepithelial cell layer. ♦♦ Occasionally forms a palpable mass <2 cm (nodular sclerosing adenosis) in size ♦♦ Usually a microscopic finding

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Macroscopic ♦♦ No distinguishing features; variably dense, rubbery, fibrous tissue

Microscopic ♦♦ Proliferation of duct-like structures in a fibrocollagenous stroma (Fig. 29.6) ♦♦ Stroma varies from densely collagenous to loose and paucicellular

Breast

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♦♦ More infiltrative growth compared to other types of adenosis ♦♦ Single epithelial cell layer, often with clear cytoplasm and no myoepithelial cell layer ♦♦ PAS positive eosinophilic (colloid-like) secretory material in lumen

Immunohistochemistry ♦♦ Epithelium of microglandular adenosis (MGA) is positive for both S-100 and cytokeratin (CK) ♦♦ No myoepithelial cell layer identified by various myoepithelial cell markers

Ultrastructure ♦♦ Preservation of basement membrane, which is often multilayered ♦♦ Absence of a myoepithelial cell layer

Differential Diagnosis (See Table 29.1)

Fig. 29.6. Microglandular adenosis. (A) Proliferating duct-like structures with luminal secretory material infiltrate in a fibrocollagenous stroma. (B) Although p63 stain demonstrates lack of a myoepithelial cell layer, the lesion is benign.

♦♦ Invasive tubular carcinoma −− Fibroblastic rather than fibrocollagenous stroma of MGA −− Angulated glands rather than round −− No luminal secretions −− Eosinophilic rather than clear cytoplasm in lining cells −− Apocrine snouting rather than truncated luminal cell border −− No basement membrane −− Pitfall: MGA may also extend into fat ♦♦ Atypical MGA −− Some cases of MGA show cytologic atypia and mitotic figures; regarded as intermediate stage between MGA and carcinoma −− Carcinomas may arise in MGA; most retain S-100 positivity ♦♦ Tubular adenosis −− Has a myoepithelial cell layer on immunostaining for actin

Table 29.1. Distinguishing Features of Tubular Carcinoma, Sclerosing Adenosis, and Microglandular Adenosis Tubular carcinoma

Sclerosing adenosis

Microglandular adenosis

Shape of lesion

Stellate, irregular

Lobulated

Irregular

Shape of glands

Angulated

Round to oval

Round

Luminal contents

Sometimes

Rarely

Frequent, “colloid”

Cell layers

1 (epithelial)

2 (epithelial and myoepithelial)

1 (epithelial)

Cell luminal surface

Snouting

Occasional snouting

Smooth

Cytoplasm

Eosinophilic

Inconspicuous

Clear

Stroma

Desmoplastic

Around lobules

Dense collagenous

Basement membrane

Usually none

Present

Prominent

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Complex Sclerosing Lesion/Radial Scar Clinical ♦♦ Middle age to elderly women ♦♦ Frequently multiple and bilateral incidental microscopic findings

Radiology ♦♦ May form a stellate mass on mammogram, described as suspicious or highly suggestive of malignancy ♦♦ Rarely associated with calcification

Macroscopic ♦♦ A minority may form a palpable mass indistinguishable from invasive carcinoma grossly

Microscopic ♦♦ Central fibroelastotic or fibrocollagenous scar ♦♦ Stellate arrangement of ducts; zonal pattern may be obscured if only part of lesion is sampled or in core biopsy (Fig. 29.7) ♦♦ Maximum epithelial proliferation is at periphery ♦♦ Thirty percent have some atypical hyperplasia or carcinoma; however, complex sclerosing lesion/radial scar (CSL/RS) per se is not an independent risk factor for carcinoma

Differential Diagnosis ♦♦ Tubular carcinoma −− Distinction may be impossible on needle biopsy −− CSL/RS shows preservation of myoepithelial layer on immunostaining

Duct Ectasia (Periductal Mastitis) Clinical ♦♦ Majority of cases are subclinical ♦♦ Patients may have pain and tenderness around nipple or chronic nipple discharge or distortion

Fig. 29.7. Radial scar is characterized by a central fibroelastotic or fibrocollagenous scar surrounded by a stellate arrangement of ducts.

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Macroscopic ♦♦ Periareolar (large) ducts affected ♦♦ Dilated ducts with yellow material in lumen, mimicking comedocarcinoma

Microscopic ♦♦ Acute stages rarely seen; acute inflammation around and in duct ♦♦ Fibrosis leads to duct distortion ♦♦ Periductal lymphoplasmacytic infiltrate, pigmented histiocytes ♦♦ Foam cells in epithelium and lumen ♦♦ Duct may be obliterated by process; “ectasia” a misnomer at this stage

Collagenous Spherulosis ♦♦ Incidental microscopic finding; importance is in differential diagnosis

Microscopic ♦♦ Spheres of eosinophilic material (20–100  mm) surrounded by myoepithelial cells, in duct lumens or TDLU (terminal duct-lobular unit) (Fig. 29.8) ♦♦ Material may be fibrillar, asteroid, or dense and amorphous ♦♦ Eosinophilic “cuticle” at periphery characteristic ♦♦ Spheres may contain flocculent basophilic material: “mucinous spherulosis” ♦♦ The epithelial cell population around collagenous spherulosis may be benign, atypical, or malignant; judge separately from collagenous spherulosis

Immunohistochemistry ♦♦ Spheres positive for collagen IV ♦♦ Surrounding myoepithelial cells positive for S-100 or SMA

Fig. 29.8. Collagenous spherulosis. Spheres of eosinophilic material with a peripheral “cuticle” are surrounded myoepithelial cells.

Breast

Differential Diagnosis ♦♦ Ductal carcinoma in situ (DCIS), cribriform type −− May also show basophilic material in spaces; no myoepithelial cells around cribriform spaces ♦♦ Adenoid cystic carcinoma −− More cellular atypia, usually forms a mass ♦♦ Lobular neoplasia with signet-ring cells −− Look for other cells with intracytoplasmic lumina

Mastitis Acute Mastitis/Periareolar Abscess Clinical ♦♦ Reproductive years ♦♦ Crack in skin of nipple, frequently in nursing women, allows bacterial entry ♦♦ Congenital abnormality/inversion of nipple increases risk ♦♦ Rarely a surgical specimen

Microscopic ♦♦ Squamous metaplasia of large ducts ♦♦ Thick-walled abscess cavity in untreated cases ♦♦ S. aureus and anaerobes are usual organisms

Granulomatous Mastitis ♦♦ Idiopathic accounts for most cases in the West (Fig. 29.9) ♦♦ Other causes include the following −− Tuberculosis: necrotizing granulomas; isolation of M. tuberculosis required for diagnosis −− Fungi and protozoa −− Reaction to duct rupture −− Reaction to carcinoma −− Sarcoid: usually in context of established disease elsewhere; rule out other causes −− Wegener granulomatosis

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Idiopathic Granulomatous Mastitis Clinical ♦♦ Usually reproductive age, but wide range ♦♦ Tender, palpable nodule; may be bilateral ♦♦ Etiology unknown; epithelial damage may be primary event

Microscopic ♦♦ Granulomatous inflammation centered on lobules ♦♦ Mixed inflammatory cell infiltrate ♦♦ Diagnosis based on excluding other causes of granulomatous inflammation

Silicone Reaction Clinical ♦♦ Leakage of silicone from implants/implant rupture usual cause ♦♦ Injection of silicone for augmentation no longer performed ♦♦ Reaction may be to additives and/or silicone

Microscopic ♦♦ Empty spaces or spaces with refractile foreign material ♦♦ Histiocytic or foreign body giant cell reaction with fibrosis ♦♦ Similar changes frequent in regional nodes

Differential Diagnosis ♦♦ Fat necrosis ♦♦ Metastatic mucinous carcinoma (lymph nodes or bone marrow)

Lymphocytic Mastitis (Diabetic Mastopathy, Fibrous Mastopathy) Clinical ♦♦ Painless mass ♦♦ Wide age range of 24–72 years; occasional cases in male patients ♦♦ Often associated with type I diabetes mellitus or other human leukocyte antigen (HLA)-associated autoimmune disease

Macroscopic ♦♦ Dense rubbery fibrous tissue

Microscopic

Fig. 29.9. Granulomatous mastitis. Most cases are idiopathic.

♦♦ Extensive stromal collagen with atrophy of acini (Fig. 29.10) ♦♦ Dense lymphocytic infiltrate surrounds residual lobules – may have germinal centers; however, association with mucosa-associated lymphoid tissue (MALT) lymphoma unlikely ♦♦ Lymphocytic perivasculitis or vasculitis a constant feature ♦♦ Prominent epithelioid stromal cells, some binucleate

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Fig. 29.10. Lymphocytic mastitis typically has extensive stromal collagen with atrophy of acini and a dense lymphocytic infiltrate surrounding residual lobules.

Fig. 29.11. Fat necrosis is characterized by anucleate fat cells surrounded by foamy histiocytes. Fibrosis and calcification may develop in later lesions.

Immunohistochemistry

♦♦ Pink on Congo Red stain, apple green birefringence on polarizing

♦♦ Stromal cells negative for keratin; may be KP1 positive ♦♦ Lymphocytes are B-cells

Differential Diagnosis ♦♦ Infiltrating carcinoma −− Hypocellularity and atypia of stromal cells may suggest lobular carcinoma ♦♦ Fibrocystic change −− Inflammation in fibrocystic change (FCC) more periductal than perilobular

Amyloidosis Clinical ♦♦ May occur as an amyloid tumor (elderly women) or microscopic finding ♦♦ Patients have systemic disease (e.g., rheumatoid arthritis or amyloidosis)

Differential Diagnosis ♦♦ May be mistaken for carcinoma clinically and grossly ♦♦ Microscopically, elastosis may resemble amyloid ♦♦ Areas of collagen in lymphocytic mastitis may resemble amyloid

Fat Necrosis Clinical ♦♦ Usually an incidental microscopic finding, occasionally a palpable mass ♦♦ Although most cases are believed to be due to trauma, history of trauma or radiotherapy is elicited in less than half ♦♦ May be accompanied by pain/tenderness/bruising/skin retraction

Macroscopic

♦♦ Nodule with granular or waxy cut surface

♦♦ Well-defined, firm area usually <2 cm in size ♦♦ Early lesions show hemorrhage ♦♦ Late lesions show scar with cyst formation

Microscopic

Microscopic

Macroscopic

♦♦ Amorphous eosinophilic material with giant cell reaction ♦♦ Vascular and adipose tissue deposition in nonnodular forms

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♦♦ Anucleate fat cells surrounded by foamy histiocytes (Fig. 29.11) ♦♦ Fibrosis and calcification in later lesions

Breast

29-11

BENIGN NEOPLASMS Benign Epithelial Neoplasms Adenomas and Variants ♦♦ Ductal adenoma – see sclerosing papilloma ♦♦ Syringomatous adenoma – see “Nipple Lesions” ♦♦ Nipple duct adenoma – see “Nipple Lesions”

Tubular Adenoma ♦♦ Benign, well-circumscribed proliferation of tubular structures, lined by epithelium and myoepithelium

Clinical

Apocrine Adenoma ♦♦ Rare adenomas with complete replacement of epithelial cells by metaplastic apocrine cells ♦♦ Sharply demarcated from the surrounding breast tissue ♦♦ Compact proliferation of ductules lined by a single layer of epithelial cells overlying myoepithelial cells

Lactating Adenoma Clinical ♦♦ Women in reproductive age group; discovered when pregnant or nursing

♦♦ 90% of patients <40 years; rare in men ♦♦ Mobile mass, may be tender; frequently discovered in pregnancy

Macroscopic

Macroscopic

♦♦ May vary according to time of removal ♦♦ Sharply circumscribed, lobular arrangement maintained (Fig. 29.13) −− Pregnancy: secretory material in lumen, vacuolated cytoplasm −− Postpartum: marked distention, hobnail cells, vacuolated cytoplasm ♦♦ Infarction may be seen ♦♦ Attenuated myoepithelial cell becomes inconspicuous

♦♦ Solid, firm, tan-yellow nodule >1 cm in size

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Encapsulated or well-defined Closely packed tubules (Fig. 29.12) Hypocellular stroma with scanty lymphocytes Epithelium may show mitotic figures, apocrine metaplasia, and lactational or secretory changes; atypia is rare

♦♦ Well-circumscribed, yellow, soft

Microscopic

Differential Diagnosis

Differential Diagnosis

♦♦ Fibroadenoma has a neoplastic stromal component: lesions with features of both may occur (combined tubular and fibroadenomas) ♦♦ Nodular adenosis: less well-defined/not encapsulated

♦♦ Lactational change: more diffuse process, similar cytologically ♦♦ Carcinoma: pitfall on FNA, look for bubbly background, myoepithelial cells

Pleomorphic Adenoma (Benign Mixed Tumor) Clinical ♦♦ Rare ♦♦ Usually in elderly women, but also reported in teenagers and men

Macroscopic ♦♦ Well-circumscribed, lobulated, myxoid, or chondroid appearance

Microscopic ♦♦ Identical to those of the salivary glands morphologically ♦♦ Epithelial/myoepithelial proliferation in a myxochondroid background with focal ossification

Immunohistochemistry Fig.  29.12. Tubular adenoma presents as an encapsulated or well-defined mass composed of closely packed tubules in a hypocellular stroma with scant lymphocytes.

♦♦ Cytokeratin: positive in epithelial cells ♦♦ SMA/S-100/p63/CD10/calponin: positive in myoepithelial cells ♦♦ Glial fibrillary acidic protein: Myoepithelial cells are less commonly positive than in salivary gland lesions

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Fig. 29.14. Mammary hamartoma presents as a mass composed of variable quantities of otherwise unremarkable fibroadipose and glandular breast tissue which by definition must be surrounded by a capsule, even if it is only a delicate one.

Benign Mesenchymal Tumors Fibromatosis Clinical

Fig. 29.13. Lactating adenoma. (A) A well-circumscribed mass in women who are pregnant or nursing is typical. (B) On higher magnification, there is lactational-type change with vacuolization and hobnail cells.

Hamartoma Clinical ♦♦ Wide age range, usually 30s or 40s ♦♦ Detected on screening; well-delineated density on mammo­ grams

Macroscopic ♦♦ Oval, usually approximately 3 cm in size; rubbery consistency

Microscopic ♦♦ Well-circumscribed, may be encapsulated ♦♦ Variable quantities of fibroadipose or glandular tissue, showing alterations seen in normal breast (fibrocystic change, apocrine metaplasia, adenosis) (Fig. 29.14)

Differential Diagnosis ♦♦ Normal breast −− May not be possible to distinguish unless sectioned to show capsule

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♦♦ ♦♦ ♦♦ ♦♦

Less common in breast than other sites Female patients, median age = 25; occasionally bilateral Mass and skin retraction mimics carcinoma Stellate pattern on mammography also suggests carcinoma

Prognostic Significance ♦♦ Higher risk of recurrence in breast compared to extramammary fibromatosis; inking and extensive sampling of specimen important to ensure adequate excision ♦♦ No metastatic potential

Macroscopic ♦♦ Ill-defined, soft, gray-white lesion, 1–10 cm in size

Microscopic ♦♦ Irregular margin with fingers extending into breast tissue and surrounding ducts ♦♦ Variably cellular, with intervening collagen; spindle cells are in sheets and occasionally show a storiform pattern of growth ♦♦ No or mild atypia ♦♦ Mitoses <3/10 high power field (HPF) with no atypical forms ♦♦ In younger women (childbearing age) there is usually more cellularity, atypia, and mitotic activity than in perimenopausal and postmenopausal women ♦♦ No calcification or necrosis; chronic inflammatory cells frequent, especially in older patients

Immunohistochemistry ♦♦ Spindle cells are positive for vimentin and beta catenin; a minority for actin; negative for keratin and S-100 protein

Breast

♦♦ Despite arising from breast stroma, the vast majority are negative for hormone receptors

Differential Diagnosis ♦♦ Low grade fibrosarcoma −− Difficult on occasion; fibrosarcoma has more mitoses and at least some nuclear atypia ♦♦ Spindle cell carcinoma −− More pleomorphism and mitotic figures with keratin-positive spindle cells ♦♦ Nodular fasciitis −− Rare diagnosis in breast, but may occur on adjacent chest wall; contains occasional multinucleated cells; inflammatory infiltrate is at periphery of lesion

Myofibroblastoma Clinical ♦♦ Usually solitary, slow-growing, painless, firm, mobile mass ♦♦ Mostly occurs in older men and postmenopausal women ♦♦ Excision is curative

Macroscopic ♦♦ Nodular, well-circumscribed but unencapsulated rubbery lesions

Microscopic ♦♦ Spindle cell proliferation arising from mammary stroma arranged in fascicles and interspersed by bands of dense collagen ♦♦ Mitoses are absent or rare ♦♦ Occasional cases show fat or cartilage ♦♦ Some breast ducts may be entrapped in the lesion ♦♦ Numerous mast cells ♦♦ Variants: cellular, infiltrating, epithelioid, deciduoid-like, lipomatous, collagenized/fibrous, myxoid, and mixed

Immunohistochemistry ♦♦ Typically positive for vimentin, desmin, CD34 ♦♦ Variable positivity for actin, CD99, bcl-2 ♦♦ Negative for cytokeratin, epithelial membrane antigen (EMA), S-100, homatropine methylbromide (HMB) 45, c-kit (CD117) ♦♦ Often positive for estrogen receptors (ER), progesterone receptors (PR), and androgen receptors (AR)

Ultrastructure ♦♦ Bundles of 6 nm diameter myofilaments and no tonofilaments ♦♦ Rare pinocytotic vesicles ♦♦ Elongated nuclei; cytoplasm with prominent rough endoplasmic reticulum and Golgi apparatus

Cytogenetics ♦♦ Partial loss of 13q and 16q suggests relationship to spindle cell lipoma

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Differential Diagnosis ♦♦ Fibromatosis −− Has a more infiltrative pattern; may be mistaken with infiltrating variant −− Negative for hormone receptor immunohistochemistry ♦♦ Nodular fasciitis −− Stellate pattern, plumper mesenchymal cells ♦♦ Neurofibroma −− More angulated nuclei ♦♦ Neurilemmoma (schwannoma) −− Antoni A and B areas, Verocay bodies ♦♦ Spindle cell lipoma −− Intermixed fat; may be difficult to distinguish from lipomatous variant ♦♦ Carcinoma (versus epithelioid or deciduoid-like variants) −− Keratin positive

Granular Cell Tumor Clinical ♦♦ Uncommon in the breast; wide age range (mean 40 years); women > men ♦♦ More common in African-Americans ♦♦ May be detected as stellate lesions on mammogram ♦♦ May be near the nipple, distorting it ♦♦ Cured by excision; <1% malignant

Macroscopic ♦♦ Frequently small (~1 cm) sharply circumscribed firm lesions ♦♦ May mimic carcinoma with a stellate shape and firm consistency

Microscopic ♦♦ Has a focally infiltrative margin in areas, despite gross appearance ♦♦ Sheets, nests, or cords of large, polygonal cells with granular eosinophilic cytoplasm ♦♦ Small eccentric nuclei, occasionally mild pleomorphism ♦♦ Mitoses rare; no necrosis ♦♦ A highly infiltrative variant is often mistaken for carcinoma

Immunohistochemistry ♦♦ Diffuse positivity for S-100 protein ♦♦ Negative for cytokeratin, EMA, and ER/PR

Differential Diagnosis ♦♦ Invasive ductal carcinoma −− Principally mimics this on gross appearance and FNA ♦♦ Normal nipple −− Small granular cell tumor may be difficult to see in this region ♦♦ Leiomyoma −− May arise from smooth muscle in the periareolar region

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Macroscopic

Neurilemmoma (Schwannoma) Clinical

♦♦ Soft, yellow, well-demarcated

♦♦ Rare in breast; men and women; wide age range

Microscopic

Microscopic ♦♦ Hypercellular (Antoni A) and hypocellular (Antoni B) areas, with Verocay bodies ♦♦ Identical to these tumors elsewhere ♦♦ Degenerative stromal and nuclear changes may occur

♦♦ Mature adipose tissue; thin fibrous capsule necessary to make the diagnosis ♦♦ Variants −− Prominent spindle cell component: spindle cell lipoma −− Prominent vessels with fibrin thrombi: angiolipoma

Lipoma Clinical

Differential Diagnosis

♦♦ Solitary soft mass; occurs in women in their 40s and 50s

♦♦ Normal breast adipose tissue

INTRAEPITHELIAL PROLIFERATIONS ♦♦ General term = mammary intraepithelial neoplasia (MIN) ♦♦ Divided into ductal intraepithelial neoplasia (DIN) and lobular intraepithelial neoplasia (LIN) ♦♦ The designation of MIN may be appropriate when an in situ proliferation has both ductal and lobular characteristics or does not quite match one or the other

Summary of Cytologic Characteristics ♦♦ See microscopic description of individual categories and Table 29.2

Features of Ductal Proliferations ♦♦ ♦♦ ♦♦ ♦♦

Distinct cell borders Secondary lumen formation (rosettes) Larger nuclei than lobular neoplasia Variants: stratified spindle cell, spindle cell, and apocrine

Features of Lobular Proliferations ♦♦ ♦♦ ♦♦ ♦♦

Indistinct cell borders Solid or loosely cohesive pattern of growth Intracytoplasmic lumens Small, uniform nuclei (variant: pleomorphic lobular)

Ductal Intraepithelial Neoplasia Clinical ♦♦ Discovered incidentally on biopsy specimen or following biopsy for mammographically detected micro­calcifications ♦♦ DIN 1b and higher is a marker for ipsilateral breast tumor recurrence; half of these are invasive (see Table 29.3) ♦♦ Risk increases with increasing grade ♦♦ Risk for an individual patient depends on family history

Table 29.2. Ductal Hyperplasia (Low Risk DIN) Versus Atypical Ductal Hyperplasia (DIN 1b, £2 mm): Distinguishing Features Low Risk DIN

DIN 1b (£2 mm)

Cellular proliferation

Two cell types (mixed pattern)

Epithelial only (monotonous pattern)

Secondary lumina

Slit-like, irregular

Rigid “Roman bridges”

Cell borders

Indistinct

Distinct

Nuclei

Variable in shape

Round contour

Nucleoli

Usually absent

Frequently present

Necrosis

May be present

If present = DIN 2 or 3

High molecular weight cytokeratin

Present

Absent or significantly reduced

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Table 29.3. Spectrum of Preinvasive Mammary Ductal Proliferations (Ductal Intraepithelial Neoplasia, DIN) Current designation

Significant Atypiaa

Necrosis

Abs risk of invasion

IDH

−

− or +b

1.9%

Clonalb/MSI

No

Flat epithelial atypia

−

−

questionable, probably minimal

Clonal/LOH

No

DIN 1b (£2 mm)

AIDH

−

−

5.1–12%

Clonal/LOH

Yes, if extensive (≥ partially involved ducts)

DIN 1c (>2 mm)

DCIS, grade 1

−

−

10–32%

Clonal/LOH

Yes

DIN 2

DCIS, grade 2

−/+(+)

+/−

20–75%

Clonal/LOH

Yes

DIN 3

DCIS, grade 3

+++

Usually

20–75%

Clonal/LOH

Yes

DIN Low risk DIN Flat DIN 1a

Molecular Reexcision for findings positive/close margin

IDH (usual) intraductal hyperplasia, AIDH atypical intraductal hyperplasia, DCIS ductal carcinoma in situ, MSI microsatellite instability a At least a minor degree of atypia is assumed in all forms of DIN b A few cases of ductal hyperplasia have been shown to be clonal; the presence of necrosis does not exclude the diagnosis of low risk DIN ♦♦ Adequacy of surgical margin is increasingly recognized as being of importance in determining the efficacy of breastconserving therapy for DIN 1b and higher grades

Low Risk DIN (Usual Ductal Hyperplasia) Microscopic ♦♦ Proliferation of cells characterized by difference in cell populations (epithelial and myoepithelial cells participate, heterogenous population), nuclear overlapping, indistinct cell borders, and irregular slit-like secondary lumina (Fig. 29.15)

Immunohistochemistry ♦♦ Cells react with high molecular weight (HMW) cytokeratins (CK903 and CK5/6)

DIN 1a (Flat DIN 1, Flat Epithelial Atypia) Clinical ♦♦ Represents one of the earliest morphologically recognizable neoplastic alterations of the breast ♦♦ Risk for subsequent malignancy is unknown ♦♦ Recognition important for early detection of intraductal neoplasia and to prevent misinterpretation as normal control in studies ♦♦ May explain a portion of the 20% recurrence rate of breast carcinomas excised with “negative” margins

Microscopic ♦♦ Replacement of native epithelial cells by one to five layers of mildly atypical cells (Fig. 29.16) ♦♦ Monomorphous variant (so-called “clinging carcinoma”): frequently a single layer of abnormal cells around a duct space ♦♦ A variant of flat DIN with high grade nuclear atypia is designated as flat DIN 3 (pleomorphic variant of clinging carcinoma)

Fig. 29.15. Low risk DIN (intraductal hyperplasia). Prominence of peripheral irregularly sized and shaped fenestrations is characteristic. This proliferation is associated with a slightly increased risk for subsequent development of invasive carcinoma.

Immunohistochemistry ♦♦ Cells do not react with HMW cytokeratin ♦♦ Cells react with E-cadherin

DIN 1b (£2 mm; Atypical Ductal Hyperplasia) Microscopic ♦♦ Proliferation with some cytologic (monotonous population, rounded nuclei, distinct cell borders) and architectural (rounded secondary lumina) atypia (Fig. 29.17)

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Fig. 29.17. DIN 1b, £2 mm (atypical intraductal hyperplasia). Micropapillae composed of uniform cells partially involve the duct cross section. This limited neoplastic proliferation has a moderately increased risk for subsequent development of invasive carcinoma.

Fig. 29.16. DIN 1a (flat epithelial atypia). (A) Distended TDLUs contain floccular secretory material. (B) Higher magnification shows the native epithelium to be replaced by one to five layers of monotonous atypical columnar cells.

♦♦ Quantitatively limited: maximum complete involvement of one or more ducts not exceeding 2  mm in aggregate cross sectional diameter ♦♦ Incomplete duct involvement by a process that is otherwise cytologically and architecturally similar to low grade ductal carcinoma in situ (DCIS) also qualifies as DIN 1b ♦♦ Uncommon: DIN 1b is usually focal

DIN 1c (>2 mm; Ductal Carcinoma In Situ, Low Grade) ♦♦ Patterns of low grade DCIS including cribriform and micropapillary patterns without necrosis measuring greater than 2 mm in aggregate cross sectional diameter (Fig. 29.18) ♦♦ Small monomorphic cells with round nuclei, regular chromatin pattern, and inconspicuous nucleoli

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Fig. 29.18. DIN 1c, >2 mm (DCIS, grade 1). (A) A sieve-like/ cribriform proliferation of uniform cells. (B) Microcalcifications are the basis for mammographic detection of these lesions.

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DIN 2 (Ductal Carcinoma In Situ, Intermediate Grade) Microscopic

Cytologic Variants of DIN (DCIS) Papillary DIN (DCIS)

♦♦ Low grade patterns promoted one grade by the presence of necrosis, or low grade patterns with moderate cytologic atypia ♦♦ Necrosis is nuclear debris of five or more cells; apoptosis of individual cells or granular amorphous luminal debris should not be used to diagnose it

Apocrine DIN (DCIS) Clinical

Immunohistochemistry ♦♦ Cells negative for HMW cytokeratin ♦♦ Cells positive for E-cadherin

DIN 3 (Ductal Carcinoma In Situ, High Grade) Macroscopic ♦♦ May be recognized grossly as multiple punctate yellow areas approximately 1 mm in size ♦♦ May be up to 8–9 cm in size, with fibrosis around ducts mimicking an invasive carcinoma

♦♦ See separate section (“Papillary Lesions”)

♦♦ No definitive clinical significance; importance is in differential diagnosis ♦♦ High proportion have androgen receptors and are devoid of estrogen and progesterone receptors

Microscopic ♦♦ Apocrine cytology: granular eosinophilic cytoplasm, prominent nucleoli ♦♦ Apical snouting and cytoplasmic vacuolization variable ♦♦ Architectural patterns include solid or cribriform, rarely papillary types ♦♦ Two variants described

Microscopic ♦♦ Any case with severe cytologic atypia is grade 3 ♦♦ Cases with moderate atypia and necrosis are also grade 3 ♦♦ Comedocarcinoma should be reserved for grade 3 nuclei with necrosis (Fig. 29.19) ♦♦ Extensive periductal fibrosis and inflammation common

Immunohistochemistry ♦♦ Cells negative for HMW cytokeratin ♦♦ Cells positive for E-cadherin ♦♦ HER2/neu and p53 status correlates with grade; ER/PR usually shows inverse correlation with grade

Fig. 29.19. DIN 3 (DCIS, grade 3), comedo type. Intraluminal necrosis and cytologic atypia are present. DIN 3 is a preinvasive lesion with the highest risk for progression to an invasive carcinoma.

Fig.  29.20. Early infiltrating ductal carcinoma. (A) Low power magnification shows microinvasion. (B) At higher magnification, there is infiltration of stroma in irregular angulated clusters.

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−− Necrotic variant shows luminal necrosis and severe atypia (Fig. 29.21) −− Nonnecrotic variant has more variable atypia, usually solid or cribriform

Differential Diagnosis ♦♦ Apocrine metaplasia/hyperplasia −− No nuclear atypia; papillary fronds have fibrovascular cores ♦♦ Atypical apocrine metaplasia −− Atypia = threefold variation in nuclear size ♦♦ Atypical apocrine hyperplasia −− Atypia and more than two cell layers −− Epithelial bridges lacking fibrovascular cores, even with bland cytology, imply a diagnosis of atypical apocrine hyperplasia

Clear Cell DIN (DCIS) Microscopic ♦♦ Cells with optically clear cytoplasm and distinct cell borders ♦♦ May be mixed with other patterns

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ May have associated invasive clear cell carcinoma ♦♦ Usually DIN 2 showing moderate nuclear atypia with or without necrosis

Signet-Ring DIN (DCIS) Microscopic ♦♦ Rare variant, composed of cells with a signet-ring morphology

Differential Diagnosis ♦♦ Intraductal papillary carcinoma −− May have a signet-ring component ♦♦ Mammary intraepithelial neoplasia −− Proliferation may have mixed ductal and lobular features ♦♦ Collagenous spherulosis −− Flattened myoepithelial cell nuclei at periphery of aggregates of collagen may mimic signet-ring cells

Secretory DIN (DCIS) Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Rare variant Dilated ducts with eosinophilic luminal secretion Epithelial tufting (papillary), cribriform growth most usual Mitotic figures present Moderate nuclear atypia Cytoplasmic vacuolization

Differential Diagnosis ♦♦ Lactational change −− More generalized change (but not invariably); cribriform growth not a feature ♦♦ Low risk DIN with secretory change −− Heterogenous cell population; typical architecture of low risk DIN −− HMW keratin positive

Spindle Cell DIN (DCIS) Microscopic ♦♦ Rare variant; importance lies in differential diagnosis ♦♦ Monotonous proliferation of elongated cells, forming solid pattern ♦♦ Often admixed with a relatively solid variant of cribriform DIN; this may lead to a misinterpretation of the two-cell population as low risk DIN ♦♦ May show neuroendocrine differentiation

Differential Diagnosis

Fig.  29.21. Apocrine DIN (DCIS). (A) Necrotic variant. (B) Higher magnification shows severe cytologic atypia.

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♦♦ Intraductal hyperplasia −− Has a spindle cell population, but does not display the monotony of pure spindle cell IDCA −− Irregular peripheral fenestrations as opposed to the “punched out” cribriform pattern of mixed cribriform and spindle cell IDCA −− Positive for HMW keratin

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♦♦ Solid papillary carcinoma −− May have spindle cell component

Lobular Intraepithelial Neoplasia Clinical ♦♦ A pathologic diagnosis; encompasses atypical lobular ­hyperplasia and lobular carcinoma in situ ♦♦ Occurs in 0.3–3.8% of all breast biopsies ♦♦ Natural history difficult to determine ♦♦ Marks patients as being at increased risk of invasive ­carcinoma, both lobular and ductal, in both breasts (risk is higher in the ipsilateral breast) ♦♦ Patients with grade 3 lesions are at higher risk ♦♦ Ductal involvement is not a risk factor for recurrence ♦♦ Role of family history in increasing risk not determined

Macroscopic ♦♦ Not detectable macroscopically

Microscopic ♦♦ Generally, a population of small uniform cells lacking ­nucleoli (Fig. 29.22) ♦♦ Intracytoplasmic lumina present ♦♦ Cell borders indistinct; cells frequently loosely cohesive ♦♦ Extension into terminal ducts found in approximately ­two-thirds of cases (Fig. 29.23) ♦♦ Necrosis and calcification denote a higher grade (Fig. 29.24) ♦♦ “Clover-leaf pattern” due to unfolding of terminal duct ­lobular unit (TDLU)

Immunohistochemistry ♦♦ Cells are negative for E-cadherin ♦♦ Cells are positive for HMW cytokeratin

Fig.  29.22. Lobular intraepithelial neoplasia. (A) Solid occlusive proliferation of uniform, loosely cohesive small cells. (B) Intracytoplasmic lumens are typical of LIN.

Grading ♦♦ LIN grade 1 −− Partial or complete replacement of normal acinar epithelium; lobules are not distended ♦♦ LIN grade 2 −− Distention of some acini, but preservation of interlobular stroma ♦♦ LIN grade 3 −− Massive distention and confluence of acini (macroacinar type) −− Necrotic, pleomorphic, and signet-ring cell types are also grade 3 −− For practical purposes, LIN can be designated as classic (LIN 1 and 2) or high grade (LIN 3)

Differential Diagnosis ♦♦ DIN 1 (atypical intraductal hyperplasia) −− See cytologic features listed above −− Some cases may be impossible to distinguish from DIN 1 beca­use of overlapping morphologic and immunohis-

Fig.  29.23. Pagetoid extension of neoplastic lobular cells to adjacent ducts.

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tochemical features; these could be designated as MIN. For management purposes, E-cadherin negative lesions are managed as LIN and E-cadherin positive lesions as ductal, regardless of reactivity with CK903 or CK5/6 ♦♦ Collagenous/mucinous spherulosis −− Increased difficulty when LIN involves a preexisting benign lesion that alters architectural pattern (e.g., sclerosing adenosis, complex sclerosing lesions)

Microinvasive Breast Carcinoma ♦♦ A cluster of tumor cells breaking through the basement membrane infiltrating the periductal stroma, with or without visible continuity with that duct, the diameter of the area not exceeding 2 mm ♦♦ If multiple, up to three foci, each up to 1 mm in diameter

Clinical ♦♦ If clearly defined, cases with microinvasion can be managed as DCIS ♦♦ Up to 3% of cases diagnosed as DCIS reportedly have lymph node metastases. These arise from areas of invasive carcinoma not detected in the biopsied or sampled areas

Macroscopic ♦♦ Cannot be distinguished from intraepithelial neoplasia

Microscopic ♦♦ Tongue-like projection from a duct or small group of cells beside a duct with DCIS (Fig. 29.20) −− Stroma frequently fibroblastic and myxoid Fig.  29.24. LIN with necrosis is considered high grade or LIN 3 (A). Although the necrosis is comedo-type – reminiscient of DIN 3 – negative E-cadherin confirms this is a lobular proli­ feration (B); note the positive internal control.

INFILTRATING CARCINOMA Reporting of Infiltrating Breast Carcinoma

Grading of Invasive Carcinomas

♦♦ Essential features include the following −− Laterality −− Type of biopsy specimen −− Tumor histologic type −− Size of tumor (at least maximum dimension in cm) −− Grade of tumor −− Margin status −− Type, size, and grade of in situ component, if present −− Presence or absence of lymphovascular invasion −− ER, PR, and HER2/neu status; MIB-1 (Ki-67) also helpful −− TNM classification

♦♦ Modified Scarff–Bloom–Richardson system is the one most commonly used ♦♦ Tumor is graded by scoring each of the following features −− Tubule formation (a) >75% = 1 (b) 10–75% = 2 (c) <10% = 3 −− Nuclear pleomorphism * This is both a qualitative and a quantitative assessment (a) Uniform small regular nuclei = 1 (b) Moderate variation in size and shape, occasional nucleoli = 2

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(c) Marked variation in size and shape, prominent ­nucleoli = 3 −− Mitotic activity * Unequivocal mitotic figures are counted at the ­periphery of the tumor * At least ten high power fields are counted * The range of figures that gives each score correlates with field diameter (and field area); for example, for Olympus BX 40, HPF (×400) = 0.55  mm diameter, scores are (a)  0–7/10 HPF = 1 (b)  8–15/10 HPF = 2 (c)  >15/10 HPF = 3 ♦♦ The scores are added to give the grade −− 3–5 = well-differentiated, grade 1 −− 6–7 = moderately differentiated, grade 2 −− 8–9 = poorly differentiated, grade 3

Axillary Lymph Node Status Clinical

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♦♦ ♦♦

♦♦

♦♦

♦♦

comprising approximately 15–20% of breast carcinomas; these tumors also variably express HMW cytokeratins Immunohistochemical definition of these “basal-like breast cancers” (BLBCs) remains elusive BLBCs display high proliferative activity and are over-represented in breast cancer 1 gene (BRCA1) germline mutation carriers and premenopausal African Americans Histologically, most BLBCs are high grade ductal with a pushing border, stromal lymphocytic infiltrate, and necrosis (Fig. 29.25) Most initial studies have shown decreased overall and disease-free survival for BLBCs compared to their luminal A counterparts; it is unclear if this is truly independent of ER status and histologic grade As more tumors are studied at the molecular level, we will most likely find expansion of the spectrum of tumors that fall in this category; these will include adenoid cystic, metaplastic, and a variety of other carcinomas that are also triple negative and positive for HMW CK, but may have excellent

♦♦ Clinical assessment of nodal status is incorrect in 50% of cases ♦♦ Nodes should be submitted entirely, unless grossly involved (sampled) ♦♦ Highest node should be designated by the surgeon (i.e., level 2 or level 3)

Macroscopic ♦♦ Metastatic tumor gives firm yellow-white appearance ♦♦ Sinus histiocytosis (especially with previous biopsy) may give soft enlarged pale node

Microscopic ♦♦ Metastatic tumor fills and expands sinuses first, may replace node ♦♦ May resemble primary tumor pattern or show variation in pattern ♦♦ Extracapsular extension should be documented in report

Differential Diagnosis ♦♦ Negative lymph node −− Deeper levels will increase yield in 9–39% of cases −− Immunostain for keratin may be necessary to detect small metastases, especially lobular carcinoma ♦♦ Sinus histiocytosis −− Bland reniform nuclei, sinuses expanded ♦♦ Metastatic melanoma −− Breast cancer may also be S-100 positive; only melanoma is HMB 45 positive ♦♦ Benign inclusions −− Epithelial or melanocytic, located in capsule of node

Molecular Genetics of Breast Cancer ♦♦ Gene-expression profiling has identified a group of ­carcinomas that lack ER, PR, and HER2/neu expression (triple negative)

Fig.  29.25. Basal-like breast cancer. (A) Most are high grade ductal carcinoma with (B) a pushing border and dense lymphocytic infiltrate.

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prognosis or a prognosis no worse than infiltrating ductal carcinoma, NOS

Infiltrating Ductal Carcinoma, NOS Clinical ♦♦ Constitutes the majority of invasive breast cancers (Table 29.4) ♦♦ Increasing proportion detected mammographically; average size has decreased from 2 cm to less than 1 cm ♦♦ Some still detected on clinical examination ♦♦ If there is “extensive ductal carcinoma in situ” (i.e., DCIS comprising >25% of the tumor and extending beyond the invasive component), conservative therapy is less likely to be successful ♦♦ Mutations in BRCA1 (located on chromosome 17q21) and BRCA2 (located on chromosome 13q12–13) genes are responsible for approximately 80% of familial early-onset cases ♦♦ Individuals who carry BRCA1 mutation have high risk (up to 85%) of developing breast cancer by age 70 ♦♦ Patients with HER2/neu oncogene amplification usually have higher grade tumors but are also often amenable to treatment with Herceptin (Fig. 29.26)

Fig. 29.26. HER2/neu overexpression is usually associated with higher grade tumors.

Macroscopic ♦♦ ♦♦ ♦♦ ♦♦

Firm, gray, stellate or discrete nodule (Fig. 29.27) Adjacent fat shows deep yellow-orange tinge Cutting gives a texture described as “unripe pear” May have punctate yellow foci representing in situ component with comedo necrosis

Table 29.4. Infiltrating Ductal Carcinoma Versus Infiltrating Lobular Carcinomaa Ductal carcinoma

Lobular carcinoma

Fig. 29.27. Infiltrating ductal carcinoma. An invasive carcinoma may appear sharply delineated grossly. In this case, a sharply delineated mass was clinically palpable in a 69-year old.

Relative frequency

80–85%

<10%b

Pattern of infiltration

Nests/sheets of cells

Single file, “targetoid”

Microscopic

Intervening stroma

Often scanty

Extensive

Tubule formation

Present

Absent

♦♦ A diagnosis of exclusion: designated as NOS when does not meet criteria for any special type ♦♦ Proliferation of epithelial cells with varying degrees of glandular differentiation and nuclear atypia (Fig. 29.28) ♦♦ Intraepithelial neoplasia present in 80% of cases; confirms a primary breast neoplasm ♦♦ Variable lymphoplasmacytic reaction

Cell size

Moderate to large

Usually small

Signet-ring cells

Rare

Frequent

Associated lesionsc

DIN 1, 2 or 3

LIN

Borderline forms occur (i.e., ductal carcinoma with lobular features); rarely, the two types coexist as a combined pattern – tubulolobular carcinoma b This frequency is increasing c An in situ component is not necessary for diagnosis a

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Immunohistochemistry ♦♦ ER/PR can be performed on formalin-fixed paraffin embedded material; called positive if ³1% of tumor cell nuclei are positive (Fig. 29.29) ♦♦ SMA or other myoepithelial markers are useful in ­confirming invasive carcinoma

Breast

Fig.  29.28. Low magnification microscopic appearance of the well delineated infiltrating duct carcinoma shown in Fig. 29.27.

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Fig. 29.30. Tubular carcinoma shows a haphazard distribution of tubules in a prominent reactive stroma.

Variants of Infiltrating Ductal Carcinoma Tubular Carcinoma Clinical ♦♦ Overrepresented in carcinomas detected by screening/carcinomas <1 cm (8%) ♦♦ Appears as a stellate lesion on mammogram ♦♦ Median age is slightly younger than in other breast carcinomas

Prognostic Significance ♦♦ Lower incidence of axillary nodal metastases (8–20%, 1.4% if tumor is <1 cm) ♦♦ Excellent survival (>90% 10 years) for pure variety ♦♦ Misdiagnosis as radial scar is a pitfall

Macroscopic Fig. 29.29. Nearly all well differentiated invasive carcinomas – particularly nuclear grade 1 tumors – show immunoreaction for estrogen receptor. Estrogen receptor immunostain shows nuclear positivity in 100% of tumor cells in this case. ♦♦ Neuroendocrine markers (chromogranin A and synaptophysin) confirm neuroendocrine differentiation in some tumors; no definitive prognostic significance ♦♦ Gross cystic disease fluid protein-15 is positive

Differential Diagnosis ♦♦ Intraepithelial neoplasia −− Most important differential; establishing this is more important than keeping frozen tissue for markers ♦♦ Specific subtypes of breast carcinoma (see below) ♦♦ Metastatic carcinoma −− In situ component is not present

♦♦ No distinguishing features from other ductal carcinomas; usually small (<2 cm), firm, gray/white lesion

Microscopic ♦♦ Requirement of a pure pattern for this diagnosis ascertains a distinctive category with excellent prognosis ♦♦ Many authors also accept up to 25% of other (usually cribriform) component ♦♦ Haphazard arrangement of tubules with open lumens, ­frequently comma-shaped (Fig. 29.30) ♦♦ Single cell lining ♦♦ Nuclei show little pleomorphism; mitoses rare ♦♦ Apical snouting common ♦♦ Classic lesions show a reactive fibroblastic stroma, but it may be densely collagenous, or show smooth muscle metaplasia ♦♦ Basement membrane patchy/absent (periodic acid-Schiff (PAS) stain)

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Differential Diagnosis (See Table 29.1) ♦♦ Radial scar −− Similar mammographic appearance; immunostain for actin shows myoepithelial layer present in radial scar −− Secondary features that help make the distinction include elastotic core in RS ♦♦ Mixed tubular carcinoma (75–99% tubular) −− Term is used where tubular pattern is not pure (solid areas, higher grade nuclei) ♦♦ Sclerosing adenosis −− Retains a lobulated outline, lumens compressed/obliterated, two cell layer present ♦♦ Microglandular adenosis −− More rounded glands with central secretory material and stroma densely collagenous

Mucinous (Colloid) Carcinoma Clinical ♦♦ Rare carcinoma (1–6% of infiltrating ductal carcinomas) ♦♦ Mean age = 60 years, slightly older than other forms

Prognostic Significance ♦♦ Low rate of axillary node metastases (3–15%) in pure form ♦♦ Better survival (>80% at 10 years) than ductal carcinoma NOS ♦♦ Increased size, hypercellularity, marked atypia, and nodal metastases predict more aggressive course

Macroscopic ♦♦ Well-circumscribed, gray, gelatinous nodule; may be multiple

Microscopic ♦♦ May occur in pure or mixed (with infiltrating ductal carcinoma NOS) forms ♦♦ Pure form can be divided into hypocellular and hypercellular variants ♦♦ Small clusters of tumor cells in solid, papillary, or glandular patterns, floating in abundant extracellular mucin (Fig. 29.31)

Immunohistochemistry ♦♦ Among the family of MUC genes predominantly express MUC2 and MUC6 ♦♦ Chromogranin and S-100 protein frequently positive ♦♦ ER positive in ~50–75% of cases, PR positive in 14%

Differential Diagnosis ♦♦ Infiltrating ductal carcinoma NOS −− Lacks pools of mucin ♦♦ Invasive micropapillary carcinoma −− Malignant cell clusters are in empty spaces rather than pools of mucin −− Express MUC1 rather than MUC2 and MUC6 ♦♦ Mucocele-like lesion

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Fig.  29.31. Mucinous carcinoma. Clusters of carcinoma cells float in lakes of mucin. This uncommon variant of invasive mammary carcinoma is associated with an excellent prognosis and a low frequency of node metastases. −− A ruptured cyst with benign epithelial and myoepithelial elements in mucin −− Usually <5 mm in size −− Immunostain for actin may help in the demonstration of myoepithelial cells

Medullary Carcinoma Clinical ♦♦ Uncommon (5–7% of ductal carcinomas); see below ♦♦ Occurs at younger age (common pattern among BRCA1 patients) ♦♦ Despite sharing clinical and histologic features with BRCA1 breast cancers, not an indication for genetic screening

Prognostic Significance ♦♦ Better prognosis: 80–90% 10-year survival ♦♦ The so-called “atypical medullary carcinoma” does not differ in prognostic terms from poorly differentiated invasive ductal carcinoma NOS; this term should not be used ♦♦ Lymph node metastasis also portends a poor outcome

Macroscopic ♦♦ Well-circumscribed, soft, fleshy tumor, yellow/hemorrhagic appearance; may show necrosis and cyst formation

Microscopic ♦♦ When strict criteria are used in diagnosis, this is a rare tumor ♦♦ Essential features −− Circumscribed, noninfiltrative periphery −− Lymphoplasmacytic infiltrate of at least moderate degree at periphery −− Syncytial growth pattern makes up >75% of tumor mass; no discrete cell borders

Breast

−− No tubule formation −− Fine (not dense) collagen bands intersect tumor −− Grade 2–3 nuclei; usually vesicular with prominent nucleoli −− Absence of intraductal component ♦♦ Also seen are the following −− Lymphoplasmacytic infiltrate extending into fibrous septa −− Necrosis/cyst formation −− Prominent mitoses −− Squamous metaplasia −− Granulomatous reaction

Immunohistochemistry ♦♦ ER positive in <1/3 of cases

Differential Diagnosis ♦♦ “Atypical medullary carcinoma” −− An infiltrating ductal carcinoma with some, but not all, of the above features; far more common than true medullary carcinoma −− This term no longer utilized: such cases should be designated as poorly differentiated invasive ductal carcinoma

Apocrine Carcinoma ♦♦ Carcinoma composed predominantly (>90%) of cells with abundant granular, eosinophilic cytoplasm; distinct cell borders; and central nuclei with prominent nucleoli

Clinical ♦♦ Frequency depends on application of definition, probably <0.5% of carcinomas ♦♦ Men and women, generally older ages

Prognostic Significance ♦♦ Usually high grade, but no conclusive evidence of better or worse behavior than ductal carcinoma NOS of same grade

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♦♦ S-100 protein negative

Differential Diagnosis ♦♦ Apocrine metaplasia, with or without atypia, in sclerosing adenosis −− Presence of myoepithelial cell layer as highlighted by immunohistochemistry ♦♦ Sclerosing adenosis −− Lobular configuration retained ♦♦ Histiocytoid variant of lobular carcinoma −− Has eosinophilic cytoplasm, intracytoplasmic lumina, and mucin −− Smaller nuclei with dense chromatin and inconspicuous nucleoli ♦♦ Lipid-rich carcinoma −− More vacuolated and foamy cytoplasm −− Oil red O stain positive ♦♦ Squamous cell carcinoma −− May be cytologically similar, but contains glycogen on PAS staining ♦♦ Granular cell tumor −− Small nuclei, usually without atypia or prominent nucleoli −− S-100 positive ♦♦ Oncocytic carcinoma −− Rare variant distinguished by electron microscopy; immunohistochemistry not helpful

Histiocytoid Carcinoma ♦♦ See lobular carcinoma, histiocytoid variant

Lipid-Rich Carcinoma

Macroscopic

♦♦ Invasive carcinoma, in which at least 80% of cells contain neutral lipid and show cytoplasmic vacuolization; extremely rare subtype

♦♦ Firm, partly cystic, occasionally tan color

Clinical

Microscopic

♦♦ Few distinctive features; chalky elastotic foci less likely

♦♦ Should be reserved for neoplasms in which all or nearly all the epithelium shows apocrine cytological features ♦♦ Nuclear pleomorphism may be marked and overlap with that seen in benign apocrine lesions ♦♦ Cytoplasm may contain coarse eosinophilic granules and lipofuscin ♦♦ Luminal/cystic areas show decapitation secretion ♦♦ Intraepitheliial component is usually apocrine DIN (DCIS)

Prognostic Significance

Immunohistochemistry ♦♦ Gross cystic disease fluid protein (GCDFP-15) staining is variable (~75%) ♦♦ Androgen receptor positive; high grade lesions lose AR expression ♦♦ B72.3, carcinoembryonic antigen (CEA), cytokeratins also positive

♦♦ May be a more aggressive variant; too few cases reported to reach a definitive conclusion

Microscopic ♦♦ Fixed material shows cells with foamy cytoplasm and nuclei with prominent nucleoli ♦♦ Infiltrating pattern of growth ♦♦ Frozen tissue stained with oil red O (ORO) demonstrates fat. Diagnosis must be considered at time of frozen section to enable confirmation by optimal ORO stain

Immunohistochemistry ♦♦ ER/PR negative

Differential Diagnosis ♦♦ Ductal carcinoma NOS

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−− May have sebaceous foci and lipid on ORO staining ♦♦ Pleomorphic lobular carcinoma −− Negative E-cadherin immunohistochemistry ♦♦ Sebaceous carcinoma −− Lobulated, well-defined solid growth pattern

Essentials of Anatomic Pathology, 3rd Ed.

Clear Cell Carcinoma Clinical ♦♦ Uncommon variant; middle aged to elderly women

Prognostic Significance ♦♦ More aggressive course than ductal carcinoma NOS; higher incidence of nodal metastases

Secretory Carcinoma Clinical

Macroscopic

♦♦ Younger age than in other breast carcinomas (median = 25 years); also known as juvenile-type carcinoma ♦♦ Has been reported in male patients pre- and postpuberty

Microscopic

Prognostic Significance ♦♦ Age dependent: patients <20 years do well, recurrences may be years later and the course indolent; axillary node metastases rare in children, but occur in adults ♦♦ Course resembles ductal carcinoma NOS in older patients

Macroscopic

♦♦ Mass 2–8 cm in size, no specific gross features ♦♦ More than 90% of cells should have clear or finely granular eosinophilic cytoplasm for diagnosis ♦♦ Clear pattern is due to glycogen (PAS positive, removed by diastase) ♦♦ Grows in solid nests, occasionally papillary formations ♦♦ Intraductal clear cell component may be present ♦♦ Nuclei are usually grade 2; tumor is usually grade 3 on Scarff-Bloom-Richardson (SBR) grading

♦♦ Firm, usually well-circumscribed, lobulated, gray-white lesions; can mimic fibroadenoma

Immunohistochemistry

Microscopic

Differential Diagnosis

♦♦ Abundant intra- and extracellular eosinophilic secretory material (Fig. 29.32) ♦♦ Bland nuclei; scanty mitotic figures ♦♦ Intraductal component may be present and have a secretory pattern ♦♦ Papillary pattern may be present ♦♦ Pushing margin ♦♦ Histochemistry: PAS and DPAS positive, alcian blue positive, focal mucicarmine positivity

♦♦ Few cases studied are ER/PR negative ♦♦ Ductal carcinoma NOS −− Clear cell areas comprising <90% of tumor ♦♦ Adenomyoepithelioma −− Shows positivity for actin and/or S-100 ♦♦ Clear cell hidradenoma (eccrine acrospiroma) −− Look for two cell types and evidence of duct differentiation ♦♦ Lipid-rich carcinoma −− ORO and PAS stains positive ♦♦ Metastatic clear cell tumors, especially renal cell carcinoma −− Does not have intraductal component

Carcinoma with Osteoclast-Like Giant Cells Clinical ♦♦ No specific features: uncommon variant ♦♦ Frequently well-circumscribed on mammography

Prognostic Significance ♦♦ Recurrences and metastases in one-third of cases: no significant prognostic difference from ductal carcinoma NOS

Macroscopic ♦♦ Soft, hemorrhagic, red-brown tumor in contrast to most breast carcinomas

Microscopic

Fig. 29.32. Secretory carcinoma has abundant intra- and extracellular secretory material.

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♦♦ Numerous osteoclast-like giant cells present adjacent to tumor cells ♦♦ Characteristic hemorrhagic fibroblastic stroma with chronic inflammatory cell infiltrate ♦♦ Giant cells may be present in metastatic deposits

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Immunohistochemistry

Macroscopic

♦♦ Giant cells are acid phosphatase, KP1, and alpha-1 ­antitrypsin positive and keratin negative, confirming histiocytic origin

♦♦ Large tumors (mean size >5 cm)

Differential Diagnosis ♦♦ Metaplastic carcinoma −− May have giant cells in addition to chondroid and osseous differentiation ♦♦ Poorly differentiated carcinoma with tumor giant cells −− Keratin positive ♦♦ Granulomatous inflammation with giant cells −− Keratin negative

Tubulolobular Carcinoma Clinical ♦♦ Typically low grade carcinoma with mixed ductal and lobular differentiation ♦♦ Considered to be a well-differentiated variant of ductal carcinoma with a lobular growth pattern ♦♦ Median age 60 years

Prognostic Significance ♦♦ Excellent prognosis, especially when <2 cm and unilateral

Macroscopic ♦♦ Small (usually <2.5 cm) indurated gray-tan mass

Microscopic ♦♦ Intermixed small tubules and cords of neoplastic cells with a permeating lobular pattern of infiltration in >75% of the tumor ♦♦ Does not qualify if collision of separate components or greater than 25% pure tubular or lobular pattern ♦♦ Majority are associated with both DIN and LIN, LIN only, or less commonly DIN only

Immunohistochemistry ♦♦ In general, intensely positive for E-cadherin (ductal differentiation) ♦♦ Vast majority show variable positivity for HMW keratin (lobular differentiation) ♦♦ Some show variable immunoreactivity ranging from positive reactivity with both E-cadherin and HMW CK, negative for both, or sometimes only positive for E-cadherin in the tubules and only positive for HMW CK in the lobular regions ♦♦ Mostly ER/PR positive, HER2/neu negative

Pleomorphic Carcinoma Clinical ♦♦ Uncommon, aggressive carcinoma with rapid growth and often presenting at high stage ♦♦ Wide age range; mean age 53 years

Prognostic Significance ♦♦ Unfavorable; seems to represent extreme end of spectrum of grade 3 invasive ductal carcinoma

Microscopic ♦♦ More than 50% of the tumor composed of highly pleomorphic cells (>6-fold variation in nuclear size) ♦♦ Solid sheets, nests, and cords of pleomorphic giant tumor cells transition to a spindle cell component in up to one-third of cases ♦♦ High mitotic rate (often >20 mitotic figures/10 HPFs) with many atypical mitoses ♦♦ Squamous, mucinous or apocrine change not uncommon ♦♦ Contiguous foci of DIN (typically high grade) or conventional invasive ductal carcinoma often seen

Immunohistochemistry ♦♦ Strong, diffuse staining for pancytokeratin ♦♦ Vimentin and S-100 positive in spindle areas ♦♦ Almost all ER/PR negative

Differential Diagnosis ♦♦ Metaplastic carcinoma −− No striking giant and pleomorphic cell component ♦♦ Carcinoma with osteoclast-like giant cells −− Cytologically bland giant cells with monomorphic nuclei −− Giant cells are keratin negative ♦♦ Pleomorphic lobular carcinoma −− Typically lacks multinucleated giant cells −− Characteristic lobular growth pattern (single file, targetoid) ♦♦ Metastases −− No associated intraductal component ♦♦ Sarcoma −− Keratin negative

Inflammatory Carcinoma Clinical ♦♦ Characterized by the clinical appearance of red, tender/painful, warm lesion with skin dimpling/peau d’orange, and diffuse induration of the breast (Fig. 29.33) ♦♦ The clinical diagnosis is more frequent (5–10%) than the pathologic counterpart (0.5–1%) (see below)

Prognostic Significance ♦♦ Axillary nodal metastases are present in most cases ♦♦ Tumors with either clinical or pathological features of inflammatory carcinoma are aggressive; fatal within 2 years before chemotherapy ♦♦ Currently, 25–50% 5-year survival; worse than ductal carcinoma NOS

Macroscopic ♦♦ Large tumor or diffuse mammary involvement ♦♦ Skin thickening apparent

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Fig. 29.33. Inflammatory carcinoma. (A) Clinically, the breast appears red, inflamed and with a peau d’orange appearance of skin. (B) This aggressive form of breast carcinoma with an inflamed appearance to the skin and nipple retraction is due to plugging of dermal lymphatics by tumor emboli. ♦♦ Changes may spread to chest wall

Microscopic ♦♦ Invasive ductal carcinoma with plugging of dermal lymphatics by tumor emboli is the usual pathologic finding ♦♦ This may be prominent or focal ♦♦ May show a mononuclear infiltrate ♦♦ Increase in dermal collagen and lymphatic dilatation also seen ♦♦ There is no absolute correlation between the clinical and pathological picture; there may be clinically inflammatory carcinoma without lymphatic plugging and vice versa ♦♦ “Occult” inflammatory carcinoma (pathologic findings without clinical features) are less aggressive and should not be reported as pT4d but should be documented in the report

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 29.34. Invasive micropapillary carcinoma. (A) Small clusters of malignant cells seem to lie in empty spaces as a result of retraction artifact. (B) HER2/neu is positive.

Invasive Micropapillary Carcinoma Clinical ♦♦ Rare variant with poor clinical outcome basically because of propensity for lymphovascular space involvement and high frequency of axillary node metastases

Macroscopic ♦♦ Expansive growth pattern resulting in lobulated outline

Microscopic ♦♦ Small clusters of malignant cells with tubular cross section ♦♦ Clusters seem to lie in empty stromal spaces as a result of retraction artifact (Fig. 29.34)

Immunohistochemistry

Metaplastic Carcinomas

♦♦ ER negative in >one-half of tumors, PR negative in two-thirds

♦♦ Malignant tumors with an epithelial or mesenchymal population different from or in addition to adenocarcinoma ♦♦ Histogenesis is uncertain and designation is on the basis of morphology and immunohistochemistry and/or ultrastructure

Differential Diagnosis ♦♦ Clinical picture resembles acute inflammation/erysipelas −− Skin contains neutrophils

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♦♦ Traditionally, the more common metaplastic carcinomas (i.e., apocrine carcinomas) are not designated as such

Squamous Cell Carcinoma Clinical ♦♦ Very rare tumor in pure form; significantly <1% of primary breast carcinomas ♦♦ To qualify as breast primary should not be connected to epidermis

Prognostic Significance

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Microscopic ♦♦ Variable mixture of adenocarcinoma (often peripheral) and squamous carcinoma (often more central) ♦♦ Mucin stains demonstrate adenocarcinomatous component ♦♦ Histologic grading of tumor should be performed

Adenocarcinoma with Spindle Cell Metaplasia Prognostic Significance ♦♦ Too few cases reported to provide clear information

♦♦ Variable reports claiming better or worse than ductal carcinoma NOS; prognosis may be more related to grade than squamous features

Microscopic

Macroscopic

Immunohistochemistry

♦♦ Characteristic feature is multiple cysts

Microscopic

♦♦ Adenocarcinoma cells merge with malignant spindle cells ♦♦ Necessary for diagnosis: demonstration of cytokeratin in the spindle cell component

♦♦ Variable appearance: keratinizing, acantholytic, and spindled forms are described ♦♦ Intercellular bridges and keratohyaline granules seen in benign or well-differentiated squamous elements ♦♦ Mixtures of these types are common ♦♦ Central cyst and prominent reactive stroma are frequent

Carcinoma with Chondroid and/or Osseous Metaplasia Clinical

Immunohistochemistry

Prognostic Significance

♦♦ HMW keratins and p63: positive in squamous cells ♦♦ Vimentin ± actin and desmin in mesenchymal cells

♦♦ Difficult to ascertain, as studies have not always separated them from carcinosarcomas

Ultrastructure ♦♦ Squamous cells show desmosomes and tonofilaments

Differential Diagnosis ♦♦ Primary squamous cell carcinoma of the skin −− Connection to epidermis confirms a skin primary ♦♦ Metastatic squamous cell carcinoma −− Clinical history of extramammary primary ♦♦ Syringomatous adenoma −− Usually near nipple, infiltrative, but cytologically bland

♦♦ Rare tumors, cases show wide age range and may reach a large size (20 cm)

Microscopic ♦♦ Variable extent and distribution of cartilage and/or bone ♦♦ Associated carcinoma is usually an infiltrating ductal carcinoma (Fig. 29.35)

Adenocarcinoma with Squamous Differentiation Clinical ♦♦ Also known as adenosquamous carcinoma, mucoepidermoid carcinoma ♦♦ No significant difference from ductal carcinoma NOS ♦♦ Incidence unknown; squamous component may not be reported if small

Prognostic Significance ♦♦ Low grade tumors mainly recur ♦♦ High grade tumors are aggressive and metastasize

Macroscopic ♦♦ Poorly defined mass; median = 2.5 cm with variable foci of white keratinous debris

Fig.  29.35. Carcinoma with chondroid metaplasia. This high grade infiltrating ductal carcinoma is associated with a chondroid matrix.

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Adenoid Cystic Carcinoma Clinical ♦♦ Rare salivary-gland type tumor in this location (along with the extremely rare acinic cell carcinoma) ♦♦ Presents as painless mass, occasionally of some years duration; median age = 50–63 years; women > men

Prognostic Significance ♦♦ Much less aggressive than its salivary gland counterpart; reason unclear ♦♦ Lymph node metastases basically nonexistent ♦♦ Pulmonary metastasis rare, but long-term followup required ♦♦ Most cases treated by mastectomy in older literature; has usually been curative

Macroscopic ♦♦ Variable size, mean = 2 cm ♦♦ Well-circumscribed, firm, gray/yellow mass; occasionally cysts present

Microscopic ♦♦ Histologically identical to salivary gland ACCs ♦♦ Two cell types −− Basaloid cells and cells with eosinophilic or clear cytoplasm ♦♦ Lumens contain three types of material in very variable proportions −− Hyaline bodies: dense eosinophilic, PAS positive replicated basal lamina −− Mucoid secretory material −− Eosinophilic “cuticle” with or without luminal material ♦♦ Sebaceous differentiation seen in a minority of tumors ♦♦ Perineural invasion occasionally seen ♦♦ Histologic grading of limited use: low grade shows dominant cribriform pattern; high grade shows predominant solid basaloid pattern

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Detection may be difficult −− Lack of calcification hampers mammographic detection −− Tumor may be poorly defined on palpation −− Tumor may be multifocal

Prognostic Significance ♦♦ Studies vary as to survival; may be better or the same as infiltrating ductal ♦♦ Patterns of metastases differ: lobular has predilection for viscera, bone marrow, and meninges; ductal for lung/pleura ♦♦ Metastases in nodes and other sites may be difficult/impossible to detect on H&E; keratin immunostain useful ♦♦ Histologic variants (e.g., signet-ring) may have poorer prognosis than classic form

Macroscopic ♦♦ Small foci are not visible ♦♦ Larger tumors appear as indurated, ill-defined masses ♦♦ Less commonly a multinodular texture, “grains of sand”

Microscopic ♦♦ Classic form and variant forms −− Classic (a) Small cells with ovoid nuclei and little cytoplasm, arranged in single file, frequently in a targetoid ­pattern around ducts (Fig. 29.36) (b) Intracytoplasmic lumens present in a minority of cells; mucin stains useful (c) Signet-ring forms occasionally seen (d) Stroma is desmoplastic, but with an overall e­osinophilic appearance (e) Lobular neoplasia present in 90% of all cases −− Solid (a) Closely packed small cells forming large nests with thin fibrous trabeculae

Immunohistochemistry ♦♦ Basaloid cells are vimentin positive and variably positive for actin, S-100, p63, calponin, CD10, and HMW cytokeratins ♦♦ Eosinophilic cells are keratin and EMA positive

Differential Diagnosis ♦♦ Collagenous spherulosis −− Usually an incidental microscopic finding; spherules are surrounded by myoepithelial cells with no atypia ♦♦ Invasive cribriform carcinoma −− Does not have two cell types

Infiltrating Lobular Carcinoma Clinical ♦♦ Less common pattern: 0.7–14% of invasive carcinomas (Table 29.4) ♦♦ Same median age (fifth and sixth decades) as invasive ductal carcinoma

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Fig.  29.36. Infiltrating lobular carcinoma, pleomorphic type. Infiltrating tumor cells are arranged in single files.

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−− Alveolar (a) Smaller, closely packed islands of uniform small cells −− Histiocytoid (a) Bland, histiocytoid-appearing cells (b) Comprises ~5% of infiltrating lobular carcinoma (c) Similar growth pattern, intracytoplasmic lumens, association with LIN, and/or admixture with ­classic ­pattern confirm its interpretation as a lobular ­carcinoma variant −− Pleomorphic (a) Larger cells, more pleomorphic nuclei than other variants ♦♦ Mixed patterns common (30% of cases); a pattern should comprise >70% of the tumor to justify designation as a subtype ♦♦ Variants show a lower incidence of coexistent lobular neoplasia in some series ♦♦ Grading −− Should be performed as for infiltrating ductal carcinoma −− Lobular carcinoma will score 3 for tubules; usually has little pleomorphism or mitoses (except pleomorphic ­variant), so it usually qualifies as a well- or moderatelydifferentiated carcinoma

Immunohistochemistry ♦♦ 70–90% are ER positive; ³70% are PR positive ♦♦ 60% positive for S-100 protein ♦♦ Generally HER2/neu negative, but about 25% of ­pleomorphic lobular carcinomas are positive ♦♦ As with other carcinomas, keratin and EMA positive and LCA negative

Differential Diagnosis ♦♦ Inflammation −− Lobular carcinoma cells can resemble lymphocytes, especially on frozen section ♦♦ Lymphoma −− Especially solid variant; lymphoma cells do not have intracytoplasmic lumens (but rare signet-ring forms have been described); immunostains for LCA and keratin useful ♦♦ Infiltrating ductal carcinoma −− Tubulolobular variant is a well-differentiated ductal carcinoma with lobular features (see above) ♦♦ Infiltrating apocrine carcinoma −− Differential with pleomorphic lobular carcinoma, which does not have nucleoli

Carcinoma of the Male Breast Clinical ♦♦ ~1% of incidence of breast cancer in women ♦♦ Occurs in an older age group than in women (mean = 60+ years vs. 50+ years) ♦♦ May present as an asymptomatic mass, nipple discharge, or Paget disease ♦♦ Most are located centrally in the breast ♦♦ Risk factors include Klinefelter syndrome (47 XXY): 3–6% develop breast carcinoma

Prognostic Significance ♦♦ Formerly thought to have a much worse prognosis; more recent studies suggest that it is similar to that of stagematched female patients ♦♦ High incidence of metastases (55%) ♦♦ Central location means increased internal mammary lymph node metastases ♦♦ Tumors should be graded as in carcinomas from female patients

Macroscopic ♦♦ Most tumors <3 cm

Microscopic ♦♦ All tumor types; most (~85%) are infiltrating ductal carcinoma ♦♦ Papillary carcinomas are twice as common as in women; probably because of the predominance of larger ducts ♦♦ Intraepithelial and invasive lobular carcinoma are extremely rare ♦♦ Metastases to the breast are twice as common as in women, with melanoma comprising ~60%

Immunohistochemistry ♦♦ A higher proportion are ER positive (80–90%) than in women, and >50% of these are hormone-responsive ♦♦ PR is positive in 25–75% of cases ♦♦ Prostate-specific antigen (PSA) has been demonstrated in primary breast carcinomas; PSAP is negative

Differential Diagnosis ♦♦ Metastatic adenocarcinoma −− Especially from prostate, in a male treated with estrogen for prostate cancer −− Less common with antiandrogen treatment (now preferred) −− Clinical history and PSA and PSAP needed for diagnosis

PAPILLARY LESIONS ♦♦ Lesions characterized by an arborizing growth pattern and fibrovascular cores (Fig. 29.37)

♦♦ May be either central, in large periareolar ducts/lactiferous sinuses (frequently solitary), or peripheral (usually smaller and multiple)

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Fig.  29.37. Papilloma is characterized by papillary processes with fibrovascular cores. ♦♦ Differential diagnosis is of lesions in the spectrum and is discussed below

Intraductal Papilloma Clinical ♦♦ Most frequent in women >50; may occur in men ♦♦ Serous or serosanguinous discharge from the nipple in a majority (87%) of cases

Macroscopic ♦♦ Papillary lesion frequently visible in dilated ducts ♦♦ If duct is dilated such that it appears like a cyst, the term intracystic papilloma is appropriate

Microscopic ♦♦ Epithelial and myoepithelial cell layer supported by fibrovascular core (Fig. 29.38) ♦♦ Secondary changes are common −− Torsion/hemorrhagic infarction of papilloma −− Squamous metaplasia secondary to infarction −− Sclerosis/hemosiderin deposition in duct wall and papillary stalk; occasionally, extensive sclerosis dictates the diagnosis of “sclerosing papilloma” ♦♦ “Ductal adenoma”: well-circumscribed, nodular adenosislike proliferation occluding duct lumen and associated with a band-like fibrotic duct wall; extensive fibrosis may obscure the nature of the process −− Prominent myoepithelial proliferation; epithelial component resembles sclerosing adenosis −− Apocrine metaplasia, sometimes with atypia, may occur −− Most likely a variant of sclerosing papilloma

Fig.  29.38. Intraductal papilloma. In this case the epithelial component shows low risk DIN (top). Stain for calponin shows preservation of the myoepithelial cell layer (bottom). ♦♦ Associated with a discharge from the nipple in a minority (33%) of cases

Prognostic Significance ♦♦ Not completely established: currently believed not to have a significantly increased risk for cancer unless there is associated atypia

Macroscopic ♦♦ Not visible grossly

Microscopic ♦♦ Papillary fronds with a myoepithelial cell layer; in multiple TDLUs ♦♦ Ducts smaller and walls less sclerotic ♦♦ Multiple foci of mural attachment and smaller size mean degenerative changes less prominent

Intraductal Papillomatosis Clinical

Atypical Papilloma

♦♦ Occurs in women ~10 years younger than in the case of solitary papilloma

♦♦ Papilloma with variable amounts of DIN1 confined to no more than 90% of the lesion

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♦♦ Atypical papilloma contains papillary lesions with the following features −− Up to one-third of papillary fronds lacking myoepithelial cells, or −− Up to one-third of area composed of an atypical epithelial proliferation, or −− Fronds covered by a stratified spindle cell proliferation ♦♦ Carcinoma arising in a papilloma −− Similar changes involving 33–90% of the lesion −− Study suggests a similar course for lesions in these two categories; therefore, these can be combined under the designation of atypical papilloma or papilloma with X% DIN 1 ♦♦ Papillary carcinoma −− More than 90% of lesion involved (see below)

Papillary DIN (DCIS) Clinical ♦♦ Accounts for ~2% of carcinomas ♦♦ Similar demographics to papilloma; nipple discharge less common (one-fourth of patients) ♦♦ May present with nipple distortion or a mass if invasive

Prognostic Significance ♦♦ Criteria for atypical papilloma and carcinoma arising in a papilloma are arbitrary; complete excision is advisable; behavior of these entities may not differ significantly ♦♦ Presence of atypia in adjacent ducts increases risk of subsequent invasive carcinoma ♦♦ Invasive papillary carcinoma is only rarely associated with nodal metastases; when they occur, involve lower axillary nodes; systemic metastases and death from the lesion are rare

Microscopic ♦♦ Myoepithelial layer is central diagnostic point: complete absence of myoepithelial cells in the papillary processes invariably indicates a papillary DIN (DCIS), but its presence does not exclude the diagnosis

♦♦ Cytology may be bland, but cellular monotony is a key factor in recognition ♦♦ Patterns of papillary carcinoma include the following −− Cribriform epithelial proliferation between fibrovascular stalks −− Solid: may be difficult to see the few residual stalks; minority of cells have eosinophilic cytoplasmic granules −− Spindle cell proliferation: often associated with mucin production −− Transitional cell: rare variant ♦♦ Adjacent duct spaces often contain DIN1b

Immunohistochemistry ♦♦ Myoepithelial layer stains for SMA, p63, calponin, and CD10 ♦♦ With very fine fibrovascular cores, actin positive endothelial cells may cause problems; endothelial cells are Factor VIII positive, but they are negative for p63 which stains myoepithelial cells ♦♦ Some solid and spindle cell variants are positive for chromogranin and synaptophysin

Invasion Associated with Papillary DIN (DCIS) ♦♦ Occurs in minority of cases ♦♦ Unequivocal invasion in tumor cells infiltrating beyond the duct wall and into surrounding fibroadipose tissue ♦♦ Distorted tubules trapped in sclerotic duct wall or stalk is common; these retain a myoepithelial cell layer

Differential Diagnosis ♦♦ Application of percentage criteria distinguishes benign/ atypical/carcinoma ♦♦ Application can be on H&E slides or sections stained with any of the ME markers ♦♦ If diagnosis of carcinoma is made, should be qualified as either “intraductal” or “invasive” ♦♦ Skin adnexal tumors may mimic central papillomas, especially eccrine acrospiroma (clear cell hidradenoma) ♦♦ “Ductal adenoma” may be mistaken for invasive carcinoma

BIPHASIC TUMORS Fibroadenoma Clinical ♦♦ Women in reproductive age range, average 25–35 years ♦♦ African American > Caucasian ♦♦ Usually presents as a solitary mobile breast mass

Prognostic Significance ♦♦ Myxoid variant: increased risk of recurrence; may be part of complex of myxomas (cardiac and cutaneous), spotty pigmentation, and endocrine overactivity (Carney complex) ♦♦ Carcinoma arising in a fibroadenoma: rarely ever results in death from tumor, may be managed conservatively

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Macroscopic ♦♦ Gray/white, well-circumscribed nodule “shells out” (Fig. 29.39) ♦♦ Characteristic bulging surface ♦♦ Lesions from older women more fibrous and may be calcified

Microscopic ♦♦ A proliferation of mesenchymal and epithelial elements (Fig. 29.40)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Fully developed form shows different patterns of stromal proliferation (no clinical significance) −− Intracanalicular: around compressed, cleft-like ducts −− Pericanalicular: around tubular ducts ♦♦ Margin is usually pushing, with some irregularities ♦♦ Myxoid change may occur in stroma: association with Carney complex ♦♦ Epithelium shows two cell layers and hyperplasia is frequent ♦♦ Apocrine metaplasia seen in some fibroadenomas (about 10%) ♦♦ Multiple adjacent TDLUs may show these changes without a well-defined mass; this is called fibroadenomatoid change ♦♦ Fibroadenomas in elderly women often show stromal hyalinization, epithelial atrophy, and calcification ♦♦ Fibroadenomas having cysts over 3 mm, sclerosing adenosis, epithelial hyperplasia or papillary apocrine metaplasia have been designated as complex fibroadenomas ♦♦ Carcinoma arising in fibroadenoma: >50% of these are lobular in type; there is often (50%) invasive carcinoma elsewhere in the breast

Differential Diagnosis ♦♦ Phyllodes tumor: leaf-like processes, cystic spaces, stromal hypercellularity with subepithelial stromal condensation (Table 29.5) ♦♦ Juvenile fibroadenoma (occurs in adolescent female patients): rapid growth, cellular stroma, and pericanalicular growth pattern usual

Phyllodes Tumor

Fig.  29.39. Fibroadenoma. Grossly, a firm, sharply circumscribed nodule is typical.

♦♦ Previously called cystosarcoma phyllodes; however, majority do not behave like a sarcoma ♦♦ Phylloides = leaf-like; phyllodes = leafy

Clinical ♦♦ Accounts for 2.5% of fibroepithelial breast tumors ♦♦ Wide age range, but on average 20 years older (average age of 45 years) than women with fibroadenoma ♦♦ Present as painless breast mass, often longstanding with sudden enlargement ♦♦ Median size = 6.4 cm, but size is not a diagnostic criterion

Macroscopic ♦♦ Fleshy, white tumor, with bulging leaf-like processes

Microscopic

Fig.  29.40. Fibroadenoma shows a combined proliferation of mesenchymal and epithelial elements.

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♦♦ Leaf-like processes and cystic spaces lined by epithelium with two-cell layer (Fig. 29.41) ♦♦ Hypercellular stroma: assessment of this is subjective ♦♦ Chondroid, osseous, and lipoid metaplasia are more frequent than in fibroadenoma ♦♦ Squamous metaplasia is more frequent than in fibroadenoma; apocrine metaplasia not a feature of phyllodes tumor ♦♦ Stromal overgrowth is assessed differently by different authors; should be confined to cases where there is ­extensive

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Table 29.5. Biphasic Neoplasms – Diagnostic Features Fibroadenoma

Low grade phyllodes

High grade phyllodes

Size

Variable

Variable

Variable

Architecture/spaces

Tubular or slit-like

Leaflike, cystic

Leaflike, cystic

Stromal cellularity

Variable

Moderate to high, subepithelial stroma condensation (cambium layer)

High, subepithelial stroma condensation (cambium layer)

Margins

“Pushing”

“Pushing”

Infiltrative

Stromal overgrowth

Absent

Absent

Present in some

Stromal nuclear atypia

Minimal

Mild to moderate

Moderate to severe

Mitotic figures

Variable

<3/10 HPF

>3/10 HPF

Benign heterologous elements

Rare

Frequent

Frequent

proliferation of sarcomatous elements (multiple low power fields, multiple slides) ♦♦ Rare variant shows stromal cells with intracellular accumulations of actin (identical to infantile digital fibromatosis)

Grading ♦♦ No single feature is predictive of biologic behavior ♦♦ Low grade tumors may recur, but do not metastasize −− Pushing margin −− <3 mitoses per 10 HPF −− Lack of moderate or severe cytologic atypia ♦♦ High grade tumors tend to recur and may metastasize −− Infiltrative margin −− Moderate to severe cytologic atypia −− Three or more mitoses/10 HPF −− Presence of specific sarcoma subtypes (liposarcoma, osteosarcoma) classifies a tumor as high grade ♦♦ Metastases −− Wide range, probably <10% of cases −− Hematogenous, especially to lungs; axillary node dissection unnecessary

Periductal Stromal Sarcoma ♦♦ Term has been used loosely; when defined as below, it is a rare biphasic tumor

Prognostic Significance ♦♦ Not well-defined

Microscopic Fig.  29.41. Phyllodes tumor. (A) Cellular leaf-like processes protrude into cystic spaces lined by epithelial and myoepithelial cells. (B) Higher magnification demonstrates hypercellular stroma.

♦♦ Proliferation of stromal spindle cells around tubules with open lumens ♦♦ Leaf-like pattern not apparent ♦♦ Intervening normal fibroadipose tissue

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NIPPLE LESIONS ♦♦ Lesions that are usually, but not exclusively, found in the region of the nipple

Paget Disease Clinical ♦♦ Presents as unilateral, eczematoid change of nipple, ulceration or distortion of nipple, or more diffuse irregularity of the nipple/periareolar area ♦♦ Noted in 1–5% of breast carcinomas

Macroscopic ♦♦ See Clinical; ~50% have an underlying mass ♦♦ If a mass is felt in a case of Paget, an invasive carcinoma is extremely likely

Microscopic ♦♦ Intraepithelial proliferation of malignant cells, with or without an associated intraductal or infiltrating carcinoma (usually ductal) ♦♦ Paget cells are large, with pale cytoplasm and large nuclei (Fig. 29.42) ♦♦ Present singly or in basally located nests, undermining native epithelium ♦♦ Occasional acinar formation ♦♦ Paget cells are positive for mucin (PAS, mucicarmine) in 50–60% of cells

Immunohistochemistry ♦♦ Paget cells are positive for HER2/neu, Cam 5.2, and CK7 ♦♦ Variable positivity is seen for EMA and polyclonal CEA ♦♦ They are negative for S-100 protein and HMB 45

Differential Diagnosis ♦♦ Eczema −− Particularly because of clinical appearance

♦♦ Toker cells −− Normal variant, clear cells in nipple epithelium; these are not cytologically malignant ♦♦ Squamous cell carcinoma −− Rare in nipple ♦♦ Melanoma −− Rare in nipple also, immunostains as above confirm Paget

Nipple Duct Adenoma (Erosive Adenosis) Clinical ♦♦ Uncommon lesion; women > men; fifth decade ♦♦ Nipple discharge, induration, nodularity, or ulceration may occur ♦♦ ~25% of cases are asymptomatic/incidental findings

Prognostic Significance ♦♦ Clinically, may be mistaken for Paget disease; not a pathologic diagnosis ♦♦ May recur if incompletely excised ♦♦ May occur in association with carcinoma, but generally not felt to be premalignant

Macroscopic ♦♦ Well-circumscribed lesion; may cause cystic dilatation of ducts

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Proliferation of tubules replacing the nipple Sclerosis of adjacent stroma Associated papilloma formation/papillomatosis Epithelial proliferation of the low risk DIN type (intraductal hyperplasia) and squamous metaplasia frequent ♦♦ Atypia may also be present

Immunohistochemistry ♦♦ Actin confirms retention of myoepithelial cell layer

Differential Diagnosis

Fig. 29.42. Paget disease. Large pale cells proliferate in the skin of the nipple.

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♦♦ Infiltrating carcinoma, especially tubular carcinoma; use actin/p63/calponin to differentiate ♦♦ Papilloma: Adenoma component of nipple duct adenoma (NDA) may be quite focal ♦♦ Sclerosing adenosis ♦♦ Syringomatous adenoma −− Tubules are closer together in NDA −− Comma-shaped tubules common in syringomatous adenoma −− Syringomatous adenoma permeates the nipple stroma; NDA replaces it

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Syringomatous Adenoma

Differential Diagnosis

Clinical

♦♦ Tubular carcinoma −− Single cell layer, apical snouting, generally no squamous metaplasia −− Rarely occurs in the nipple ♦♦ Nipple duct adenoma −− Displaces/destroys rather than permeating the nipple

♦♦ Uncommon lesion, unilateral, in region of nipple in 80% of cases ♦♦ Presents as a firm mass; nipple discharge or pain less common ♦♦ Women > men ♦♦ May recur locally if incompletely excised

Macroscopic ♦♦ Poorly defined gray nodule; may have small cystic areas ♦♦ Tend to be small in size (1–3 cm)

Microscopic ♦♦ Irregular, angulated, and comma-shaped tubules widely separated by fibrous stroma ♦♦ Occasional connections to surface epithelium, but erosion/ ulceration rare ♦♦ Permeates nipple structures ♦♦ Tubules have myoepithelial cell layer ♦♦ Squamous metaplasia common; squamous cysts may develop ♦♦ Stroma usually has few or no mitoses, with chronic inflammatory infiltrate in occasional cases

Skin Adnexal Tumors Clinical ♦♦ Rarely involve nipple

Macroscopic ♦♦ No distinguishing features

Microscopic ♦♦ Basal cell carcinoma −− Hyperchromatic basaloid cells with stromal retraction and peripheral palisading ♦♦ Eccrine acrospiroma (clear cell hidradenoma) −− Clear cells and eosinophilic cells −− May show solid or papillary pattern −− Differential diagnoses include papillary transitional cell carcinoma

MYOEPITHELIAL LESIONS ♦♦ Classified as myoepitheliosis, adenomyoepithelioma, and malignant myoepithelioma ♦♦ Differential diagnosis and ultrastructural features are discussed for the whole group

Macroscopic

Prognostic Significance

♦♦ ♦♦ ♦♦ ♦♦

♦♦ Myoepitheliosis −− No recurrences or malignant change reported ♦♦ Adenomyoepithelioma −− Tubular variant appears most likely to recur: histologic features do not predict which cases will recur −− Metastases may develop from carcinoma arising in this lesion ♦♦ Malignant myoepithelioma −− Small number of cases, but a risk of nodal metastases exists

♦♦ May be detected as firm areas within breast biopsy specimen

Microscopic Multifocal proliferation of spindle cells in TDLU Intraductal or periductal pattern Epithelial cells may be entrapped and lumens obliterated No atypia or mitotic figures seen in spindle cells

Immunohistochemistry (See Table 29.6) ♦♦ Intense positivity for S-100 protein, CD10, p63, calponin, and HMW cytokeratins ♦♦ Moderate positivity for actin ♦♦ Weak positivity for broad spectrum keratin cocktails ♦♦ Negative for GFAP

Myoepitheliosis Clinical

Adenomyoepithelioma Clinical

♦♦ Does not form a palpable mass ♦♦ It is the most common of the three groups in this class

♦♦ Women; median age = 62 years ♦♦ Solitary, centrally located lesions

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Table 29.6. Myoepithelial Lesions of the Breast Myoepitheliosis

Adenomyoepithelioma

Myoepithelial carcinoma

Frequency

Common

Uncommon

Rare

Gross

Usually not seen

Solitary mass

Mass(es)

Microscopic

Spindle cells

Variable, usually spindle

Spindle cells

S-100 protein

+++

+++

++

Smooth muscle actin

++

+

++/+++

High molecular weight cytokeratins, p63, calponin, CD10

Positive

Positive

Positive

+ = weakly positive; ++ = moderately positive; +++ = strongly positive

(c) Up to three mitoses per 10 HPF seen (d) Margin shows focal irregularity −− Lobulated (a) Solid nests with fibrous capsule and some marginal irregularity (b) Myoepithelial cells are clear, eosinophilic, or plasmacytoid (c) Stroma is hyalinized, with frequent calcification or infarction (d) Mitoses usually <3/10 HPF, occasionally more

Immunohistochemistry (See Table 29.6) ♦♦ Intense positivity for S-100 protein (less in clear cells), p63, calponin, CD10, and HMW cytokeratins ♦♦ Weak positivity for actin and broad spectrum keratin cocktails ♦♦ Generally negative for GFAP, unlike the salivary gland counterpart Fig.  29.43. Adenomyoepithelioma, tubular type. Rounded tubules are lined by both epithelial and myoepithelial cells. Myoepithelial cells may be hyperplastic and obliterate lumens.

Malignant Myoepithelioma (Myoepithelial Carcinoma) Clinical

♦♦ May have an associated nipple discharge

♦♦ Women, middle aged to elderly ♦♦ Central breast mass, with or without nipple discharge

Macroscopic ♦♦ Usually well-circumscribed, white-gray nodules 1–7 cm in size

Microscopic ♦♦ Spindle cell, tubular, and lobulated types −− Spindle cell (a) Solid mass with small foci of epithelium, frequently apocrine in type −− Tubular (a) Rounded tubules lined by both epithelial and ­myoepithelial cells (Fig. 29.43) (b) Myoepithelial cells may be hyperplastic and obliterate lumens

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Macroscopic ♦♦ Stellate or well-circumscribed masses 1–21 cm in size ♦♦ Satellite nodules may be visible grossly

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Spindle cell proliferation only Cellular pleomorphism present; cells may be plump or oval Mitotic figures > 3/10 HPF Infiltrative margins

Immunohistochemistry (See Table 29.6) ♦♦ Positive for actin, S-100 protein, p63, CD10, calponin, and HMW cytokeratins

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Ultrastructure ♦♦ Features vary somewhat according to cell type studied ♦♦ Constant features are the following −− Multilayered basal lamina −− Desmosomes and hemidesmosomes −− Aggregates of myofibrils with dense bodies −− Pinocytotic vesicles (fewer in clear cells) −− Occasional tonofilaments (in malignant myoepithelioma)

Differential Diagnosis ♦♦ Myoepitheliosis is an incidental microscopic finding and blends with myoepithelial prominence in sclerosing adenosis ♦♦ Lobulated adenomyoepithelioma may be mistaken for high grade DIN (DCIS). Look for hyalinized stroma and clear/ plasmacytoid cells ♦♦ Malignant myoepithelioma resembles the following

−− Spindle cell carcinoma: both epithelial and myoepithelial (ME) cells form malignant spindle cell tumors; those with ME differentiation are positive for HMW cytokeratins as well as p63; immunoreactivity for actin, calponin, and S-100 is often patchy to absent and of moderate intensity −− Fibromatosis: more infiltrative, little or no atypia, <3  mitoses/10 HPF, negative for keratin and S-100 protein −− Stromal (spindle cell) sarcoma: negative for epithelial markers ♦♦ Ultrastructural demonstration of pinocytotic vesicles strongly favors myoepithelial origin over epithelial origin

Carcinoma Arising in Adenomyoepithelioma ♦♦ Either component (epithelial or myoepithelial) may give rise to carcinoma ♦♦ Epithelial tumors reported include ductal carcinoma and adenoid cystic carcinoma

VASCULAR AND VASCULAR-LIKE LESIONS Pseudoangiomatous Hyperplasia Clinical

♦♦ Mondor disease involves a vein

Prognostic Significance

♦♦ Most cases are incidental microscopic findings (23% of breast biopsies) ♦♦ Symptomatic cases present as a painless mass in women with a mean age of 40 years

♦♦ Arteritis should prompt systemic assessment ♦♦ Mondor disease may be secondary to trauma and needs symptomatic treatment only

Macroscopic

Microscopic Hemangioma Microscopic

♦♦ Firm, rubbery lesion, 2–7 cm in size

Microscopic ♦♦ Usually discrete and multifocal, resembling a vascular lesion on low power ♦♦ Dense collagenous stroma with slit-like channels lined by stromal, not endothelial, cells

Immunohistochemistry ♦♦ Lining cells are vimentin and PR positive, but negative for vascular markers Factor VIII and CD34

Vasculitis Clinical ♦♦ Rare, accompanied by systemic symptoms ♦♦ Tender nodules, cord-like lesion if a superficial vein (Mondor disease)

♦♦ Incidental microscopic findings <5 mm in size ♦♦ Perilobular hemangioma is most common form: aggregate of red blood cell-filled vascular channels in perilobular stroma ♦♦ No atypia or endothelial proliferation

Palpable Hemangioma Clinical ♦♦ Definition: >5 mm in size ♦♦ Women > Men

Prognostic Significance ♦♦ No convincing evidence that hemangiomas are precursors of angiosarcoma ♦♦ Atypical hemangiomas do not recur or require reexcision

Microscopic

Macroscopic

♦♦ Giant cell arteritis and polyarteritis nodosa have been described

Microscopic

♦♦ May be apparent as well-defined blood-filled lesions

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♦♦ Vascular proliferation in intra- and interlobular stroma ♦♦ Cavernous, capillary, and arteriovenous forms described ♦♦ Some lesions show focal endothelial hyperplasia or anastomosing channels: “atypical hemangiomas”

Atypical Vascular Lesion Clinical ♦♦ Solitary or multiple skin or breast nodules ♦♦ Occurs 2–5 years after radiotherapy to the breast ♦♦ Generally not associated with skin discoloration

Prognostic Significance ♦♦ Atypical vascular lesion does not recur and has no metastatic potential

Macroscopic

Essentials of Anatomic Pathology, 3rd Ed.

Macroscopic ♦♦ Well-circumscribed, pink/tan mass

Microscopic ♦♦ Well-circumscribed cellular lesions ♦♦ Densely packed spindle cells surround endothelial-lined spaces ♦♦ Larger spaces classically show a staghorn shape; smaller may be slit-like ♦♦ Hemorrhage, necrosis, and significant mitotic activity are uncommon ♦♦ Stroma may have myxoid change

Immunohistochemistry ♦♦ Positive for vimentin, CD 34, and Factor XIIIa ♦♦ Tumor cells are negative for Factor VIII or Ulex (endothelial cells are positive for these) and negative for keratin and SMA

♦♦ Pink or tan-white nodules

Microscopic ♦♦ Located in dermis or present as circumscribed lesions in breast ♦♦ Dilated vascular spaces with anastomosing pattern ♦♦ Endothelium is plump, with occasional projections or tufting ♦♦ No endothelial mitoses or stromal blood lakes

Differential Diagnosis ♦♦ Angiosarcoma: more atypia, endothelial proliferation

Angiomatosis Clinical ♦♦ A rare, congenital lesion; often manifests in young women, mean age = 33 years ♦♦ One case reported in a man

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Extensive in distribution Proliferation of irregular vascular channels No anastomosing pattern or endothelial atypia Does not dissect into lobular stroma

Differential Diagnosis ♦♦ Low grade angiosarcoma (see below)

Hemangiopericytoma Clinical ♦♦ Rare lesion; men and women

Prognostic Significance ♦♦ Complete local excision appears adequate; no recurrence reported ♦♦ Followup is recommended when there is hemorrhage, necrosis, or significant mitotic activity

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Angiosarcoma Clinical ♦♦ Rare neoplasm; women > men; mean age = 35 years ♦♦ May present as a well-defined, painless, rapid growing mass ♦♦ A minority present with diffuse discoloration of the overlying skin ♦♦ May develop postradiotherapy (typically after 12 years, but reported within 4 years of treatment)

Prognostic Significance ♦♦ Well- and moderately differentiated lesions have median cancer-free survival of 12–15 years ♦♦ Poorly differentiated lesions have 15 months median survival ♦♦ Metastases to lungs, liver, and skin; axillary nodes rarely involved

Macroscopic ♦♦ Spongy, hemorrhagic tissue in breast; may extend to overlying skin ♦♦ Extensive sampling is necessary for grading

Microscopic ♦♦ Variable appearance is basis for grading ♦♦ Low grade (well differentiated) −− Anastomosing vascular channels −− 1–2 cell layer lining −− No necrosis or pleomorphism; mitoses rare −− No blood lakes ♦♦ Intermediate grade (moderately differentiated) −− Solid areas comprise <20% of total tumor mass −− Endothelial tufts present ♦♦ High grade (poorly differentiated) −− Predominance of solid spindle cell areas −− Mitoses, pleomorphism, necrosis, and hemorrhage present

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Immunohistochemistry ♦♦ Positivity for vascular markers (FVIII-related antigen, Ulex, CD 31) is maximal in better differentiated tumors, and very variable in poorly differentiated ones

Ultrastructure ♦♦ Malignant cells show pinocytotic vesicles, desmosomes, tight junctions, and Weibel–Palade bodies; the latter are seen mainly in some low grade lesions

Differential Diagnosis ♦♦ Pseudoangiomatous hyperplasia −− Does not infiltrate lobules and is negative for vascular markers

♦♦ Hemangioma (microscopic, perilobular) −− No angiosarcomas have been found with this pattern ♦♦ (Postradiation) atypical vascular lesion −− Lacks atypia, mitoses, or endothelial proliferation and does not infiltrate subcutis ♦♦ Angiolipoma −− Well-demarcated/noninfiltrative, vessels contain microthrombi ♦♦ Angiomatosis −− Lacks atypia, mitotic activity (<1 mitosis/10 HPF, if any), endothelial cell proliferation, and dissection into lobular stroma

LYMPHOID LESIONS ♦♦ May be primary in the breast or in an intramammary/ axillary node

Lymphoma Clinical ♦♦ Primary lymphoma is rare. There is concurrent axillary node disease in 30–50% of all cases ♦♦ Secondary involvement of the breast by disseminated disease is more common ♦♦ Primary: bimodal incidence reported (38 and 58 years) ♦♦ Usually unilateral, but may be bilateral; small number in men ♦♦ Presentation can be with mass, pain, or constitutional (B-type) symptoms

Prognostic Significance ♦♦ Prognosis depends on stage and type ♦♦ Primary mammary lymphoma recurs locally in ~50% of all cases

Macroscopic ♦♦ Fleshy, gray-white tissue

Microscopic ♦♦ Non-Hodgkin lymphoma (NHL) is much more common than Hodgkin lymphoma ♦♦ B-cell is far more common than T-cell ♦♦ NHL types include diffuse large cell and diffuse, noncleaved, small cell (Burkitt-like) ♦♦ No histologic features can distinguish primary from secondary forms ♦♦ Lymphocytic infiltration of epithelium may be seen in benign and malignant breast disease

Immunohistochemistry ♦♦ Appropriate panel to type lymphoma should be performed (see Chapter 15) ♦♦ Immunoglobulin or T-cell receptor gene rearrangement studies as needed

Differential Diagnosis ♦♦ Poorly differentiated carcinoma −− Keratin positive −− LCA negative ♦♦ Solid and alveolar variants of infiltrating lobular carcinoma −− Keratin positive −− Intracytoplasmic lumens best seen in periphery −− Mucicarmine positive ♦♦ “Pseudolymphoma” −− Many of these atypical lymphoid proliferations evolve into lymphoma; they have a mixed cell population ♦♦ Lymphocytic mastitis −− Localized; no atypia; associated with dense collagen and atypical epithelioid stromal cells

Plasmacytoma Clinical ♦♦ Rare lesion in the breast; may be presentation of myeloma

Microscopic ♦♦ Similar to extramedullary plasmacytoma at other sites; cellular aggregate of variably atypical plasma cells (see Lymph Nodes, Chapter 15)

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Granulocytic Sarcoma Clinical ♦♦ Uncommon; occurs either synchronously with, or shortly prior to, onset of acute myeloid leukemia ♦♦ Presents as a unilateral breast mass in patients aged 34–56 years

Macroscopic

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai–Dorfman Disease) Clinical ♦♦ Rare in breast, but may involve axillary nodes ♦♦ Occurs at any age, but especially in younger women

Microscopic

♦♦ May show the characteristic green color

Microscopic ♦♦ Immature myeloid cells: mononuclear forms with granular eosinophilic cytoplasm, chloroacetate esterase (Leder) stain positive

♦♦ Selective involvement of sinuses with expansion by S-100 positive histiocytes ♦♦ Emperipolesis: engulfment of lymphocytes by histiocytes is characteristic ♦♦ Prominent polyclonal plasmacytosis

METASTASES TO THE BREAST Clinical

Microscopic

♦♦ Metastases to the breast are rare (~2%) ♦♦ Most common source is contralateral breast ♦♦ Melanomas and lymphomas are common extramammary sources, followed by lung, ovary, or stomach (also prostate in men) ♦♦ May be first presentation of extramammary malignancy ♦♦ Should be distinguished from a primary breast tumor to avoid unnecessary surgery

♦♦ Usually sharply defined ♦♦ Usually not associated with microcalcifications (except ­ovarian mets) ♦♦ Histology of extramammary component not typical for breast primary ♦♦ Periductal and/or perilobular distribution ♦♦ Lacks associated intraepithelial component

Macroscopic ♦♦ Single or multiple firm to hard, circumscribed masses with slightly irregular margins

TNM CLASSIFICATION OF CARCINOMA OF THE BREAST (2010 Revision) ♦♦ Primary Tumor (pT) −− pTX: Primary tumor cannot be assessed −− pT0: No evidence of primary tumor −− pTis: Carcinoma in situ −− pTis (DCIS): Ductal carcinoma in situ −− pTis (LCIS): Lobular carcinoma in situ −− pTis (Paget): Paget disease of the nipple is NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted −− pT1: Tumor ≤20 mm in greatest dimension

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pT1mic: Tumor ≤1 mm in greatest dimension pT1a: Tumor >1 mm but ≤5 mm in greatest dimension pT1b: Tumor >5 mm but ≤10 mm in greatest dimension pT1c: Tumor >10 mm but ≤20 mm in greatest dimension pT2: Tumor >20 mm but ≤50 mm in greatest dimension pT3: Tumor >50 mm in greatest dimension pT4: Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)* −− pT4a: Extension to the chest wall, not including only pectoralis muscle adherence/invasion

−− −− −− −− −− −− −−

*Note: Invasion of the dermis alone does not qualify as T4.

Breast

−− pT4b: Ulceration and/or ipsilateral satellite nodules and/ or edema (including peau d'orange) of the skin which do not meet the criteria for inflammatory carcinoma −− pT4c: Both T4a and T4b −− pT4d: Inflammatory carcinoma** **Note: Inflammatory carcinoma is restricted to cases with typical skin changes involving a third or more of the skin of the breast. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer. ♦♦ Regional Lymph Nodes (pN) −− pNX: Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for pathologic study) −− pN0: No regional lymph node metastasis identified histologically −− pN0(i−): No regional lymph node metastases histologically, negative IHC −− pN0(i+): Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including ITC) −− pN0(mol−): No regional lymph node metastases histologically, negative molecular findings (RT-PCR) −− pN0(mol+): Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC −− pN1: Micrometastases; or metastases in 1 to 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected** −− pN1mi: Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm) −− pN1a: Metastases in 1 to 3 axillary lymph nodes, at least one metastasis greater than 2.0 mm −− pN1b: Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected** −− pN1c: Metastases in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected** −− pN2: Metastases in 4 to 9 axillary lymph nodes; or in clinically detected*** internal mammary lymph nodes in the absence of axillary lymph node metastases −− pN2a: Metastases in 4 to 9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm) −− pN2b: Metastases in clinically detected*** internal mammary lymph nodes in the absence of axillary lymph node metastases −− pN3: Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected*** ipsilateral internal mammary lymph nodes in the presence of 1 or more positive level I,

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II axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected**; or in ipsilateral supraclavicular lymph nodes −− pN3a: Metastases in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes −− pN3b: Metastases in clinically detected*** ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected** −− pN3c: Metastases in ipsilateral supraclavicular lymph nodes *Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for “sentinel node,” for example, pN0(sn). **Note: Not clinically detected is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination. ***Note: Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with cytologic examination. Note: Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic crosssection. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated ♦♦ Distant Metastases (m) −− M0: No clinical or radiographic evidence of distant metastases (no pathologic M0; use clinical M to complete stage group) −− cM0(i+): No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases −− pM1: Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm

Based on AJCC/UICC TNM, 7th edition

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Rosen PP, Oberman HA. Tumors of the mammary gland. Atlas of Tumor Pathology, 3rd series, Fascicle 7. Washington, DC: Armed Forces Institute of Pathology. 1993:78–87. Salarieh A, Sneige N. Breast carcinoma arising in microglandular adenosis: a review of the literature. Arch Pathol Lab Med 2007;131:1397–1399. Santen RJ, Mansel R. Benign breast disorders. N Engl J Med 2005;353:275–285. Sastre-Garau X, Jouve M, Asselain B, et al. Infiltrating lobular carcinoma of the breast: clinicopathologic analysis of 975 cases with reference to data on conservative therapy and metastatic patterns. Cancer 1996;77:113–120. Schwartz IS, Strauchen AJ. Lymphocytic mastopathy: an autoimmune disease of the breast? Am J Clin Pathol 1990;93:725–730. Seal MD, Chia SK. What is the difference between triple-negative and basal breast cancers? Cancer J 2010;16:12–16. Silver SA, Tavassoli FA. Pleomorphic carcinoma of the breast: clinicopathological analysis of 26 cases of an unusual high grade phenotype of ductal carcinoma. Histopathology 2000;36:505–514. Silverstein MJ, Gierson ED, Colburn WJ, et  al. Can intraductal breast carcinoma be excised completely by local excision? Cancer 1994;73:2985–2989. Tan PH, Tse GM, Bay BH. Mucinous breast lesions: diagnostic challenges. J Clin Pathol 2008;61:11–19 Tavassoli FA. Breast pathology: rationale for adopting the ductal intraepithelial neoplasia (DIN) classification. Nat Clin Pract Oncol 2005;2: 116–117. Tavassoli FA. Challenges in breast pathology: new twists on old problems. Arch Pathol Lab Med 2009;133:852–854. Tavassoli FA. Correlation between gene expression profiling-based molecular and morphologic classification of breast cancer. Int J Surg Pathol 2010;18:167S–169S. Tavassoli FA. Ductal carcinoma in situ: introduction of the concept of ductal intraepithelial neoplasia. Mod Pathol 1998;11:140–154. Tavassoli FA. Ductal intraepithelial neoplasia of the breast. Virchows Arch 2001;438:221–227. Tavassoli FA. Lobular neoplasia: evolution of its significance and morphologic spectrum. Int J Surg Pathol 2010;18:174S–177S. Tavassoli FA. Mammary intraepithelial neoplasia: a translational classification system for the intraductal epithelial proliferations. Breast J 1997; 3:48–58. Tavassoli FA. Myoepithelial lesions of the breast: myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma. Am J Surg Pathol 1991;15:554–568. Tavassoli FA. Pathology of the Breast. Stamford, CT: Appleton & Lange; 1999;205–323, 373–570.

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30 Vulva and Vagina Sharon X. Liang, md, phd and Wenxin Zheng, md

contents PART A: THE VULVA..................................30-3 V. Benign Tumors.................................30-12

I. Inflammatory Lesions.........................30-4 Vulvar Vestibulitis............................................30-4 Plasma Cell Vulvitis.........................................30-4 Lichen Simplex Chronicus..............................30-4 Behçet Disease..................................................30-4 Fox–Fordyce Disease........................................30-5 Hidradenitis Suppurativa................................30-5

II. Infectious Lesions..............................30-6 Human Papilloma Virus Infections................30-6 Candidiasis........................................................30-6 Molluscum Contagiosum.................................30-7 Herpesvirus Infection......................................30-7 Cytomegalovirus Infection..............................30-8 Syphilis..............................................................30-8 Lymphogranuloma Venereum........................30-8

III. Cystic Lesions....................................30-8 Bartholin Duct Cyst and Abscess...................30-8 Skene Duct Cyst...............................................30-8 Epidermal Inclusion Cyst................................30-9 Mesonephric (Gartner Duct) Cyst..................30-9

IV. Benign Discolored Lesions.................30-9 Lichen Sclerosus...............................................30-9 Squamous Cell Hyperplasia............................30-9 Lichen Planus.................................................30-10 Seborrheic Keratosis......................................30-10 Lentigo Simplex and Melanosis....................30-10 Melanocytic Nevi............................................30-11

Fibroepithelial Polyp (Acrochordon)...........30-12 Squamous Vestibular Papillomatosis...........30-12 Papillary Hidradenoma (Hidradenoma   Papilliferum)...............................................30-12 Granular Cell Tumor.....................................30-12 Angiokeratoma...............................................30-12 Aggressive Angiomyxoma.............................30-13 Angiomyofibroblastoma................................30-14 Cellular Angiofibroma...................................30-14 Leiomyoma.....................................................30-14 Endometriosis.................................................30-15 Other Benign Mesenchymal Tumors............30-15

VI. Premalignant and Malignant Epithelial Tumors.............................30-15 Vulvar Intraepithelial Neoplasia...................30-15 Invasive Squamous Cell Carcinoma.............30-16 Verrucous Carcinoma....................................30-17 Basal Cell Carcinoma....................................30-18 Keratoacanthoma...........................................30-18 Paget Disease..................................................30-18 Carcinoma of Bartholin Gland.....................30-19 Adenocarcinoma of   Skin Appendage Origin.............................30-20

VII. Malignant Nonepithelial Tumors.............................................30-21 Malignant Melanoma.....................................30-21 Sarcoma Botryoides   (Rhabdomyosarcoma)................................30-21 Epithelioid Sarcoma.......................................30-21

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_30, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Yolk Sac Tumor..............................................30-22 Merkel Cell Tumor.........................................30-22 Other Sarcomas, Hematopoietic Tumors   and Secondary Tumors..............................30-22

VIII. Tnm Classification and FIGO Staging System of Vulvar Carcinomas (2010 Revision)................................30-22

XI. Premalignant and Malignant Epithelial Tumors.............................30-28 Vaginal Intraepithelial Neoplasia.................30-28 Squamous Cell Carcinoma............................30-28 Atypical Adenosis...........................................30-29 Clear Cell Carcinoma....................................30-29 Endometrioid Adenocarcinoma....................30-30 Mesonephric Adenocarcinoma.....................30-30

PART B:  VAGINA.....................................30-25 XII. Other Malignant Tumors..................30-30 IX. Benign Nonneoplastic Lesions.........30-26 Müllerian Papilloma......................................30-26 Vaginal Adenosis............................................30-26 Prolapse of Fallopian Tube............................30-26 Postoperative Spindle Cell Nodule...............30-26 Emphysematous Vaginitis.............................30-27 Ectopic Decidua..............................................30-27

X. Benign Tumors.................................30-27 Condylomas....................................................30-27 Tubular, Tubulovillous, and Villous   Adenomas....................................................30-27 Superficial Myofibroblastoma of the   Lower Female Genital Tract.....................30-27 Brenner Tumor...............................................30-28 Benign Mixed Tumor (Spindle Cell   Epithelioma)...............................................30-28

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Sarcoma Botryoides (Embryonal   Rhabdomyosarcoma).................................30-30 Malignant Melanoma.....................................30-30 Carcinosarcoma.............................................30-31 Primitive Neuroectodermal Tumor   (PNET)........................................................30-31 Gastrointestinal Stromal Tumors of the   Vagina and Rectovaginal Septum.............30-31 Leiomyosarcoma............................................30-31 Yolk Sac Tumor..............................................30-31 Hematopoietic Tumors..................................30-31 Secondary Tumors.........................................30-31

XIII. Tnm Classification and FIGO Staging System of Vagina Carcinoma (2010 Revision)................................30-33 XIV. Suggested Reading...........................30-33

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Part A The Vulva

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INFLAMMATORY LESIONS Vulvar Vestibulitis

Lichen Simplex Chronicus

Clinical

Clinical

♦♦ Vulvar vestibulitis, also referred to as vulvar vestibular syndrome, is a clinical complex that represents a part of a spectrum of vulvar pain-related disorders affecting up to 15% of gynecologic patients. It occurs in women of reproductive age, usually in their 30s ♦♦ The typical presentations include severe pain on vaginal entry, “pinpoint” tenderness to pressure around the vestibule, and variable vulvar erythema ♦♦ The etiology is unknown. An infectious origin has not been supported. An increased number of nerve fibers per square unit in the vulvar vestibule were identified in one study ♦♦ There is no effective therapy. Local excision, interferon, and biofeedback training of pelvic muscle have been used with some response. More than 50% of patients will have recurrent symptoms

♦♦ Lichen simplex chronicus (LSC) is a chronic eczematous inflammation of skin that results in thickening of the epidermis in the affected areas. It is often associated with excoriation and fissures ♦♦ The characteristic feature is intermittent pruritus relieved temporarily by scratching ♦♦ The disease can be controlled if the itch–scratch cycle is blocked

Microscopic ♦♦ A variable degree of chronic inflammatory infiltrate is present in the lamina propria of the squamous mucosa. Fibrous tissue surrounding the vestibular glands and ducts can also be involved. Occasionally, lymphoid follicles may be seen in some cases ♦♦ Squamous metaplasia of the vestibular glands and ducts is a common finding. When extensive, the entire vestibular glands and ducts can be replaced by squamous epithelium

Plasma Cell Vulvitis Clinical

Microscopic ♦♦ Epidermal acanthosis with a superficial dermal chronic inflammatory infiltrate is the typical histologic finding. A superficial dermal collagen zone is usually present (Fig. 30.1) ♦♦ Hyperkeratosis and parakeratosis may be present. ♦♦ Surface erosion with exocytosis may be seen secondary to scratching ♦♦ If there is no inflammation and dermal collagen zone, the diagnosis of squamous cell hyperplasia is pertinent (see Section Squamous Cell Hyperplasia)

Behçet Disease Clinical ♦♦ Behçet disease occurs most commonly in Japan and Eastern Mediterranean countries. The mean age at onset is in the 30s. There is a slight male predominance ♦♦ Behçet disease is a clinical syndrome characterized by systemic vasculopathy and presents as a triad of oral aphthous ulcers, genital ulcers or skin lesions such as ­pustules or

♦♦ Plasma cell vulvitis (vulvitis of Zoon) presents with erythematous macules in the vulvar vestibules (single or multiple) with itching and burning sensation ♦♦ The etiology is unknown. Local irritation and poor hygiene may be the contributing factors ♦♦ Perineal hygiene, supportive care, and topical corticosteroid are the treatments of choice

Microscopic ♦♦ Typical epithelial changes include a thinned epidermis, flattened rete ridges, absence of granular or keratin layer, and spongiosis of parabasal keratinocytes containing spindled nuclei with horizontal orientation ♦♦ There is a lichenoid inflammatory infiltrate predominantly composed of plasma cells. Perivascular plasma cell infiltrate is also present ♦♦ Prominent dermal blood vessels with dermal hemorrhage and hemosiderin are present ♦♦ The differential diagnosis includes syphilis, lichen planus, and other chronic dermatoses

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Fig. 30.1. Lichen simplex chronicus. Acanthosis, hyperkeratosis, and chronic inflammation in the dermis are typical features.

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erythema nodosa-like lesions, and eye lesions such as uveitis or retinal vasculitis ♦♦ The vulvar and oral ulcers are often simultaneous; they characteristically heal and relapse ♦♦ Administration of appropriate, systemic colchicine, and pentoxyfylline are the main therapies for vulvar and oral ulcers

Microscopic ♦♦ The cardinal pathologic finding is necrotizing vasculitis that may involve all calibers and types of vessels in the dermal and subcutaneous areas. The vasculitis may be associated with mural necrosis and thrombosis

Fox–Fordyce Disease Clinical ♦♦ Fox–Fordyce disease is a disorder of the apocrine glands, commonly seen in the genital region and axilla. It usually occurs after puberty and presents as multiple pruritic and papular eruptions. About 90% of cases occur in women ♦♦ It is a chronic condition from inflammatory responses to the leakage of the apocrine secretion into the dermis. The condition may progress during pregnancy or after menopause ♦♦ No effective therapy is known

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♦♦ Intraepidermal vesicle formation may be seen, secondary to rupture of the intraepithelial portion of the duct and spongiosis ♦♦ Chronic inflammatory changes are present in the dermis. ♦♦ Additional changes include dilation of apocrine gland acini and epidermal acanthosis

Hidradenitis Suppurativa Clinical ♦♦ Hidradenitis suppurativa is a chronic debilitating disease of the apocrine glands, commonly occurs in the vulva, perineum, and axilla. It presents as deep-seated, painful, subcutaneous nodules. The lesions may progress toward surface that causes ulceration of the epidermis, draining sinus, and extensive scarring ♦♦ Intercourse may be extremely uncomfortable and even impossible due to the inflammatory reaction in the affected area

Microscopic ♦♦ In early stage, there is perifolliculitis with acute and chronic inflammatory infiltrate within the dermis (Fig.  30.3). Destruction of the epithelial appendages with sinus tract formation occurs at the later stages

♦♦ A typical papule contains a hair follicle and apocrine sweat gland duct plugged by keratin in the center (Fig. 30.2)

Fig.  30.2. Fox–Fordyce disease. Apocrine gland dilatation ­associated with epidermal and dermal inflammation, acanthosis, and melanosis is demonstrated in this vulvar biopsy from a 17-year-old female.

Fig. 30.3. Hidradenitis supparativa.

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INFECTIOUS LESIONS Human Papilloma Virus Infections Clinical ♦♦ Human papilloma virus (HPV) infection of the vulva is common and causes lesions like vulvar condyloma acuminata. Most vulvar condyloma acuminata are caused by HPV-6 and some by HPV-11. They are usually associated with condylomas of the perineal and perianal skin and the anal and ­urethral mucosa, and more commonly associated with condylomas on other sites in the female genital tract such as vagina and cervix ♦♦ Grossly, condylomas vary from those visible only colposcopically to a large sessile or exophytic growth. They are often multiple and can become confluent. Typically, they involve labia majora and vestibules ♦♦ The lesions may be influenced by patients’ hormonal and immune status. It has been reported that vulvar condylomas may enlarge or increase in number during pregnancy and regress postpartum. However, there is no particular association between oral contraceptive use and vulvar condyloma development. The lesions may be associated with or progress to vulvar intraepithelial neoplasia (VIN) or  invasive squamous cell carcinoma (ISCC), especially in immunosuppressed women

♦♦ Warty VINs usually have significant degrees of nuclear atypia and more obvious mitosis ♦♦ Vestibular papillomatosis typically lack koilocytosis and hyperkeratosis ♦♦ Condyloma lata is a secondary lesion of syphilis (see below)

Candidiasis Clinical ♦♦ Vulvar candidiasis is often an external manifestation of a vaginal infection by Candida ♦♦ Patients commonly present with intensive pruritus ♦♦ Diagnosis is usually made by skin scraping. Biopsy is rarely needed

Microscopic ♦♦ The diagnostic feature of condylomas is the presence of koilocytes in the superficial layers (Fig. 30.4b). Koilocytes are HPV-infected keratinocytes that have atypical nuclei with a perinuclear clear zone (halo) of clear cytoplasm. The atypical nuclei have three features including enlargement, hyperchromasia or coarse chromatin, and irregular nuclear membrane. Practically, a nucleus with any two of the three features is qualified as atypical ♦♦ Binucleated or multinucleated koilocytes are commonly seen. The koilocytes may vary in size and shape ♦♦ Architecturally, condylomas are characterized by complex branching papillae composed of acanthotic squamous epithelium and fibrovascular cores (Fig.  30.4A). Some­ times, endophytic or downward growth of rete pegs is seen ♦♦ MIB-1 or Ki-67 stained nuclei in the upper two-thirds of the squamous epithelium may aid the diagnosis when unequivocal diagnostic features are absent ♦♦ Some authorities group condylomas under low grade VIN (VIN I). Attention should be paid to the presence of any high grade VINs (see Section  Vulvar Intraepithelial Neoplasia) when you examine the condylomas

Differential Diagnosis ♦♦ Verrucous carcinomas (VCs) sometimes are referred to as “giant condylomas.” These tumors are usually large and solitary and lack the fine branching papillae and ­koilocytosis of condylomas. Patients with VC are usually older (see Premalignant and Malignant Epithelial Tumors in Part A-VI)

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Fig. 30.4. Condyloma acuminatum. (A) Typical complex branching papillae are composed of acanthotic squamous ­epithelium and fibrovascular cores. (B) Koilocytes are present in the squamous epithelium.

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Microscopic

Microscopic

♦♦ Identification of fungal hyphae within the keratin or superficial epithelium by GMS or PAS stains in a background of acute inflammation is diagnostic of fungal infection.

♦♦ Marked acanthosis and presence of characteristic intracytoplasmic viral inclusions (Molluscum bodies or Henderson– Paterson bodies) are the main histologic features of a typical lesion (Fig. 30.5B)

Molluscum Contagiosum

Herpesvirus Infection

Clinical

Clinical

♦♦ Molluscum contagiosum is a contagious viral disease, transmitted through intimate or sexual contact. It is more commonly seen in immunosuppressed patients. The lesions are usually asymptomatic, but can become pruritic ♦♦ The causative agent is a DNA poxvirus ♦♦ The characteristic lesions are multiple, small and smooth papules (3–6 mm diameter) with a central punctum or umbilication (Fig. 30.5A) ♦♦ It is usually diagnosed clinically without biopsy. No therapy is needed

♦♦ The causative agent is herpes simplex virus (HSV), predominantly type 2 ♦♦ Dysuria or urinary retention with vulvar pain is the initial presentation ♦♦ Systemic symptoms with fever and inguinal lymphadenopathy are present in about two-thirds of the patients ♦♦ Vesicles, pustules, and painful shallow ulcers appear sequentially, usually within a week of infection ♦♦ The acute ulcers persist for 2–6 weeks (average 19 days) and then heal without scarring ♦♦ Acyclovir is the main therapy given early in the course of illness

Microscopic ♦♦ The HSV-infected epithelial cells are characterized by “ground-glass” appearance of the nuclei or eosinophilic intranuclear inclusions at the periphery of the vesicles or ulcers (Fig. 30.6) ♦♦ Tzank preparation of a fresh lesion is an effective method for diagnosis ♦♦ Anti-HSV can be used to aid the diagnosis in certain clinical settings

Fig. 30.5. Molluscum contagiosum. (A) A small smooth papule with a central punctum is a typical gross appearance. (B) Molluscum bodies consist of homogeneous intracytoplasmic DNA virus inclusions.

Fig.  30.6. Herpes simplex virus of vulva. Ulceration with a marked acute and chronic inflammation is evident. Multinucleation with typical ground-glass appearance is noted.

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Cytomegalovirus Infection ♦♦ Cytomegalovirus (CMV) infection presents with vulvar ulcer ♦♦ CMV infections are mostly seen in HIV infected women ♦♦ The viral inclusion bodies are both intranuclear and intracytoplasmic, involving epithelial cells and vascular endothelial cells. This is highly characteristic of CMV infection

Syphilis Clinical ♦♦ Syphilis is a venereal disease caused by the spirochete Treponema pallidum ♦♦ Chancre is the primary lesion and occurs within days or months of initial sexual contact. A typical chancre appears as a painless, indurated, shallow, and clean-based ulcer with raised edges. Chancre can be single or multiple and usually heals within 2–6 weeks without leaving a scar ♦♦ The secondary phase becomes evident within several months. It is characterized by rashes of mucous membranes and skin in the palms of the hands and soles of the feet. The characteristic lesion in the vulva is condyloma lata, which is an elevated plaque of several centimeters in diameter ♦♦ The tertiary gumma is rarely seen on vulva

Microscopic ♦♦ A large quantity of perivascular plasma cell infiltrate is characteristically seen in both chancre and condyloma lata (Fig. 30.7) ♦♦ Condyloma lata have marked acanthosis, hyperkeratosis, and papillomatosis with some neutrophils in the epidermis ♦♦ Warthin–Starry stain, dark-field examination, or immunofluorescence stain can be used to demonstrate the spirochetes in these lesions

Fig. 30.7. Stromal fibrosis, squamous hyperplasia, and chronic inflammation with a perivascular plasma cell-rich component may be seen in the secondary lesions of syphilis.

Lymphogranuloma Venereum ♦♦ Lymphogranuloma venereum (LGV) is caused by Chlamydia trachomatis ♦♦ It is more common in the tropical and subtropical regions and rarely seen in the United States ♦♦ Patients typically present with nontender skin ulcers, followed by painful inguinal lymphadenitis. Fibrosis and chronic lymphatic obstruction occur in later phase of the infection ♦♦ Chronic inflammation is extensive, but not specific ♦♦ Diagnosis is relied on the characteristic clinical findings, culture, and complement fixation tests

CYSTIC LESIONS Bartholin Duct Cyst and Abscess

Microscopic

Clinical

♦♦ Bartholin cysts are lined by squamous, transitional, mucinous, ciliated, or flattened nonspecific epithelium ♦♦ A typical location and the presence of normal Bartholin glands adjacent to the cyst facilitate distinction from cysts arising in minor vestibule glands (Fig. 30.8)

♦♦ Bartholin duct cyst accounts for a majority of the symptomatic vulvar cysts in a gynecologic clinic. It occurs secondary to obstruction of the vestibular orifice of Bartholin ducts and accumulation of secretions from the glands ♦♦ Bartholin abscess occurs as a result of acute infection of the Bartholin glands ♦♦ An average size of the cyst or abscess is 1–2 cm but can be much larger ♦♦ Recurrent cysts or a palpable mass after cyst drainage in postmenopausal women may require excision to rule out malignancy of the Bartholin gland

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Skene Duct Cyst Clinical ♦♦ Skene glands are periurethral glands, located adjacent to the distal urethra. Cysts form if the duct is obstructed, usually because of infection. Cysts may form abscesses or cause urethral obstruction and recurrent UTIs. They occur mainly in women of reproductive age

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♦♦ Diagnosis is usually clinical. Symptomatic cysts are treated by excision

Microscopic ♦♦ Excised cysts are lined by a single layer of columnar mucinous epithelium, ciliated nonmucinous epithelium, or by a combination of the two. Squamous metaplasia or urothelial like epithelium may be seen

Epidermal Inclusion Cyst

Fig.  30.8. Bartholin gland cyst. The cyst is lined by cuboidal mucinous and transitional or indifferent cells. Atrophic changes are seen in an adjacent Bartholin gland. ♦♦ Most cysts are <1 cm in diameter and asymptomatic. Some cysts are larger, causing dyspareunia, urinary outflow obstruction, or UTI, and can be painful if there is an abscess formation

♦♦ They are commonly seen in the vulva, usually the labia majora, and may result from obstruction of the ­pilosebaceous ducts and glands ♦♦ Patients may present with complains of a palpable ­nodularity within the vulva ♦♦ Excised cyst is lined by flattened stratified squamous epithelium and filled with keratinaceous debris

Mesonephric (Gartner Duct) Cyst ♦♦ It is very rare and located in the lateral aspects of the vulva or vagina ♦♦ The cysts are lined by cuboidal to flattened epithelial cells that are devoid of cytoplasmic mucin

BENIGN DISCOLORED LESIONS Lichen Sclerosus

Microscopic

Clinical

♦♦ The characteristic features include atrophic epidermis with loss of rete ridges and a zone of homogeneous subepithelial hyalinization or edema (Fig. 30.9B) ♦♦ There is a loss of elastic fibers and vasculature. ♦♦ A band of chronic lymphocytic infiltration may be present in the superficial dermis ♦♦ The epithelium may be strikingly thinned, eroded, or ulcerated; however, markedly thickened epithelium with hyperkeratosis and parakeratosis may be seen in adjacent areas

♦♦ Lichen sclerosus (LS) accounts for 30–40% of nonneoplastic epithelial lesions of the vulva. Women of peri and postmenopausal age are more commonly affected than younger patients. A similar condition in male patients is called balanitis xerotica obliterans ♦♦ The etiology is unclear. Proposed mechanisms include immunologic, genetic, and hormonal abnormalities. Deficiencies of androgen receptor and epidermal growth factor were reported in some studies ♦♦ Typical lesions of vulvar LS are irregular, ill-defined hypopigmented patches, often multiple, bilateral, and sometimes symmetric. In advanced stages, the affected skin is shiny and wrinkled (“cigarette paper”); the labia are atrophic, and the introitus is narrowed (Fig. 30.9A) ♦♦ Although LS is not considered as a premalignant lesion, areas of hyperplastic epithelium occurring within LS may undergo premalignant or malignant changes. More than 60% of vulvar invasive or in situ squamous cell carcinomas may have LS in adjacent areas

Squamous Cell Hyperplasia ♦♦ The term squamous cell hyperplasia was proposed in 1987 to replace the term hyperplastic dystrophy. It is a ­descriptive term applicable, both clinically and ­histologically, to an epithelial thickening of the vulva without identifiable causes or with difficulties in classification ♦♦ Localized pruritus is the most common presenting ­symptom. Upon examination, unilateral irregular white plaque-like lesions may be identified

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Fig. 30.10. Squamous cell hyperplasia. Epidermis shows prominent acanthosis with elongated rete pegs. No dysplasia or nuclear atypia is present.

Fig. 30.9. Lichen sclerosis. (A) Gross appearance of lichen sclerosis at an advanced stage. (B) Epidermal atrophy, loss of rete ridges and hyalinization in the upper dermis are the typical ­histologic features.

♦♦ Thickening of the vulvar epithelium is nonspecific and demonstrated by acanthosis with elongation, widening and deepening of the rete ridges. Hyperkeratosis and ­parakeratosis may be present. Cellular atypia, dermal inflammation, and fibrosis are absent (Fig. 30.10) ♦♦ If significant inflammation is present, a diagnosis of LSC should be considered (see Section Inflammatory Lesions) ♦♦ If cellular atypia is present, the lesion should be classified as VIN. When lichen sclerosis or squamous hyperplasia is associated with VIN, both diagnoses should be reported

Lichen Planus ♦♦ Lichen planus (LP) is an uncommon inflammatory disease of unknown etiology

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♦♦ It typically involves vulvar vestibule and vagina. The affected areas may be markedly erythematous. Serosanguinous discharge may be present ♦♦ Involvement of vulva, oral mucosa, and vaginal mucosa is referred to as the vulvo-vaginal–gingival syndrome ♦♦ Diagnostic features of vulvar LP include a lichenoid interface chronic inflammatory infiltrate (predominantly lymphocytic with no or rare plasma cells) and pointed rete ridges (Fig.  30.11A). Wedge-shaped hypergranulosis and hyperkeratosis may be prominent. Severe cases may have colloid bodies (civatte bodies) with keratinocyte liquification necrosis, bullae, and ulceration (Fig. 30.11B) ♦♦ Special stains for bacteria or fungi are negative ♦♦ LP can be difficult to differentiate from early LS. Features favoring LP include civatte bodies, wedge-shaped hypergranulosis, pinpoint rete ridges, and frequent mucosal involvement

Seborrheic Keratosis ♦♦ Seborrheic keratosis (SK) is a raised and pigmented warty lesion occurring on the hair-bearing areas of the vulva ♦♦ SK may be single or multiple and can form clusters ♦♦ Microscopically, it consists of a basaloid cell proliferation with acanthosis, papillomatosis, hyperkeratosis, and epithelial invaginations forming horn cysts (Fig. 30.12) ♦♦ Increased melanin pigment in basal and parabasal layers may be seen in the lesion ♦♦ Multiple SK presenting over a short period of time may be associated with internal malignancy (referred to as Leser– Trelat syndrome)

Lentigo Simplex and Melanosis ♦♦ These hyperpigmented macular lesions result from a localized excessive production of melanin by melanocytes. They typically occur in white women of reproductive age

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Fig. 30.12. Seborrheic keratosis with a horn cyst.

Fig.  30.11. Lichen planus. (A) Lichenoid interface inflam­ mation with band-like lymphoid infiltrate and acanthosis are  seen. (B) Necrotic keratinocytes and colloid bodies are identified.

♦♦ Microscopically, the lesions show basilar keratinocytic hyperpigmentation and melanocytic hyperplasia without nesting or atypia. Epidermal hyperplasia is usually seen in lentigo simplex (Fig. 30.13) ♦♦ There are no distinctive histologic features to differentiate lentigo simplex from melanosis other than size of the pigmented area (arbitrarily <4 mm for lentigo simplex). Some vulvar melanosis can reach or exceed 10 cm ♦♦ Both conditions usually have no clinical significance ♦♦ The presence of atypical melanocytes, especially in nests and in all layers of the epidermis, warrants a diagnosis of malignant melanoma in situ (see Section  Malignant Nonepithelial Tumors)

Melanocytic Nevi ♦♦ Vulvar melanocytic nevi are much less common than those occurring in extravulvar sites

Fig. 30.13. Lentigo simplex or melanosis (depending on the size).

♦♦ Most vulvar nevi are either compound or intradermal in type. Pure junctional type is rare on the vulva ♦♦ A small percentage of vulvar nevi show distinctive, atypical features that differ from those of the usual dysplastic nevus and have been referred to as atypical melanocytic nevi of genital type (AMNGT) by Clark and colleagues ♦♦ AMNGT are typically symmetrical on cross-sections and show maturation of the melanocytes in the dermis. They usually lack significant pagetoid spread and mitosis ♦♦ Differential diagnosis of AMNGT includes dysplastic nevi and superficial spreading melanoma (see Section Malignant Nonepithelial Tumors). Please read a comprehensive chapter by Clark et al., if any concerns of the differential diagnosis arise ♦♦ The vast majority of vulvar nevi require no therapy. However, concerns regarding the malignant potential results in excision in most cases

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BENIGN TUMORS Fibroepithelial Polyp (Acrochordon) ♦♦ Fibroepithelial polyp (acrochordon or skin tag) is a benign polypoid mass and relatively uncommon on the hair-bearing skin of the vulva ♦♦ These tumors are soft and fleshy and may be pigmented ♦♦ A typical polyp consists of a fibrovascular stalk covered by a stratified keratinizing squamous epithelium ♦♦ Stroma within the stalk may be edematous and hypocellular. Occasionally, some stromal cells may have nuclear pleomorphism with atypia, particularly when patient is pregnant

Squamous Vestibular Papillomatosis ♦♦ Squamous vestibular papillomatosis (SVP) refers to multiple to numerous, small papillary projections in the medial aspect of the labia minora and in the vestibule exterior to the hymenal ring. Each papilloma is about 1–2 mm in diameter ♦♦ This condition occurs almost exclusively in women of reproductive age ♦♦ There is no causal relationship between HPV infection and SVP ♦♦ Presenting symptoms include pruritus, burning sensation, and dyspareunia. Some women may be asymptomatic ♦♦ Histologic features are papillary fronds of a plain, ­nonkera‑ tinized, glycogenated squamous epithelium with an underlying proliferation of capillaries in the dermal papillae. There are no koilocytes or nuclear atypia in the glycogenated epithelium, which is the key feature of SVP

Papillary Hidradenoma (Hidradenoma Papilliferum) Clinical ♦♦ Papillary hidradenoma is a benign tumor of a specialized anogenital sweat gland origin ♦♦ It usually presents as a painless nodule <2 cm in diameter in women of reproductive age ♦♦ The most common location is interlabial sulci

Microscopic ♦♦ The tumor is composed of complex proliferation of papillae, tubules, and cysts lined by a single or double layer of cuboidal cells (epithelial cells of the inner layer and myoepithelial cells in the outer layer, Fig. 30.14) ♦♦ The epithelial cells are well-defined and have an apocrine appearance. They may exhibit mild atypia and stratification and have occasional mitotic figures ♦♦ Malignant transformation is extremely rare. Atypical papillary hidradenoma with a borderline malignancy potential has never been reported

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Fig. 30.14. Papillary hidradenoma (Hidradenoma papilliferum).

♦♦ Differential diagnosis includes intraductal papillomas arising in ectopic breast tissue. Presence of benign ectopic breast tissue adjacent to the tumor favors the latter

Granular Cell Tumor Clinical ♦♦ Granular cell tumor (GCT) is probably of peripheral nerve sheath origin. Between 5% and 15% of GCT arise in the vulva ♦♦ The patients are usually of reproductive or postmenopausal age. They typically present with a solitary or rarely with several subcutaneous nontender nodules in the labia majora or in the vicinity of the clitoris ♦♦ The tumors are almost always clinically benign

Microscopic ♦♦ A typical tumor is composed of nests and sheets of large eosinophilic granular cells. The tumor cells have bland nuclei and ill-defined cell borders, and they are intermingled with strands of collagen and occasional chronic inflammatory cells ♦♦ Pseudoepitheliomatous hyperplasia of the overlying squamous epithelium is a striking feature (Fig.  30.15). This can be confused with a well-differentiated squamous cell carcinoma, especially in a superficial biopsy specimen ♦♦ PAS, S-100, and myelin basic protein stains are positive in the granular cytoplasm

Angiokeratoma ♦♦ Angiokeratomas are vascular lesions and occurs almost exclusively on the scrotum and vulva of the child-bearing women

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Fig. 30.16. Angiokeratoma of Fordyce.

Aggressive Angiomyxoma Clinical

Fig. 30.15. Granular cell tumor. (A) The tumor is localized in the dermis. The tumor cells are large and contain coarsely granular and eosinophilic cytoplasm. The nuclei are uniformly bland. The epidermis shows pseudoepitheliomatous hyperplasia. The pattern could be misdiagnosed as invasive squamous cell carcinoma. An area from (A) is magnified in (B) to appreciate the pseudoinvasive pattern.

♦♦ The cause is unknown, but a patient with multiple angiokeratomas on the vulva and other sites should receive consultation for Fabry disease, which is an X-linked recessive disease associated with a deficiency of galactosidase A ♦♦ Patients are usually asymptomatic. The lesions are small, 2–5 mm, red to purple papules ♦♦ Microscopically, the tumors are characterized by prominent endothelial-lined blood vessels immediately beneath the basement membrane of the overlying epithelium and separated by the rete ridges. The rete ridges form epithelial cords, which separate the vascular channels, resulting in a multilocular appearance of the lesions (Fig. 30.16)

♦♦ Aggressive angiomyxoma (AA) is synonymously referred to as deep angiomyxoma ♦♦ It is a locally infiltrative tumor of the deep soft tissue of the pelvic–perineal region ♦♦ AA mainly occurs in women in the third to fourth decades ♦♦ Typical presentation is a large, often greater than 10 cm in size, slow-growing and painless mass that is often thought to be Bartholin gland cyst clinically ♦♦ The masses are often substantially larger on image studies than clinically suspected ♦♦ Symptoms are usually vague and may have slightly increased pressure in the urogenital or anorectal areas ♦♦ These tumors are indolent but locally infiltrative. Recurrence rate is high, but distant metastasis generally does not happen (although one recent case report showed lung metastasis following multiple local recurrence) ♦♦ Hormonal therapy with gonadotropin releasing hormone (GnRH) agonist may be effective in reducing the tumor size

Microscopic ♦♦ The tumors are paucicellular and composed of fibroblasts, myofibroblasts, and numerous characteristically thin- and thick-walled vessels in an abundant myxoid matrix (Fig. 30.17) ♦♦ Multinucleated cells may be present. Mitosis is absent ♦♦ Local invasiveness can be identified such as perineural invasion ♦♦ Sometimes, there is a morphologic overlap with ­angiomyofibroblastoma (see below) ♦♦ The tumor cells are immunoreactive for desmin, CD34, smooth muscle actin, ER, and PR but negative for S-100.

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Fig. 30.17. Aggressive angiomyxoma with bland spindle-shaped cells in a hypocellular myxoid stroma containing a mixture of thick- and thin-walled blood vessels.

Fig. 30.18. Angiomyofibroblastoma with small groups of epithelioid or spindle-shaped cells and capillary-like vascular channels.

A new marker HMGA2 (formerly known as HMGIC) is positive in over 50% of AA and seems to be specific and useful in differentiating from its histological mimics ♦♦ Differential diagnosis includes myxoid lesions such as superficial angiomyxoma (cutaneous myxoma), myxoid neurofibroma, myxoid liposarcoma, myxoid smooth muscle tumors, and myxoid malignant fibrous histiocytoma. Superficial location, small size, nonreactivity for desmin and ER/PR, and occasional association with Carney complex facilitate a diagnosis of superficial angiomyxoma. Distinctive vascular pattern is not present in other myxoid tumors

hyalinized wall, absence of perivascular epithelioid cells, and negative desmin stain favor the diagnosis of cellular angiofibroma ♦♦ These tumors are generally benign and rarely recur, but rare cases of sarcoma arising in recurrent tumors have been reported

Angiomyofibroblastoma ♦♦ Angiomyofibroblastoma (AMF) occurs almost exclusively in the vulvovaginal region of middle-aged women ♦♦ These tumors are slow-growing, well-circumscribed, painless, and mostly <5 cm in greatest dimension ♦♦ Characteristic histologic features are alternating hypercellular and hypocellular zones with numerous irregularly distributed vessels ♦♦ The vessels are small to medium, thin-walled, arborizing, and composed predominantly of capillaries ♦♦ The tumor cells have variable appearance (spindled, ovoid, plasmacytoid, or epithelioid) and separated by wavy strands or thick bundles of collagen (Fig. 30.18). They tend to concentrate around the vessels in the hypercellular zone ♦♦ Most nuclei are bland. Occasional cells are binucleated or multinucleated. The plasmacytoid cells have eccentric nuclei. Mitotic features are absent or rare ♦♦ The tumor cells are positive for vimentin, desmin, ER and PR, rarely positive for actin and CD34, and negative for S-100 or keratin ♦♦ Major differential diagnosis includes AA (see below) and cellular angiofibroma. Larger vessels with thickened and

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Cellular Angiofibroma ♦♦ Cellular angiofibroma of the vulva was first described as a distinct entity in 1997 ♦♦ Only a small number of cases have been reported in the vulva of middle-aged women ♦♦ These tumors are benign, probably of fibroblastic nature, well-circumscribed, and often less than 3 cm in size ♦♦ The tumors are composed of a moderately cellular proliferation of uniform bland spindled cells, numerous thick-walled often hyalinized vessels, short bundles of wispy collagen, and a sparse component of adipose tissue at the periphery (Fig. 30.19). Mitotic figures can be brisk ♦♦ Some unusual histologic features have been reported, including a hemangiopericytomatous vascular pattern, stromal lymphoid aggregates, myxoid areas, and symplastic changes ♦♦ The tumor cells are positive for vimentin, CD34, ER and PR, and negative for actin, desmin, S-100, keratin, and EMA ♦♦ Differential diagnosis includes AMF (see below), spindle cell lipoma (rarely occur in the vulva), leiomyoma (smooth muscle differentiation, positive desmin), solitary fibrous tumor (“patternless” architecture), and perineurioma (EMA positive)

Leiomyoma ♦♦ Leiomyomas of the vulva are not common. They usually occur in the fourth and fifth decades

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f­ ollowing features: >5  cm in size, infiltrative margins, more than 5  MF/10  HPF, and moderate to severe atypia. Coagulative tumor necrosis, if present, is a reliable feature of malignancy ♦♦ Vulvar leiomyomatosis and esophageal leiomyomatosis may be associated with Alport syndrome

Endometriosis

Fig.  30.19. Cellular angiofibroma with bland spindle-cell p­ roliferation admixed with many small vessels; some have a hyalinized wall. ♦♦ They may arise from smooth muscle in blood vessels, erectile tissue surrounding the crura of the clitoris, and the erector pili of the vulvar skin ♦♦ The tumors may show three histological patterns (spindled, epithelioid, and myxohyaline), in pure or mixed form ♦♦ The term atypical smooth muscle tumor should be used for lesions that show one of the following features (regardless of the tumor size): infiltrative margin, nuclear atypia, or any mitosis ♦♦ Current criteria for vulvar leiomyosarcoma proposed by Tavassoli and Norris include any three or more of the

♦♦ Endometriosis of the vulva occurs almost always in the episiotomy sites secondary to implantation of endometrial tissue at the time of delivery ♦♦ Symptoms of the vulvar endometriosis are not different from those of endometriosis elsewhere ♦♦ Vulvar endometriosis can present as a tumor-like mass (endometrioma) ♦♦ Some studies suggested that endometriosis may be a clonal process, which raises a concern of a neoplastic disease

Other Benign Mesenchymal Tumors ♦♦ Prepubertal vulvar fibroma has been reported recently as a specific entity. These tumors occur in young girls aged 3–13 years, almost always involve the labium majus and often are unilateral. A typical tumor is composed of haphazard admixture of hypocellular fibrous tissue, adipose tissue, and vascular channels. These tumors are poorly circumscribed. The reported recurrence rate is as high as 50% ♦♦ Lipomas and lipoma variants, rhabdomyomas, desmoid tumors, neurofibromas, schwannomas, glomus tumors, and hemangiomas are occasionally seen in the vulva ♦♦ Histologic features of these tumors are not different from those of similar tumors elsewhere

PREMALIGNANT AND MALIGNANT EPITHELIAL TUMORS Vulvar Intraepithelial Neoplasia Clinical ♦♦ VIN refers to all noninvasive dysplastic squamous lesions of the vulva ♦♦ Main risk factor of the most common type of VIN is HPV, identical to that of cervical cancer ♦♦ VIN typically presents as a slightly pigmented macular/papular or plaque-like lesion (Fig. 30.20A). The lesion can be pruritic, burning, or asymptomatic. Multifocality is common ♦♦ More than 50% of women with VINs have similar HPV lesions in the cervix, vagina, urethra, perineum, or anus ♦♦ VIN 3 encompasses Bowen disease, erythroplasia of Querat, and carcinoma in situ

♦♦ Bowenoid papulosis is not a histopathologic diagnosis, but a clinical presentation

Microscopic ♦♦ Histological subtypes are basaloid (undifferentiated), warty (condylomatous), and differentiated (simplex VIN). Basaloid and warty types are HPV-related, while ­differentiated type is often HPV negative occurring more frequently in postmenopausal women ♦♦ Basaloid or warty VIN is graded as VIN 1 (mild dysplasia), VIN 2 (moderate dysplasia), and VIN 3 (severe dysplasia or carcinoma in situ). Differentiated VIN is considered VIN 3 ♦♦ Basaloid VIN is composed of small uniform basaloid cells with scanty cytoplasm, ill-defined cell borders, large hyperchromatic nuclei, clumped chromatin, nonapparent nucleoli,

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Fig.  30.20. Vulvar intraepithelial neoplasia 3. (A) Vulva with extensive leukoplakia, biopsy proven to be VIN 3. (B) Basaloid VIN 3. (C) Positive p16 immunostain in basaloid VIN 3. (D) Differentiated VIN 3 with prominent nucleoli.

and many mitoses (Fig.  30.20B). It is positive for HPV marker p16 (Fig. 30.20C) ♦♦ Warty VIN is characterized by acanthotic epithelium, sometimes hyperkeratotic and parakeratotic, with a spiky or warty surface. The neoplastic cells are large with abundant eosinophilic cytoplasm, well-defined cell borders, ­dyskeratosis, coarse chromatin, and easily visible mitotic figures ♦♦ Differentiated VIN is associated with LS and/or with ISCC of the vulva. It is characterized by large basal keratinocytes with abundant eosinophilic cytoplasm, abnormal nuclei, and prominent nucleoli (Fig.  30.20D). Keratin pearls may be present near the base of the rete. Maturation is maintained. Positive p53 stain of the atypical basal cells is helpful for diagnosis

Differential Diagnosis ♦♦ Warty VIN vs. condyloma. The latter has koilocytes in the superficial layer and less number of mitosis within lower one-third of the epithelium

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♦♦ PD and radial growth of malignant melanoma. In both conditions, the malignant cells are individually dispersed and surrounded by benign keratinocytes. Special stains will help facilitate a correct diagnosis (see below) ♦♦ Inflammatory or reactive changes. Prominent inflammation, spongiosis, prominent nucleoli, and lack of mitosis favor a reactive lesion

Invasive Squamous Cell Carcinoma Clinical ♦♦ Usually, ISCC is the most common type (90%) of vulvar malignancies ♦♦ Patients are often in the seventh or eighth decade. Rare exceptions occur in young women less than 30 years who are immunocompromised ♦♦ Typical presentation is a vulvar or groin mass, which may be pruritic or painful. Multifocal tumors are seen in about 10% of the patients (Fig. 30.21A)

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♦♦

♦♦

♦♦

♦♦

♦♦

tion, and absence of koilocytes. Adjacent areas may show LS, squamous cell hyperplasia, or ­differentiated VIN (Fig. 30.21B) Basaloid ISCC resembles basaloid VIN. The neoplastic basaloid cells are in sheets or nests within a desmoplastic stroma. Focal cellular maturation and keratinization may occur. Adjacent basaloid or warty VIN is present in majority of the cases Warty ISCC is similar to warty VIN except for apparent invasion. Similarly, adjacent basaloid or warty VIN is present in majority of the cases Tumor grading is controversial. The GOG grading scheme for KISCC is based on the proportion of tumor that is undifferentiated (grade 1–4) Unfavorable prognostic features include the following: increasing tumor size, deep invasion, high nuclear grade, infiltrating pattern, and presence of lymphatic space invasion. These should be reported The term microinvasion is not recommended. Tumors invading 1  mm or less have a negligible risk of nodal spread

FIGO Staging of the Vulvar Carcinoma ♦♦ See later discussion

Differential Diagnosis

Fig. 30.21. Vulvar invasive squamous cell carcinoma. (A) Gross picture of a vulvar SCC at advanced stage. The tumor extensively involves bilateral labia with ulcerations. The clitoris is also involved by the tumor. (B) A microscopic picture of early invasive SCC.

♦♦ Vulvar ISCC usually follows one of the two pathogenic pathways: HPV-related or HPV- unrelated. Two pathways occasionally act in synchrony ♦♦ Similar to VINs, there are three histological subtypes: basaloid, warty, and keratinizing ♦♦ Basaloid and warty types are HPV-related and occur mostly in relatively younger women with risk factors similar to those of cervical cancers ♦♦ Keratinized ISCC is often HPV-unrelated, occurs in older women and is associated with lichen sclerosis, squamous cell hyperplasia and differentiated VIN

Microscopic ♦♦ Keratinizing ISCC resembles typical ISCC elsewhere. There are variable degrees of squamous maturation, keratin forma-

♦♦ Poorly differentiated KISCC vs. amelanotic malignant melanoma. The latter has a junctional component and is positive for melanoma markers ♦♦ BISCC vs. basal cell carcinoma. The latter has a lobular contour, peripheral palisading, and absence of VIN ♦♦ BISCC vs. Merkel cell carcinoma or metastatic small cell carcinoma. The latter tumors tend to have a highly infiltrative pattern and evidence of neuroendocrine differen‑ tiation ♦ ♦ Poorly differentiated KISCC vs. epithelioid sarcoma. The deep location, absence of VIN, zonal necrosis, absence of keratinization, and positive stains for mesenchymal markers facilitate the diagnosis of epithelioid sarcoma ♦♦ WISCC vs. verrucous carcinoma (see below)

Verrucous Carcinoma ♦♦ VCs account for 1–2% of all vulvar cancers ♦♦ The tumors are highly differentiated with indolent growth and little or no metastatic potential ♦♦ Giant condyloma of Buschke–Lowenstein was once considered synonymous with VC by some authorities ♦♦ The tumors invade underlying stroma with a deep pushing border in a form of broad bulbous pegs (Fig. 30.22) ♦♦ The tumor cells show no or minimal nuclear atypia, abundant eosinophilic cytoplasm and rare mitoses that, if present, are confined to the basal layers. There is no koilocytosis

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Fig. 30.22. Verrucous carcinoma.

Basal Cell Carcinoma Clinical ♦♦ Basal cell carcinomas (BCCs) account for 2–3% of vulvar carcinomas. They typically occur in elderly white women with a peak incidence in the 70s. They are not related to HPV ♦♦ Presenting symptoms include pruritus, irritation, soreness, bleeding, and an ulcerated nodular lesion on the vulva, mainly on the labia majora ♦♦ The tumors are slow-growing, locally invasive, and rarely metastasize ♦♦ Primary treatment is wide local excision

Microscopic ♦♦ Histologic features are identical to those of typical ­cutaneous BCCs ♦♦ They can be of superficial, solid, or adenoid type ♦♦ No morphic BCCs were reported in the vulva ♦♦ The tumor cells are small uniform basal cells with ­peripheral palisading arrangement (Fig. 30.23A). Sebaceous differentiation is occasionally seen (Fig. 30.23B)

Differential Diagnosis ♦♦ Basaloid ISCC (see above) ♦♦ Adenoid BCC vs. adenoid cystic carcinoma (ACC). ACC tends to be larger, more widely infiltrative, more surface involvement, more glandular component, lack squamous nests, and shows prominent perineural invasion

Keratoacanthoma ♦♦ These tumors are a rare form of well-differentiated ISCC ♦♦ They have a central keratin-filled crater with focal ­infiltration at its superficial dermis

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Fig. 30.23. Basal cell carcinoma. (A) Adenoid pattern. (B) With sebaceous differentiation.

♦♦ They are rapidly growing but generally are self-limited

Paget Disease Clinical ♦♦ Extramammary PD is regarded as an intraepidermal adenocarcinoma with tumor cells involving the epidermis and the underlying skin adnexal structures, probably originates from intraepidermal stem cells of the sweat ducts ♦♦ PD occurs mostly in peri and postmenopausal women. It accounts for about 1% of all vulvar malignancies ♦♦ PD presents as pruritic, eczematoid, erythematous, and weeping patches interspersed with white hyperkeratotic or ulcerated areas ♦♦ Approximately 5% of patients are associated with internal carcinomas, including carcinomas of the breast, low GI tract (rectum), and urogenital system (cervix and bladder)

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♦♦ Clinically unsuspected dermal invasion is present in up to 30% of the cases ♦♦ Treatment for primary PD without invasion is surgical excision, but recurrence occurs in nearly 40–50% of cases

Microscopic ♦♦ Distinctive “Paget cells” are present within epidermis as single cells or in clusters, more concentrated in the basal and parabasal layers (Fig. 30.24A) ♦♦ Typical Paget cells are large with abundant amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli ♦♦ There is high incidence of proliferative epidermal lesions associated with PD, including squamous hyperplasia (NOS), fibroepithelioma-like hyperplasia, and papillomatous hyperplasia, which can distort or mask PD cells ♦♦ When invasion is present (Fig.  30.24B), the depth of invasion is measured from the epidermal–dermal border immediately overlying the deepest point of invasive focus. Lymphatic vascular space involvement should be reported, if any

Immunohistochemistry and Special Stains ♦♦ The primary Paget cells are immunoreactive for CK7, GCDFP, CAM 5.2, and CEA ♦♦ Mucin stain is positive in Paget cells ♦♦ Primary PD is reported to be immunoreactive for HER2/neu, which might be of considerable value in the management of recurrent PD ♦♦ Additional markers might be needed to differentiate primary PD from secondary PD

Differential Diagnosis ♦♦ Pagetoid VIN has evidence of keratinization and is associated with typical VIN. There is no cytoplasmic mucin and no immunoreactivity for CK7, GCDFP, and CEA ♦♦ Superficial spreading malignant melanoma lacks cytoplasmic mucin in the tumor cells and is negative for CK7 but positive for melanoma markers ♦♦ Clear cell papulosis, Merkel cell carcinoma, and histiocytosis X are rarely encountered

Carcinoma of Bartholin Gland Clinical ♦♦ These tumors occur predominantly in peri- and postmenopausal women and account for less than 5% of vulvar carcinomas ♦♦ They present as enlarging or cystic masses in the area near Bartholin gland opening ♦♦ Some tumors (squamous carcinoma) are associated with HPV infections ♦♦ 40% of patients present with advanced stages at the time of diagnosis

Fig. 30.24. Paget disease. (A) Noninvasive Paget disease. The Paget cells have abundant clear, vacuolated cytoplasm and atypical nuclei. The number of Paget cells decreases from the basal layer to the superficial layer of the epidermis. (B) Paget disease with microinvasion. Paget cells migrate through the epidermis and superficially invade the dermis.

♦♦ Five-year survival rate is about 80%

Microscopic ♦♦ Various types of carcinoma have been described. These include squamous cell carcinoma (40%), adenocarcinoma (25%), adenoid cystic carcinoma (15%), adenosquamous cell carcinoma (5%), and rarely transitional and small cell carcinomas ♦♦ Perineural invasion is very common, especially in adenoid cystic carcinoma (Fig. 30.25A, B). CD117 is often uniformly expressed in this tumor (Fig. 30.25C) ♦♦ Diagnostic criteria for a tumor of Bartholin gland origin include

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Fig.  30.25. Adenoid cystic carcinoma of Bartholin gland. (A) The tumor cells are arranged in a cribriform (cylin­dromatous) pattern. (B) Perineural invasion is typical. (C) Immunohistochemical stain for c-kit is uniformly positive.

−− Identifying transitional areas between the normal glands and carcinoma −− Excluding primary tumors elsewhere, particularly other carcinomas in the vulva −− Histologically compatible with a primary tumor of Bartholin origin

Adenocarcinoma of Skin Appendage Origin ♦♦ These tumors are of an eccrine origin and include mucinous adenocarcinoma, clear cell hidradenocarcinoma, and eccrine porocarcinoma ♦♦ Some vulvar adenocarcinomas resemble mammary carcinomas, which may arise from apocrine sweat glands (Fig. 30.26) ♦♦ Occasional sebaceous carcinomas have been reported ♦♦ These tumors generally have an aggressive behavior

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Fig. 30.26. Mucinous adenocarcinoma of sweat gland origin in vulva.

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MALIGNANT NONEPITHELIAL TUMORS Malignant Melanoma ♦♦ Malignant melanomas of the vulva account for 5–10% of all vulvar cancers ♦♦ The peak incidence is in the sixth or seventh decade ♦♦ Some melanomas can be mimicked by a benign pigmented lesion (see section Benign Discolored Lesions in Part A-IV) ♦♦ Histologic features are not different from those of ­malignant melanoma in other sites ♦♦ The superficial spreading or acral lentiginous type is more common than the nodular type in the vulva (Fig. 30.27A) ♦♦ The melanoma cells can be of spindle, epithelioid, or mixed spindle–epithelioid type

♦♦ Striking neurotropism and prominent desmoplasia are often present ♦♦ The AJCC staging incorporates depth −− Stage I – <1.5  mm deep or Clark level III and no metastasis −− Stage II – >1.5 but <4  mm or Clark level IV and no metastasis −− Stage III – >4  mm or Clark level V or nodal metastasis −− Stage IV – distant metastasis ♦♦ Diagnosis of melanoma should always be considered when a poorly differentiated malignant tumor that is difficult to classify is encountered ♦♦ Melanoma markers (HMB 45, S-100, Melan-A) are positive ♦♦ Local recurrence, lymph node and hematogenous spread are common (Fig. 30.27B). Five-year survival is less than 50% in most studies

Sarcoma Botryoides (Rhabdomyosarcoma) ♦♦ Typical clinical and histologic features are described in the section Other Malignant Tumors in Part B-XII

Epithelioid Sarcoma Clinical ♦♦ Most epithelioid sarcomas (ES) of the vulva, perineum, and pelvic soft tissues are of the proximal type ♦♦ The histogenesis is obscure. It is believed to arise from the reticular dermis ♦♦ These tumors typically affect young individuals ♦♦ Tumors are usually indolent. Vulvar ES is more aggressive with a higher rate of local recurrence and a tendency for early metastasis compared with other sites ♦♦ Wide local excision, regional lymphadenectomy, and local radiation are the treatments of choice

Microscopic

Fig. 30.27. Malignant melanoma of the vulva. (A) This spindle shaped melanoma was seen in a 63-year-old female. There were melanin pigments. The tumor stage was pT1bN0Mx. (B) Two years later, the patient had widespread metastatic melanoma in the endometrium, myometrium, and ovarian surfaces.

♦♦ Vulvar ES shares similar morphologic, ­immunohistochemical, and ultrastructural features with a typical epithelioid sarcoma, extrarenal rhabdoid tumor, (Fig. 30.28) and undifferentiated carcinoma ♦♦ The tumor cells have prominent epithelioid or rhabdoid features and marked cellular atypia and grow in a nodular pattern ♦♦ Central necrosis is common, but a granuloma-like ­appearance is rarely seen ♦♦ Typical immunohistochemical staining pattern is ­cytokeratin-, EMA-, and vimentin-positive. Desmin and CD34 can be positive as well

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Fig. 30.28. Malignant rhabdoid tumor of the vulva in a 34-year-old female. The tumor consists of a solid growth of cells with vesicular nuclei with prominent nucleoli and abundant eosinophilic granular cytoplasm. Cytokeratin, EMA, and vimentin were positive in the tumor cells. All muscle markers were negative. There was no central necrosis, which is often seen in epithelioid sarcoma.

Yolk Sac Tumor ♦♦ Vulvar yolk sac tumors (YSTs) morphologically resemble ovarian yolk sac tumors ♦♦ Only few vulvar YSTs have been reported in children and young women

Merkel Cell Tumor ♦♦ Merkel cell tumors (MCTs) of the vulva are rare and more aggressive than their extravulvar counterparts ♦♦ They arise from neuroendocrine cells in the epidermis ♦♦ The tumors usually present as intradermal nodules with erythema of the overlaying skin ♦♦ The histological features are similar to those of MCTs in other sites ♦♦ The tumor cells are small, uniform, and hyperchromatic with scant cytoplasm and finely stippled chromatin without nucleoli. Glandular and squamous differentiation may be seen

Fig.  30.29. Diffuse large B-cell lymphoma of the vulva in a 37-year-old female.

♦♦ Characteristic CK20 stain shows perinuclear cytoplasmic dots. Neuroendocrine markers are usually positive

Other Sarcomas, Hematopoietic Tumors and Secondary Tumors ♦♦ The following vulvar soft tissue sarcomas are rare but have been reported: leiomyosarcoma, liposarcoma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, malignant schwannoma, fibrosarcoma, angiosarcoma (including Kaposi sarcoma), alveolar soft part sarcoma, Ewing sarcoma, and chondrosarcoma ♦♦ Vulva can be the initial site of involvement of widespread lymphomas. Rarely lymphoma can occur primarily in the vulva (Fig. 30.29). A case of large cell lymphoma involving Bartholin gland has also been reported ♦♦ Vulva with metastatic tumor accounts for 8% of all vulvar malignancies. The most common primary sites include cervical squamous cell carcinoma, endometrial carcinoma, renal cell carcinoma, urethra or urinary bladder carcinoma, and anorectal carcinoma

TNM CLASSIFICATION AND FIGO STAGING SYSTEM OF VULVAR CARCINOMAS (2010 Revision) The definition of the T categories correspond to the stage accepted by the Federation Internationale de Gynecologie et d’Obstetrique (FIGO)

♦♦ Primary Tumor (T) TNM FIGO Categories Stages TX Primary tumor cannot be assessed

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T0 No evidence of primary tumor a Tis Carcinoma in situ (preinvasive car­ cinoma) T1a IA Lesions 2 cm or less in size, confined to the vulva or perineum and with stromal invasion 1.0 mm or lessb

Vulva and Vagina

T1b

IB Lesions more than 2 cm in size or any size with stromal invasion more than 1.0 mm, confined to the vulva or perineum II Tumor of any size with extension to T2c adjacent perineal structures (lower/distal 1/3 urethra, lower/distal 1/3 vagina, anal involvement) d IVA Tumor of any size with extension to T3 any of the following: upper/proximal 2/3 of urethra, upper/proximal 2/3 vagina, bladder mucosa, rectal mucosa, or fixed to pelvic bone a FIGO no longer includes Stage 0 (Tis) b The depth of invasion is defined as the measurement of the tumor from the epithelial -stromal junction of the adjacent most superficial dermal papillae to the deepest point of invasion c FIGO uses the classification T2/T3. This is defined as T2 in TNM d FIGO uses the classification T4. This is defined as T3 in TNM ♦♦ Regional Lymph Nodes (N) TNM FIGO Categories Stages NX Regional lymph nodes cannot be assessed

30-23

N0 No regional lymph node metastasis N1 One or two regional lymph nodes with the following features N1a IIIA One lymph node metastasis each 5 mm or less N1b IIIA One lymph node metastasis 5 mm or greater N2 IIIB Regional lymph node metastasis with the following features N2a IIIB Three or more lymph node metastases each less than 5 mm N2b IIIB Two or more lymph node metastases 5 mm or greater N2c IIIC Lymph node metastasis with extracapsular spread N3 IVA Fixed or ulcerated regional lymph node metastasis ♦♦ Distant Metastasis (M) TNM FIGO Categories Stages M0 No distant metastasis M1 IVB Distant metastasis (including pelvic lymph node metastasis)

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Part B Vagina Many vaginal lesions are similar to the lesions either in the vulva or in the cervix. More specific lesions of the vagina are described as follows.

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BENIGN NONNEOPLASTIC LESIONS Müllerian Papilloma

Microscopic

♦♦ Müllerian papillomas are also known as benign mesonephric papilloma of childhood ♦♦ These tumors typically occur in girls younger than 10 years of age ♦♦ They present as a polypoid papillary tumor of 1–3  cm in diameter in the upper vaginal or cervical mucosa. Usual manifestation is vaginal bleeding or discharge ♦♦ The histological features are fibrovascular-cored papillae covered by bland appearing epithelial cells. Ultrastructure supports a müllerian origin ♦♦ These tumors are clinically benign

♦♦ VA is characterized by the presence of benign glandular epithelium that replaces the normal squamous epithelium or forms glands in the superficial stroma (Fig. 30.30) ♦♦ The glandular epithelium is typically of the endocervical type. Endometrioid epithelium may be seen. Squamous metaplasia in the glandular areas is a common finding. When this process is striking, it can be confused with ISCC

Differential Diagnosis ♦♦ Atypical adenosis (see below) ♦♦ ISCC involving VA

Vaginal Adenosis

Prolapse of Fallopian Tube

Clinical

♦♦ Tubal prolapse rarely occurs after a hysterectomy, especially a vaginal hysterectomy ♦♦ A red granular mass mimicking granulation tissue is visible at the vaginal apex ♦♦ Histologically, it may be confused with adenocarcinoma when tubal plicae and tubal linings are not correctly recognized (Fig. 30.31). Both diligence and an awareness of the condition are required to avoid misdiagnosis ♦♦ Occasionally, cases of tubal prolapse associated with a florid mesenchymal proliferation have been described, which can be confused with AMF or AA

♦♦ Vaginal adenosis (VA) refers to the presence of glandular epithelium in the vagina, which is derived from embryonic müllerian epithelium ♦♦ About 30% cases are related to the exposure of diethylstilbestrol (DES) in utero. Those patients may have other congenital malformations of the cervix and vagina ♦♦ Congenital VA may be seen in less than 10% of unexposed women ♦♦ Acquired adenosis can also occur in women with vaginal dysplasia treated with topical 5-fluorouracil ♦♦ Women with VA are usually asymptomatic. Increased discharge, bleeding, or dyspareunia may occur ♦♦ VA lesions have a red, granular appearance, and lack of iodine stain ♦♦ VA is associated with clear cell carcinoma (CCC) of the vagina in patients with a history of DES exposure, but it not considered as an immediate precursor for the carcinoma

Fig. 30.30. Vaginal adenosis.

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Postoperative Spindle Cell Nodule ♦♦ Postoperative spindle cell nodule (PSCN) is a proliferative pseudosarcomatous spindle cell lesion that occurs shortly after a surgical procedure in the lower genital tract ♦♦ Vaginal involvement is more commonly seen than in the cervix or endometrium

Fig. 30.31. Prolapse of fallopian tube.

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30-27

Fig. 30.32. Postoperative spindle cell nodule.

Fig. 30.33. Ectopic decidua.

♦♦ PSCN typically occurs in the operation site, 1–12 weeks after a procedure, as a soft polypoid mass less than 4  cm in size ♦♦ The lesion is composed of spindle cells arranging in intersecting fascicles often with a prominent network of small blood vessels. The cells have plump vesicular nuclei with one to two nucleoli, but they lack significant cellular atypia (Fig. 30.32) ♦♦ Mitotic figures can be abundant, up to 25/10 HPF ♦♦ Inflammatory component is usually present ♦♦ Differential diagnosis includes low grade leiomyosarcoma. History of a recent operation, bland cytology, and prominent delicate network of small blood vessels facilitate the diagnosis of PSCN

♦♦ It occurs mostly in women of reproductive or ­postmenopausal age ♦♦ The etiology is not clear. It may be caused by gas-­producing bacteria ♦♦ Vaginal discharge is the most common symptom ♦♦ The histologic changes include gas-filled cystic spaces in the stroma lined by a squamous epithelium or foreign body giant cells and chronic inflammatory cells

Emphysematous Vaginitis ♦♦ This is a rare and self-limited condition

Ectopic Decidua ♦♦ Histologically, the lesions are similar to those of eutopic or ectopic deciduas in other sites (Fig. 30.33) ♦♦ Differential diagnosis includes squamous cell or glassy cell carcinoma ♦♦ Pregnancy status or recent delivery is extremely helpful ♦♦ They are cytokeratin negative and vimentin positive

BENIGN TUMORS Condylomas ♦♦ Vaginal condylomas have the same histological features as condylomas in the vulva (see above)

Tubular, Tubulovillous, and Villous Adenomas ♦♦ Rare vaginal tubulovillous adenomas of enteric type have been reported ♦♦ These tumors have goblet and Paneth cells similar to those in the gastrointestinal tract

Superficial Myofibroblastoma of the Lower Female Genital Tract ♦♦ This is a distinctive mesenchymal tumor arising in the superficial lamina propria of the vagina and cervix ♦♦ Some patients may have a prior history of tamoxifen therapy ♦♦ These tumors present as well-circumscribed polypoid or nodular masses ♦♦ Histological features are similar to those of a cellular fibroepithelial stromal polyp (FESP), except that a ­subepithelial Grenz

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zone is usually seen in the superficial myofibroblastoma of the lower female genital tract, not in the FESP

Brenner Tumor ♦♦ Occasional Brenner tumors have been reported in the literature ♦♦ Histologic appearance shows no difference from those of ovarian Brenner tumors

Benign Mixed Tumor (Spindle Cell Epithelioma) Clinical ♦♦ These are benign tumors occurring in young to middle aged women ♦♦ They present as a slow-growing painless mass near the hymenal ring. Sometimes, they are discovered incidentally ♦♦ The tumors are 1–6  cm in size and are usually well-­ circumscribed but not encapsulated ♦♦ Tumor is cured by local excision

Microscopic ♦♦ The tumor resembles the mixed tumor of salivary glands (Fig. 30.34) ♦♦ The tumors are biphasic and composed of both the stromal and epithelial components ♦♦ The stromal component is more predominant and consists of spindle cells arranged in cords, nests, whorls, and intersecting fascicles. There is no cytologic atypia, and mitosis is insignificant ♦♦ The epithelial component is sparse and consists of benign glands with mucinous or nonspecific lining. Squamous metaplasia is common ♦♦ Hyaline globular aggregates of stromal matrix are also frequently seen ♦♦ Cytokeratin is strongly positive in both the epithelial and stromal components

Fig.  30.34. Benign mixed tumor (spindle cell epithelioma). (A) Low power view shows a well-circumscribed nodule in the dermis. (B) Medial power view shows islands and strands of bland appearing epithelial cells in a fibrous stroma. Squamous differentiation can be seen in many epithelial islands.

PREMALIGNANT AND MALIGNANT EPITHELIAL TUMORS Vaginal Intraepithelial Neoplasia ♦♦ Vaginal intraepithelial neoplasia (VAIN) occurs only 1% as frequent as the cervical intraepithelial neoplasia (CIN) ♦♦ It tends to occur in women who are older than those with CIN ♦♦ In majority of the cases, there is a prior or synchronous noninvasive or invasive squamous carcinoma elsewhere in the lower female genital tract ♦♦ HPV infection is a known risk factor of VAIN as well as its corresponding invasive carcinoma

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♦♦ Colposcopy helps identify the lesions ♦♦ Histologic features as well as grading are the same as those for CIN ♦♦ About 3–10% of cases progress to ISCC

Squamous Cell Carcinoma ♦♦ A primary vaginal SCC is defined by the presence of vaginal SCC without involvement of the cervix or vulva as demonstrated by clinical or histologic examination

Vulva and Vagina

♦♦ It is the most common cancer of the vagina and occurs in postmenopausal women who are about 10 years older than those with invasive SCC in the cervix ♦♦ In a limited form, the SCC may present as an indurated, ulcerated nodule or as an exophytic growth. In advanced disease, a friable mass with fistula may occur ♦♦ Histologic diagnosis is the same as that in cervical SCC ♦♦ Microinvasion is defined as a stromal invasion less than 2.5 mm in diameter ♦♦ FIGO staging is discussed in section XIII

Atypical Adenosis ♦♦ Atypical adenosis occurs mostly in the tuboendometrioid type of adenosis and is often associated with adjacent CCC of the vagina (see below) ♦♦ Atypical adenosis is characterized by a more complexed glandular proliferation (Fig.  30.35). They are lined by atypical cells with prominent nucleoli. Atypical cells with hobnail features may also be present, but mitosis is rare ♦♦ Atypical adenosis is considered as an immediate precursor lesion of the vaginal CCC

30-29

♦♦ CCCs mostly occur in the upper third of the vagina on the anterior wall ♦♦ Large CCCs form nodular or polypoid masses. Ulceration may occur ♦♦ DES-related CCCs have a better prognosis than DESunrelated cases

Microscopic ♦♦ Adenosis or atypical adenosis usually is seen in adjacent areas ♦♦ Microscopic features of vaginal CCCs resemble to those in other sites of the female genital tract (Fig. 30.36)

Differential Diagnosis ♦♦ Vaginal adenosis with microglandular hyperplasia ♦♦ Atypical vaginal adenosis (see above) ♦♦ Vaginal adenosis with Arias–Stella reaction

Clear Cell Carcinoma Clinical ♦♦ About 80% of vaginal CCCs are associated with diethystillboestrol (DES) exposure in utero ♦♦ They mostly occur in young adult women with a mean age of 19 years ♦♦ Patients are either asymptomatic or manifest with abnormal bleeding ♦♦ A history of DES exposure should prompt a careful vaginal examination

Fig. 30.35. Atypical vaginal adenosis.

Fig. 30.36. Vaginal clear cell carcinoma with solid pattern. This 36-year-old patient had no history of DES exposure. Her tumor was in the upper third of the posterior vaginal wall. Endometriosis was present in the cul-de-sac.

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Endometrioid Adenocarcinoma

Mesonephric Adenocarcinoma

♦♦ Occasional endometrioid adenocarcinoma may occur in the vagina ♦♦ There is a strong association with prior hysterectomy ♦♦ Patients may have been exposed to unopposed estrogen following hysterectomy ♦♦ These tumors are associated with endometriosis and rarely related to DES exposures

♦♦ Rare cases of mesonephric adenocarcinoma have been reported ♦♦ They are derived from paravaginal mesonephric remnants ♦♦ Histologic features are the same as those in the cervix

OTHER MALIGNANT TUMORS Sarcoma Botryoides (Embryonal Rhabdomyosarcoma) Clinical

size, depth of invasion, and lymphatic space involvement should be mentioned in the pathology report

♦♦ The most common site involved by sarcoma botryoides in the female genital tract is the vagina, followed by the uterus. Vulva is the least common site. When both the vulva and vagina are involved, the tumor is considered as of vaginal origin ♦♦ The tumors exclusively occur in young girls less than 10 years of age ♦♦ They typically present as a solid mass in the labial or perineal areas and have a characteristic appearance of a “bunch of grapes.” Bleeding and ulceration can occur in the tumors ♦♦ Excision and chemotherapy are the treatments of choice with a good response rate

Microscopic ♦♦ The tumor is characterized by a subepithelial dense cellular zone (cambium layer) and a large edematous hypocellular zone underneath the cambium layer. The tumor cells in both zones are small, primitive-appearing, and mitotically active (Fig. 30.37) ♦♦ The tumor has an infiltrative growth with inconspicuous vessels ♦♦ Rhabdomyoblasts with evidence of cross striation may be present in the edematous zone ♦♦ The tumor cells are immunoreactive for desmin, myogenin, and myo D1

Malignant Melanoma ♦♦ Malignant melanoma of the vagina is rare but very aggressive ♦♦ It is mostly located in the lower third of the anterior vaginal wall ♦♦ The tumor is typically 2–3 cm in size ♦♦ Histologic features are the same as those of melanomas in other sites ♦♦ Clark level assessment is not practical in the vagina due to lack of normal cutaneous anatomic landmarks, but the tumor

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Fig. 30.37. Sarcoma botryoides. (A) A subepithelial cambium layer is present. The deeper zones of the tumor are composed of sparse spindle-shaped tumor cells within an edematous stroma. (B) High power view of cellular cambium layer.

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30-31

Leiomyosarcoma Clinical ♦♦ Primary vaginal leiomyosarcoma (LMS) is the most common vaginal sarcoma in adult women and the second most common vaginal sarcoma in all age groups ♦♦ It usually presents as a multilobulated solid tumor mass ranging from 3 to 5 cm in size ♦♦ As in uterus, leiomyomas are not considered as precursors to leiomyosarcoma

Microscopic (Fig. 30.39C)

Fig. 30.38. Vaginal carcinosarcoma.

Carcinosarcoma ♦♦ Primary carcinosarcoma of the vagina is rare ♦♦ It has a very poor prognosis ♦♦ Diagnosis of primary vaginal carcinosarcoma requires exclusion of metastasis from elsewhere in the female genital tract ♦♦ Macroscopic and microscopic features resemble to that of the endometrial counterpart (Fig. 30.38)

Primitive Neuroectodermal Tumor (PNET) ♦♦ Three cases have been reported in the vagina ♦♦ This tumor represents those tumors of an uncertain lineage within the small round blue cell family ♦♦ Histologic characteristics are similar to PNET or Ewing sarcoma elsewhere ♦♦ Tumor cells are CD99 positive ♦♦ The diagnosis can be further confirmed by the presence of MIC2 gene and EWS/FL-1 chimeric transcripts

Gastrointestinal Stromal Tumors of the Vagina and Rectovaginal Septum ♦♦ Gastrointestinal stromal tumors (GISTs) can arise in the vagina or rectovaginal septum without connection to the rectal wall (referred to as extragastrointestinal stromal tumors) ♦♦ These tumors typically present as a vaginal mass ♦♦ Morphologically they are identical to GISTs arising at more usual locations (Fig. 30.39A) ♦♦ They are often misdiagnosed as a smooth muscle neoplasm, especially when GIST is not considered ♦♦ Most GISTs in this location are positive for c-kit (Fig. 30.39B) and CD34, and negative for desmin, ER and PR, whereas vaginal smooth muscle tumors are negative for c-kit and CD34, but positive for desmin, smooth muscle actin (Fig. 30.39D), ER and PR

♦♦ Diagnostic criteria of a vaginal leiomyosarcoma include −− Smooth muscle tumors larger than 3 cm in size −− Nuclear atypia moderate to severe −− Mitosis at least 5/10 HPF −− Coagulative tumor necrosis −− Infiltrating margins ♦♦ Differential diagnosis includes PSCNs, GIST (see above)

Yolk Sac Tumor ♦♦ Vagina is the most common extragonadal site of yolk sac tumor. Simultaneous involvement of the cervix occasionally occurs ♦♦ YST occurs in young girls usually under 3 years of age ♦♦ Vaginal discharge and bleeding are common symptoms ♦♦ Serum AFP may be elevated ♦♦ Pathologic features resemble its ovarian counterpart ♦♦ Differential diagnosis includes CCC and endometrioid adenocarcinomas

Hematopoietic Tumors ♦♦ Lymphomas rarely occur in the vagina ♦♦ Primary vaginal lymphomas may present as abnormal bleeding ♦♦ They usually occur in women younger than those with secondary lymphomas involving the vagina ♦♦ The most common type is diffuse large B-cell lymphoma ♦♦ Definitive diagnosis requires histology and immunophenotyping similar to lymphomas elsewhere

Secondary Tumors ♦♦ Most invasive carcinomas in the vagina are secondarily involved by tumors in other pelvic sites ♦♦ Metastasis is either from a direct extension or through lymphatic or hematogenous spread ♦♦ Direct extension mostly comes from cervix and vulva ♦♦ Other primary sites include endometrium (Fig. 30.40), colon, rectum, urinary bladder, ovary, kidney and breast ♦♦ Uterine choriocarcinoma is known to have a high tendency to involve vagina

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Fig.  30.39. Spindle cell neoplasms of the vagina. (A) Gastrointestinal stromal tumor of the vagina and rectovaginal septum. (B) Positive c-kit in GIST. (C) Leiomyosarcoma. (D) Positive smooth muscle actin in leiomyosarcoma.

Fig. 30.40. Metastatic endometrioid adenocarcinoma. (A) Hematoxylin–eosin stained section. (B) Immunostain for ER.

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TNM CLASSIFICATION AND FIGO STAGING SYSTEM OF VAGINA CARCINOMA (2010 Revision) The definition of the T categories correspond to the stage accepted by the Federation Internationale de Gynecologie et d’Obstetrique (FIGO) ♦♦ Primary Tumor (T) TNM

TNM

FIGO

Categories Stages NX Regional lymph nodes cannot be assessed

FIGO

N0

Categories Stages TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tisa Carcinoma in situ (preinvasive carcinoma)

a

♦♦ Regional Lymph Nodes (N)

T1

I

T2

II Tumor invades paravaginal tissues but not to pelvic wall

Tumor confined to vagina

T3

III

T4

IVA Tumor invades mucosa of the bladder or rectum and/or extends beyond the true pelvis (bullous edema is not sufficient evidence to classify a tumor as T4)

No regional lymph node metastasis

N1 Pelvis or inguinal lymph node metastasis

♦♦ Distant Metastasis (M) TNM

FIGO

Categories Stages M0

No distant metastasis

M1

Distant metastasis

IVB

Tumor extends to pelvic wallb

FIGO no longer includes Stage 0 (Tis)

Pelvic wall is defined as muscle, fascia, neurovascular structures, or skeletal portions of the bony pelvis. On rectal examination, there is no cancer-free space between the tumor and pelvic wall

b

SUGGESTED READING Clark WH Jr., Hood AF, Tucker MA, Jampel RM. Atypical melanocytic nevi of the genital type with a discussion of reciprocal parenchymal–stromal interactions in the biology of neoplasia. Hum Pathol 1998;29:S1–S24. Clement PB, Young RH. Atlas of gynecologic surgical pathology. W.B. Saunders Company, Philadelphia, Pennsylvania, 2nd edition, 2008. Fu YS. Pathology of the uterine cervix, vagina, and vulva. W.B. Saunders Company, Philadelphia, Pennsylvania, 2nd edition, 2002. Iwasa Y, Fletcher CDM. Distinctive prepubertal vulvar fibroma. A hitherto unrecognized mesenchymal tumor of prepubertal girls: analysis of 11 cases. Am J Surg Pathol 2004;28:1601–1608. Kurman RJ, Norris HJ, Wilkinson EJ. Tumors of the cervix, vagina, and vulva. Atlas of tumor pathology, 3rd series, #4, AFIP, Washington, D.C., 1992. Kurman RJ. Blaustein’s pathology of the female genital tract. Springer, New York, 5th edition, 2002. Lam MM, Corless CL, Goldblum JR, et al. Extragastrointestinal stromal tumors presenting as vulvovaginal/rectovaginal septal masses: a diagnostic pitfall. Int J Gynecol Pathol 2006;25:288–292. McCluggage WG. Recent developments in vulvovaginal pathology. Histopathology 2009;54:156–173. McCluggage WG, Ganesan R, Hirschowitz L, et  al. Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series with a morphological spectrum wider than previously described. Histopathology 2004;45:360–368. Medeiros F, Nascimento AF, Crum CP. Early vulvar squamous neoplasia: advances in classification, diagnosis, and differential diagnosis. Adv Anat Pathol 2005;12:20–26.

Misago N, Suse T, Uemura T, Narisawa Y. Basal cell carcinoma with ­sebaceous differentiation. Am J Dermatopathol 2004;26:298–303. Nucci MR, Fletcher CDM. Vulvovaginal soft tissue tumors: update and review. Histopathology 2000;36:97–108. O’Connell TX, Nathan LS, Satmary WA, Goldstein AT. Non-neoplastic ­epithelial disorders of the vulva. Am Fam Physician 2008;77:321–326. O’Neill CJ, McCluggage WG. P16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol 2006;13:8–15. Regauer S. Extramammary Paget’s disease – a proliferation of adnexal ­origin? Histopathology 2006;48:723–729. Ridley CM, Frankman O, Jones IS, et al. New nomenclature for vulvar ­disease: International Society for the study of vulvar disease. Hum Pathol 1989;201:495–496. Santos M, Landolfi S, Olivella A, et  al. P16 overexpression identifies ­HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol 2006; 30:1347–1356. Staats PN, Clement PB, Young RH. Primary endometrioid adenocarcinoma of the vagina: a clinicopathologic study of 18 cases. Am J Surg Pathol 2007;31:1490–1501. Tavassoli FA, Devilee P. World Health Organization Classification of Tumors. Pathology and genetics, tumors of the breast and female genital organs, IARC Press, Lyon, France, 2003. Wilkinson ED, Stone IK. Atlas of vulvar disease. Williams and Wilkins Press, Baltimore, Maryland, 1995. Woida FM, Ribeiro-Silva A. Adenoid cystic carcinoma of the Bartholin gland: an overview. Arch Pathol Lab Med 2007;131:796–798.

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31 Uterus and Fallopian Tube Maritza Martel, md and Fattaneh A. Tavassoli, md

contents

I. Uterus – Cervix..................................31-3 Nonneoplastic Lesions......................................31-3 Noninfectious Cervicitis.........................31-3 Papillary Endocervicitis.........................31-3 Infectious Cervicitis................................31-3 Atypia of Repair.....................................31-5 Radiation Induced Atypia......................31-5 Tubal Metaplasia....................................31-6 Tuboendometrioid Metaplasia...............31-6 Transitional Cell Metaplasia.................31-6 Arias-Stella Reaction..............................31-6 Microglandular Endocervical Hyperplasia........................................31-6 Nabothian Cyst.......................................31-7 Tunnel Clusters.......................................31-7 Mesonephric Remnants and Mesonephric Hyperplasia.................31-7 Endometriosis.........................................31-8 Ectopic Prostatic Tissue.........................31-8 Lymphoma-Like Lesion.........................31-9 Postoperative Spindle Cell Nodule........31-9 Decidual Pseudopolyp and Decidualization...................................31-9 Mesodermal Stromal Polyp (Pseudosarcoma Botryoides).............31-9 Arteritis...................................................31-9 Epithelial Tumors and Precursors..................31-9 Benign Squamous Cell Lesions..............31-9 Benign Glandular Lesions...................31-10 Squamous Tumors and Precursor Lesions..............................................31-11 Glandular Tumors and Precursor Lesions..............................................31-15

Glassy Cell Carcinoma Variant...........31-19 Neuroendocrine Tumors......................31-20 Undifferentiated Carcinoma................31-20 Mesenchymal Tumors....................................31-20 Smooth Muscle Tumors........................31-20 Other Benign Mesenchymal Tumors..............................................31-21 Other Malignant Mesenchymal Tumors..............................................31-21 Mixed Epithelial and Mesenchymal Tumors........................................................31-21 Adenomyoma........................................31-21 Adenofibroma.......................................31-21 Adenosarcoma.......................................31-21 Carcinosarcoma (Malignant Mixed Mesodermal Tumor)........................31-21 Melanocytic Tumors.......................................31-21 Blue Nevus.............................................31-21 Malignant Melanoma...........................31-22 Tumors of Germ Cell Type............................31-22 Lymphoid and Hematopoietic Tumors.........31-22 Secondary Tumors..........................................31-22

II. Uterus – Corpus...............................31-22 Morphology of the Endometrium.................31-22 Endometrial Cycle................................31-22 Inactive Endometrium.........................31-23 Atrophic Endometrium........................31-23 Pregnancy-Related Changes................31-23 Effects of Hormone Administration....31-24 Dysfunctional Uterine Bleeding....................31-24 Glandular and Stromal Breakdown Associated with Anovulation..........31-24

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_31, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Inadequate Luteal Phase/Luteal Phase Defect.....................................31-24 Irregular Shedding...............................31-25 Nonneoplastic Lesions....................................31-25 Acute and Chronic Endometritis........31-25 Specific Types of Chronic Endometritis.....................................31-25 Lymphoma-Like Lesion.......................31-26 Changes Related to Intrauterine Devices..............................................31-26 Adenomyosis..........................................31-26 Endometrial Metaplasias.....................31-26 Miscellaneous Lesions..........................31-27 Epithelial Tumors and Related Lesions.......31-27 Endometrial Polyps..............................31-27 Precursor Lesions of Endometrial Carcinoma........................................31-28 Endometrial Carcinoma......................31-30 Mesenchymal Tumors and Related Lesions........................................................31-36 Smooth Muscle Tumors........................31-36 Endometrial Stromal and Related Tumors..............................................31-39 Miscellaneous Mesenchymal Tumors..............................................31-42 Mixed Epithelial and Mesenchymal Tumors........................................................31-42 Adenomyoma........................................31-42 Miscellaneous Tumors....................................31-44 Sex Cord-Like Tumors.........................31-44 Neuroectodermal Tumors....................31-45 Melanotic Paraganglioma....................31-45 Lymphomas and Leukemias..........................31-45 Tumors of Germ Cell Type............................31-45 Metastatic (Secondary) Tumors....................31-45 Tumors from Other Genital Organs...31-45 Tumors from Extragenital Sites..........31-45

Other Granulomatous Salpingitis.......31-47 Salpingitis Isthmica Nodosa.................31-47 Ectopic Pregnancy................................31-47 Inclusion Cysts and Walthard Nests..................................................31-47 Paratubal Cysts.....................................31-48 Tubal Prolapse......................................31-48 Epithelial Tumors...........................................31-48 Benign....................................................31-48 Carcinoma In Situ................................31-49 Borderline Epithelial Tumors..............31-49 Malignant Epithelial Tumors..............31-49 Mixed Epithelial Mesenchymal Tumors........................................................31-50 Carcinosarcoma (Malignant Mixed Mesodermal Tumor)........................31-50 Mesenchymal Tumors....................................31-50 Mesothelial Tumors..............................31-50 Germ Cell Tumors..........................................31-50 Teratoma................................................31-50 Trophoblastic Disease....................................31-50 Lymphoid and Hematopoetic Tumors..........31-50 Secondary Tumors..........................................31-51 Tumors of the Uterine Ligaments.................31-51 Epithelial Tumors of Müllerian Type............................31-51 Miscellaneous Tumors . .......................31-51 Other Tumors of the Uterine Ligaments.........................................31-51

IV. TNM Classification and Figo Staging System for Cervical Carcinoma (2010 Revision)..............31-51 V. TNM Classification and FIGO Staging System for Endometrial Carcinoma (2010 Revision)..............31-52

III. Fallopian Tubes................................31-45 VI. TNM Classification and FIGO Nonneoplastic Lesions....................................31-45 Staging System for Fallopian Tube Acute Salpingitis...................................31-45 Carcinoma (2010 Revision)..............31-52 Chronic Salpingitis...............................31-46 Granulomatous Salpingitis..................31-46

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VII. Suggested Reading...........................31-53

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UTERUS – CERVIX Nonneoplastic Lesions Noninfectious Cervicitis

Bacterial and Chlamydial Cervicitis Clinical

♦♦ Usually results from chemical irritation or mechanical trauma ♦♦ Nonspecific inflammatory response

♦♦ Most common cause of infectious cervicitis ♦♦ Chlamydia trachomatis and Neisseria gonorrhea are the most common cause of mucopurulent cervicitis ♦♦ Infection rates are greater in women of 15–21 years of age ♦♦ Approximately two-thirds of women are asymptomatic ♦♦ Associated endometritis in 40% and salpingitis in 11% of cases ♦♦ C. trachomatis cervicitis is most accurately diagnosed by culture or molecular diagnostic methods (PCR or LCR)

Acute Cervicitis ♦♦ Swollen, erythematous, and friable cervix, and purulent endocervical discharge may be present ♦♦ Neutrophilic infiltration of the stroma and epithelium ♦♦ Stromal edema and vascular congestion

Chronic Cervicitis ♦♦ Extremely common in adult females ♦♦ Commonly affects the squamocolumnar junction and endocervix ♦♦ Cervical mucosa is hyperemic, and epithelial erosions may be present ♦♦ Inflammatory infiltrate consists predominantly of lymphocytes, plasma cells, and histiocytes ♦♦ Granulation tissue and fibrosis in variable amounts

Follicular Cervicitis ♦♦ Seen in noninfectious and infectious cervicitis (commonly with Chlamydia trachomatis) ♦♦ Lymphoid follicles beneath the epithelium ♦♦ Differential diagnosis with nodular lymphoma includes the presence of follicles with germinal centers, a mixed inflammatory infiltrate, and the absence of a mass lesion

Papillary Endocervicitis ♦♦ ♦♦ ♦♦ ♦♦

Secondary to an inflammatory process Cervicitis with a papillary growth pattern Nuclei with finely stippled and prominent nucleoli It should not be mistaken with glandular neoplasia; absence of cellular stratification and cytologic atypia are distinguishing features of villoglandular endocervical adenocarcinoma

Macroscopic ♦♦ Yellow-green endocervical exudates ♦♦ Erythema, friable cervical ectropion

Microscopic ♦♦ Dense diffuse inflammatory exudates, acute and chronic inflammatory cell infiltrates in the stroma and epithelium ♦♦ Reactive squamous and endocervical atypia ♦♦ C. trachomatis cervicitis is a major cause of follicular cervicitis in young women ♦♦ Intracytoplasmic inclusions in endocervical columnar or metaplastic cells may be seen in C. trachomatis infection but are nonspecific

Actinomycosis Clinical ♦♦ Actinomyces israelii is a frequent commensal organism found in the female genital tract ♦♦ Seen in 3–27% of asymptomatic women without any risk factors ♦♦ Most frequently identified in women with intrauterine devices ♦♦ Identification of A. israelii in asymptomatic patients has little clinical significance and does not warrant therapy ♦♦ Rarely can be associated with pelvic abscesses

Macroscopic ♦♦ Yellow and granular lesions

Infectious Cervicitis

Microscopic

♦♦ Central role in the pathogenesis of pelvic inflammatory disease and endometrial infections ♦♦ Initial event in the pathogenesis of pelvic inflammatory disease ♦♦ Primary focus in postpartum and postabortal endometritis ♦♦ Spontaneous abortion, premature delivery, chorioamnionitis, stillbirth, neonatal pneumonia and septicemia have been related to bacterial infection of the cervix ♦♦ Infectious agents causing endocervicitis and exocervicitis tend to differ, but some can cause both conditions

♦♦ Branching, gram positive filaments with peripheral palisading clubs (sulfur granules) ♦♦ Pseudoactinomycotic radiate granules can be identified in endocervical curettings of asymptomatic women ♦♦ Granulomas may be present

Tuberculosis Clinical ♦♦ Typically associated with pulmonary tuberculosis and almost always secondary to tuberculous salpingitis or endometritis

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Macroscopic ♦♦ Unremarkable or erythematous ♦♦ May simulate invasive carcinoma

Microscopic ♦♦ Caseating granulomas, but may also appear as a noncaseating granulomatous lesions ♦♦ Heavy lymphocytic infiltrate surrounding the granulomas ♦♦ Diagnosis requires identification of acid-fast Mycobacterium tuberculosis

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Foreign body giant cell granulomas Lymphogranuloma venereum Sarcoidosis Schistosomiasis

Other Granulomatous Infections ♦♦ Syphilis, lymphogranuloma venereum, granuloma inguinale, and chancroid ♦♦ Clinically, all may resemble carcinoma

Herpesvirus Infection (HSV) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Caused mainly by HSV-2 HSV-2 is acquired through sexual contact Up to 70% of HSV-2 infections are asymptomatic Cervical involvement is detected in 70–90% of primary infections and 15–20% of recurrent infection ♦♦ May result in spontaneous abortion, fetal morbidity, and mortality ♦♦ Diagnosed by culture, PCR, Pap smear, and serology

Macroscopic ♦♦ Multiple painful vesicles evolving into shallow, painful ulceration (Fig. 31.1A)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Extensive ulcerations that can be mistaken for carcinoma may occur ♦♦ Vulva, vagina, perineum, and cervix may be involved

Microscopic ♦♦ Papanicolaou smear shows large multinucleated cells with intranuclear ground glass viral inclusions (Fig. 31.1B) ♦♦ Cervical biopsy during the vesicular phase shows suprabasal intraepidermal vesicles filled with serum, degenerated epidermal cells, and multinucleated giant cells, some with eosinophilic intranuclear inclusions ♦♦ Positive staining with HSV immunostain confirms the diagnosis

Cytomegalovirus (CMV) ♦♦ CMV may infect endocervical epithelial or endothelial cells in either immunosuppressed or normal individuals ♦♦ Characteristic enlarged cells with basophilic nuclear inclusions and sometimes granular cytoplasmic inclusions ♦♦ Positive staining with CMV immunostain confirms the diagnosis

Human Papilloma Virus Infection Clinical ♦♦ >35 of different types of HPV can infect the anogenital tract ♦♦ The resulting infections produce a variety of gross and histological lesions ♦♦ Linked to a variety of cervical diseases ranging from condyloma acuminatum to invasive carcinoma and its precursors ♦♦ Most prevalent anogenital HPVs are divided into three oncogenic risk groups −− Low risk: 6,11,42,43, and 44, usually associated with condyloma acuminatum, low grade SIL, only rarely with high grade SIL, and almost never with invasive carcinoma −− High risk: 16,18,45,56, and 58, type most frequently associated with invasive squamous cell carcinoma

Fig. 31.1. Herpetic cervicitis. (A) Shallow ulcers are present in the cervix. (B) Large multinucleated cell with characteristic ground glass viral inclusions in herpesvirus infection in a pap smear.

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♦♦ Typically, a foamy yellow-green vaginal discharge is present ♦♦ Intense inflammatory response with prominent reparative atypia may be present ♦♦ Diagnosis made by wet mount, culture, and Pap smear

Parasitic Diseases ♦♦ Schistosomiasis (bilharziasis) caused by Schistosoma mansoni, very common in Africa (Egypt), South America, Puerto Rico, and Asia ♦♦ Associated with urinary schistosomiasis and sterility ♦♦ Noncaseating granulomas with ova, often calcified, surrounded by multinucleated giant cells ♦♦ May be associated with extensive pseudoepitheliomatous hyperplasia of the cervical squamous epithelium Fig. 31.2. Cytopathic effects of HPV. −− Intermediate risk: 31,33,35,39,51,52,59, and 68; features of high oncogenic risk viruses, but found less frequently in invasive squamous cell carcinoma; however, recent evidence suggests that they should also be considered high risk types ♦♦ “Gold standard” for HPV identification is Southern blot hybridization ♦♦ Two HPV vaccines are currently available, one targets HPV types 16 and 18, the types that cause 70% of cervical cancers, and the other targets HPV types 16, 18 plus types 6 and 11, which cause 90% of genital warts

Atypia of Repair Clinical ♦♦ Can be associated with severe, acute long-standing chronic inflammation or epithelial injury

Microscopic

♦♦ Cytopathic effects of HPV (Fig. 31.2) −− Perinuclear cytoplasmic vacuolization −− Nuclear atypia: enlargement, hyperchromasia, irregularity, and wrinkling of the nuclear membrane. (Koilocytosis = nuclear atypia and perinuclear vacuolization) −− Anisocytosis −− Binucleation and multinucleation

♦♦ Epithelial disorganization and nuclear atypia of the squamous and endocervical epithelium ♦♦ Squamous epithelium −− Well-defined cytoplasmic membrane −− Uniform nuclei and chromatin in prominent aggregates or clumps −− Infiltration by migrating inflammatory cells −− Normal mitotic figures confined to the basal and parabasal layers −− Cells of the upper half of the epithelium are normal, showing orderly maturation ♦♦ Endocervical columnar cells −− Nuclear enlargement and hyperchromasia −− Irregular nuclear size and shape and smudgy chromatin −− Cytoplasmic eosinophilia and loss of mucinous droplets

Fungal Diseases

Differential Diagnosis

♦♦ Mostly caused by Candida albicans ♦♦ Usually part of a generalized lower genital tract infection involving the vagina and vulva ♦♦ Antibiotic therapy, poorly controlled diabetes mellitus, and immunosuppression favor fungal overgrowth ♦♦ Viscous vaginal discharge containing white flakes and vulvar pruritus ♦♦ Increased number of polymorpholeukocytes in the epithelium ♦♦ Fungal hyphae can be identified with PAS

Radiation Induced Atypia

Microscopic

Protozoal Diseases ♦♦ Cervical infestation by Trichomonas vaginalis is frequent ♦♦ Most often associated with concurrent trichomonal vaginitis

♦♦ CIN: loss of normal maturation, increased mitotic activity, and abnormal mitotic figures can be present ♦♦ Adenocarcinoma in situ: epithelial stratification, increased nuclear atypia and mitotic figures

♦♦ May be found weeks or years after radiation ♦♦ Squamous cells have nuclear enlargement with abundant vacuolated cytoplasm; multinucleation may occur ♦♦ Changes in the endocervical glandular epithelium include cellular enlargement, loss of nuclear polarity, and dense enlarged eosinophilic nucleoli that can be multiple ♦♦ Fibrotic and hyalinized stroma ♦♦ Blood vessels often have intimal hyaline thickening and can be totally occluded

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Tubal Metaplasia Clinical ♦♦ Found in up to 31% of surgically excised cervices ♦♦ Does not appear to be related to inflammatory changes or low grade SIL ♦♦ Atypical tubal metaplasia is frequently found in association with adenocarcinoma in situ

Microscopic ♦♦ The epithelium lining the endocervical glands is replaced by a single layer composed of admixed ciliated, nonciliated, and peg cells. The noncilitated cells may have apical snouts ♦♦ Bland cytologic features; absent or rare mitotic figures ♦♦ Typically confined to the superficial third of the cervical wall (extends <7 mm into the cervical stroma) ♦♦ Only slight variation in size and shape of the glands ♦♦ The surrounding stroma appears normal ♦♦ Atypical tubal metaplasia, a form of tubal metaplasia in which the glands are lined by ciliated and nonciliated cells that are crowded with larger and more hyperchromatic nuclei

Tuboendometrioid Metaplasia ♦♦ Occurs commonly after cervical conization ♦♦ Similar to tubal metaplasia, fewer ciliated cells and nonciliated cells may have apical snouts ♦♦ Superficial location, minimal variation in size and shape, and lack of desmoplastic stromal response differentiates them form a neoplastic process

Differential Diagnosis ♦♦ Endometriosis ♦♦ Adenocarcinoma in situ (AIS) −− Cytologic atypia, significant mitotic activity, and cribriforming and papillary projections −− The presence of an admixture of cell types in tubal and tuboendometrioid metaplasia helps in the disctinction from AIS −− Tubal metaplasia and tuboendometrioid metaplasia can be focally positive for p16 but lack the diffuse and strong positivity for p16 and the high proliferation index with Ki-67 evident in AIS

Transitional Cell Metaplasia Clinical ♦♦ Typically an incidental microscopic finding, almost always in postmenopausal women, but occasionally in premenopausal women ♦♦ Usually seen in association with atrophy

Microscopic ♦♦ Can arise in the transformation zone, exocervix, or vagina ♦♦ The epithelium is composed of >10 cell layers of cells

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♦♦ The cells have oval to spindle-shaped nuclei, with occasional longitudinal nuclear grooves and are oriented vertically in the deeper layers ♦♦ The cells in the superficial layer resemble the umbrella cells of the normal urothelium ♦♦ Lacks cytologic atypia and mitotic activity ♦♦ Immunoreactive for CK13, CK17, and CK18, similar to urothelium but lack staining for CK20

Differential Diagnosis ♦♦ High grade CIN −− Cytologic atypia and high mitotic activity −− P16 positive and high proliferation index with Ki-67 immunostain

Arias-Stella Reaction Clinical ♦♦ Occurs in association with intrauterine and extrauterine pregnancies and gestational trophoblastic disease

Microscopic ♦♦ Can develop in endocervical glands or ectopic endometrial glands within the cervix ♦♦ Identical to that occurring in the endometrium ♦♦ Usually focal, superficial, and in the proximal portion of the endocervix ♦♦ Glands with markedly enlarged cells with hyperchromatic nuclei that can project into the lumen in a hobnail pattern and with vacuolated cytoplasm ♦♦ Rare mitotic activity ♦♦ Atypical Arias-Stella reaction, even with p53 positivity, may develop; the history of pregnancy is an important clue

Differential Diagnosis ♦♦ Clear cell carcinoma −− Mass lesion, stromal invasion, high mitotic rate, and classic tubular and papillary areas with hyalinized cores ♦♦ Adenocarcinoma in situ −− More uniform nuclei, less cytoplasmic vacuolation, and increased mitoses

Microglandular Endocervical Hyperplasia Clinical ♦♦ Benign proliferation of endocervical glands ♦♦ Most common in women of reproductive age, usually with history of oral contraceptive use or of pregnancy ♦♦ Frequently represents an incidental finding ♦♦ Postcoital bleeding or spotting when presenting as a polyp

Macroscopic ♦♦ May be polypoid, 1–2 cm

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Fig. 31.3. Microglandular hyperplasia.

Fig. 31.4. Endocervical tunnel cluster.

Microscopic (Fig. 31.3)

Tunnel Clusters Clinical

♦♦ Single or multiple foci ♦♦ Crowded glandular or tubular units of varying size lined by flattened to cuboidal cells with eosinophilic cytoplasm and scant mucin ♦♦ Predominantly uniform nuclei, with occasional pleomorphism and hyperchromasia ♦♦ Low mitotic activity (1 mf/10 hpf) ♦♦ Squamous metaplasia and subcolumnar reserve cells hyperplasia usually present ♦♦ Stroma is infiltrated with acute and chronic inflammatory cells ♦♦ Solid proliferations and signet-ring cells can be present

Differential Diagnosis ♦♦ Endocervical adenocarcinoma −− Stromal invasion and high mitotic activity −− Clear cell carcinoma contains intracellular glycogen −− The rare adenocarcinoma with microglandular pattern is generally admixed with other classic patterns of adenocarcinoma

Nabothian Cyst Clinical ♦♦ Most common cervical cyst ♦♦ Develop within the transformation zone secondary to squamous metaplasia covering and obstructing endocervical glands

Macroscopic ♦♦ Yellow-white cysts measuring up to 1.5  cm, frequently multiple

Microscopic ♦♦ Lined by a flattened single layer of mucin-producing (endocervical) epithelium ♦♦ Squamous metaplasia of the lining epithelium may occur

♦♦ Benign collections of endocervical glands ♦♦ Common and become more prevalent with increasing age, also common in pregnant women ♦♦ Asymptomatic, incidental finding

Microscopic (Fig. 31.4) ♦♦ Usually located close to the surface epithelium of the cervix ♦♦ Cluster of closely packed glands (noncystic, lined by columnar epithelium or cystic, lined by cuboidal or flattened epithelium) ♦♦ Well demarcated, do not extend beyond the depth of normal endocervical glands ♦♦ Nucelar atypia and mitotic activity are absent

Differential Diagnosis ♦♦ Minimal deviation adenocarcinoma of the cervix: nuclear atypia, increased mitotic activity, and deep stromal invasion

Mesonephric Remnants and Mesonephric Hyperplasia Clinical ♦♦ Vestigial elements of the distal ends of the mesonephric ducts ♦♦ Seen in up to 20% of cervices and prevalence is samplingdependent ♦♦ Commonly present in the lateral aspects of the cervix ♦♦ Incidental finding, almost always asymptomatic ♦♦ Differentiation between remnant and hyperplasia may be arbitrary and of no clinical significance

Microscopic (Fig. 31.5) ♦♦ Small tubules or cysts, arranged in small clusters, lined by nonciliated low columnar or cuboidal epithelium without glycogen or mucin ♦♦ Tubular lumen often filled with pink, homogeneous, and PAS positive secretions

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♦♦ May become hyperplastic (mesonephric hyperplasia) resulting in a florid tuboglandular proliferation ♦♦ Mitotic activity absent

Immunoprofile ♦♦ Typically positive for CD10, focal moderate to strong cytoplasmic positivity for p16, and low proliferation with Ki-67

Differential Diagnosis ♦♦ Mesonephric carcinoma −− Complex glandular pattern and mitoses ♦♦ Cervical adenocarcinoma: CEA positive, strong nuclear staining with p16, and high Ki-67

Endometriosis Clinical ♦♦ Mechanism unknown, but frequently develops following cervical trauma ♦♦ Large lesions may present with abnormal vaginal bleeding

Essentials of Anatomic Pathology, 3rd Ed.

Macroscopic ♦♦ One or more small, blue or red nodules, several millimeters in diameter ♦♦ Occasionally may be larger or cystic

Microscopic ♦♦ May be superficial (mucosal) or deep ♦♦ Composed of ectopic endometrial glands and stroma, resembling proliferative endometrium ♦♦ Rarely, the glands are secretory, and decidua may be seen in pregnancy or during progestin therapy ♦♦ In some cases, the stromal component may be sparse; CD10 may not be very helpful as endocervical stromal cells can be positive ♦♦ Occasional positivity for p16 may be seen

Differential Diagnosis ♦♦ Endocervical AIS: marked nuclear atypia, numerous apoptotic bodies, and absence of periglandular endometrial stroma

Ectopic Prostatic Tissue (Fig. 31.6) ♦♦ Reportedly rare, although possibly more common as many cases may be unrecognized ♦♦ Possibly results from metaplasia of endocervical glands or derivation from mesonephric remnants ♦♦ Usually located deep in the stroma at the transformation zone or ectocervix ♦♦ Characterized by a combination of glandular and squamous elements, and a double layer of glandular epithelium is present with both basal and luminal cells ♦♦ PSA and PSAP are usually positive; CK903 highlights the basal layer of the glandular epithelium and squamous elements

Differential Diagnosis Fig.  31.5. Mesonephric remnants. Tubules lined by cuboidal epithelium with eosinophilic luminal secretion.

Fig. 31.6. (A) Prostatic ectopic tissue (B) PSAP immunostain.

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♦♦ Adenoid basal carcinomas are more basaloid, show more nuclear atypia of the squamous epithelium, and occur in older women

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♦♦ Well-differentiated adenosquamous carcinomas show infiltrative pattern and more cytologic atypia

Lymphoma-Like Lesion ♦♦ Extensive marked inflammatory lesions that may cause confusion with a lymphoproliferative lesion ♦♦ Composed of a superficial band of large lymphoid cells admixed with mature lymphocytes and plasma cells ♦♦ Features that help distinguish them from lymphoma −− Macrophages and germinal centers are commonly present −− Superficial, rarely infiltrate deeper than 3  mm from the surface epithelium −− Polyclonal staining pattern with immunohistochemistry

Postoperative Spindle Cell Nodule ♦♦ Clinically and histologically identical to those found in the vagina and vulva ♦♦ May develop after cervical biopsy or other traumas ♦♦ Actively proliferating spindle cells with oval nuclei arranged in interlacing bundles ♦♦ Mitotic figures are often present ♦♦ Neutrophils and erythrocytes are characteristic, giving an appearance of granulation tissue

Decidual Pseudopolyp and Decidualization Clinical ♦♦ The cervical stroma can undergo focal decidual changes during gestation

Macroscopic ♦♦ In the exocervix, it presents as a raised plaque or pseudopolyp

Microscopic ♦♦ The decidual cells, present just underneath the surface epithelium, have oval bland nuclei, abundant eosinophilic cytoplasm, and prominent cytoplasmic membranes (Fig. 31.7) ♦♦ Cervical polyps may also have focal and rarely massive decidual changes

Differential Diagnosis ♦♦ Invasive nonkeratinizing squamous cells carcinoma: nuclear atypia, high mitotic activity, and cytokeratin positive ♦♦ Extruded fragments of decidua

Mesodermal Stromal Polyp (Pseudosarcoma Botryoides) ♦♦ ♦♦ ♦♦ ♦♦

Benign exophytic proliferations of stroma and epithelium Occurs more commonly in the vagina Seen most frequently in pregnant patients Composed of an edematous stroma covered by a benignappearing, stratified squamous epithelium ♦♦ Stroma composed of bland-appearing plump stromal fibroblasts

Fig. 31.7. Decidual change of cervical stroma in pregnancy.

♦♦ Focal areas of bizarre fibroblasts with hyperchromatic nuclei, occasionally multinucleated and simulating the appearance of sarcoma botryoides, may be present ♦♦ Cambium layer and rhabdomyoblasts are absent

Arteritis ♦♦ Vasculitis such as polyarteritis nodosa (PAN) or giant cell arteritis (GCA) can affect the female genital tract. PAN most commonly affects the cervix, while GCA involves all gynecologic sites with similar frequency ♦♦ Both types of arteritis are usually an incidental and isolated microscopic finding; however, rare cases have been associated with systemic disease and may be the initial manisfestation

Epithelial Tumors and Precursors Benign Squamous Cell Lesions Fibroepithelial Polyp Clinical ♦♦ Can occur at any age, but has a predilection for pregnant women

Macroscopic ♦♦ Polypoid lesions, usually solitary

Microscopic ♦♦ Single papillary frond composed of a central fibrovascular stalk covered by mature squamous epithelium ♦♦ Aypia and koilocytosis are absent

Differential Diagnosis ♦♦ Condyloma acuminatum: koilocytosis

Squamous Papilloma ♦♦ Similar to squamous papillomas of the vagina and vulva ♦♦ Usually solitary, arising on the ectocervix or squamocolumnar junction

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♦♦ Single papillary frond, in which mature squamous epithelium without atypia or koilocytosis lines a fibrovascular stalk and lacks the complex arborizing architecture of condylomas

Condyloma Acuminatum Clinical ♦♦ One of the most common manifestations of HPV infection in the lower anogenital tract ♦♦ Most investigators consider cervical condylomas as a form of low grade SIL ♦♦ Usually caused by HPV types 6 and 11 ♦♦ Commonly multifocal ♦♦ Usually, spontaneous regression and good response to conservative therapy ♦♦ Recurrences are unpredictable, may be persistent ♦♦ Immunosuppression may modify the natural history ♦♦ Increasing concern for vertical transmission during pregnancy

Macroscopic (Fig. 31.8A) ♦♦ Raised, white papillary projections

Microscopic (Fig. 31.8B) ♦♦ Cervical condylomas are most commonly flat, but they can be papillary or show endophytic growth pattern in endocervical glands ♦♦ Papillomatosis, acanthosis, hyperkeratosis ♦♦ Koilocytosis (squamous cell with sharply demarcated perinuclear vacuolization and enlarged nucleus, with wrinkled nuclear membrane) ♦♦ Binucleated or multinucleated cells are frequently seen

Benign Glandular Lesions Endocervical Polyps Clinical ♦♦ Very common lesion, probably not neoplastic

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Most often found between the fourth and sixth decades and in multigravida ♦♦ Commonly an incidental finding in asymptomatic women but may present with leukorrhea or abnormal bleeding due to ulceration of the surface epithelium ♦♦ Extremely uncommon for in situ or invasive carcinoma to arise in cervical polyps

Macroscopic ♦♦ Rounded or elongated with a smooth or lobulated surface ♦♦ Most are single, measuring between a few millimeters and 2–3 cm; rarely, they may reach gigantic proportions

Microscopic ♦♦ Variety of patterns according to the tissue components ♦♦ Most common type is the endocervical mucosal polyp, composed of mucinous epithelium that lines crypts with or without cystic changes ♦♦ Squamous metaplasia involving the surface or glands is often seen ♦♦ They may be mainly fibrous, or blood vessels may predominate (vascular polyp) ♦♦ The stroma is composed of loose connective tissue with centrally placed thick-walled vessels, usually infiltrated by a chronic inflammatory infiltrate

Müllerian Papilloma Clinical ♦♦ Rare; occurs almost exclusively in children; age range 1–9 years ♦♦ Present with bleeding or discharge

Macroscopic ♦♦ Usually <2 cm, polypoid to papillary mass

Microscopic ♦♦ Multiple small polypoid projections composed of fibrous stroma lined by simple epithelium

Fig. 31.8. (A) Condyloma acuminata, gross appearance. (B) Exophytic condyloma acuminata.

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♦♦ Occasional cells may have hobnail appearance ♦♦ Clear cells and mitoses are absent

Differential Diagnosis ♦♦ Clear cell carcinoma

Squamous Tumors and Precursor Lesions ♦♦ Cervical carcinoma is the third most common cancer among females worldwide ♦♦ The incidence has been declining in the last four decades in most developed countries predominantly due to cervical screening programs ♦♦ Adenocarcinoma of the cervix, which accounts for 10–15% of all cervical cancers, has shown an increased incidence in the last three decades ♦♦ HPV is the major etiologic factor in both squamous and glandular tumors ♦♦ Host and environmental factors contribute to enhance the probability of HPV persistence and progression to cervical neoplasia ♦♦ The products of two early genes, E6 and E7, have been shown to play a major role in HPV-mediated cervical carcinogenesis ♦♦ Increased risk with increased number of sexual partners, decreased age at time of initial sexual intercourse, promiscuity of male partner, and cigarette smoking ♦♦ Stage is the most important prognostic factor; histologic typing and grading have little direct influence on survival within any stage

Cervical Intraepithelial Neoplasia (CIN) Clinical ♦♦ Conventionally divided into three grades: CIN 1, 2, and 3 ♦♦ Increasing tendency to use a two-tiered classification: low grade (CIN 1) and high grade (CIN 2 and 3) ♦♦ Also referred to as low and high grade squamous intraepithelial lesion (LSIL and HSIL) ♦♦ Because of the difficulty in distinguishing pure HPV infection from unequivocal CIN 1, HPV infection alone is included in the low grade SIL ♦♦ Natural history of CIN (difficult to study) −− CIN 1 (low grade SIL) (a) ~44% regress spontaneously (b) ~46% persist (c) ~15% have the potential for progression to high grade CIN (d) 1–5% of untreated cases eventually progress to invasive cancer −− High grade CIN (CIN 2 and 3, high grade SIL) (a) Fewer high grade lesions regress spontaneously, and more lesions progress to invasive cancer (b) Progression rates of CIN 3 (carcinoma in situ) to invasive carcinoma ranges from 22 to 72% in different studies

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Macroscopic ♦♦ Best evaluated by colposcopic examination after application of 3–5% acetic acid ♦♦ Evaluation of the surface contour, color tone, and border of the lesions ♦♦ The subepithelial vascular network undergoes alterations, resulting in a variety of colposcopic patterns

Microscopic ♦♦ Begins in the transformation zone and replaces adjacent squamous and glandular epithelium ♦♦ Abnormal cellular proliferation beginning in the basal layer ♦♦ Abnormal maturation with loss of polarity and cellular disorganization ♦♦ Microscopic grading is based on extent of replacement of epithelium by abnormal proliferating parabasal cells, degree of nuclear atypia, and level at which mitotic figures are found ♦♦ CIN 1 (Fig. 31.9A) −− Maturation is present in the upper two-thirds of the epithelium −− Mild atypia, including viral cytopathic effect (koilocytosis) of the superficial cells −− Nuclear abnormalities are present throughout, but slight −− Mitotic figures are present in the basal third, but not numerous; abnormal forms are rare ♦♦ CIN 2 (Fig. 31.9B) ♦♦ Maturation is present in the upper half of the epithelium ♦♦ Nuclear atypia is conspicuous in both the upper and lower epithelial layers ♦♦ Mitotic figures are confined to the basal two-thirds of the epithelium ♦♦ Abnormal mitotic figures may be seen ♦♦ CIN 3 (Fig. 31.9C) −− Maturation absent or confined to the superficial third of the epithelium −− Nuclear abnormalities are marked throughout most or all of the thickness −− Numerous mitotic figures, found at all levels −− Abnormal mitoses are frequent

Immunoprofile ♦♦ Ki-67 (MIB1) and p16, used together, are useful markers in the evaluation of squamous intraepithelial lesions (Fig. 31.10) ♦♦ P16, a cyclin dependent kinase inhibitor, is expressed strongly in lesions associated with intermediate and high risk HPV types. Because high risk HPVs are common in both low grade and high grade SIL, p16 may not always discriminate the two; however, the following patterns of staining are usually encountered −− In high grade SIL, there is diffuse immunoreactivity in the upper two-thirds of the epithelium to full thickness −− In low grade SIL, nuclear and cytoplasmic p16 staining can be seen, usually focal and confined to the intermediate and superficial layers

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Fig.  31.9. (A) CIN 1. The upper two-thirds of the epithelium show focal koilocytosis. (B) CIN 2. The upper third of the epithelium shows maturation; mitoses are confined to the basal two-thirds and nuclear abnormalities are more striking than in CIN 1. (C) CIN 3. Nuclear abnormalities throughout the entire thickness of the epithelium and numerous mitotic figures at all levels of the epithelium. −− In cases of low grade SIL with integrated high risk HPV, staining with p16 may be seen in the lower third of the epithelium −− Most studies report minimal or negative staining with p16 in normal, atrophic and inflamed squamous epithelium and immature squamous metaplasia ♦♦ Ki-67 (Mib1), a cell cycle proliferative marker −− In high grade CIN, there is a high proliferation index with staining in the upper two-thirds to full-thickness −− In low grade SIL, Ki-67 is positive predominantly within the lower one-third of the epithelium, with occasional cells within the middle third −− In normal mucosa, Ki-67 is typically confined to the suprabasal cells of the lower third of epithelial cells

Differential Diagnosis ♦♦ Immature metaplasia: nuclear pleomorphism is absent, smooth nuclear contours, mitoses are uncommon and if present are typical and confined to the basal layers; p16 is negative and Ki-67 is typically confined to the suprabasal cells of the lower third of epithelial cells ♦♦ Atrophic epithelium and transitional metaplasia: nuclear ­atypia and mitoses absent; p16 negative, and little or no

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p­ roliferative activity, with only focal staining of the basal and parabasal cells with Ki-67 ♦♦ Reactive atypia: p16 negative, Ki-67 should be interpreted with caution in differentiating reactive atypias from CIN since increased proliferation activity may be seen in reactive atypias ♦♦ Cauterized nondysplastic squamous epithelium: p16 negative and Ki-67 confined to the parabasal cells ♦♦ Microinvasive carcinoma

Early Invasive (Microinvasive) Squamous Cell Carcinoma Clinical ♦♦ Controversial, with lack of agreement over diagnostic criteria ♦♦ FIGO stage IA1 (stromal invasion no greater than 3 mm in depth and 7 mm or less in horizontal spread) tumors are frequently referred to as microinvasive carcinoma ♦♦ The diagnosis is always based on histologic examination of a cone biopsy that includes the entire lesion ♦♦ Lymphovascular space involvement (LVSI) does not affect stage but should be indicated in the report

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Fig. 31.10. (A) High grade SIL in immature squamous metaplasia. (B) Strong and diffuse p16 positivity and (C) Ki-67 supporting a high grade SIL. (D) In low grade SIL p16 staining can be seen, usually focal and confined to the intermediate and superficial layers.

♦♦ Lymph node metastases are very uncommon (<1%) in patients with stromal invasion of 3 mm or less; in contrast to 5.8% in patients with 3.1–5 mm of invasion ♦♦ The risk of lymph node metastases is higher in tumors with LVSI (8.2%) compared to (0.8%) those without it ♦♦ Can be treated using cone biopsy with negative margins; treatment of cases with LVSI is individualized and in some centers treated as IA2 lesions ♦♦ The first sign of invasion is referred to as “early stromal invasion” (encompassed in the term microinvasive carcinoma) −− Unmeasurable lesion <1 mm in depth −− Can be managed in the same way as high grade CIN −− Focus of early stromal invasion appears to be better differentiated than overlying CIN

Macroscopic ♦♦ Similar to CIN on colposcopic examination ♦♦ Variety of patterns including abnormal vessels

Microscopic ♦♦ One or more tongues of malignant cells penetrating through the basement membrane of the squamous epithelium ♦♦ The intraepithelial lesion is usually CIN 3 ♦♦ Invasive cells have increased eosinophilic cytoplasm and may show keratinization (paradoxic maturation) ♦♦ The margin of the invading nest has irregular contours ♦♦ Desmoplastic response of the adjacent stroma and often lymphoplasmacytic infiltrate

Differential Diagnosis ♦♦ CIN 3 with gland involvement −− Borders of the glands involved are round and regular, and stromal desmoplastic response is absent −− If luminal necrosis and intraepithelial squamous maturation within the epithelium are present, one should carefully search for microinvasion

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♦♦ Nests of intraepithelial neoplastic epithelium disrupted and incorporated into the stroma by previous biopsy

Squamous Cell Carcinoma Clinical ♦♦ Uncommon before age 30, but can occur almost at any age between 17 and 90 years (mean 51.4 years) ♦♦ HPV DNA is detected in more than 90% of cases ♦♦ Presenting symptoms depend on size and stage and include postcoital bleeding, intermittent spotting, discharge; patients with stage I disease are usually asymptomatic ♦♦ Diagnosis include cytology and cervical biopsy ♦♦ Risk of nodal involvement increases with depth of invasion ♦♦ Stage is the most important prognostic factor; 5-year survival rates range for stage I is 90–95%

Macroscopic ♦♦ May be exophytic, often as a polypoid excrescence or mainly endophytic infiltrating into surrounding structures ♦♦ Early lesions may present as focally indurated, ulcerated, or as granular area that bleeds readily on touch

Microscopic ♦♦ Considerable morphologic variation ♦♦ Infiltrating nests and clusters with irregular contours ♦♦ May infiltrate as single cells or large masses of neoplastic squamous cells ♦♦ Cells in the center of the invading nests frequently become necrotic or undergo extensive keratinization ♦♦ Individual cells are generally polygonal or oval with eosinophilic cytoplasm ♦♦ Nuclei vary from uniform to pleomorphic ♦♦ Mitotic figures common, including abnormal forms

Differential Diagnosis ♦♦ Squamous metaplasia with extensive endocervical gland involvement: significant nuclear atypia is absent, and mitotic activity is low ♦♦ High grade SIL with extensive endocervical gland involvement: borders of the endocervical glands involved are rounded and distinct, and they lack desmoplastic stroma ♦♦ Epithelioid trophoblastic tumor: presence of a generally lobulated outline, central necrosis, and the immunoprofile ­(placental alkaline phosphatase and human placental ­lactogen positivity) are helpful in making the distinction ♦♦ Small cell undifferentiated carcinoma: hyperchromatic molded nuclei lacking nucleoli, smudged chromatin, prominent lymphatic invasion, and negative staining with p63 ♦♦ Marked decidual reaction

Histologic Types of Squamous Cell Carcinoma Keratinizing ♦♦ Contain keratin pearls composed of circular whorls of squamous cells with central nests of keratin (Fig. 31.11)

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Fig. 31.11. Squamous cell carcinoma of the cervix, keratinizing type.

♦♦ Intercellular bridges, keratohyaline granules, and cytoplasmic keratinization are usually observed ♦♦ Mitotic figures are not frequent, usually seen in a few welldifferentiated cells

Nonkeratinizing ♦♦ Polygonal squamous cells, individual cell keratinization may be present, but keratin pearls are absent ♦♦ Mitotic figures are usually numerous

Basaloid ♦♦ Aggressive tumor ♦♦ Composed of nests of immature, basal type squamous cells with scanty cytoplasm ♦♦ Keratin pearls are rarely present

Verrucous Clinical ♦♦ Highly differentiated squamous cell carcinoma ♦♦ Have a tendency to recur locally after excision, but do not metastasize

Macroscopic ♦♦ Large bulky tumors with warty and fungating appearance

Microscopic ♦♦ Hyperkeratotic, undulating, and warty surface ♦♦ Invades the underlying stroma in the form of bulbous pegs with a pushing border with a subjacent band of inflammatory infiltrate ♦♦ Tumor cells have abundant cytoplasm with minimal, if any, nuclear atypia or mitotic activity

Differential Diagnosis ♦♦ Condyloma: fibrovascular cords and koilocytosis ♦♦ More common types of squamous cell carcinoma:higher nuclear atypia

Uterus and Fallopian Tube

Warty ♦♦ Warty surface and cellular features of HPV infection

Papillary ♦♦ Thin or broad papillae with connective tissue stroma covered by epithelium showing the features of CIN ♦♦ The underlying invasive carcinoma is usually a typical squamous cell carcinoma

Lymphoepithelioma-Like ♦♦ Similar to the nasopharingeal tumor of the same name ♦♦ Poorly defined islands of undifferentiated cells in a background intensely infiltrated by lymphocytes ♦♦ The tumor cells have uniform nuclei with prominent nucleoli and eosinophilic cytoplasm ♦♦ Indistinct cell borders, with a syncytial-like appearance ♦♦ EBV may play a role in the etiology of this tumor

Differential Diagnosis ♦♦ Glassy cell carcinoma ♦♦ Lymphoproliferative disorders

Squamotransitional Cell ♦♦ Rare, apparently indistinguishable from transitional cell carcinomas of the urinary bladder ♦♦ May occur in a pure form or may contain epithelial elements ♦♦ Characterized by papillary architecture with fibrovascular cores lined by a multilayered atypical epithelium resembling CIN 3 ♦♦ Appear to be more closely related to squamous cell carcinomas than to urothelial tumors

Glandular Tumors and Precursor Lesions Adenocarcinoma In Situ (AIS) (Fig. 31.12) Clinical ♦♦ Less common than CIN ♦♦ Mean age at diagnosis 28.8 years ♦♦ Patients are usually 1–2 decades younger than those with invasive carcinoma ♦♦ Risk factors similar to those of squamous lesions ♦♦ Occurs in association with CIN in at least 50% of cases ♦♦ ~90% contain high risk HPV, usually 18

Macroscopic ♦♦ Difficult to detect colposcopically ♦♦ Often superior to squamocolumnar junction ♦♦ No distinctive gross lesion

Microscopic ♦♦ Involves the surface and glands in most cases and multifocal in at least 10–15% of cases ♦♦ Glandular and surface epithelia lined by atypical columnar cells with elongated, cigar-shaped, hyperchromatic nuclei; the cytoplasm is reduced with minimal intracytoplasmic mucin ♦♦ Cells are crowded and pseudostratified

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♦♦ Glands may be focally, multifocally, or diffusely involved ♦♦ Transition between AIS and normal epithelium may be abrupt in some glands ♦♦ Mitotic figures, including abnormal forms and apoptotic bodies, are common ♦♦ Cribriform outpouchings and papillary infoldings may be seen ♦♦ The neoplastic glands do not extend beyond the deepest normal crypt ♦♦ Other types include intestinal (goblet cell) and endometrioid

Immunoprofile ♦♦ Strong diffuse positivity for p16 and high Ki-67 index

Differential Diagnosis ♦♦ Reparative/reactive glandular atypia: nuclear clearing, lack of hyperchromasia, and minimal or no mitotic activity ♦♦ Reactive glandular atypia secondary to irradiation: vacuolated cytoplasm and absence of mitotic figures ♦♦ Adenocarcinoma with early invasion ♦♦ Arias-Stella reaction ♦♦ Microglandular hyperplasia ♦♦ Endometriosis ♦♦ Mesonephric remnants ♦♦ Tubal metaplasia

Atypical Hyperplasia (Glandular Dysplasia) ♦♦ Glandular lesion characterized by nuclear abnormalities but fall short of the criteria for adenocarcinoma in situ; the clinical and pathological features are poorly characterized ♦♦ Prominent pseudostratification of hyperchromatic, enlarged cells, but uniform size and shape ♦♦ Cribriform and papillary formations are absent ♦♦ The nuclei are not cytologically malignant, and mitoses are less numerous than in AIS

Early Invasive (Microinvasive) Adenocarcinoma ♦♦ Controversy as to whether stage IA1 adenocarcinomas exist ♦♦ Usually defined by a depth of invasion of <5 mm measured from the tumor’s origin within the overlying surface or glandular epithelium (if origin not visible, tumor thickness <5 mm) and a horizontal measurement of <7 mm ♦♦ Irregular distribution and architecture of normal endocervical crypts make the distinction between early stromal invasion and adenocarcinoma in situ very difficult ♦♦ Histologic patterns considered indicative of invasion −− Small detached tumor cell islands adjacent to AIS that elicit a stromal response −− Closely packed collections of glands that have lost their smooth outlines −− Smooth-countered, dilated glands with complex intraglandular cribriform or papillary growth pattern ♦♦ The prognosis is excellent and essentially the same as its squamous counterpart

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Fig. 31.12. Adenocarcinoma in situ. (A) Low power, the involved glands maintain a lobular architecture, (B) Higher power, showing nuclear hyperchromasia and mitoses, (C) strong and diffuse positivity with p16 and (D) many Ki-67 positive nuclei. (E) AIS intestinal type.

Adenocarcinoma (Figs. 31.13 and 31.14) Clinical ♦♦ Accounts for 15–25% of cervical carcinomas (compared to 10% 30 years ago) ♦♦ HPV is identified in most cases (particularly types 18 and 16)

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♦♦ 75% of patients present with abnormal vaginal bleeding ♦♦ May present with vaginal discharge and pelvic pain, or asymptomatic ♦♦ At diagnosis, up to 85% will have stage I or stage II disease ♦♦ Rarely, tumors only superficially invasive have presented with ovarian metastases and mimic a primary ovarian tumor

Uterus and Fallopian Tube

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Histologic Subtypes Mucinous Adenocarcinoma

Fig. 31.13. Invasive endocervical adenocarcinoma.

♦♦ 5-year survival rate for patients with negative lymph nodes has been reported to be 92% and 65% for patients with positive lymph nodes

Macroscopic ♦♦ Majority arise in the transformation zone ♦♦ Fungating, polypoid, or papillary mass; diffusely enlarged or nodular cervix ♦♦ In 15%, no gross lesion is visible

Differential Diagnosis ♦♦ Cervical involvement by endometrial adenocarcinoma −− Site of dominant mass clinically and distribution of tumor in a fractional curettage −− Presence of AIS or endometrial hyperplasia in curettage may support one or the other −− Immunohistochemistry may be useful, but not completely reliable −− Almost all endocervical adenocarcinomas show strong diffuse positivity for p16 but should be interpreted with caution since a variety of endometrial carcinomas can be positive but often display a weaker intensity and focal or patchy distribution; endometrial serous carcinoma is usually intensely and diffusely positive for p16 −− Positivity for ER and vimentin favors endometrial carcinoma, and negativity favors endocervical adenocarcinoma −− Detection of HPV DNA in ~80% of endocervical adenocarcinomas

♦♦ Most common type ♦♦ Histologic variants −− Endocervical (a) Accounts for 70% of cervical adenocarcinomas (b) Cells with basal nuclei and abundant pale granular cytoplasm and positive with mucicarmine stain, ­resembling the columnar cells of the normal ­endocervical mucosa −− Intestinal variant (a) Composed of cells similar to those of adenocarcinomas of the large intestine (b) Pseudostratified cells with only small amounts of intracellular mucin (c) Frequently contain goblet cells and more rarely Paneth cells −− Signet ring variant (a) Rare in pure form (b) More commonly a focal finding in poorly differentiated mucinous adenocarcinomas and adenosquamous carcinomas −− Minimal deviation variant (Fig. 31.15) (a) Rare, highly differentiated mucinous adenocarcinoma, originally referred to as adenoma malignum (b) Commonly precede or develop coincidentally with an ovarian carcinoma (c) Associated with ovarian sex cord tumors with annular tubules and Peutz-Jeghers syndrome (d) Cytologically low grade, but architecturally atypical glands that vary in size, shape, and location (e) Glands lined by a single layer of tall columnar epithelium with minimal atypia (f) Occasional mitoses (g) Neoplastic glands extend deeper than the normal endocervical glands (>7 mm from the surface epithelium) −− Villoglandular variant (a) Generally occurs in young women and has an excellent prognosis (b) Surface component composed of papillae lined by one or several layers of columnar cells, some containing mucin (c) If intracellular mucin is absent, it is considered as the endometrioid variant (d) The epithelium has only mild cytologic atypia; scattered mitoses are present (e) Usually superficially invasive, but deep invasion may occur (f) Invasive component is composed of elongated branching glands separated by fibrous stroma

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Fig. 31.14. (A) Endocervical adenocarcinoma. (B) strong and diffuse positivity for p16, (C) mostly negative for ER, and (D) usually negative for vimentin. ♦♦ Histologic features of an endometrioid adenocarcinoma of the endometrium, however, squamous elements are less common ♦♦ Little or no intracellular mucin is present

Clear Cell Adenocarcinoma ♦♦ Rare and histologically similar to their ovarian counterparts ♦♦ Associated with in uteru DES exposure

Serous Adenocarcinoma ♦♦ Rare and histologically identical to their ovarian counterparts ♦♦ Spread from the endometrium, ovaries, or peritoneum should be excluded

Mesonephric Adenocarcinoma

Fig. 31.15. Minimal deviation adenocarcinoma.

Endometrioid Adenocarcinoma ♦♦ Up to 30% of cervical adenocarcinomas

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♦♦ Rare and arise from mesonephric remnants ♦♦ Tubular glands lined by mucin-free cuboidal epithelium containing eosinophilic, hyaline secretions in their lumens ♦♦ Other patterns include branching slit-like spaces with intraluminal fibrous papillae, sex cord-like and solid ♦♦ Cytologic atypia and increased mitotic activity

Uterus and Fallopian Tube

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Immunoprofile

Differential Diagnosis

♦♦ Usually postive for cytokeratins, EMA, vimentin, calretinin, and CD10 ♦♦ Typically negative for ER, PR, and CEA

♦♦ Poorly differentiated nonkeratinizing squamous cell carcinoma: lacks ground glass cytoplasm and macronucleoli

Other Epithelial Tumors Adenosquamous Carcinoma Clinical ♦♦ Accounts for 5–25% of all cervical cancers ♦♦ Occurs in both young and old women, can be associated with pregnancy

Macroscopic ♦♦ Ulcerated and nodular or polypoid

Microscopic ♦♦ Admixure of histologically malignant squamous and glandular cells ♦♦ Squamous component generally contains either keratin pearls or sheets of cells with individual keratinization ♦♦ Histologically recognizable glands must be present for the diagnosis

Differential Diagnosis ♦♦ Poorly differentiated endometrial adenocarcinoma with squamous differentiation involving the cervix ♦♦ Collision tumor of adenocarcinoma with intraepithelial neoplasia or squamous cell carcinoma ♦♦ Endometrioid adenocarcinoma of the cervix with squamous differentiation

Glassy Cell Carcinoma Variant Clinical

Adenoid Cystic Carcinoma Clinical ♦♦ Rare; most patients above 60 years of age ♦♦ Majority present with postmenopausal bleeding and mass on pelvic exam ♦♦ Frequently recurs locally or metastasizes to distant organs; unfavorable prognosis

Microscopic ♦♦ Histologic appearance similar to its counterpart in the salivary glands but with greater nuclear pleomorphism, high mitotic rate, and necrosis ♦♦ Characteristic spaces filled with eosinophilic hyaline material or basophilic mucin and surrounded by palisaded epithelial cells ♦♦ Collagen type IV and laminin positive; S-100 and HHF35 positive suggesting myoepithelial differentiaton

Differential Diagnosis ♦♦ Small cell carcinoma; adenoid basal cell carcinoma and nonkeratinizing squamous cell carcinoma

Adenoid Basal Carcinoma (Fig. 31.16) Clinical ♦♦ Rare; usually above 50 years of age ♦♦ Usually asymptomatic, often discovered as an incidental finding ♦♦ Low grade and rarely metastasizes

♦ ♦ Poorly differentiated variant of adenosquamous carcinoma ♦♦ Accounts for <1% of cervical cancers ♦♦ Younger mean age (31–41 years) than patients with cervical adenocarcinoma or squamous cell carcinoma ♦♦ Reported to have an extremely aggressive clinical course

Macroscopic ♦♦ Large and produce a barrel-shaped cervix

Microscopic ♦♦ Uniform, large polygonal cells with finely granular ground glass-type cytoplasm ♦♦ Distinct cell membranes ♦♦ Prominent nucleoli ♦♦ The cells lack intercellular bridges, dyskeratosis, and intra­ cellular collagen ♦♦ Abundant mitotic figures ♦♦ Stroma is heavily infiltrated by lymphoplasmacytic and eosinophilic inflammatory cells

Fig. 31.16. Adenoid basal carcinoma. Nests of tumor infiltrate the cervical stroma. Surface epithelium shows CIN 3.

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Microscopic ♦♦ Small nests of basaloid cells; the cells are small with scanty cytoplasm and arranged in nests and cords with focal glandular or squamous differentiation ♦♦ Frequently associated with CIN or small invasive squamous cell carcinomas

Neuroendocrine Tumors Carcinoid ♦♦ Generally benign ♦♦ Characteristic organoid appearance as seen in other sites ♦♦ Chromogranin and synaptophysin positive

Atypical Carcinoid ♦♦ Carcinoid with cytologic atypia, increased mitotic activity (5–10 mf/10 hpf), and foci of necrosis

Small Cell Carcinoma Clinical ♦♦ Accounts for 2–5% of all carcinomas of the cervix ♦♦ Tends to occur in younger women than squamous cell carcinoma ♦♦ Aggressive neoplasm with early metastases ♦♦ Frequently associated with HPV 18; type 16 has also been found

Macroscopic ♦♦ Often large ulcerated lesions ♦♦ Frequently deeply infiltrative

Microscopic ♦♦ Histologically identical to their counterparts at other sites such as the lung ♦♦ Sheets and cords of small anaplastic cells with scant cytoplasm, finely stippled chromatin and inconspicuous nucleoli ♦♦ Hyperchromatic nuclei, high nuclear cytoplasmic ratio, and high mitotic rate ♦♦ Areas of squamous or glandular differentiation, if present, should represent <5% of the total tumor volume ♦♦ Necrosis common

Immunoprofile ♦♦ Chromogranin and synaptophysin are positive in only about 40% of the cases; therefore, negative immunostains for these markers does not exclude the diagnosis and are not required to make the diagnosis ♦♦ p16 positive ♦♦ p63 negative

Differential Diagnosis ♦♦ Poorly differentiated squamous cell carcinoma composed of small cells −− Lack nuclear molding and crush artifact; may have focal positivity for neuroendocrine markers

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−− p63 may be useful for differentiating neuroendocrine carcinoma (p63 negative) from squamous cell carcinoma (p63 positive) ♦♦ Poorly differentiated adenocarcinoma with neuroendocrine features

Large Cell Neuroendocrine Carcinoma ♦♦ Rare tumor that often has adenocarcinomatous differentiation ♦♦ The tumor cells have abundant cytoplasm, large nuclei, and prominent nucleoli; mitoses are frequent ♦♦ Geographic necrosis ♦♦ Lymphovascular invasion often present ♦♦ Chromogranin and synaptophysin positive; p16 positive and p63 negative ♦♦ Aggressive tumors with outcome similar to that in small cell carcinoma

Undifferentiated Carcinoma ♦♦ Carcinoma lacking specific differentiation

Mesenchymal Tumors Smooth Muscle Tumors Leiomyoma ♦♦ Most common benign mesenchymal tumor of the cervix ♦♦ ~8% of uterine leiomyomas are primary in the cervix ♦♦ Usually single, and produce unilateral enlargement of the cervical portio ♦♦ May protrude through the canal resembling an endocervical polyp ♦♦ Grossly and microscopically similar to those observed in the myometrium (see smooth muscle tumors of the uterine corpus) ♦♦ A variety of histologic patterns may be encountered

Leiomyosarcoma Clinical ♦♦ Primary cervical sarcomas are extremely rare; leiomyosarcoma is the most common. (<30 cases reported) ♦♦ Usually in perimenopausal women, most present with vaginal bleeding

Macroscopic ♦♦ Mass replacing and expanding the cervix or as a polypoid growth

Microscopic ♦♦ Hypercellular interlacing fascicles of large spindle-shaped or round cells ♦♦ Diffuse moderate to marked nuclear atypia ♦♦ High mitotic rate, including atypical forms ♦♦ Tumor cell necrosis ♦♦ Infiltrative borders and vascular invasion are frequent

Uterus and Fallopian Tube

Other Benign Mesenchymal Tumors ♦♦ ♦♦ ♦♦ ♦♦

Lipoma Hemangioma Schwannoma Paraganglioma

Other Malignant Mesenchymal Tumors ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Endometrial stromal sarcoma, low grade Undifferentiated endocervical sarcoma Sarcoma botryoides (embryonal rhabdomyosarcoma) Alveolar soft-part sarcoma Malignant peripheral nerve sheath tumor Osteosarcoma

Mixed Epithelial and Mesenchymal Tumors Adenomyoma Clinical ♦♦ Rare in the cervix ♦♦ Benign and may recur following local excision

Macroscopic ♦♦ Usually polypoid with a firm surface and small cystic areas may be present ♦♦ Rare tumors are intramural

Microscopic ♦♦ Consists of a benign glandular and benign mesenchymal component composed exclusively or predominantly of smooth muscle ♦♦ The glandular component may be lined by endocervical-type epithelium, or endometrial-type glands surrounded by endometrial-type stroma

Adenofibroma Clinical ♦♦ Uncommon in the cervix ♦♦ Benign and recurrence may follow incomplete removal

Macroscopic ♦♦ Polypoid, usually protrude into the endocervical canal ♦♦ Small cystic spaces may be present

Microscopic ♦♦ Papillary fronds lined by glandular type epithelium, cuboidal, columnar, ciliated, mucinous, or attenuated ♦♦ Benign squamous epithelium may be present ♦♦ Mesenchymal component composed of nonspecific fibrous tissue, with minimal mitotic activity

Differential Diagnosis ♦♦ Adenosarcoma

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Adenosarcoma Clinical ♦♦ Much less common than their counterparts in the uterine corpus ♦♦ Reported in women between 14 and 67 years of age ♦♦ Present with vaginal bleeding or recurrent cervical polyps ♦♦ Prognosis is typically good after surgical therapy; recurrent tumor and death can occur

Macroscopic ♦♦ Broad-based polyp arising from the cervix

Microscopic ♦♦ Biphasic tumor composed of malignant stroma admixed with benign epithelial elements ♦♦ Similar to its counterpart in the endometrium, however, the epithelium is more likely to be squamous or mucinous ♦♦ The sarcomatous component may consist of mitotically active spindle cells forming periglandular cuffs or contain foci with a more embryonic appearance with small undifferentiated mitotically active cells ♦♦ Heterologous sarcomatous elements may be present ♦♦ May or may not invade the underlying cervical stroma

Carcinosarcoma (Malignant Mixed Mesodermal Tumor) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Much less common than their uterine counterparts Usually occur in postmenopausal women Aggressive neoplasms Compared to their uterine counterparts, they appear to be more often confined to the uterus and may have a better prognosis

Macroscopic ♦♦ Polypoid or pedunculated masses

Microscopic ♦♦ Composed of an admixture of malignant epithelial and mesenchymal components ♦♦ Histologic features are similar to its counterpart in the uterine corpus, however, the carcinomatous component is most commonly a basaloid pattern ♦♦ Other epithelial patterns include squamous cell carcinoma, endometrioid adenocarcinoma, and less commonly adenoid basal and adenoid cystic components

Melanocytic Tumors Blue Nevus ♦♦ Benign, typically incidental finding ♦♦ Most occur in the endocervical canal ♦♦ Poorly circumscribed collections of heavily pigmented, bland, spindle-shaped cells in the superficial cervical stroma

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Malignant Melanoma Clinical

♦♦ Polyploid friable masses ♦♦ Histological features similar to their counterparts at other sites

♦♦ Rare and considerably less common than vulvar or vaginal melanoma ♦♦ Present with abnormal vaginal bleeding ♦♦ Spread to vagina is often present at the time of presentation ♦♦ Poor prognosis

Mature Cystic Teratoma

Macroscopic

Lymphoid and Hematopoietic Tumors

♦♦ Polypopid or fungating pigmented masses ♦♦ May also be amelanotic

♦♦ Lymphomas and leukemias can involve the cervix ♦♦ Most often are secondary, as a manifestation of a systemic disease ♦♦ Primary lymphomas can occasionally arise in the cervix, usually in premenopausal women; 70% are of diffuse large cell type, and 20% are lower grade follicular lymphomas

Microscopic ♦♦ Similar histologic features as those in the skin, vulva, and vagina ♦♦ Spindle-shaped cells are frequently present ♦♦ Junctional component is present in 50% of cases

Differential Diagnosis ♦♦ Metastatic melanoma involving the cervix

Tumors of Germ Cell Type Yolk Sac Tumor ♦♦ Second most common site in the lower genital tract after the vagina ♦♦ Present with abnormal vaginal bleeding

♦♦ Presents as smooth cervical polyps ♦♦ Glial and squamous epithelial elements are common ♦♦ It has been suggested that they represent implanted fetal tissues rather than true neoplasms

Secondary Tumors ♦♦ Most common source represents direct extension from local pelvic tumor (endometrial, rectal, and bladder carcinomas) ♦♦ Up to 50% result from direct extension from an endometrial primary tumor ♦♦ Lymphatic or vascular metastasis is less frequent, associated with ovarian carcinoma ♦♦ Metastases from distant primary tumors are rare; the most common sites are gastrointestinal tract (colon and stomach) and breast

UTERUS – CORPUS Morphology of the Endometrium Endometrial Cycle ♦♦ The morphologic variations of the endometrium throughout the cycle allow documentation of whether ovulation has occurred and diagnosis of specific causes of infertility ♦♦ The first day of bleeding is considered day 1 of the cycle

Proliferative Phase ♦♦ Preovulatory phase, variable in length ♦♦ Daily morphologic alterations are not sufficiently obvious to allow accurate dating and can be divided into early, mid, and late phases ♦♦ Early proliferative −− Thin regenerating surface epithelium −− Straight short narrow glands with mitoses −− Compact stroma with some mitotic activity and large nuclei with scant cytoplasm (“naked nuclei”) ♦♦ Midproliferative −− Columnar surface epithelium −− Longer curving glands

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−− Variable stromal edema and numerous mitoses in naked nuclei ♦♦ Late proliferative −− Somewhat undulant surface −− Tortuous glands with active pseudostratified epithelium −− Moderately dense stroma

Interval Phase ♦♦ Scattered subnuclear vacuoles are present (less than 50% of the glands exhibit uniform subnuclear vacuolization) ♦♦ Although the normal endometrium from POD 1 to POD 2 has this appearance, this pattern does not guarantee that ovulation has occurred

Secretory Phase ♦♦ Postovulatory phase ♦♦ Daily morphologic changes are distinct and allow accurate dating ♦♦ Early secretory −− POD 2: More than 50% of the glands exhibit uniform subnuclear vacuolization, exaggerated nuclear pseudostratification; mitotic figures are present

Uterus and Fallopian Tube

−− POD 3: Subnuclear vacuoles and nuclei uniformly aligned; scattered mitotic figures −− POD 4: Vacuoles in luminal position −− POD 5: Vacuoles infrequent and secretion in gland lumens ♦♦ Midsecretory −− POD 6: Secretion prominent −− POD 7: Beginning stromal edema −− POD 8: Maximal stromal edema ♦♦ Late secretory −− POD 9: Spiral arteries first prominent −− POD 10: Thick periarterial cuffs of predecidua −− POD 11: Islands of predecidua in superficial compactum −− POD 12: Beginning coalescence of islands of predecidua −− POD 13: Confluence of surface islands; stromal granulocytes prominent −− POD 14: Extravasation of red cells in stroma and prominence of stromal granulocytes

Menstrual Phase ♦♦ Normally lasts for 4 ± 1 days ♦♦ Endometrial mucosa rapidly degenerates, with 50% of menstrual detritus expelled in the first 24 h of menses ♦♦ Tissue shedding is followed by regeneration

Microscopic

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Inactive Endometrium ♦♦ Endometrium is as thick as that in early to mid proliferative phase but lacks morphologic features of active proliferation or secretion ♦♦ Glands and stroma resemble proliferative endometrium but with fewer glands usually oriented parallel rather than ­perpendicular to the surface ♦♦ Epithelium at the surface and that lining the glands is columnar to cuboidal, with pseudostratified nuclei without mitoses ♦♦ Dense stroma, without clear separation between basalis and functionalis

Atrophic Endometrium (Fig. 31.17) ♦♦ Most common cause of abnormal uterine bleeding in ­postmenopausal women ♦♦ Thinned endometrial mucosa ♦♦ Decrease in the number of glands and stromal volume ♦♦ Surface and glandular epithelia are low and cuboidal ♦♦ Stroma is often collagenized ♦♦ Cystically dilated glands are often present

Pregnancy-Related Changes ♦♦ Similar findings occasionally occur in patients receiving ­progestins or rarely with no apparent cause

Arias-Stella Reaction (Fig. 31.18)

♦♦ Dilated glands lined by flattened cells, often with frayed ­borders (secretory exhaustion) ♦♦ Fully decidualized stroma ♦♦ Karyorrhectic fragments present in the subnuclear area of some glands ♦♦ Epithelial nuclei are pyknotic ♦♦ Fibrin thrombi in vessels and stroma ♦♦ Glands break up into strips, crumbling stroma

♦♦ Histologic change within endometrial glands associated with intrauterine or extrauterine pregnancy or trophoblastic disease ♦♦ Occasionally can occur in pre- and postmenopausal women on hormonal medication ♦♦ Voluminous cells with large hyperchromatic nuclei and irregular nuclear membranes, sometimes with a hobnail appearance, and with clear vacuolated cytoplasm ♦♦ Nuclear atypia may be striking

Fig. 31.17. Atrophic endometrium, strips of attenuated surface epithelium on curettage.

Fig. 31.18. Gestational endometrium with Arias-Stella reaction. Cells with enlarged hyperchromatic nuclei and clear vacuolated cytoplasm.

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♦♦ Nuclear cytoplasmic ratio is normal ♦♦ Mitoses are absent or rare ♦♦ The focal nature, presence of other pregnancy related changes, and mitotic inactivity help in the differential diagnosis of ­adenocarcinoma, particularly clear cell carcinoma

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−− Frequent epithelial and stromal metaplasia −− Malignant transformation occurs in up to 3%: ­­endometrioid adenocarcinoma is the most frequent, but other types of malignant neoplasms may develop

Optically Clear Nuclei

Progestins and Estrogen-Progestin Combinations

♦♦ Alteration of nuclei in endometrial glandular epithelium, associated with pregnancy and trophoblastic disease ♦♦ Nuclear vacuolization, resembling the ground glass ­appearance of herpes virus inclusions

♦♦ Most commonly, atrophic, uncoiled glands embedded in a predecidualized or decidualized stroma (Fig. 31.19) ♦♦ After prolonged exposure to these agents, profound atrophy of the endometrium can occur

Decidual Reaction

Dysfunctional Uterine Bleeding

♦♦ In pregnancy or as a result of exogenous progestational ­therapy; rare examples in women with no apparent cause ♦♦ Large epithelioid decidual cells ♦♦ Unusual features associated with diagnostic problems include −− Nuclear pleomorphism and hyperchromasia may mimic sarcoma −− Marked cytoplasmic vacuolation mimics signet ring carcinoma −− May be polypoid and necrotic

♦♦ Clinical term bleeding not attributable to an underlying organic pathologic condition

Effects of Hormone Administration Tamoxifen ♦♦ Synthetic antiestrogen used in the treatment of breast carcinoma ♦♦ Acts as a partial estrogen receptor antagonists in neoplastic breast tissue and as an agonist in the endometrium ♦♦ Has been associated with an increased frequency of proliferative endometrial lesions including hyperplasias, polyps, and malignant tumors ♦♦ Tamoxifen-associated endometrial polyps may show distinctive morphology −− Large, sessile with a wide implantation base and ­frequently show a honeycomb appearance −− Bizarre stellate glands

Glandular and Stromal Breakdown Associated with Anovulation Clinical ♦♦ Characteristically occurs at menarche and menopause, and can occur at any time during reproductive years ♦♦ Patients with polycystic ovarian disease are often anovulatory ♦♦ One or more follicles develop in the ovary without development of a corpus luteum ♦♦ Stromal and glandular differentiation of the secretory phase do not develop due to lack of progesterone ♦♦ When estrogen levels decline, the endometrium can no longer be maintained and bleeding occurs

Microscopic ♦♦ The endometrium may appear extensively fragmented ♦♦ Background proliferative endometrium ♦♦ Stromal cells condense and form compact nests with hyperchromatic nuclei and little or no cytoplasm ♦♦ Papillary syncytial metaplasia is frequently associated with stromal breakdown bleeding ♦♦ Glands should be carefully examined for abnormal shape, cellular stratification, and nuclear atypia that may reflect concurrent breakdown and hyperplasia

Differential Diagnosis ♦♦ Menstrual endometrium −− Predecidual reaction is present, and the glands are typically dilated and filled with secretions −− Degenerative cytoplasmic vacuolation may be seen in either ♦♦ Hyperplasia −− Glands with abnormal shapes, stratified epithelium, and atypia

Inadequate Luteal Phase/Luteal Phase Defect Clinical Fig.  31.19. Endometrium with progestin effect, attenuated glands with pseudodecidua.

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♦♦ Thought to result from inadequate progesterone secretion due to inadequate development or early regression of the corpus luteum

Uterus and Fallopian Tube

♦♦ Usually diagnosed during evaluation for infertility or abnormal bleeding ♦♦ Diagnostic findings in at least two consecutive cycles are required for this interpretation ♦♦ Found only in 3–5% of infertile women and is of ­controversial significance

Microscopic ♦♦ Precise pathologic criteria have not been definitively established ♦♦ Endometrium resembles normal secretory endometrium, but is at least 2 days earlier than expected ♦♦ Dating may be impossible due to a discordant appearance of the glands and stroma

Irregular Shedding Clinical

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−− Identification of a specific microorganism is based on culture −− Antibiotic therapy is indicated to prevent other sequelae

Microscopic ♦♦ Criteria for the diagnosis of acute endometritis include identification of moderate to large numbers of PMNs in nonbleeding endometrium, microabscesses in the stroma, or PMNs filling and disrupting the glands ♦♦ The diagnosis of chronic endometritis is based on the identification of plasma cells ♦♦ Lymphocytes, macrophages, and PMNs may also be present ♦♦ Features suggestive of chronic endometritis include a reactive-appearing, dense spindle cell transformation of the stromal cells in a pinwheel arrangement, and the inability to date the endometrium

♦♦ Possible cause: Persistence of corpus luteum resulting in prolonged exposure to progesterone ♦♦ Diagnosed when endometrial tissue obtained at least 5 days after the onset of bleeding shows a mixture of secretory and proliferative patterns ♦♦ Rare cause of abnormal bleeding in women between 24 and 50 years of age

Specific Types of Chronic Endometritis Chlamydia

Microscopic

Mycoplasma

♦♦ Irregular star-shaped secretory glands admixed with early proliferative glands ♦♦ The stroma around the proliferative glands is dense and compact, while the one around the secretory glands is edematous and may have predecidual cells ♦♦ Frequent evidence of glandular and stromal breakdown

♦♦ Associated with infertility and fetal wastage

Nonneoplastic Lesions Acute and Chronic Endometritis Clinical ♦♦ Usually results from ascending infection through the cervix ♦♦ The cervical barrier is altered during menses, abortion, parturition, and instrumentation ♦♦ Acute endometritis −− Clinically significant acute endometritis is usually associated with pregnancy or abortion −− Most caused by hemolytic Streptococcus, Staphylococcus, Neisseria gonorrheae, and Clostridium welchii ♦♦ Chronic endometritis −− Patients may be asymptomatic or present with menometrorrhagia, mucopurulent cervical discharge, uterine tenderness, elevated erythrocyte sedimentation rate, or leukocytosis −− Associated with abortion, usually due to retained gestational tissue, with salpingitis, and with intrauterine device; in 15% of cases, a primary cause is not obvious −− Most commonly caused by Chlamydia trachomatis and Neisseria gonorrheae

♦♦ Mixed inflammatory infiltrate is composed of plasma cells, lymphocytes, and PMNs; plasma cell infiltrate is denser than that in gonococcal endometritis ♦♦ Lymphoid follicles with transformed lymphocytes

Tuberculosis ♦♦ Part of a systemic disease ♦♦ Second most frequently affected site in the female genital tract after the fallopian tube ♦ ♦ Typical caseating granulomas, may vary from a focal to ­d iffuse process; caseation may not be evident in some cases

Fungal Infections ♦♦ Granulomatous endometritis may be seen as part of a disseminated infection in blastomycosis and coccidiomycosis

Viral Infections ♦♦ Herpes simplex virus, cytomegalovirus, and human immunodeficiency virus are known to infect the endometrium

Parasitic Infections ♦♦ Schistosoma, Enterobius vermicularis and Echinococcus granulosus, and rare causes in the United States ♦♦ Schistosomiasis is endemic in Central America, Africa, the Middle East, and the Far East

Xantogranulomatous or Histiocytic Endometritis ♦♦ Postmenopausal women ♦♦ Numerous histiocytes with foamy cytoplasm

Malakoplakia ♦♦ Rare form of endometritis of probable bacterial origin ♦♦ Intracellular and extracellular calcified spherules (Michaelis– Gutman bodies)

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Lymphoma-Like Lesion Clinical ♦♦ Usually women of reproductive age ♦♦ May present with abnormal bleeding or incidental ­microscopic finding ♦♦ No history of malignant lymphoma

Macroscopic ♦♦ Usually no gross mass

Microscopic ♦♦ Aggregates of lymphoid cells resembling reactive germinal centers with a mixed inflammatory infiltrate at the periphery of the aggregates ♦♦ Usually a background of chronic endometritis ♦♦ Myometrial involvement is absent

Differential Diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Hyperplastic or carcinomatous changes may involve adeno­ myosis ♦♦ Variations in adenomyosis that should be differentiated from malignant tumors −− Intravascular endometrial tissue, consisting of pure stroma or glands and stroma −− Adenomyosis with sparse glands, typically in postmenopausal women, and adenomyotic foci consist mainly or exclusively of endometrial stroma −− Adenomyosis with atrophic stroma, typically in postmenopausal women; glands deep within the myometrium are surrounded directly by smooth muscle

Differential Diagnosis ♦♦ Normal penetration of endometrium into the myometrium ♦♦ Low grade endometrial stromal sarcoma ♦♦ Invasive adenocarcinoma

♦♦ Malignant lymphoma

Endometrial Metaplasias (Fig. 31.20)

Changes Related to Intrauterine Devices

♦♦ Variety of benign cytoplasmic alterations of the endometrial epithelium that are not encountered in normal proliferative endometrium ♦♦ Develop most commonly in response to estrogenic and progestational stimulation ♦♦ Often coexist with hyperplasia, most likely because both result from a hyperestrogenic state ♦♦ May be focal or diffuse, endometrial polyps may also be affected ♦♦ Cytoplasmic alterations by themselves have no prognostic significance, and the most important aspect is to recognize these benign processes and not to confuse them with hyperplasia or carcinoma

♦♦ Vary with the type of device and duration of use ♦♦ Include chronic endometritis, squamous metaplasia, reparative hobnail cell metaplasia, and progestational changes in progesterone impregnated devices ♦♦ Predisposes to colonization or infection with Actinomyces and infection characterized by typical sulfur granules ♦♦ Actinomyces must be distinguished from the Splendore– Hoeppli phenomenon, a pseudoactinomycotic radiate granule related to a tissue response to IUD

Adenomyosis Clinical ♦♦ Common condition characterized by the finding of endometrial glands and stroma within the myometrium ♦♦ Usually in pre- or perimenopausal women ♦♦ Commonly associated with abnormal bleeding and dysmenorrhea but may be asymptomatic ♦♦ Clinical diagnosis can be confirmed by imaging studies

Eosinophilic Metaplasia (Including Syncytial Metaplasia)

♦♦ Moderately enlarged uterus ♦♦ Focally or diffusely thickened and trabeculated myometrium ♦♦ Occasionally, small blood-filled cysts may be present

♦♦ Most common cytoplasmic alteration ♦♦ Endometrial glands or the surface epithelium is replaced by nonciliated cells with abundant eopsinophilic cytoplasm and uniform, round central nuclei ♦♦ Mitotic figures are rare ♦ ♦ On the endometrial surface, the eosinophilic cells may form a syncytium or a papillary process that lacks stromal cores ♦♦ Eosinophilic syncytial change is commonly associated with endometrial stromal breakdown

Microscopic

Squamous Metaplasia

♦♦ Exact criteria for histologic diagnosis are not clear ♦♦ Some authors recommend to make the diagnosis when the distance between the lower border of the endometrium and the adenomyosis is greater than one half of a low power field (about 2.5  mm); others use a distance of one high power field ♦♦ Variable response to ovarian hormones ♦♦ Usually proliferative or inactive endometrium

♦♦ May occur in all forms of hyperplasia as well as in carcinoma, most commonly in atypical hyperplasias and low grade carcinoma ♦♦ It is rare in normal cycling endometrium or hyperplasia without atypia ♦♦ Typically cytologically bland squamous cells with moderate amount of eosinophilic cytoplasm and well-defined cell membrane; mitotic activity is rare

Macroscopic

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Fig. 31.20. (A) Endometrium with surface eosinophilic change associated with breakdown changes. (B) Hobnail change after curettage.

♦♦ The squamous cells may be spindle-shaped forming intraglandular nests (morules), reflecting immature or incomplete squamous differentiation

Tubal Metaplasia ♦♦ Refers to the presence of a significant number of ciliated glandular cells with intercalated (peg) cells resembling the epithelium of the fallopian tube; rarely, cilia develop without associated intercalated cells ♦♦ Reflects estrogenic stimulation and is frequently associated with simple, complex, or atypical hyperplasia ♦♦ The glands with ciliated cell change may show architectural and/or cytologic atypia (atypical hyperplasia with ciliated cell change)

Secretory Change, Clear Cell, and Hobnail Metaplasia ♦♦ Secretory change is characterized by columnar cells with sub or supranuclear vacuoles with clear glycogenated cytoplasm, resembling glandular cells of early secretory endometrium; it is seen more often in association with hyperplasia or carcinoma ♦♦ Hobnail change may be an idiopathic change but often represents a reactive change seen after curettage or the one seen on the surface of an infracted polyp. Rarely the cells in ­secretory change can display hobnail morphology resembling Arias-Stella reaction ♦♦ Clear cell change refers to polygonal cells with clear cytoplasm containing glycogen and bland nuclei in glands or on the surface endometrial epithelium. Distinguished from clear cell carcinoma by the noninvasive nature of the glands and absence of mitotic activity

Mucinous Metaplasia ♦♦ Endometrial glands or the surface endometrial epithelium is replaced by mucinous epithelium resembling that of the endocervix ♦♦ Mucinous metaplasia can be accompanied by a papillary proliferation

♦♦ Mitotic figures are rare ♦♦ Perimenopausal and postmenopausal women with complex mucinous proliferations have a high risk of coexistent carcinoma

Miscellaneous Lesions ♦♦ ♦♦ ♦♦ ♦♦

Inflammatory pseudotumor Postoperative spindle cell nodule Arteriovenous malformations Heterologous tissues (bone, cartilage, smooth muscle, and glial tissue) ♦♦ Giant cell arteritis ♦♦ Intravascular menstrual endometrium

Epithelial Tumors and Related Lesions Endometrial Polyps (Fig. 31.21) Clinical ♦♦ Common after 40 years of age, rare before menarche ♦♦ Most commonly present with intermenstrual bleeding or menometrorrhagia in young women and with postmenopausal bleeding ♦♦ There is no evidence that polyps have a significantly higher propensity for developing carcinoma than adjacent endometrium, but may represent a marker of increased cancer risk

Macroscopic ♦♦ Sessile or pedunculated ♦♦ Vary in size from 1 mm to large masses filling the ­endometrial cavity ♦♦ Large pedunculated polyps may protrude through the cervix ♦♦ Surface is usually smooth and glistening but may have focal erosion or hemorrhage

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 31.21. Endometrial polyp. (A) Grossly hemorrhagic surface can be seen in infarcted polyps. (B) Endometrial polyp composed of irregularly distributed glands and surface epithelium on three sides.

Microscopic ♦♦ Composed of irregularly distributed endometrial glands and stroma ♦♦ Glands may be inactive, exhibit normal proliferative or secretory features, and focally dilated ♦♦ May be categorized as hyperplastic, atrophic, or functional ♦♦ The stroma is focally or diffusely fibrotic and contains thickwalled blood vessels ♦♦ Uncommonly, the stroma may contain foci of smooth muscle (classified as adenomyoma if prominent), multinucleated stromal giant cells and decidua ♦♦ Polyps may contain atypical hyperplasia or carcinoma

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Endometrial hyperplasia Polypoid adenocarcinomas Adenosarcoma Adenofibroma

Precursor Lesions of Endometrial Carcinoma Endometrial Hyperplasia (Fig. 31.22) Clinical ♦♦ Heterogeneous group of abnormal endometrial proliferations that develops as a result of unopposed estrogenic stimulation ♦♦ Proliferation of glands of irregular size and shape with an increase in the gland/stroma ratio compared with ­proliferative endometrium ♦♦ Usually presents with abnormal bleeding ♦♦ Endometrial hyperplasias are classified by their degree of architectural complexity as simple or complex and by their

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♦♦ ♦♦

♦♦

♦♦

cytologic (nuclear) features as hyperplasia without atypia or atypical hyperplasia The hyperplastic process may be focal or involve the entire endometrium WHO classification of endometrial hyperplasia −− Hyperplasias (typical) (a) Simple hyperplasia (b) Complex hyperplasia −− Atypical hyperplasias (a) Simple atypical hyperplasia (b) Complex atypical hyperplasia 25% of atypical hyperplasias progress to carcinoma, whereas <3% of hyperplasias without cytologic atypia progress to carcinoma Atypical hyperplasia is recognized as the precursor lesion for the endometrioid type of endometrial carcinoma

Microscopic ♦♦ Simple hyperplasia −− Cystically dilated glands with glandular outpouchings surrounded by an abundant cellular stroma −− In some cases, the glands are only minimally dilated but focally crowded −− The glands are lined by pseudostratified columnar cells without cytologic atypia −− Mitotic activity is variable ♦♦ Complex hyperplasia −− Complex glands with little intervening stroma (back-toback glandular crowding) −− Usually glandular outlines are highly complex with ­epithelial budding into both lumina and stroma, but can be tubular

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Fig. 31.22. (A) Simple hyperplasia. Slight crowding of glands with abnormal branching. (B) Complex hyperplasia. There is marked glandular crowding resulting in a “back to back” appearance and the glands show complex glandular outlines. (C) Atypical complex hyperplasia. Rounded nuclei with loss of polarity. −− Epithelial stratification can range from two to four layers lacking nuclear atypia −− Variable mitotic activity, usually <5 mf/10 hpf ♦♦ Atypical hyperplasias −− Glands lined by cytologically atypical cells (loss of polarity, increased nuclear: cytoplasmic ratio, prominent nucleoli, and cleared or dense chromatin) −− Atypia is usually focal −− Simple atypical hyperplasia is rare, features atypical glandular cytology superimposed on the architecture of simple hyperplasia −− Complex atypical hyperplasia is characterized by atypical glandular cytology superimposed on the architecture of complex hyperplasia

−− Have dense fibrous stroma with thick-walled blood vessels and usually covered on three sides by surface epithelium ♦♦ Endometrial and stromal breakdown −− Glandular fragmentation, nuclear dust, and clusters of stromal cells are usually absent in hyperplasia ♦♦ Atypical polypoid adenomyoma ♦♦ Well-differentiated carcinoma −− Evidence of stromal invasion −− Criteria that identify stromal invasion (a) Altered fibroblastic stroma (desmoplastic response) (b) Confluent glandular pattern uninterrupted by stroma, at times cribriform (c) Extensive papillary pattern

Differential Diagnosis

Endometrial Intraepithelial Carcinoma (Fig. 31.23) Clinical

♦♦ Disordered proliferative phase −− Reproductive age, premenopausal −− Irregularly shaped and enlarged glands focally ­interspread within normal proliferative glands ♦♦ Endometrial polyps −− Often have areas of simple or complex hyperplasia

♦♦ Recognized as the precursor lesion for serous carcinoma; the prototypic endometrial carcinoma not related to estrogenic stimulation ♦♦ Typically occurs in the setting of endometrial atrophy

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Fig.  31.23. (A) Endometrial intraepithelial carcinoma. Highly atypical cells replacing the surface endometrium and underlying gland. Nonneoplastic endometrium is atrophic. (B) Partial involvement of a gland by EIC. (C) p53 immunostain.

♦♦ Clinical significance similar to invasive serous carcinoma since it can be associated with disseminated disease in the absence of an invasive carcinoma in the endometrium ♦♦ Potential future application of the term for precursor lesions of other subtypes of carcinoma

Microscopic ♦♦ Noninvasive replacement of endometrial glandular ­epithelium by markedly atypical cells identical to those of invasive serous carcinomas ♦♦ Enlarged nuclei with granular or vesicular chromatin and enlarged eosinophilic nucleoli ♦♦ Numerous mitotic figures, including atypical forms ♦♦ Usually background atrophic endometrium

Immunoprofile ♦♦ Diffuse intense p53 positivity and very high proliferation index with Ki-67

Differential Diagnosis ♦♦ Serous carcinoma

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−− If glandular confluence or stromal invasion is present, or a proliferation of crowded glands ­measuring >1 cm is present, the lesion qualifies as serous carcinoma ♦♦ Benign metaplastic endometrial lesions −− Very low proliferative indices assessed with Ki-67 immunostain, and typically p53 negative (but may show weak positivity for p53)

Endometrial Carcinoma Classification (WHO) ♦♦ Endometrioid carcinoma −− Variant with squamous differentiation −− Villoglandular variant −− Secretory variant −− Ciliated variant ♦♦ Mucinous adenocarcinoma ♦♦ Serous adenocarcinoma ♦♦ Clear cell adenocarcinoma ♦♦ Mixed cell adenocarcinoma

Uterus and Fallopian Tube

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Squamous cell carcinoma Transitional cell carcinoma Small cell carcinoma Undifferentiated carcinoma Others

Epidemiology/Clinical ♦♦ Most common invasive neoplasm of the female genital tract in developed countries ♦♦ Most occur in perimenopausal and postmenopausal women ♦♦ Majority of cases present clinically with abnormal uterine bleeding ♦♦ Risk factors include −− Unopposed estrogen stimulation −− Obesity −− Nulliparity −− Hypertension −− Diabetes mellitus −− Early menarche and late menopause ♦♦ Clinically and epidemiologically, endometrial carcinoma can be classified into two types −− Type I (estrogen related) (a) Unopposed estrogen present (b) Pre-and perimenopausal (c) Precursor lesion: atypical hyperplasia (d) Tends to be low grade with minimal myometrial invasion (e) Endometrioid subtype (f) Tends to have indolent behavior (g) PTEN mutation, microsatellite instability, and K-ras mutation −− Type II (nonestrogen-related) (a) Unopposed estrogen absent (b) Postmenopausal (c) Precusrsor lesion: endometrial intraepithelial carcinoma (d) High grade, often with deep myometrial invasion (e) Serous and clear cell subtypes (f) Aggressive behavior (g) p53 mutation

Microsatellite Instability and Endometrial Carcinoma ♦♦ Up to 25% of uterine endometrioid carcinomas demonstrate high levels of microsatellite instability (MSI-H), which has been implicated in the pathogenesis of endometrioid carcinoma, but not serous carcinoma; this possibility should be considered particularly when endometrioid carcinoma develops in young women ♦♦ Detecting MSI-H endometrial carcinomas: the expression of four DNA mismatch repair proteins, MLH1, MSH2, MSH6

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and PMS2, can be detected; the loss of their expression gives rise to MSI-H −− IHC assessment of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) is an efficient method to identify microsatellite-unstable endometrial cancer −− PCR −− Tumor infiltrating lymphocyte (TIL) counts and peritumoral lymphocytes have been found by some authors to be independent predictors for MSI-H status ♦♦ MSI-H endometrial carcinomas −− In ~80%, the cause of abnormal DNA mismatch repair protein expression is hypermethylation of the MLH1 promoter (a) Tumors that arise from this pathway occur sporadically, result in loss of MLH1 and PMS2 expression, and most are well- or moderately differentiated −− ~10% result from a mutation, usually of MLH1 or MSH2 and occurs in the setting of hereditary nonpolyposis colorectal cancer/Lynch syndrome (a) Mutation of MLH1 usually gives rise to loss of MLH1 and PMS2 expression (b) Mutation in MSH2 usually leads to loss of MSH2 and MSH6 expression (c) Endometrial cancer is the most common malignancy in women with Lynch syndrome (d) There is a 40–60% lifetime risk of endometrial cancer in women with a mismatch repair mutation associated with Lynch syndrome ♦♦ Interpreting immunostains for expression of MLH1, MSH2, MSH6, and PMS2 (Fig. 31.24) −− The goal is detection of expression loss, strong and diffusely positive internal controls such as nuclei of endometrial stroma and nonneoplastic endometrium should be identified and verified for complete absence of expression in tumor cell nuclei −− Loss of MLH1 almost always accompanies loss of PMS2; loss of MSH2 almost always accompanies loss of MSH6, with only occasional exceptions

Grade and Stage ♦♦ Architectural and nuclear grading is applied to endometrioid and mucinous carcinomas ♦♦ The grading for serous, clear cell, and squamous carcinomas uses nuclear grade only ♦♦ Architectural grading is based only in the glandular component; squamous/morular areas are excluded −− Grade 1: no more than 5% of the tumor has a solid growth pattern −− Grade 2: 6–50% of the tumor has a solid growth pattern −− Grade 3: >50% of the tumor has a solid growth pattern ♦♦ Nuclear grade −− Grade 1: oval, mildly enlarged nuclei with evenly ­dispersed chromatin −− Grade 2: features intermediate to grades 1 and 2

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Fig. 31.24. MSI- H endometrial adenocarcinoma. (A) H&E showing tumor infiltrating lymphocytes (TIL). Immunostains show loss of MSH2 (B) and MSH6 (C) expression, and preserved expression of MLH1 (D) and PMS2 (E); note positive internal controls such as nuclei of endometrial stroma and lymphocytes. −− Grade 3: markedly enlarged and pleomorphic nuclei, with coarse chromatin and prominent eosinophilic nucleoli ♦♦ The grade of tumors, architecturally grade 1 or 2, should be increased by one in the presence of nuclear grade 3

Macroscopic ♦♦ Usually arises in the corpus, less frequently in the lower ­uterine segment

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♦♦ The uterus is usually enlarged, but may be small, ­particularly in serous type ♦♦ Gross appearance is similar regardless of the histologic type ♦♦ Single dominant mass, most frequently in the posterior than anterior wall

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Fig. 31.25. (A) Well-differentiated endometrioid carcinoma. (B) Well-differentiated endometrioid adenocarcinoma with squamous differentiation. ♦♦ Exophytic with a shaggy, frequently ulcerated surface, with an underlying firm tumor with variable extension into the myometrium

Endometrioid Carcinoma (Fig. 31.25) Clinical ♦♦ Most common type, accounting for 80% of all endometrial carcinomas ♦♦ Most women are postmenopausal ♦♦ Usually present with abnormal bleeding ♦♦ Typifies the type I endometrial carcinoma

(a) Thin papillary fronds covered by stratified columnar cells with mild to moderate atypia −− Ciliated (a) Rare, almost always well differentiated (b) Cells with eosinophilic cytoplasm and cilia −− Secretory (a) Rare, usually well differentiated (b) The majority of cells exhibit subnuclear or supranuclear cytoplasmic vacuoles, resembling early secretory endometrium (c) Associated with favorable prognosis

Macroscopic

Differential Diagnosis

♦♦ Similar to the various other types

♦♦ Atypical hyperplasia ♦♦ Stromal invasion is absent (see differential diagnosis for hyperplasia) ♦♦ Primary endocervical adenocarcinoma −− Usually strongly positive for p16 (noted that serous endometrial carcinomas are also strongly positive for p16, and patchy p16 positivity can also be seen in endometrial endometrioid type carcinomas) −− Usually negative for estrogen and progesterone receptor, in contrast with endometrial adenocarcinoma −− Expresses CEA more commonly and vimentin less commonly than endometrial carcinoma −− Usually contain HPV DNA detected by PCR ♦♦ Cytoplasmic alterations (metaplasias) ♦♦ Atypical polypoid adenomyoma ♦♦ Arias-Stella reaction ♦♦ Menstrual endometrium

Microscopic ♦♦ Composed of tubular glands or villoglandular structures lined by simple or pseudostratified columnar cells that have their long axes perpendicular to the basement membrane ♦♦ Spectrum of histological differentiation, from a very welldifferentiated carcinoma with a predominant glandular ­differentiation to higher grade carcinomas characterized by solid nests and sheets of cells ♦♦ Deep myometrial invasion and lymph node metastasis are more frequent in higher grade carcinomas ♦♦ Associated endometrial hyperplasia is present in 20–40% of cases ♦♦ Variants of endometrioid carcinoma −− With squamous differentiation (a) The squamous component must be at least 10% of the tumor (b) Squamous componet may be benign or malignantappearing (c) No difference in clinical features −− Villoglandular

Mucinous Adenocarcinoma Clinical ♦♦ Uncommon type of endometrial carcinoma

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♦♦ Most of the tumors are stage I and low grade ♦♦ Clinical features do not differ from that of endometrioid carcinoma

Macroscopic ♦♦ No distinctive gross features

Microscopic (Fig. 31.26) ♦♦ More than 50% of the cell population of the tumor must contain intracytoplasmic mucin ♦♦ Glands and papillary processes lined by uniform columnar cells with minimal stratification ♦♦ Papillary fronds surrounded by extracellular lakes of mucincontaining neutrophils

Differential Diagnosis ♦♦ Primary endocervical carcinoma ♦♦ Clear cell carcinoma

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Secretory carcinoma ♦♦ Microglandular hyperplasia of the endocervix

Serous Carcinoma (Fig. 31.27) Clinical ♦♦ Comprises 5–10% of all endometrial carcinomas ♦♦ Patients typically are postmenopausal with an average age that is 10 years greater than that of patients with endometrioid carcinoma ♦♦ Typifies the type II endometrial carcinoma ♦♦ Considered a high grade carcinoma by definition ♦♦ Aggressive behavior with early dissemination to pelvis and abdomen as in ovarian serous carcinoma ♦♦ The most important prognostic factor is stage; recent studies report higher survival rates than that in initial studies, probably as a result of more meticulous staging and aggressive adjuvant therapy, with survival rates of 70–100% for stage I tumors

Macroscopic ♦♦ Often, the uterus is small and atrophic ♦♦ Generally exophytic with papillary appearance ♦♦ Frequently develops within a polyp

Microscopic

Fig.  31.26. Mucinous adenocarcinoma of the endometrium. The tumor cells contain intracytoplasmic mucin.

♦♦ Papillae with broad fibrovascular cores, with secondary and tertiary papillary processes and sloughing of the cells ♦♦ A papillary pattern typically predominates but glandular and solid patterns also occur ♦♦ Cells and nuclei are usually round rather than columnar and lack a perpendicular orientation with regard to the basement membrane ♦♦ High grade nuclei, often atypically situated with large eosinophilic macronucleoli, multinucleated tumor cells are commonly present

Fig. 31.27 (A) Serous carcinoma. Papillae lined by cells with marked nuclear atypia. (B) Lymph node with metastatic serous carcinoma with pasammoma bodies.

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♦♦ Frequent mitotic figures, often atypical, and necrotic foci are common ♦♦ Psammoma bodies found in about 30% of cases ♦♦ Deep myometrial invasion and vascular invasion are frequently found ♦♦ The adjacent endometrium is atrophic in almost all cases ♦♦ Endometrial intraepithelial carcinoma is present in nearly 90% of cases

Immunoprofile ♦♦ Strong and diffuse p53 positivity ♦♦ Low frequency of estrogen and progesterone receptors expression ♦♦ Very high proliferation index with Ki-67 ♦♦ Strongly positive for p16

Differential Diagnosis ♦♦ Villoglandular carcinoma −− Delicate papillary fronds −− Lacks high grade nuclear atypia ♦♦ Endometrioid carcinoma −− Immunohistochemistry for p53, Ki-67, and hormone receptors can be useful (a) Usually ER/PR positive (b) Usually p53 negative (but high grade tumors may also be positive) ♦♦ Carcinosarcoma (MMMT) may have a dominant component of serous carcinoma, and adequate sampling is necessary ♦♦ Clear cell carcinoma ♦♦ Papillary syncytial eosinophilic change

Clear Cell Carcinoma Clinical ♦♦ Comprises 1–5% of all endometrial carcinomas ♦♦ Considered the other major type II carcinoma of the endometrium, after serous carcinoma

Macroscopic ♦♦ No distinctive gross features

Microscopic (Fig. 31.28) ♦♦ May exhibit solid, papillary, tubular, and cystic patterns ♦♦ Solid pattern composed of masses of clear cells admixed with eosinophilic cells ♦♦ Papillary, tubular, and cystic patterns composed of predominantly hobnail-shaped cells with interspread clear and eosinophilic cells, typically have hyalinized cores ♦♦ Cells are usually large with clear cytoplasm due to glycogen ♦♦ Generally marked nuclear atypia is present ♦♦ Mitotic activity is high

Fig.  31.28 Clear cell carcinoma. Large cells with clear cytoplasm and marked nuclear atypia. ♦♦ Serous carcinoma ♦♦ Yolk sac tumor −− Schiller–Duval bodies −− Elevated serum AFP −− AFP positive with immunohistochemistry

Mixed Cell Adenocarcinoma ♦♦ Tumor composed of an admixture of a type I (endometrioid carcinoma, including its variants, and mucinous carcinoma) and a type II carcinoma (serous or clear cell) ♦♦ The minor cell type must comprise at least 10% of the total tumor

Squamous Cell Carcinoma ♦♦ Extremely rare ♦♦ Diagnosed only in the absence of squamous cell carcinoma of the cervix or connection to the cervical squamous epithelium and in the absence of adenocarcinoma in the endometrium ♦♦ Associated with cervical stenosis, pyometria, and chronic inflammation ♦♦ Histologically resembles squamous cell carcinomas found in other sites ♦♦ Prognosis related to stage at diagnosis

Transitional Cell Carcinoma ♦♦ Extremely rare ♦♦ 90% or more of the tumor should be composed of cells resembling urothelial transitional cells to qualify for the diagnosis ♦♦ Polypoid or papillary tumors ♦♦ Invariably admixed with other patterns of endometrial carcinoma ♦♦ The transitional cell component is often grade 2 or 3 with papillary configuration

Differential Diagnosis

Small Cell Carcinoma

♦♦ Secretory carcinoma

♦♦ Uncommon, <1% of all carcinomas

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Fig. 31.30. Submucosal leiomyoma. ♦♦ May be submucosal, intramural, or subserosal (Fig. 31.30) ♦♦ Spherical, firm, well circumscribed and bulge from the surrounding myometrium ♦♦ White to tan cut surface with a whorled trabecular pattern ♦♦ Degenerative changes include hemorrhage, hyalinization, necrosis, calcification, and myxoid and cystic degeneration

Microscopic Fig. 31.29. Prolapsed submucosal leiomyoma.

♦♦ Histological appearance is similar to that of small cell carcinoma in other organs ♦♦ Positive for keratin and mostly positive for neuroendocrine markers ♦♦ The prognosis is better in contrast to small cell carcinoma elsewhere in the genital tract

Undifferentiated Carcinoma ♦♦ Tumors lacking any evidence of differentiation

Mesenchymal Tumors and Related Lesions Smooth Muscle Tumors Leiomyoma Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Most common uterine neoplasm Most common in the fourth and fifth decades Occurs in 20–40% of women above 30 years of age Rare in women below18 years of age Clinical presentation depends on their size and location; most common symptoms include pain, sensation of pressure and abnormal uterine bleeding ♦♦ Pedunculated leiomyomas may protrude through the cervical os (Fig. 31.29)

Macroscopic ♦♦ Multiple in two-thirds of patients

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♦♦ Composed of whorled, anastomosing fascicles of uniform fusiform smooth muscle cells ♦♦ Nuclei are uniform, elongated with blunt or tapered ends (cigar-shaped) with small nucleoli ♦♦ Mitotic figures usually infrequent ♦♦ Usually more cellular than surrounding myometrium ♦♦ Degenerative changes are common, including hyaline fibrosis, infarct-type necrosis, edema, hemorrhage and myxoid change (Fig. 31.31) ♦♦ Margins usually microscopically circumscribed

Immunoprofile ♦♦ Muscle-specific actin, SMA, desmin, and h-caldesmon positive ♦♦ Frequent cytokeratin positivity ♦♦ EMA negative ♦♦ May be focally CD10 positive

Differential Diagnosis (Table 31.1) ♦♦ Leiomyosarcoma ♦♦ Endometrial stromal tumors (see endometrial stromal tumors)

Histological Variants ♦♦ Mitotically active leiomyoma −− Occurs most frequently in premenopausal women −− Greater than or equal to 5 mf/10hpf, in a leiomyoma with otherwise typical histologic features −− The clinical evaluation is benign −− The term mitotically active leiomyoma with limited ­experience is used when the tumor contains more than 15 mitosis/10 hpf

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Fig.  31.31. (A) Infarct-type necrosis in a leiomyoma. Hyalinized fibrous tissue separating area of necrosis from viable tumor. (B) Leiomyoma with hydropic changes.

Table 31.1. Histologic Criteria for the Diagnosis of Uterine Smooth Muscle Tumors with Standard Smooth Muscle Differentiation Tumor cell necrosis Present

Absent

Atypia

Mitotic index mf/10 hpf

Diagnosis

Diffuse moderate to severe

Any level

Leiomyosarcoma

None to mild

Greater than 10

Leiomyosarcoma

Less than 10

Leiomyosarcoma (R/O, recent infarction of leiomyoma, for example, due -to torsion)

Diffuse moderate to severe

Greater than 10

Leiomyosarcoma

Less than 10

Atypical leiomyoma with low risk of recurrence

None to mild

Less than 10

Leiomyoma

Greater than 10

Mitotically active leiomyoma

Less than 15

Leiomyoma with limited experience or if MI > 15, :STUMP”

Focal moderate to severe

−− This diagnosis should not be used for neoplasms exhibiting moderate to severe atypia, abnormal mitotic figures, or coagulative tumor cell necrosis ♦♦ Cellular leiomyoma −− Significantly more cellular than surrounding myometrium −− No clinical differences from other leiomyomas ♦♦ Hemorrhagic leiomyoma (apoplectic) −− Occurs mainly in women who are taking oral contraceptives, pregnant or postpartum women −− Often also cellular −− Stellate areas of hemorrhage

−− Increased mitotic activity adjacent to hemorrhagic areas −− Coagulative tumor necrosis, abnormal mitotic figures, and nuclear atypia are absent ♦♦ Epithelioid leiomyoma −− Most are solitary, yellow or gray, and tend to be softer than the usual leiomyoma; hemorrhagic and necrotic areas may be present −− Composed of round or polygonal cells arranged in clusters or cords often with transition to more typical spindle smooth muscle cell −− Three subtypes

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Fig.  31.32. Atypical leiomyoma. Atypical enlarged cells with hyperchromatic nuclei.

(a) Leiomyoblastoma: round cells with eosinophilic cytoplasm (b) Clear cell leiomyoma: polygonal cells with abundant clear cytoplasm (c) Plexiform leiomyoma: cords or nests of round cells with scant cytoplasm, and invariably benign −− The behaviour of epithelioid leiomyomas with two or more of the following features is not well established; such tumors should be classified in the uncertain malignant potential category (a) Size >6 cm (b) 2–4 mf/10 hpf (c) Necrosis −− Neoplasms with greater than or equal to 5  mf/10hpf should be regarded as epithelioid leiomyosarcoma ♦♦ Myxoid leiomyoma −− Abundant myxoid material is present between smooth muscle cells ♦♦ Atypical leiomyoma (Fig. 31.32) −− Other names include pleomorphic, bizarre, or symplastic leiomyoma −− Benign smooth muscle tumor with atypical cells with enlarged hyperchromatic nuclei with smudged chromatin −− Large cytoplasmic pseudonuclear inclusions often present −− Atypia may be diffuse, focal, or multifocal −− Mitotic figures lesser than 10  mf/10  hpf; coagulative necrosis and abnormal mitotic figures are absent ♦♦ Lipoleiomyoma −− Significant number of adipocytes

Growth Pattern Variants ♦♦ Diffuse leiomyomatosis −− Rare, benign condition −− Numerous small smooth muscle nodules produce symmetric enlargement of the uterus

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Fig.  31.33. Itravenous leiomyomatosis. Tumor in myometrial vessels. −− Uniform, bland spindle smooth muscle cells less circumscribed than typical leiomyomas ♦♦ Dissecting leiomyoma −− Benign smooth muscle proliferation −− Border marked by the dissection of compressive tongues of smooth muscle into surrounding myometrium and occasionally, into broad ligament and pelvis ♦♦ Intravenous leiomyomatosis

Clinical ♦♦ ♦♦ ♦♦ ♦♦

Very rare smooth muscle tumor Main symptoms are abnormal bleeding and pelvic discomfort Hormonally dependent tumor Favorable overall prognosis but may cause significant morbidity and sometimes mortality ♦♦ Followup of the patient and assessment of a baseline chest x-ray would be prudent

Macroscopic ♦♦ Complex nodular growth within the myometrium with convoluted, worm-like extensions into the uterine veins in the broad ligament or other pelvic veins ♦♦ May extend into the inferior vena cava and even the heart

Microscopic ♦♦ Nodular masses of histologically benign smooth muscle cells growing within venous channels (Fig. 31.33) ♦♦ Cellular composition similar to leiomyoma, most contain prominent fibrosis or hyalinization ♦♦ Any leiomyoma histologic variant may be seen ♦♦ Mitotic figures are minimal or absent

Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP) ♦♦ Smooth muscle tumor that cannot be diagnosed reliably as benign or malignant on the basis of generally applied criteria ♦♦ This category should be used sparingly and reserved for neoplasms whose appearance is ambiguous

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Fig. 31.34. (A) Uterine leiomyosarcoma. Moderate to severe atypia and numerous mitotic figures, (B) coagulative–type necrosis, sharp transition from viable to necrotic tumor.

Leiomyosarcoma Clinical ♦♦ Most common pure uterine sarcoma, comprises ~1% of all uterine malignancies ♦♦ Usually in postmenopausal women, average age 52  years (a decade older than women with leiomyoma) ♦♦ Main symptoms are abnormal bleeding, lower abdominal pain, pelvic or abdominal mass ♦♦ Highly malignant neoplasm and may spread locally, regionally, or by hematogenous dissemination (most often to the lungs) ♦♦ A diagnosis of leiomyosarcoma should be made with great caution in women <30 years of age and only after exclusion of exposure to Leuprolide, which may induce a pattern of necrosis identical to coagulative tumor cell necrosis

Macroscopic ♦♦ Usually intramural, large, solitary, and poorly circumscribed ♦♦ Soft, fleshy, and yellow-gray with areas of hemorrhage and necrosis ♦♦ Usually not associated with leiomyomas

Microscopic (Fig. 31.34) ♦♦ Cellular tumor composed of fascicles of atypical spindleshaped cells with eosinophilic cytoplasm ♦♦ Hyperchromatic nuclei with rounded ends and prominent nucleoli ♦♦ Multinucleated giant cells present in 50% of cases ♦♦ Tumor cell necrosis is typically prominent but may be absent ♦♦ Frequently invade the surrounding myometrium ♦♦ Vascular invasion is identified in 10–22% of cases ♦♦ Diagnostic criteria −− Any coagulative tumor cell necrosis −− In the absence of coagulative tumor cell necrosis (a) Diffuse moderate to severe atypia (b) Mitotic index ³10 mf/10 hpf

Differential Diagnosis ♦♦ Leiomyoma and variants −− Coagulative tumor cell necrosis is absent −− Less cellular, no significant cytologic atypia, and minimal mitotic activity −− Strong positivity for p16 and p53 immunostains and high proliferation with Ki-67 (>10%) in leiomyosarcomas has been reported in some studies to be helpful in differentiating leiomyosarcomas from leiomyomas ♦♦ Intravascular leiomyomatosis ♦♦ Undifferentiated endometrial sarcoma (high grade endometrial stromal sarcoma) ♦♦ Poorly differentiated endometrial carcinoma

Leiomyosarcoma Variants ♦♦ Epithelioid leiomyosarcoma −− Combines the epithelioid phenotype with the features of malignancy of conventional leiomyosarcoma ♦♦ Myxoid leiomyosarcoma −− Large gelatinous neoplasm, usually appears circumscribed on gross examination −− Smooth muscle cells widely separated by myxoid material −− The characteristic low cellularity largely accounts for the low mitotic index, however, sometimes the mitotic index and degree of atypia are high −− Commonly show myometrial and vascular invasion

Endometrial Stromal and Related Tumors (Fig. 31.35) ♦♦ Rare, can be benign (endometrial stromal nodule) or malignant (endometrial stromal sarcoma) ♦♦ Endometrial stromal sarcomas have been traditionally divided into low- and high grade type; however, since the

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Fig. 31.35. (A) Endometrial stromal nodule. Noninvasive growth pattern with a circumscribed expansile margin. (B) Endometrial stromal sarcoma, low grade. The broad bands of tumor extensively permeate the myometrium. high grade endometrial stromal sarcoma lacks specific differentiation and bears no resemblance to endometrial stroma, it has been proposed that they be designated undifferentiated endometrial sarcoma

Endometrial Stromal Nodule Clinical ♦♦ Rare and benign neoplasm, represents <25% of all endometrial stromal tumors ♦♦ ~75% occur in premenopausal women, average age is 47 years ♦♦ Usually present with abnormal vaginal bleeding, ~10% are asymptomatic

Macroscopic ♦♦ May be polypoid and protrude into the endometrial cavity or grows entirely within the myometrium ♦♦ Circumscribed contour ♦♦ Fleshy yellow or tan cut surface and tend to bulge from the surrounding myometrium ♦♦ Usually single, but ~5% of patients have two or more nodules ♦♦ Cervix is seldom involved

Table 31.2. Immunohistochemical Findings in Endometrial Stromal and Smooth Muscle Tumors Antibody

Endometrial Smooth muscle stromal tumor tumor

CD10

+

−

Smooth muscle actin

−/focally+

+

h-caldesmon

−

+

Desmin

−

+

♦♦ Endometrial stromal sarcoma, low grade −− Infiltrates the myometrium and invades vascular spaces

Endometrial Stromal Sarcoma, Low grade Clinical

♦♦ Composed of cells resembling those of proliferative phase endometrial stroma ♦♦ Tumor cells have uniform, small round nuclei and inconspicuous nucleoli ♦♦ Expansile non infiltrative margins, invasion of surrounding myometrium indicates that the tumor is a stromal sarcoma ♦♦ Mitotic activity is usually low (<3  mf/10  hpf) but may be higher (rarely may exceed 10–15/mf/10 hpf)

♦♦ Rare tumor, 0.2% of all genital tract malignant neoplasms ♦♦ Generally occurs in younger women than other uterine malignancies, and mean age ranges from 42 to 58 years ♦♦ Presenting symptoms include abnormal bleeding and abdominal pain ♦♦ Characterized by indolent growth and late recurrences ♦♦ Frequently respond to progestin therapy ♦♦ Fusion of two zinc finger genes (JAZF1 and JJAZ1) by translocation t(7;17) is present in most low grade endometrial stromal tumors

Differential Diagnosis (Tables 31.2 and 31.3)

Macroscopic

♦♦ Cellular leiomyoma −− Cellular leiomyomas are strongly actin and desmin positive, and CD10 negative; while stromal nodules usually only weak patchy staining for smooth muscle actin, and typically desmin negative, and CD10 positive

♦♦ Extensive permeation of the myometrium is commonly present but may present as a solitary well-delineated intramural mass ♦♦ Cut surface is yellow to tan and softer than that of a leiomyoma

Microscopic

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Table 31.3. Pathologic Characteristics of Endometrial Stromal and Related Tumors Endometrial stromal nodule Histologic features

Uniform cells resembling proliferative endometrial cells

Endometrial stromal sarcoma, low grade

Undifferentiated endometrial sarcoma

Identical to endometrial stromal nodule

Cellular, marked nuclear atypia and pleomorphism

Significant atypia and pleomorphism absent

Tumor cells do not resemble proliferative phase endometrial stroma

Plexiform vascular pattern Mitotic activity

Usually low (<3 mf 10/hpf)

Usually low, but occasionally >10 mf 10/hpf

High (>10 mf 10/hpf), common abnormal forms

Borders

Circumscribed with pushing margins

Myometrial infiltration characterized by “tongue-like” tumor masses

Infiltrating margins with extensive myometrial infiltration

Vascular invasion

Absent

Common, grossly distinctive “worm-like” appearance

Less often grossly visible

Extension beyond the uterus

Confined to the uterus

May extend beyond the uterus

Frequently extends beyond the uterus

May metastasize

Metastases common

CD10 + Actin focally + Desmin – (usually) h-caldesman – (usually) ER/PR + Sex-cord-like areas: inhibin, CK and EMA +; may also be desmin +

ER/PR –

Immunoprofile

CD10 + Actin focally + Desmin – (usually) h-caldesman – (usually)

♦♦ Worm-like plugs of tumor within the vessels of the broad ligament and adnexae may be present

Microscopic

♦♦ Desmin and h-caldesmon negative (usually but not always) ♦♦ Areas with sex cord pattern are inhibin positive, ­cytokeratin positive, and may also be desmin positive

♦♦ The tumor permeates the myometrium as irregular tongues ♦♦ Densely cellular tumor, composed of uniform oval to spindle cells of endometrial stromal type ♦♦ By definition, significant atypia and pleomorphism are absent ♦♦ Usually low mitotic activity, but occasional >10 mf/10 hpf may be encountered not altering the diagnosis ♦♦ Small vessels and arterioles resembling endometrial spiral arteries are characteristic ♦♦ Myxoid and fibrous change may occur focally or diffusely ♦♦ Cells with foamy cytoplasm may be prominent in some cases ♦♦ Limited smooth muscle differentiation (<30%) is ­occasionally present ♦♦ Epithelial-like differentiation occurs in about 25% of cases (endometrial type glands or a pattern reminiscent of ovarian sex cord tumor) ♦♦ Invasion of lymphatic and vascular channels is a ­characteristic finding

Differential Diagnosis

Immunoprofile

♦♦ One or more fleshy, gray to yellow polypoid endometrial masses ♦♦ Necrosis and hemorrhage are often present

♦♦ CD10 positive, almost always ER/PR positive, and focally actin positive

♦♦ ♦♦ ♦♦ ♦♦

Endometrial Stromal Nodule Intravenous leiomyomatosis Adenomyosis with sparse glands The distinction of low grade endometrial stromal sarcoma, stromal nodule, a nonneoplastic stromal proliferation, or a cellular leiomyoma is often impossible in biopsy or curettage specimens

Undifferentiated Endometrial Sarcoma Clinical ♦♦ Previously designated as high grade endometrial stromal sarcoma ♦♦ Aggressive behavior, high mortality rate ♦♦ Usually does not respond to progestin therapy

Macroscopic

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Microscopic

Differential Diagnosis

♦♦ Marked cellular atypia and abundant mitotic activity, often including atypical forms ♦♦ Lack the typical growth pattern and vascularity of low grade endometrial stromal sarcoma ♦♦ Displace the myometrium in contrast to the infiltrative pattern of low grade endometrial stromal sarcoma ♦♦ Most often ER/PR negative

♦♦ Lymphangioma ♦♦ Carcinoma

Differential Diagnosis ♦♦ Carcinosarcoma ♦♦ Leiomyosarcoma

Miscellaneous Mesenchymal Tumors Mixed Endometrial Stromal and Smooth Muscle Tumor ♦♦ Rare neoplasms composed of an admixture of endometrial stromal and smooth muscle elements ♦♦ A minimum of 30% of the minor component should be present for the diagnosis ♦♦ Recommended to report them in the same way as endometrial stromal neoplasms; malignant if there is myometrial and vascular invasion, benign otherwise

Perivascular Epithelioid Cell Tumor (PEComa) ♦♦ Tumor composed predominantly or exclusively of HMB 45 positive perivascular epithelioid cells ♦♦ May have a prominent tongue-like growth pattern ♦♦ Cells have abundant clear to eosinophilic pale cytoplasm ♦♦ Should be considered of uncertain malignant potential until long-term data is available

Adenomatoid Tumor Clinical ♦♦ Benign tumor of the uterine serosa and myometrium, probably derived from serosal mesothelium ♦♦ Usually an incidental finding, seen in up to 1% of uteri

Macroscopic ♦♦ May be multiple or associated with a similar lesion in the fallopian tube ♦♦ Gray or tan, with rubbery consistency ♦♦ Well-circumscribed intramural masses that may resemble a leiomyoma, often located towards the serosal surface

Microscopic ♦♦ Multiple small, slit-like, interconnecting spaces within the myometrium ♦♦ Composed of tubules lined by cells that may be cuboidal or flat ♦♦ Nuclear atypia and mitotic activity are minimal or absent ♦♦ No stromal desmoplastic response

Immunoprofile ♦♦ Cytokeratin positive, calretinin positive, Ber-EP4 negative

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Other Rare Mesenchymal Tumors Benign ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Lipoma Hemangioma Lymphangioma Rhabdomyoma Inflammatory Myofibroblastic Tumor (ALK 1 positive)

Malignant ♦♦ ♦♦ ♦♦ ♦♦

Rhabdomyosracoma Malignant fibrous histiocytoma Angiosarcoma Osteosarcoma

Mixed Epithelial and Mesenchymal Tumors Adenomyoma ♦♦ May occur at any age ♦♦ Usually polypoid submucosal lesions, rarely intramural or subserosal ♦♦ Circumscribed, nodular aggregate of smooth muscle cells, benign endometrial glands, and usually endometrial stroma ♦♦ Designation not recommended for a localized adenomyosis forming a discrete mass

Atypical Polypoid Adenomyoma Clinical ♦♦ Characteristically occurs in premenopausal women ♦♦ Usually present with abnormal uterine bleeding ♦♦ Benign lesion that can be cured by curettage but may recur

Macroscopic ♦♦ Polypoid mass, resembling a typical polyp ♦♦ Often in the lower uterine segment

Microscopic (Fig. 31.36) ♦♦ Irregularly shaped endometrial glands with architectural and cytologic atypia within stroma containing abundant smooth muscle cells ♦♦ Extensive morular squamous metaplasia may be present ♦♦ Foci that architecturally resemble well-differentiated adenocarcinoma may be present, and the designation of atypical polypoid adenomyoma of low malignant potential has been used

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Endometrial hyperplasia Endometrial carcinoma invading myometrium Adenosarcoma Malignant mixed mesodermal tumor Adenomyoma

Uterus and Fallopian Tube

Fig.  31.36. Atypical polypoid adenomyoma. Atypical endometrial glands with squamous morules separated by a fibromuscular stroma.

Adenofibroma Clinical ♦♦ Uncommon neoplasm ♦♦ Most often in postmenopausal women but may occur in younger patients ♦♦ Benign tumor but may recur if incompletely excised or curetted

Macroscopic ♦♦ Lobulated polypoid tumor that can arise anywhere in the uterus or in the cervix ♦♦ May contain small cysts resulting in a spongy or mucoid appearance

Microscopic ♦♦ Mixture of histologically benign epithelium and mesenchyme ♦♦ Broad papillary fronds projecting from the surface into cystic spaces ♦♦ Cysts and cleft-like spaces lined by columnar or cuboidal epithelial cells, most often of endometrioid type ♦♦ The stromal component is usually fibroblastic, but benign endometrial stromal cells or a mixture of stromal cells and fibroblasts may be present ♦♦ Stromal cell atypia is absent and mitotic figures are rare

Differential Diagnosis ♦♦ Endometrial polyp ♦♦ Atypical polyploid adenomyoma ♦♦ Adenosarcoma

Adenosarcoma Clinical ♦♦ Typically occur in postmenopausal women, but 30% occur in premenopausal women

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Fig. 31.37. Adenosarcoma. Cytologically bland tubular glands of endometrioid type, surrounded by a cuff of cellular mesenchyma containing mitoses.

♦♦ Usually present with abnormal vaginal bleeding, pelvic pain, enlarged uterus, and protrusion of tumor through the cervix ♦♦ Considered a low grade neoplasm but recurs in 25–40% of cases ♦♦ Predictive factors of a poor outcome are extrauterine spread, deep myometrial invasion, and sarcomatous overgrowth

Macroscopic ♦♦ Soft or firm polypoid mass that grows into the cavity and can enlarge the uterus ♦♦ Cut surface is fleshy, tan or gray and contains small cysts ♦♦ Hemorrhage and necrosis are present in 25% of tumors

Microscopic (Fig. 31.37) ♦♦ Biphasic tumor with a characteristic leaf-like pattern on low power examination ♦♦ Glands often dilated and compressed into thin slits are dispersed throughout the mesenchymal component ♦♦ By definition, the epithelium is benign, most commonly resembles inactive or proliferative endometrial epithelium, but many other types may also occur ♦♦ The mesenchymal component is generally a homologous sarcoma such as stromal sarcoma or fibrosarcoma ♦♦ Stromal condensation surrounding the glands and clefts is a characteristic finding ♦♦ In most tumors, mesenchymal cells show mild to moderate atypia ♦♦ Mitotic figures in the mesenchymal component are generally 4  mf/10  hpf or more, but even 1 mf/hpf is enough for the diagnosis if the characteristic features are present ♦♦ Heterologous mesenchymal elements are present in 20–25% of cases, and striated muscle is the most common ♦♦ Sarcomatous overgrowth, present in 10% of cases, occurs when the sarcomatous component of the tumor represents ³25% of the total tumor volume, usually associated with increased cellularity, nuclear atypia, mitotic activity, and absence of epithelial elements

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♦♦ Myometrial invasion is present in 15–20%, and both glands are stromal ♦♦ Distant metastases are usually composed purely of the sarcomatous component

Differential Diagnosis ♦♦ Adenofibroma −− Less cellularity, mitotic activity, and stromal nuclear atypia −− Periglandular stromal cuffing is absent ♦♦ Malignant mixed müllerian tumor (carcinosarcoma) ♦♦ Endometrial polyp

Carcinosarcoma (Malignant Mixed Müllerian Tumor) Clinical ♦♦ By definition, tumors composed of malignant epithelial and mesenchymal components ♦♦ Increasing evidence that they are monoclonal and should be considered subsets of endometrial carcinoma ♦♦ Represent <5% of malignant neoplasms of the uterine corpus ♦♦ Occurs almost exclusively in postmenopausal women ♦♦ A history of pelvic radiation exists in some cases ♦♦ Most common presentation is vaginal bleeding; others include abdominal mass, pelvic pain, and enlarged uterus with tumor protruding through the cervix ♦♦ Poor prognosis, clinical behavior is significantly worse than grade 3 endometrioid carcinoma, serous and clear cell carcinoma

Macroscopic ♦♦ Large polypoid mass filling the entire endometrial cavity and frequently protruding through the cervical os ♦♦ Variably soft to firm, tan, and friable with areas of necrosis and hemorrhage

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Many invade the myometrium but may be confined to a polyp ♦♦ In ~25% of cases, the tumor extends into the endocervix

Microscopic ♦♦ Composed of histologically malignant epithelial and mesenchymal components (Fig. 31.38) ♦♦ The epithelial component is frequently endometrioid carcinoma, but any of the other subtypes of endometrial carcinoma may be present ♦♦ The sarcoma component is homologous in ~50% of cases, usually undifferentiated sarcoma, endometrial stromal sarcoma, fibrosarcoma and occasionally leiomyosarcoma ♦♦ Heterologous mesenchymal elements most commonly consist of rhabdomyosarcoma and chondrosarcoma ♦♦ The histologic appearance of metastases is variable; most commonly, pure carcinoma is encountered

Differential Diagnosis ♦♦ Poorly differentiated endometrial carcinoma ♦♦ Pure Sarcoma ♦♦ Adenosarcoma

Miscellaneous Tumors Sex Cord-Like Tumors ♦♦ Tumors of the uterine corpus that closely resemble ovarian sex cord tumors ♦♦ Only diagnosed when areas of endometrial stromal or smooth muscle tumors are not present ♦♦ Characterized by trabecular ribbons and nodules or isolated cells with luteinized or foamy cytoplasm ♦♦ Immunohistochemically, strongly positive for alpha inhibin, calretinin, and CD99 and also show frequent positivity for cytokeratins and smooth muscle actin ♦♦ A prominent tubular, retiform or glomeruloid epithelial component may be present

Fig. 31.38. Carcinosarcoma. Malignant epithelium admixed with heterologous sarcomatous elements (chondrosarcoma).

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♦♦ Most have behaved in a benign fashion, and a few have recurred or metastasized

Neuroectodermal Tumors ♦♦ Pure forms or mixed with carcinoma or carcinosarcoma ♦♦ Most often, the tumor cells differentiate into neuroblastic, neuroepithelial, glial, and neuronal elements ♦♦ Highly malignant behavior

Melanotic Paraganglioma ♦♦ Morphologically identical to paraganglioma, but produces melanin pigment instead of neuroendocrine granules ♦♦ Cases reported were free of recurrences

Lymphomas and Leukemias ♦♦ Most lymphomas and leukemias involving the uterine corpus are a manifestation of systemic disease ♦♦ On rare occasions, the corpus is the first known site of a malignant lymphoma ♦♦ Majority are of the large B-cell type ♦♦ Differential diagnosis includes lymphoma-like lesion and leiomyoma massively infiltrated by lymphocytes

Tumors of Germ Cell Type ♦♦ Teratomas and yolk sac tumors can develop in the ­endometrium as pure forms or associated with endometrioid tumors

Metastatic (Secondary) Tumors Tumors from Other Genital Organs ♦♦ Usually result from direct extension of vaginal, cervical, or tubal carcinoma or ingrowth of ovarian carcinoma involving the uterine serosa, with the primary tumor being clinically apparent ♦♦ Simultaneous cancers involving the endometrium and the ovary may represent −− Metastasis from the endometrium to the ovary −− Metastasis from the ovary to the endometrium −− Independent primary tumors ♦♦ Most likely a metastasis from the endometrium to the ovary features the following

Fig.  31.39. Metastatic breast lobular carcinoma to the endometrium. −− Small ovaries (<5 cm) −− Bilateral ovarian involvement −− Deep myometrial invasion −− Vascular invasion −− Fallopian tube involvement ♦♦ Independent tumors are usually well differentiated endometrioid tumors, whereas grade 3 endometrioid carcinoma, serous and clear cell carcinomas, and carcinosarcomas are generally primary in one organ and metastasize to the other

Tumors from Extragenital Sites ♦♦ Metastatic breast cancer is the most frequent (Fig.  31.39), followed by stomach, cutaneous melanoma, lung, colon, pancreas, and kidney ♦♦ Abnormal uterine bleeding is the most common presentation ♦♦ Usually associated with obvious dissemination, on rare occasions may represent the first sign of an extrauterine primary tumor ♦♦ Most infiltrate the endometrium diffusely, the myometrium may also be involved

FALLOPIAN TUBES Nonneoplastic Lesions Acute Salpingitis Clinical ♦♦ Usually secondary to the passage of bacteria from the uterine cavity into the tubal lumen ♦♦ Neisseria gonorrhoeae and Chlamydia trachomatis are considered the most common causative organisms, but most are polymicrobial

♦♦ Present with abdominal and pelvic pain ♦♦ In gonococcal salpingitis the onset of acute pain typically occurs a few days after menses ♦♦ Recurrent infections result in chronic salpingitis

Macroscopic ♦♦ Distended, edematous, and erythematous tube ♦♦ Fibrinous exudates on serosal surface ♦♦ Pus may be seen dripping from the fimbriated end

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Fig.  31.40. (A) Bilateral pyosalpinx. The tubes are markedly dilated and the fimbriae are obliterated. (B) Salpingitis follicularis. Agglutination of plicae result in the formation of glandlike spaces. (C) Acute and chronic salpingitis. The mucosa is hyperplastic forming cribriform pseudoglands with reactive atypia and should not be confused with carcinoma. ♦♦ May be adherent to adjacent structures, including ovary ♦♦ Tuboovarian abscess may be present

Microscopic ♦♦ Initial marked neutrophilic transmural and mucosal infiltrate with intraluminal exudate ♦♦ Plicae are distended with granulocytes, histiocytes, lymphocytes, and plasma cells ♦♦ Surface fibrin deposition resulting in adherence of mucosal plicae

♦♦ Fimbriae may occlude and form pyosalpinx; as inflammation subsides, it results in hydrosalpinx ♦♦ In hydrosalpinx, the tube contains clear serous fluid, most of the epithelium consists of low cuboidal cells, but occasional plicae may persist; a few lymphocytes may be present

Granulomatous Salpingitis ♦♦ Caused by a variety of organisms or noninfectious processes ♦♦ Tuberculous Salpingitis

Clinical Chronic Salpingitis (Fig. 31.40) Clinical ♦♦ Caused by chronic, recurrent infections ♦♦ Results in loss of tubal function

Macroscopic ♦♦ Large dilated tube with shaggy lining and thick walls ♦♦ Multiple tuboovarian adhesions ♦♦ Tuboovarian abscess may be present

Microscopic ♦♦ Healing and organization lead to permanent bridging between folds, resulting in follicular salpingitis (formation of dilated glad-like spaces between adhered plicae) ♦♦ The mucosa may become hyperplastic, forming cribriform pseudoglands, with mild to moderate atypia

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♦♦ Mycobacterium tuberculosis is the predominant etiologic agent of granulomatous salpingitis ♦♦ Most commonly occurs from secondary spread, usually from a primary pulmonary infection ♦♦ The tubes are more frequently affected than other parts of the female genital tract ♦♦ Pelvic pain, sterility, and menstrual irregularities are the most common complaints

Macroscopic ♦♦ May be dilated and nodular ♦♦ In the adhesive form, dense adhesions between the tube and ovary, and fimbriae and ostium may be obliterated ♦♦ An identifiable ostium and fimbriae in a grossly diseased tube is considered a characteristic of tuberculous salpingitis ♦♦ In the exudative form, distension mimics bacterial pyosalpinx

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Microscopic ♦♦ Mucosal granulomatous reaction with central caseation, focal or massive ♦♦ Extension to the muscularis and serosa may occur ♦♦ Progressive scarring, with plical distorsion and congluti­ nation ♦♦ Calcification may occur in areas of fibrosis

Other Granulomatous Salpingitis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Actinomycosis Parasitic Salpingitis Sarcoid Crohn Disease Pseudoxantomatous Salpingitis

Salpingitis Isthmica Nodosa Clinical

Fig.  31.41. Salpingitis isthmica nodosa. Variably sized cystic diverticuli within a thickened myosalpinx.

♦♦ Consists of one or more outpouchings or diverticula of tubal epithelium in the isthmic region usually accompanied by nodular hyperplasia of the surrounding muscularis ♦♦ Often bilateral ♦♦ Found in women between the ages of 25 and 60 years ♦♦ Unknown etiology and possible causes include postinflammatory distortion or an adenomyosis-like process ♦♦ Infertility and ectopic pregnancy are the most serious clinical complications

Macroscopic ♦♦ One or more nodular swellings in the isthmus are 1–2  cm in diameter ♦♦ Firm cut surface and dilated diverticula may be seen

Microscopic ♦♦ The diverticula appear on cross-section as dispersed glands of tubal epithelium surrounded by broad bands of muscularis (Fig. 31.41) ♦♦ Endometrial-like stromal cells beneath the epithelium may be present

Ectopic Pregnancy Clinical ♦♦ More than 95% of ectopic pregnancies occur in the fallopian tube; most are found in the ampulla (75–80%), 10–15% ­isthmic, and 5% at the fimbriae ♦♦ Previous history of pelvic inflammatory disease in 35–45% of patients ♦♦ May present with tubal rupture and hemorrhagic shock ♦♦ If not recognized, rupture typically occurs around the eighth gestational week

Macroscopic ♦♦ If unruptured, an irregular sausage-like dilatation of the tube, with a bluish discoloration is seen (Fig. 31.42) ♦♦ Chorionic villi usually identified within the lumen

Fig.  31.42. Unruptured ectopic pregnancy. Irregular dilatation of the tube, with a bluish discoloration.

♦♦ In approximately two-thirds of cases, an embryo may be identified grossly or microscopically

Microscopic ♦♦ Chorionic villi and extravillous intermediate trophoblast can grow intraluminally or penetrate deep into the tubal wall ♦♦ Evidence of chronic salpingitis found in ~50% of cases

Inclusion Cysts and Walthard Nests ♦♦ Common incidental findings of no clinical significance ♦♦ Inclusion cysts originate from invaginations of the tubal serosa and consist of 1–2  mm unilocular cysts located beneath the serosal surface, lined by one or more layers of mesothelial cells (mesothelial inclusion cysts) ♦♦ Walthard nests result from a process of metaplasia, inclusion cysts become filled with polygonal epithelial-like cells with ovoid nuclei with nuclear grooves with a coffee-bean appearance

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Paratubal Cysts ♦♦ Arise from mesonephric (wolffian) or paramesonephric (müllerian) structures or from mesothelial inclusions −− Paramesonephric cyst (a) Lined by epithelium containing ciliated cells (b) May have papillary infoldings (c) Hydatid of Morgagni is the most common * 2–10 mm ovoid or round cyst attached by a pedicle to the fimbriae * Filled with clear serous fluid with a thin ­translucent wall −− Mesonephric cysts (a) May have a more prominent muscular coat (b) Contain only a few or no ciliated cells −− Mesothelial cysts (a) More than 80% of paratubal cysts measuring 3  cm are mesothelial cysts (b) Lined by flat cells and surrounded by thin fibrous wall

Fig. 31.43. Adenofibroma of the fallopian tube.

Tubal Prolapse ♦♦ Tubal prolapse into the vagina may occur rarely as a complication of vaginal or abdominal hysterectomy ♦♦ Grossly, an excresence in the vaginal vault, suggestive of granulation tissue or carcinoma is seen

Epithelial Tumors Benign Papilloma and Cystadenoma ♦♦ Uncommon lesions ♦♦ Papillomas −− Intramural or located in the fimbriated end and are loosely attached to the tubal mucosa −− Consist of delicate branching fibrovascular stalks lined by indifferent or tubal type epithelium ♦♦ Cystadenomas are similar but lack papillary features

Adenofibroma and Cystadenofibroma (Fig. 31.43) ♦♦ Rare, majority are incidental findings ♦♦ Round solitary mass (0.5–3 cm) ♦♦ Intraluminal or attached to the fimbriated end or serosal surface ♦♦ Connective tissue stroma and papillary structures or tubal structures lined by epithelial cells, usually serous type

Fig.  31.44. Metaplastic papillary tumor. Papillae and cellular buds composed of cells with abundant eosinophilic cytoplasm.

Microscopic ♦♦ Variable sized papillae covered by cells with abundant eosinophilic cytoplasm, showing cellular budding (Fig. 31.44) ♦♦ Some cells may contain intracellular mucin, and extracellular mucin may be abundant ♦♦ Mitotic figures are rarely observed

Endometrioid Polyp Clinical ♦♦ Also referred to as adenomatous polyp ♦♦ May obstruct the lumen and result in infertility or tubal pregnancy

Metaplastic Papillary Tumor Clinical

Macroscopic

♦♦ Uncommon, usually an incidental finding in segments of fallopian tube removed during post partum for sterilization ♦♦ Only rarely occurs in women who are not recently pregnant

Microscopic

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♦♦ Most not recognized grossly, but can measure ~1 cm ♦♦ Occur in the interstitial portion of the fallopian tube

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Fig. 31.45. Carcinoma in situ of the fallopian tube.

♦♦ Often attached to the tubal epithelium by a broad base, resembling endometrial polyps ♦♦ Frequently associated with mucosal endometriosis

Carcinoma In Situ ♦♦ Not detected on macroscopic examination ♦♦ The tubal epithelium is replaced by cytologically malignant glandular epithelial cells with pleomorphic nuclei (Fig. 31.45) ♦♦ Loss of polarity of the epithelial cells and formation of papillae without stromal cores ♦♦ Numerous mitoses are present ♦♦ Florid epithelial proliferation associated with salpingitis should not be mistaken for carcinoma in situ ♦♦ Immunohistochemically, carcinoma in situ of the fallopian tube shows strong positivity for p53 and elevated Ki-67 (more than 75% of cell nuclei)

Borderline Epithelial Tumors ♦♦ Rare; include serous, mucinous and endometrioid types ♦♦ Borderline serous tumors involve the tube, including the fimbriated portion, and resemble those of the ovary ♦♦ Mucinous tumors can be associated with mucinous metaplasia of the fallopian tube or Peutz-Jegers syndrome ♦♦ In patients with multiple organ involvement or pseudomyxoma peritonei, a metastatic lesion to the tube should be excluded ♦♦ Long-term followup is limited, but the prognosis appears to be favorable

Malignant Epithelial Tumors Clinical ♦♦ Uncommon and 0.2–0.5% of all primary genital malignancies ♦♦ Usually postmenopausal, sixth or seventh decade ♦♦ BRCA and tubal carcinomas −− Women with BRCA mutations have an increased risk of tubal carcinoma

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Fig. 31.46. Primary tubal serous carcinoma. −− In some studies, tubal carcinomas have been found in 5–15% of BRCA positive women undergoing risk-reducing salpingo-oophorectomy (RRSO), most commonly occur in the fimbria but can occur in the ampulla or proximal tube −− Is recommended that RRSO specimens in BRCA patients be sectioned at 2–3 mm interval and submitted entirely for histologic examination to detect occult carcinomas ♦♦ Classic signs and symptoms include vaginal bleeding, clear or serosanguinous vaginal discharge, pelvic pain and pelvic mass ♦♦ Diagnosis is rarely made before operation ♦♦ Positive cytology associated with a negative endometrial curettage may suggest a tubal location

Macroscopic ♦♦ Swollen secondary to intraluminal growth ♦♦ Lumen filled and dilated by papillary or solid tumor ♦♦ Frequently bilateral

Microscopic ♦♦ All carcinoma subtypes documented in the ovaries have been identified in the fallopian tube ♦♦ Serous carcinoma is the most common subtype, comprising ~70% of cases; endometrioid and transitional cell types comprise ~10% each ♦♦ Serous carcinomas resemble their ovarian counterparts in the presence of papillary cellular buds, slit-like slender spaces, solid sheets, and psammoma bodies (Fig. 31.46) ♦♦ May be associated with contiguous in situ carcinoma ♦♦ Synchronous mucinous primaries have been described in the tube and endocervix

Differential Diagnosis ♦♦ Tubal extension by primary uterine or ovarian carcinoma −− In order to be considered a primary carcinoma of fallopian tube, the tumor must be located macroscopically within the tube or its fimbriated end, and the

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uterus and ovaries must either not contain carcinoma or if they do, it must be different from the fallopian tube lesion

Mixed Epithelial Mesenchymal Tumors Carcinosarcoma (Malignant Mixed Mesodermal Tumor) Clinical ♦♦ Rarely primary in the fallopian tube ♦♦ Almost always postmenopausal ♦♦ May present with abdominal pain, abnormal vaginal bleeding, or abdominal distention ♦♦ Poor prognosis

Macroscopic

Fig. 31.47. Adenomatoid tumor. Multiple small, slit-like spaces proliferate in the wall of the tube.

♦♦ Distended tube ♦♦ Usually evidence of extension to adjacent pelvic and abdominal structures

Differential Diagnosis

Microscopic

♦♦ Infiltrating adenocarcinoma

♦♦ Admixture of histologically malignant epithelial and mesenchymal elements

Germ Cell Tumors Teratoma Clinical

Mesenchymal Tumors ♦♦ Leiomyoma −− Uncommon in the fallopian tube −− May originate from the tubal muscularis, from smooth muscle of the broad ligament, or from walls of blood vessels −− Histologically similar to those found in the uterus and can also undergo similar degenerative changes ♦♦ Leiomyosarcoma −− Primary sarcomas of the fallopian tube are extremely rare; leiomyosarcoma is the most common type

Mesothelial Tumors Adenomatoid Tumor Clinical ♦♦ ♦♦ ♦♦ ♦♦

Most frequent type of benign tubal tumor Usually an incidental finding Rarely bilateral Presumed mesothelial derivation

Macroscopic ♦♦ 1–2 cm nodular swelling beneath the tubal serosa ♦♦ Yellow or whitish gray on section

Microscopic ♦♦ Multiple, small, slit-like or ovoid spaces lined by single layer of low cuboidal or flattened epithelial-like cells (Fig. 31.47) ♦♦ May infiltrate into the stroma of the luminal folds

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♦♦ Rare; usually nulliparous and in the fourth decade ♦♦ Majority are mature

Macroscopic ♦♦ Most frequently intraluminal, attached by a pedicle to the tubal wall(but may be intramural or attached to the serosa) ♦♦ Size ranges from 1 to 20 cm ♦♦ On cut section most often cystic than solid

Microscopic ♦♦ Similar to their ovarian counterparts ♦♦ Mixture of well-differentiated mature ectodermal, ­mesodermal, and endodermal tissues

Trophoblastic Disease ♦♦ ♦♦ ♦♦ ♦♦

Placental site nodule Hydatiform mole Placental site trophoblastic tumor Choriocarcinoma

Lymphoid and Hematopoetic Tumors ♦♦ Tubal involvement by lymphoma is rare ♦♦ Almost always associated with simultaneous involvement of the ipsilateral ovary ♦♦ Most often by Burkitt or Burkitt-like lymphoma or diffuse large cell lymphoma

Uterus and Fallopian Tube

Secondary Tumors ♦♦ Usually secondary to spread from carcinomas of the ovary or endometrium, in most cases by direct extension ♦♦ Much more common than primary tubal carcinoma ♦♦ Blood-borne metastasis from breast carcinoma or other extrapelvic tumors may also occur

Tumors of the Uterine Ligaments

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♦♦ ♦♦ ♦♦ ♦♦

Tumor of presumptive wolffian origin Age range 15–81 years Most present with a unilateral mass Occur mainly in the broad ligament, but also in the mesosalpinx, serosa of the fallopian tube, ovary, and retroperitoneum

Macroscopic

♦♦ Benign and malignant tumors that arise in the broad ligament and other uterine ligaments

♦♦ Solid; range in size from 0.5 to 18 cm ♦♦ Firm to rubbery, yellow-tan to gray-white cut surface with variably sized cysts

Epithelial Tumors of Müllerian Type

Microscopic

♦♦ Most frequent neoplasms of the broad and other ligaments ♦♦ Tumors of every müllerian cell type and of every degree of malignancy can occur, but are infrequent compared to their occurrence in the ovary

Miscellaneous Tumors Wolffian Adnexal Tumor Clinical ♦♦ Rare, <50 examples described

♦♦ Characterized by a variety of epithelial patterns ♦♦ Solid masses of epithelial cells may be present, or tubular areas similar to a well-differentiated Sertoli–Leydig tumor of the ovary

Other Tumors of the Uterine Ligaments ♦♦ Leiomyoma ♦♦ Papillary cystadenoma associated with von Hippel–Lindau disease

TNM Classification and FIGO Staging System for Cervical Carcinoma (2010 REVISION) ♦♦ T: Primary Tumor (FIGO Stage) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ −− T1(I): Cervical carcinoma confined to uterus (extension to the corpus should be disregarded) −− T1a(IA): Invasive carcinoma diagnosed only by microscopy; all macroscopically visible lesions, even with superficial invasion, are T1b/stage IB −− T1a1(IA1): Stromal invasion no greater than 3.0  mm in depth and 7.0 mm or less in horizontal spread −− T1a2(IA2): Stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread of 7.0 mm or less1 −− T1b(IB): Clinically visible lesion confined to the cervix or microscopic lesion greater than T1a2/ IA2 −− T1b1(IB1): Clinically visible lesion of 4.0 cm or less in greatest dimension −− T1b2(IB2): Clinically visible lesion of more than 4.0 cm in greatest dimension −− T2(II): Tumor invades beyond the uterus but not pelvic wall or lower third of the vagina

−− T2a(IIA): Without parametrial invasion −− T2b(IIB): With parametrial invasion −− T3 (III): Tumor extends to the pelvic wall, involves lower third of vagina, or causes hydronephrosis or nonfunctioning kidney −− T3a(IIIA): Tumor involves lower third of vagina with no extension to pelvic wall −− T3b(IIIB): Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney −− T4(IVA): Tumor invades mucosa of bladder or rectum and/or extends beyond true pelvis −− M1(IVB): Distant metastasis ♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ M: Distant Metastasis −− M0: No distant metastasis −− M1: Distant metastasis

The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. The depth of invasion is defined as the measurement of the tumor from the e­ pithelial–stromal junction of the adjacent most superficial epithelial papilla to the deepest point of invasion. Vascular space involvement, venous or l­ymphatic, does not affect classification.

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TNM Classification and FIGO Staging System for Endometrial Carcinoma (2010 REVISION) ♦♦ T: Primary Tumor (FIGO Stage) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ (preinvasive carcinoma) −− T1 (I): Tumor confined to corpus uteri −− T1a (IA): Tumor limited to the endometrium or invades less than one-half of the myometrium −− T1b (IB): Tumor invades one-half or more of the myometrium −− T2 (II): Tumor invades stromal connective tissue of the cervix but does not extend beyond uterus (endocervical glandular involvement only Stage I) −− T3 and/or N1(III): Local and/or regional spread as specified in T3a, b, N1, and FIGO IIIA, B, C below −− T3a (IIIA): Tumor involves serosa and/or adenexae (direct extension or metastasis)

−− T3b (IIIB): Vaginal involvement (direct extension or metastasis) −− T4 (IVA): Tumor invades bladder mucosa and/or bowel mucosa ♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1 (IIIC1): Regional lymph node metastasis to pelvic lymph nodes −− N2 (IIIC2): Regional lymph node metastasis to ­para-aortic lymph nodes, with or without positive pelvic lymph nodes ♦♦ M: Distant Metastasis −− M0: No distant metastasis −− M1 (IVB): Distant metastasis (excluding metastasis to para-aortic lymph nodes, vagina, pelvic serosa, or adnexa)

TNM Classification and FIGO Staging System for Fallopian Tube Carcinoma (2010 REVISION) ♦♦ T: Primary Tumor (FIGO Stage) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ (limited to tubal mucosa) −− T1(I): Tumor limited to fallopian tube(s) −− T1a(IA): Tumor limited to one tube without penetrating the serosal surface; no ascites −− T1b(IB): Tumor limited to both tubes without ­penetrating the serosal surface; no ascites −− T1c(IC): Tumor limited to one or both tube(s) with extension onto or through the tubal serosa, or with malignant cells in ascites or peritoneal washings −− T2(II): Tumor involves one or both fallopian tube(s) with pelvic extension −− T2a(IIA): Extension and/or metastasis to uterus and/or ovaries −− T2b(IIB): Extension to other pelvic tissues −− T2c(IIC): Pelvic extension (T2a or T2b/IIA or IIB) with malignant cells in ascites or peritoneal washings

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−− T3 and/or N1(III): Tumor involves one or both fallopian tube(s) with peritoneal implants outside pelvis and/or positive regional lymph nodes −− T3a(IIIA): Microscopic peritoneal metastasis ­outside the pelvis −− T3b(IIIB): Macroscopic peritoneal metastasis ­outside the pelvis 2 cm or less in greatest dimension −− T3 and or N1(IIIC): Peritoneal metastasis more than 2 cm in greatest dimension and/or positive regional lymph nodes −− M1(IV): Distant metastasis (excludes peritoneal metastasis) ♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ M: Distant Metastasis −− M0: No distant metastasis −− M1: Distant metastasis

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SUGGESTED READING General Clement P, Young RH (eds.). Atlas of Gynecologic Surgical Pathology, 2nd ed. Philadelphia, PA: Saunders Elsevier; 2008. Crum C, Lee K (eds.). Diagnostic Gynecologic and Obstetric Pathology. Philadelphia, PA: Elsevier Saunders; 2006. Kurman RJ (ed.). Blaustein’s Pathology of the Female Genital Tract, 5th ed. New York: Springer Verlag; 2002. Mittal K, Soslow R, McCluggage WG. Application of immunohisto­ chemistry to gynecologic pathology. Arch Pathol Lab Med 2008; 132:402–423.

Weir MM, Bell DA. Transitional cell metaplasia of the cervix: a newly described entity in cervicovaginal smears. Diagn Cytopathol 1998;18:222–226. Young RH, Scully RE. Invasive adenocarcinoma and related tumors of the uterus cervix. Semin Diagn Pathol 1990;7:205–227. Young RH, Scully RE. Uterine carcinomas simulating microglandular ­hyperplasia: a report of six cases. Am J Surg Pathol 1992;16:1092–1097.

Uterus – Corpus Chen L, Yang B. Immunohistochemical analysis of p16, p53, and Ki-67 expression in uterine smooth muscle tumors. Int J Gynecol Pathol 2008;27:326–332.

Tavassoli F, Devitee P. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. In: Tavassoli FA, Devilee P (eds.). World Health Organization Classification of Tumors. IARC Press, Lyon, 2003.

Clement PB. Pathology of the uterus corpus. Hum Pathol 1991;22:77–791.

Uterus – Cervix

Eschenbach DA, Buchanan TM, Pollock HM, et al. Polymicrobial ­etiology of acute pelvic inflammatory disease. N Engl J Med 1975;29:166–171.

Crum CP. Genital papillomaviruses and related neoplasms: causation, diagnosis and classification (Bethesda). Mod Pathol 1994;7: 138–145.

DeFusco PA, Gaffey TA, Malkasian GD Jr, et  al. Endometrial stromal ­sarcoma: review of Mayo Clinic experience. Gynecol Oncol 1989;35:8–14.

Egan AJM, Russell P. Transitional (urothelial) cell metaplasia of the ­uterine cervix: morphological assessment of 31 cases. Int J Gynecol Pathol 1997;16:89–98.

Gagne E, Tetu B, Blondeau L, et  al. Morphologic prognostic factors of malignant mixed Müllerian tumor of the uterus: a clinicopathologic study of 58 cases. Mod Pathol 1989;2:433–438.

Ferry JA, Scully RE. Mesonephric remnants, hyperplasia and neoplasia in the uterine cervix: a study of 49 cases. Am J Surg Pathol 1990;14: 1100–1111.

Gordon MD, Ireland K. Pathology of hyperplasia and carcinoma of the endometrium. Semin Oncol 1994;21:64–70.

Kiviat NB, Paavonen JA, Wolner-Hanssen P, et  al. Histopathology of endocervical infection caused by Chlamydia trachomatis, herpes simplex virus, Trichomonas vaginalis, and Neisseria gonorrhoeae. Hum Pathol 1990;21:831–837. Lesack D, Wahab I, Gilks CB. Radiation-induced atypia of endocervical epithelium: a histological, immunohistochemical and cytometric study. Int J Gynecol Pathol 1996;15:242–247. Leslie KO, Silverberg SG. Microglandular hyperplasia of the cervix: unusual clinical and pathological presentations and their differential diagnosis. Prog Surg Pathol 1984;5:95–114. McCluggage WG. Immunohistochemistry as a diagnostic aid in cervical pathology. Pathology 2007;39:97–111. Oliva E, Clement PB, Young RH. Tubal and tubo-endometrioid metaplasia of the uterine cervix? unemphasized features that may cause problems in differential diagnosis. A report of 25 cases. Am J Clin Pathol 1995;103: 618–623. Oster AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 1993;12:186–192. Oster AG. Pandora’s box or Ariadne’s thread? Definition and prognostic significance of microinvasion in the uterine cervix: squamous lesions. Pathol Annu 1995;30:103–135. Schammel DP, Silver SA, Tavassoli FA. Combined endometrial stromal/ smooth muscle neoplasms of the uterus: a clinicopathological study of 38 cases [abstract]. Mod Pathol 1999;12:124A. Suh K, Silverberg SG. Tubal metaplasia of the uterine cervix. Int J Gynecol Pathol 1990;9:122–128.

Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990;94:434–438.

Hendrickson MR, Kempson RL. Endometrial epithelial metaplasias – proliferations frequently misdiagnosed as adenocarcinoma: report of 89 cases and proposed classification. Am J Surg Pathol 1980;4:525–542. Jones MW, Norris HJ. Clinicopathologic study of 28 uterine leiomyosarcomas with metastasis. Int J Gynecol Pathol 1995;14:243–249. Kurman RJ, Norris HJ. Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinomas. Cancer 1982;49:2547–2559. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–412. Modica I, Soslow RA, Black D, Tornos C, Kauff N, Shia J. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinom. Am J Surg Pathol 2007;31:744–751. Norris HJ, Tavassoli FA, Kurman RJ. Endometrial hyperplasia and ­carcinoma: diagnostic considerations. Am J Surg Pathol 1983;7: 839–846. Rotterdam H. Chronic endometritis: a clinicopathologic study. Pathol Ann 1978;13:209–231. Shia J, et  al. Routinely assessed morphological features correlate with ­microsatellite instability status in endometrial cancer. Hum Pathol 2008;39:116–25 Silverberg SG, Mullen D, Faraci JAS, et  al. Endometrial carcinoma: ­clinical-pathologic comparison of cases in post-menopausal women receiving and not receiving exogenous estrogens. Cancer 1980;45: 3018–3026.

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Fallopian Tubes Green TH, Scully RE. Tumors of the fallopian tube. Clin Obstet Gynecol 1962;5:886–906. Mazur MT, Hsueh S, Gersell DJ. Metastases to the female genital tract: analysis of 325 cases. Cancer 1984;53:1978–1984. Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006;30:230–236.

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Podratz KC, Podczaski ES, Gaffey TA, et al. Primary carcinoma of the fallopian tube. Am J Obstet Gynecol 1986;154:1319–1326. Stock RJ. Tubal pregnancy: associated histopathology. Obstet Gynecol Clin North Am 1991;18:73–94. Thor AD, Young RH, Clement PB. Pathology of the fallopian tube, broad ligament, peritoneum, and pelvic soft tissues. Hum Pathol 1991;22:856–867.

32 Ovary and Peritoneum Robert E. Emerson, md

Contents PART A:  The Ovary.................................32-3

I. Inflammatory Lesions.........................32-4

Pelvic Inflammatory Disease...........................32-4 Actinomyces Infection......................................32-4 Tuberculous Oophoritis...................................32-4 Malakoplakia....................................................32-4 Fungal Infections..............................................32-4 Viral Infections.................................................32-4 Granulomatous Oophoritis.............................32-4

II. Nonneoplastic Lesions.......................32-5 Congenital Abnormalities................................32-5 Surface Epithelial Inclusions and Cysts......................................................32-5 Follicular Cyst..................................................32-5 Corpus Luteum Cyst........................................32-5 Large Solitary Luteinized Follicle Cyst of Pregnancy and Puerperium...................32-5 Hyperreactio Luteinalis (Multiple Luteinized Follicular Cysts).......................32-6 Luteoma of Pregnancy.....................................32-6 Polycystic Ovary Syndrome (Stein-Leventhal Syndrome).......................32-6 Stromal Hyperthecosis/Stromal Hyperplasia..................................................32-7 Leydig Cell Hyperplasia (Hilus Cell Hyperplasia).............................32-7 Rete Cyst...........................................................32-7 Massive Ovarian Edema..................................32-7 Ovarian Torsion................................................32-8

Ectopic Decidual Reaction...............................32-8 Endometriosis...................................................32-8

III. Surface Epithelial Tumors...................32-9 General Information Concerning Surface Epithelial Tumors........................................32-9 Serous Carcinoma............................................32-9 Serous Tumors of Low Malignant Potential (Serous Borderline Tumors).......................32-9 Benign Serous Tumors...................................32-12 Mucinous Carcinoma.....................................32-12 Mucinous Tumors of Low Malignant Potential (Mucinous Borderline Tumors)......................................................32-12 Mucinous Cystadenoma.................................32-12 Mucinous Tumors with Mural Nodules.......32-12 Pseudomyxoma Peritonei..............................32-13 Endometrioid Tumors....................................32-13 Clear Cell Tumors..........................................32-14 Transitional Cell Tumors...............................32-15 Squamous Cell Tumors..................................32-16 Mixed Epithelial-Stromal Tumors................32-16 Undifferentiated carcinomas.........................32-16

IV. Sex Cord-Stromal Tumors.................32-16 Granulosa Cell Tumor, Adult-Type..............32-16 Granulosa Cell Tumor, Juvenile Type..........32-17 Sertoli–Leydig Cell Tumor............................32-18 Thecoma..........................................................32-18 Fibroma...........................................................32-19 Fibrosarcoma..................................................32-19

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_32, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Sclerosing Stromal Tumor.............................32-19 Stromal Luteoma............................................32-19 Leydig Cell Tumors........................................32-20 Gynandroblastoma.........................................32-20 Sex Cord Tumor with Annular Tubules.......32-20

V. Germ Cell Tumors............................32-21 General Information Concerning Ovarian Germ Cell Tumors.....................................32-21 Dysgerminoma................................................32-21 Yolk Sac Tumor (Endodermal Sinus Tumor).............................................32-21 Embryonal Carcinoma..................................32-22 Choriocarcinoma............................................32-22 Mature Cystic Teratoma (Dermoid Cyst)..........................................32-22 Monodermal Teratoma..................................32-23 Immature Teratoma.......................................32-23 Gonadoblastoma.............................................32-24

VI. Miscellaneous Tumors Including Stromal Neoplasms, Secondary Carcinomas, and Other Neoplasms.......................................32-24 Small Cell Carcinoma (Hypercalcemic Type)...............................32-24 Small Cell Carcinoma, Pulmonary Type............................................................32-25 Hepatoid Carcinoma......................................32-25 Ovarian Tumor of Probable Wolffian Origin.........................................................32-25 Benign Stromal Neoplasms............................32-25 Sarcomas.........................................................32-25 Metastatic Carcinomas..................................32-25 Lymphomas and Leukemias..........................32-27

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PART B:  The Peritoneum....................32-29 VII. Mesothelial Lesions..........................32-30 Peritonitis........................................................32-30 Mesothelial Hyperplasia................................32-30 Endometriosis.................................................32-30 Endosalpingiosis.............................................32-30 Splenosis..........................................................32-30 Peritoneal Inclusion Cysts.............................32-30 Well-Differentiated Papillary Mesothelioma.............................................32-30 Peritoneal Malignant Mesothelioma (Diffuse Malignant Mesothelioma)..........32-31 Desmoplastic Small Round Cell Tumor.......32-31

VIII. Epithelial Tumors of Müllerian Type.................................................32-32 Primary Peritoneal Carcinoma.....................32-32

IX. Miscellaneous Peritoneal Lesions.............................................32-32 Infarcted Appendix Epiploica.......................32-32 Walthard Nest.................................................32-32 Tailgut Cyst (Retrorectal Cystic Hamartoma)..............................................32-32 Ectopic Decidual Reaction.............................32-33 Metastatic Tumors..........................................32-33 Pseudomyxoma Peritonei..............................32-33

X. Tnm Classification of Ovarian Tumors (2010 Revision)...................32-33 XI. Suggested Reading...........................32-33

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Part A The Ovary

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INFLAMMATORY LESIONS Pelvic Inflammatory Disease Clinical ♦♦ Pelvic inflammatory disease is related to bacterial infection, most commonly with gonococcus or Chlamydia, and presents with abdominal/pelvic pain, fever, vaginal discharge, or urinary tract symptoms ♦♦ The number of sexual partners is the greatest risk factor ♦♦ The infection may begin as salpingitis and progress to a tuboovarian abscess, which may be a palpable adnexal mass ♦♦ Organisms are mixed and commonly include anaerobes

Macroscopic ♦♦ The disease commonly begins as pyosalpinx and perioophoritis and may later become an abscess involving the parenchyma of the ovary with a fibrous wall ♦♦ Chronic infection may cause xanthogranulomatous oophoritis, which may mimic a neoplasm. Bacteroides may be involved in some cases of xanthogranulomatous oophoritis

Microscopic ♦♦ Peri-oophoritis is seen as neutrophils and fibrin on the surface of the ovary. A tuboovarian abscess may have a fibrous wall, central necrotic debris and neutrophils, and sometimes granulation tissue or lipid-containing macrophages

Actinomyces Infection Clinical ♦♦ Pelvic actinomycosis is usually related to chronic intrauterine device (IUD) use

Macroscopic ♦♦ Grossly, actinomycosis is seen as a mass-like lesion with multiple abscesses with a necrotic center. Yellow granules composed of the organisms (“sulfur granules”) may be seen

Microscopic ♦♦ The lesion is composed of zones of necrotic debris and acute inflammatory cells with chronic inflammatory cells lining the abscess. Clusters of filamentous bacteria with a basophilic core corresponding to the sulfur granules are seen. The organisms are Gram positive and may stain positively with modified acid-fast stains

Tuberculous Oophoritis Clinical ♦♦ Tuberculous oophoritis is rare and less common than tuberculous salpingitis, with which it is usually associated. It may clinically mimic ovarian carcinoma in the enlargement of the ovary and an elevated serum CA-125 level

Macroscopic ♦♦ Caseating granulomas may be seen

1400

Microscopic ♦♦ Histologically, granulomas with central necrosis are seen. The organisms may be identified with acid-fast stains

Differential Diagnosis ♦♦ Other causes of granulomatous inflammation (see granulomatous oophoritis below) should be considered

Malakoplakia Clinical ♦♦ Malakoplakia of the ovary occurs in postmenopausal women and is rare. It is much less common than malakoplakia of the urinary tract. It is thought to represent a granulomatous process related to the reduced the ability of histiocytes to kill bacteria after phagocytosis

Macroscopic ♦♦ It is seen grossly as a yellow, focally necrotic mass

Microscopic ♦♦ Microscopically, the lesion is composed of histiocytes with a eosinophilic granular cytoplasm (von Hansemann histiocytes); some of which may have 5–8 µm cytoplasmic inclusions that are spherical, concentrically laminated, basophilic, and calcified (Michaelis–Guttman bodies). Staining for calcium (von Kossa stain) may help demonstrate the Michaelis–Guttman bodies. E. coli or other bacteria are only occasionally identified by culture

Differential Diagnosis ♦♦ Other causes of granulomatous inflammation and possibly neoplasms with a clear-to-eosinophilic cytoplasm should be excluded

Fungal Infections ♦♦ Fungal infections are very rare but may occur in association with a pulmonary or disseminated infection. Infections with Blastomyces, Coccidioides, and Aspergillus have been described

Viral Infections ♦♦ Viral infections are infrequently identified, but cytomegalovirus infections may be seen with eosinophilic intranuclear and cytoplasmic inclusions. Cytomegalovirus oophoritis may occur in immunosuppressed patients ♦♦ Mumps oophoritis is less common than mumps orchitis but may result in premature menopause

Granulomatous Oophoritis Clinical ♦♦ Granulomatous oophoritis may be iatrogenic (suture material, starch granules, talc, or hysterosalpingographic contrast) or due to keratin (ruptured mature cystic teratoma or squamous cell carcinoma), sarcoidosis, Crohn disease, or infection (mycobacterial or fungal)

Ovary and Peritoneum

32-5

Macroscopic

Differential Diagnosis

♦♦ The granulomas are usually small and bilateral

♦♦ Acid-fast bacterial and fungal staining should be performed to attempt to identify the organisms. Polarization microscopy may identify starch or talc granules

Microscopic ♦♦ Noncaseating granulomas, with or without giant cells, are seen

NONNEOPLASTIC LESIONS Congenital Abnormalities ♦♦ Absence of one or both ovaries may be associated with gonadal dysgenesis, ataxia telangiectasia, or with abnormalities of the ipsilateral fallopian tube, kidney, and/or ureter ♦♦ Supernumerary or ectopic ovaries are very rare but may be present in the pelvis as an attachment to the bladder, the omentum, or the retroperitoneum ♦♦ Splenic–gonadal fusion is also very rare and results from fusion during embryologic development. A cord-like structure may connect the spleen to the left ovary or the splenic tissue may be seen on the surface of the ovary. This must be distinguished from splenosis ♦♦ Adrenal cortical rests may be seen in the ovary but less common than in the fallopian tube or broad ligament

Surface Epithelial Inclusions and Cysts ♦♦ Surface epithelial inclusions and cysts are thought to result from the invaginations of the ovarian surface epithelium (Fig. 32.1). When >1 cm, they may be considered a serous cystadenoma. When outside the ovary, similar inclusions are called endosalpingiosis. Ovarian epithelial inclusions and endosalpingiosis may include psammoma bodies. Neither the presence of psammoma bodies or endosalpingi-

osis within the subcapsular sinus of lymph nodes indicates malignancy

Follicular Cyst Clinical ♦♦ Follicular cysts develop from preovulatory follicles and can be associated with pain, vomiting, diarrhea, constipation, and dysfunctional uterine bleeding. Most will regress within 2 months ♦♦ Occasionally, ovarian torsion may occur

Macroscopic ♦♦ By definition, these cysts are >3  cm in diameter, but they may reach 10 cm or more. They have a smooth lining

Microscopic ♦♦ Follicle cysts are lined by granulosa cells, but the lining may be inapparent or absent in some areas. The surrounding theca cells may be luteinized

Corpus Luteum Cyst Clinical ♦♦ Corpus luteum cysts develop from postovulatory follicles (corpora lutea) during menstruation or pregnancy. They are usually asymptomatic ♦♦ Similar to follicular cysts and spontaneous regression is typical

Macroscopic ♦♦ These cysts are usually 2–3 cm in diameter and have a central hemorrhage surrounded by a lining of fibrous connective tissue that in turn is surrounded by a convoluted yellow layer of tissue

Microscopic ♦♦ The yellow layer is composed of luteinized granulosa cells with abundant eosinophilic cytoplasm

Large Solitary Luteinized Follicle Cyst of Pregnancy and Puerperium

Fig. 32.1. Ovarian serous surface inclusion lined by a flattened serous epithelium. Serous surface inclusions lack associated granulosa cells or luteinized stromal cells.

♦♦ This is a variant of follicular cyst that may present as a palpable adnexal mass or may be seen during a cesarean section. It may be up to 25  cm in diameter, and the wall is composed of luteinized granulosa and theca cells (Fig. 32.2). Prominent nuclear atypia may be seen, but mitotic figures are absent and behavior is benign

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32-6

Fig. 32.2. Large solitary luteinized follicle cyst of pregnancy and puerperium. The cyst is lined by granulosa cells and luteinized stromal cells are present in the fibrous tissue of the cyst wall.

Hyperreactio Luteinalis (Multiple Luteinized Follicular Cysts) Clinical ♦♦ Hyperreactio luteinalis is a bilateral ovarian enlargement due to multiple luteinized follicular cysts resulting from hCG stimulation. The hCG elevation may result from a molar gestation, multiple gestation, or a hydropic fetus. Hyperreactio luteinalis occurs in up to 25% of cases of gestational trophoblastic disease ♦♦ This lesion regresses following the removal of the hCG stimulus

Macroscopic ♦♦ The ovaries are enlarged (up to 15 cm) and are composed of multiple smooth-walled cysts

Microscopic ♦♦ Microscopically, the cysts are lined by granulosa cells surrounded by theca cells, both of which may be luteinized

Differential Diagnosis ♦♦ The ovaries may grossly resemble the ovaries of polycystic ovary syndrome, but the clinical situation differs (while hyperreactio luteinalis is usually associated with an abnormal gestation, polycystic ovary syndrome is commonly associated with infertility). Also, the ovaries lack the thick fibrous capsule and smooth surface of polycystic ovary syndrome

Luteoma of Pregnancy Clinical ♦♦ These nodular hyperplastic masses are found most commonly incidentally during cesarian section or postpartum tubal ligation ♦♦ About one-quarter of patients will have virilization or hirsutism

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Fig. 32.3. Luteoma of pregnancy. The tumor was an incidental finding during a cesarian section and was composed of polygonal luteinized cells with abundant eosinophilic cytoplasm. ♦♦ Incompletely resected tumors regress following the pregnancy

Macroscopic ♦♦ Grossly, they are composed of red-brown soft tissue, and they may be multiple or bilateral. They are commonly 6–12 cm in diameter. Necrosis may be seen postpartum

Microscopic ♦♦ Microscopically, they are composed of polygonal luteinized cells in nodules or of a diffuse pattern with abundant eosinophilic cytoplasm and round nuclei (Fig.  32.3). Small cysts may be present

Differential Diagnosis ♦♦ Some sex-cord stromal tumors may resemble luteoma of pregnancy, but it is unusual for those to be bilateral, in contrast to the commonly bilateral luteoma of pregnancy. The tumors that may appear histologically similar include Leydig cell tumor, thecoma, sclerosing stromal tumor, and juvenile granulosa cell tumors

Polycystic Ovary Syndrome (Stein-Leventhal Syndrome) Clinical ♦♦ Polycystic ovary syndrome is a relatively common (5–10% of the female population) disorder characterized by chronic anovulation, multicystic ovaries with a fibrotic cortex, and hyperandrogenism. Clinical findings include dysfunctional uterine bleeding, infertility, obesity, and hirsutism ♦♦ Many patients will have androgen excess, with an elevation of serum testosterone, dehydroepiandrosterone, or other androgens ♦♦ Some patients may also have abnormal glucose tolerance, insulin resistance, and acanthosis nigricans (“HAIR-AN syndrome”: hyperandrogenism, insulin resistance, and acanthosis nigricans)

Ovary and Peritoneum

Macroscopic ♦♦ The ovaries are grossly enlarged (approximately twice the normal size) with a smooth outer surface, a thick fibrous cortex, and with multiple small (<1  cm) cysts just under the fibrotic cortex

Microscopic ♦♦ A thickened fibrous capsule at the surface of the ovary is seen with multiple follicle cysts underneath. The cysts are lined by a thinned granulosa cell layer with surrounding theca cells. Evidence of ovulation (such as corpora albicantia or corpora lutea) is not seen

Differential Diagnosis

32-7

Rete Cyst Clinical ♦♦ Cysts of the rete ovarii may occur in the ovarian hilus

Macroscopic ♦♦ They are usually unilocular and small, but occasionally, cysts up to 12 cm can occur

Microscopic ♦♦ Microscopically, they are lined by flattened or cuboidal cells. Smooth muscle and nests of hyperplastic Leydig cells may be seen adjacent to the cyst

♦♦ See hyperreactio luteinalis above

Massive Ovarian Edema Clinical

Stromal Hyperthecosis/Stromal Hyperplasia Clinical

♦♦ Massive ovarian edema may clinically mimic a neoplasm and often presents with abdominal pain. Patients are young (usually in the second or third decade) ♦♦ The frequent association with torsion suggests that development of massive ovarian edema may be related to intermittent or partial ovarian torsion that impairs lymphatic and venous drainage from the ovary

♦♦ These disorders occur in perimenopausal or postmenopausal women and may be associated with virilization, increased serum testosterone, hypertension, or decreased glucose tolerance and are seen as bilateral ovarian enlargements

Macroscopic ♦♦ Grossly, the ovaries are enlarged (up to twice normal size), firm and white, tan, or yellow in color. In some cases, stromal hyperthecosis may be grossly nodular

Microscopic ♦♦ Microscopically, the ovaries have a hyperplastic stroma with luteinized stromal cells (stromal hyperthecosis) or densely arranged nonluteinized stromal cells (stromal hyperplasia)

Leydig Cell Hyperplasia (Hilus Cell Hyperplasia) Clinical

Macroscopic ♦♦ The ovary is grossly greatly enlarged (over 10 cm and occasionally up to 35 cm) and white in color. The cut surface is an edematous-appearing fibrous tissue

Microscopic ♦♦ Microscopically, the ovary is composed of cytologically bland stromal cells widely separated by edema fluid (Fig. 32.4)

Differential Diagnosis ♦♦ Grossly, metastatic carcinomas with mucin production or edematous tumors (such as some lymphomas) may resemble

♦♦ Small nests of Leydig cells can be found in the ovarian hilus where they are known as hilus cells and they occasionally may be found elsewhere in the ovary or in the fallopian tube. Proliferation of hilus cells is observed in pregnancy, after menopause, and in several pathologic conditions including stromal hyperplasia and rete cysts. Leydig cell hyperplasia is usually not clinically significant, but can be associated with increased serum testosterone

Macroscopic ♦♦ Leydig cell hyperplasia is not grossly apparent

Microscopic ♦♦ Leydig cell hyperplasia is seen as nodules of polygonal Leydig cells with abundant eosinophilic granular cytoplasm and round nuclei. Reinke crystals (eosinophilic rod-shaped cytoplasmic crystalloids) and cytoplasmic yellow-brown lipofuscin pigment may be seen

Differential Diagnosis ♦♦ Masses >1 cm composed of Leydig cells may be considered Leydig cell tumors

Fig.  32.4. Massive ovarian edema. This massively enlarged ovary was grossly white in color with a fibrous and edematous cut surface. Microscopically, cytologically bland, widely spaced spindle cells were seen with occasional collagen fibers.

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32-8

massive ovarian edema. Sclerosing stromal tumors may have edematous areas that microscopically resemble massive ovarian edema

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Rarely, carcinomas may arise within endometriosis in the colon or elsewhere

Macroscopic

♦♦ The ovary is grossly swollen (up to 6 cm), hemorrhagic, and, sometimes, infarcted

♦♦ Grossly, small lesions may be seen as patches of blue, red, or brown on a serosal surface. Microscopically, endometrial glands, stroma, and hemosiderin-containing macrophages are seen ♦♦ The ovary is the most common location for endometriotic cysts. These cysts may present as a large mass lesion and may largely replace the normal ovarian tissue. The cysts contain brown degenerated blood (“chocolate cysts”) ♦♦ Other locations for endometriosis include the fallopian tube, uterine serosa, uterine cervix, colon, and the peritoneum (especially in the cul-de-sac). Very rarely, the lung or pleura may be involved

Microscopic

Microscopic

Ovarian Torsion Clinical ♦♦ Ovarian torsion is frequently associated with a mass lesion, usually a benign cyst or tumor, but torsion of an otherwise normal ovary may also occur. It occurs most commonly in women of reproductive age , but about one-fourth of cases occur in children. Patients present with abdominal pain that may mimic appendicitis

Macroscopic

♦♦ Hemorrhage, edema, and ischemic necrosis are seen. A search should be made for a possible associated neoplasm, but identification of one, even if present, may be difficult due to infarction

Ectopic Decidual Reaction ♦♦ Decidual reaction may be seen in the ovarian stroma as a result of pregnancy or progestin treatment or adjacent to a corpus luteum . The stromal cells are in the form of small nodules or large sheets and have the typical abundant eosinophilic cytoplasm of endometrial decidual cells. Focally, nuclear atypia or cytoplasmic vacuolization (a potential mimic of signet-ring adenocarcinoma but PAS negative) may be seen

Endometriosis Clinical ♦♦ Endometriosis is defined as the presence of benign endometrial glands and stroma, often with evidence of hemorrhage outside the uterus. While the etiology of the condition is incompletely understood, most cases probably result from retrograde menstruation through the fallopian tube with implantation of endometrial tissue on the ovary or peritoneum. Other possibilities include metaplasia of the pelvic peritoneum or, rarely, lymphovascular dissemination of benign endometrial tissue ♦♦ Endometriosis affects 4–10% of women of reproductive age, and it is associated with dysmenorrhea and chronic pelvic pain. Up to 30% of women with endometriosis are infertile ♦♦ Low parity and cervical stenosis are risk factors ♦♦ Serum CA-125 may be elevated in women with endometriosis. The ovary and any pelvic or abdominal serosal surface may be involved. Surgical scars (cesarian section scars, episiotomy sites, or scars from other abdominal surgeries) may be involved

1404

♦♦ Noncystic lesions of endometriosis are seen as endometrioid glands, which commonly are inactive-appearing but may have a proliferative or secretory appearance. The stroma may be densely cellular (resembling proliferative endometrial stroma), edematous-appearing (resembling secretory phase stroma), or may show decidual change. Macrophages are commonly seen, but hemosiderin pigment may or may not be visible ♦♦ Endometriotic cysts are lined by a endometrial epithelium with underlying endometrial stroma, hemorrhage, and pigmented (hemosiderin-containing) macrophages ♦♦ Decidual reaction, Arias-Stella reaction, hyperplasia, and cytologic atypia may be seen in endometriosis. Malignant tumors also may arise within endometriosis. Clear cell adenocarcinomas are the most common endometriosis-associated carcinoma, but endometrioid adenocarcinomas may also be seen ♦♦ Occasional cases of endometriosis, usually in the ovary, may have a paucity or absence of glands (“benign stromatosis”) ♦♦ Occasionally, the endometrial stroma in an endometriotic cyst may undergo smooth muscle metaplasia (“endomyometriosis”). This phenomenon may result in the presence of a “uterus-like mass” in the ovary or elsewhere

Differential Diagnosis ♦♦ Grossly, corpus luteum cysts appear as a hemorrhagic cystic lesion in the ovary similar to endometriosis but have a surrounding rim of yellow tissue ♦ ♦ The epithelium of endometriosis may be focally ciliated, but uniformly ciliated glands not associated with endometrial stroma are considered endosalpingiosis (see endosalpingiosis in the peritoneum section below) ♦♦ Endometriotic glands may be irregular in outline but should not have extensive confluent growth. If this is seen, endometrioid carcinoma must be considered

Ovary and Peritoneum

32-9

SURFACE EPITHELIAL TUMORS General Information Concerning Surface Epithelial Tumors ♦♦ Ovarian carcinomas comprise approximately 30% of all gynecologic tract malignancies. Surface epithelial tumors (also known as surface epithelial–stromal tumors) are the most common type, comprising 90% of ovarian malignancies ♦♦ Risk factors for ovarian surface epithelial malignancies include postmenopausal estrogen replacement therapy and obesity. A history of oral contraceptive use and high parity are associated with a decreased risk ♦♦ The mean 5-year survival for ovarian malignancies is only 32% as most patients present with advanced stage (outside the pelvis) disease ♦♦ The most common genetic abnormality in familial cases of ovarian carcinoma is BRCA1. BRCA2 and hereditary nonpolyposis colorectal carcinoma syndrome (Lynch syndrome) gene abnormalities (MLH1 and MSH2) are less important ♦♦ Immunophenotyping is useful in the differential diagnosis (Table 32.1)

Serous Carcinoma Clinical ♦♦ Serous carcinoma is thought to arise from ovarian surface epithelium invaginations or inclusions, but origin from implants of neoplastic fallopian tube epithelial cells has also been proposed. Support for this concept includes the frequent identification of dysplastic changes (tubular intraepithelial neoplasia) in the epithelium of the fimbriated end of the fallopian tubes in prophylactic salpingo-oophorectomy specimens from patients with BRCA mutations

Macroscopic ♦♦ Serous carcinoma is bilateral in two-thirds of cases ♦♦ Tumors vary from microscopic to over 20 cm. The cut surfaces of the tumor are commonly white to tan, and grossly apparent papillary structures, cysts, necrosis, and hemorrhage may be seen

Microscopic ♦♦ Neoplastic serous epithelium ranges from cytologically bland columnar epithelium resembling fallopian tube epithelium to solid nests of epithelium with markedly pleomorphic, enlarged, and hyperchromatic nuclei and scant cytoplasm ♦♦ Serous carcinoma is commonly papillary but may also be solid or cribriform in architecture ♦♦ Psammoma bodies are seen in about one-third of high grade serous carcinomas and a larger fraction of low grade serous carcinomas. They are not, however, proof of the presence of serous carcinoma by themselves as they are seen in serous tumors of low malignant potential, nonovarian neoplasms, and in benign mesothelial hyperplasia. Some cases of low grade serous carcinoma may have a greater volume of psammoma bodies than residual epithelium (“psammocarcinoma,” Fig. 32.5)

♦♦ Serous carcinoma is usually positive for keratin 7, EMA, and CA125 and is negative for keratin 20 and calretinin ♦♦ Various grading systems have been used for serous carcinomas including a three-grade and a two-grade system. Support for the two-grade system includes the observation that the high grade tumors (which make up approximately 90% of serous carcinomas) usually have TP53 mutations, lack KRAS mutations, and only rarely arise from a serous tumor of low malignant potential, while low grade serous carcinomas (Fig.  32.6) commonly have KRAS mutations, lack TP53 mutations, and are more likely to arise from a serous tumor of low malignant potential

Differential Diagnosis ♦♦ Endometrioid carcinoma, especially when poorly differentiated, may resemble serous carcinoma. Both may have papillary, glandular, or solid architecture or a mixture of these patterns. High grade serous carcinomas have higher grade nuclear atypia with occasional large, hyperchromatic nuclei, and the glands and papillary structures tend to have scalloped or irregular surfaces and slit-like lumens. Psammoma bodies are seen in about one-third of cases. Endometrioid carcinoma glands tend to have round lumens with flat or continuous luminal surfaces and cells with a more columnar appearance; squamous differentiation is seen in about one-third of cases ♦♦ Metastatic carcinomas, especially breast carcinoma, may also resemble serous carcinoma

Serous Tumors of Low Malignant Potential (Serous Borderline Tumors) Clinical ♦♦ Patients with serous tumors of low malignant potential are on average younger than patients with serous carcinoma (approximately 45-year-old vs. 60 years for serous carcinoma). At least one-third of cases are bilateral ♦♦ Prognosis is better than serous carcinoma, with 99% 5-year survival for stage I cases and 55–75% 5-year survival for stage III. The tumor is, however, resistant to platinum-based chemotherapy

Macroscopic ♦♦ These tumors are commonly cystic with grossly identifiable nodularity or papillary structures in the cyst lining

Microscopic ♦♦ Serous tumors of low malignant potential (serous borderline tumors) have papillary architecture (with fibrovascular cores) and low grade nuclear atypia (Fig.  32.7). Papillary tufting and epithelial hyperplasia of several cells in thickness is present, but stromal invasion and extensive solid or cribriform architecture are absent ♦♦ A micropapillary variant of serous tumor of low malignant potential (comprising 5–10% of cases) has been described. This tumor has thin micropapillae, without stromal support that are at least five times as long as they are wide arising

1405

1406

−

v

+

+

Clear

Brenner

v

−

−

nd

+

u+

−

u−

v

nd

nd

nd

−

nd

−

+

u+

nd

+

nd

+

+

+

+

nd

−

nd

v

nd

−

u−

−

nd

nd

−

v

u+

nd

u+

u+

−

v

v

−

CEAp

v

v

nd

nd

nd

nd

nd

−

−

−

−

u−

nd

nd

u−

−

−

u−

u−

u+

CA125

nd

v

v

nd

nd

v

−

−

nd

nd

−

v

v

nd

v

nd

−

v

u−

u+

P53

nd

−

nd

nd

nd

−

nd

u−

nd

nd

−

−

v

+

+

nd

v

u−

v

−

CDX2

nd

−

nd

v

nd

−

nd

nd

nd

nd

nd

−

−

−

−

−

−

−

−

v

TTF1

nd

−

−

−

+

−

−

−

u+

+

+

−

−

nd

+

−

−

−

−

−

Inh

u−

u+

−

−

nd

−

−

−

u+

+

+

u−

−

−

−

u−

u−

u−

v

u−

Cal

nd

v

−

+

−

−

−

−

nd

nd

nd

nd

−

nd

−

nd

nd

nd

nd

−

Ch

nd

−

−

−

−

+

−

u+

−

−

−

−

−

nd

−

−

u−

−

−

−

OCT

nd

−

−

−

+

u+

v

+

−

−

−

−

nd

nd

nd

nd

v

v

v

v

PLAP

−

−

nd

nd

−

v

u+

−

−

v

−

−

−

nd

−

nd

u−

−

nd

−

AFP

−

−

+

nd

−

−

−

−

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

LCA

nd

u−

v

−

−

u+

−

−

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

nd

CD30

Serous serous carcinoma, Mucinous mucinous carcinoma, Endometrioid endometrioid carcinoma, Clear clear cell carcinoma, Brenner Brenner/transitional tumors, Colorectal metastatic colorectal adenocarcinoma, Appendiceal appendiceal adenocarcinoma, Gastric metastatic gastric adenocarcinoma, Breast metastatic breast adenocarcinoma, Granulosa adult-type granulosa cell tumor, Sertoli–Leydig Sertoli–Leydig cell tumor, Embryonal embryonal carcinoma, Carcinoid ovarian carcinoid tumor, Lymphoma non-Hodgkin lymphoma, DSRCT desmoplastic small round cell tumor CK7 cytokeratin 7, CK20 cytokeratin 20, EMA epithelial membrane antigen, CEAp polyclonal carcinoembryonic antigen, Inh inhibin-alpha, Cal calretinin, OCT OCT3/4, PLAP placental-like alkaline phosphatase, AFP alpha-fetoprotein, LCA leukocyte common antigen (CD45) + positive in at least 90% of cases, u+ usually positive, v variable, u− usually negative, − negative (less than 10% of cases staining), nd no data available

nd

DSRCT

nd

nd

nd

Lymphoma

nd

Carcinoid

Mesothelioma

nd

nd

Choriocarcinoma

nd

−

u−

u+

nd

Yolk sac tumor

nd

Dysgerminoma

nd

nd

v

Embryonal

v

Fibroma-thecoma

nd

nd

−

Granulosa

+

Breast

Sertoli–Leydig

−

v

Gastric

+

v

v

Colorectal

Appendiceal

−

u−

+

+

Mucinous

u−

+

Endometrioid

Serous

CK7 CK20 EMA

Table 32.1. Immunohistochemical Findings in Ovarian Tumors

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32-11

Fig.  32.5. Low grade serous carcinoma with abundant psammoma bodies (“psammocarcinoma”). This low grade ovarian serous carcinoma has numerous laminated calcifications (psammoma bodies) that compose almost the same area on the slide as the malignant epithelium.

Fig.  32.7. Serous cystadenomatous tumor of low malignant potential (serous borderline tumor). This cystic tumor has papillary architecture with papillae covered by serous epithelium with mild nuclear atypia, nuclear stratification, and papillary tufting. Solid, cribriform, or invasive growth is not seen.

Fig. 32.6. Low grade serous carcinoma. The nuclei are enlarged but relatively uniform with only mild-to-moderate nuclear atypia and less than 12 mitoses per 10 high power fields.

Fig. 32.8. Micropapillary architecture. This serous tumor of low malignant potential had focal micropapillary architecture with thin micropapillae, with length greater than five times their width and lacking stromal cores.

directly from the surface of papillary structures with stromal cores (“nonhierarchical branching” or “medusa-head” appearance, Fig.  32.8) in at least a continuous 5  mm area. This variant is associated with an increased likelihood of ovarian surface involvement, bilaterality, and advanced stage, but worse prognosis has been demonstrated only in some studies ♦♦ Peritoneal surface implants may be seen in association with serous tumors of low malignant potential. Noninvasive implants have minimal impact on prognosis, but invasive implants are associated with a recurrence rate of greater than 50% in 10 years

♦♦ Inclusions of serous epithelium with features of a low malignant potential tumor may be seen in pelvic lymph nodes in association with ovarian serous tumors of low malignant potential. These may represent metastatic or independently arising tumors

Differential Diagnosis ♦♦ The usual considerations in the differential diagnosis are serous carcinoma (which has an invasive, cribriform/interconnecting glandular, or solid pattern) and serous cystadenoma/serous cystadenofibroma (which may have papillary

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architecture within the cyst but lacks nuclear stratification and papillary tufting) ♦♦ Occasional metastatic tumors, such as pancreatic adenocarcinoma, may mimic serous low malignant potential tumors

Benign Serous Tumors Macroscopic ♦♦ Benign serous tumors (serous cystadenoma and serous cystadenofibroma) are cystic and are bilateral in approximately 20% of cases. Nodularity/papillary structures may be apparent in the cyst wall (this does not necessarily indicate that the tumor is a low malignant potential tumor)

Microscopic ♦♦ Serous cystadenomas are lined by a flat (one cell layer) epithelium that may be ciliated ♦♦ Serous cystadenofibromas have papillary architecture with the flat epithelium covering broad, “club-like” fibrous stromal cores. Some cases may also have a glanular pattern with dense fibrous stroma surrounding the glands

Mucinous Carcinoma Clinical ♦♦ Ovarian mucinous carcinomas have a good prognosis if in stage I and a poor prognosis if in a higher stage; however, many older case series of ovarian mucinous carcinomas have likely contained cases of metastatic carcinoma involving the ovary

Macroscopic ♦♦ Mucinous carcinomas are usually large unilateral cystic masses filled with mucoid material

Microscopic ♦♦ Invasive growth pattern, complex papillary architecture, or closely arranged glands with minimal intervening stroma must be seen for the diagnosis of ovarian mucinous carcinoma. Mucinous carcinomas are commonly seen with areas of mucinous tumor of low malignant potential and/or mucinous cystadenoma

Differential Diagnosis ♦♦ Mucinous carcinoma of the ovary must be distinguished from metastatic tumors involving the ovary. Colorectal adenocarcinoma, low grade appendiceal mucinous carcinoma, pancreatic adenocarcinoma, and gastric adenocarcinoma may all be mistaken for a primary ovarian adenocarcinoma. The presence of bilaterality, ovarian surface involvement, and lymphovascular invasion should all raise suspicion of a metastatic carcinoma

Mucinous Tumors of Low Malignant Potential (Mucinous Borderline Tumors) Clinical ♦♦ These tumors are large (commonly 15–20 cm and sometimes larger) and cystic. Prognosis is excellent (recurrence in 2%

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or less of cases) if the tumor is limited to the ovary at the time of resection

Macroscopic ♦♦ These tumors are multicystic and are bilateral in about 5% of cases

Microscopic ♦♦ The epithelium is stratified (2–3 cells) and shows greater nuclear atypia than in a mucinous cystadenoma; it has a“filiform” papillary architecture, and epithelial tufting is commonly seen ♦♦ Most of these tumors are of intestinal type (with goblet cells, 85% of cases). Endocervical-like (lacking goblet cells in 15% of cases) tumors may also be seen ♦♦ Focal intraepithelial carcinoma or microscopic foci of invasion may be seen, but these findings do not appear to influence the prognosis

Differential Diagnosis ♦♦ As with mucinous carcinoma, the primary consideration is metastatic neoplasia, especially colorectal adenocarcinoma and low grade appendiceal mucinous neoplasm. Metastatic colorectal carcinoma commonly has “dirty necrosis” with basophilic nuclear debris and a keratin7−/keratin20+ immunophenotype. Ovarian mucinous tumors usually have a keratin7+/keratin20 variable immunophenotype

Mucinous Cystadenoma Clinical ♦♦ Mucinous cystadenomas are commonly large, commonly seen in young women, and may be associated with pregnancy or torsion. These tumors are only rarely bilateral

Macroscopic ♦♦ Mucinous cystadenomas are large cystic mucin-containing tumors

Microscopic ♦♦ The epithelium has minimal stratification and nuclear atypia. Most mucinous cystadenomas have an endocervical-like morphology, but some cases may have an intestinal (containing goblet cells) or mixed pattern ♦♦ A mature cystic teratoma may be seen in association with the tumor in 3–5% of cases

Differential Diagnosis ♦♦ Mucinous cystadenoma may have broad papillary structures, but lacks the epithelial tufting and nuclear atypia seen in a mucinous tumor of low malignant potential

Mucinous Tumors with Mural Nodules ♦♦ Rarely, cystic mucinous tumors may contain mural nodules composed of histologically distinct anaplastic carcinoma (Fig. 32.9) or sarcoma. The anaplastic carcinoma in such a nodule is composed of spindle-shaped cells with keratin positivity. A sarcomatous nodule may be rhabdomyosarcoma or undifferentiated sarcoma. Cytologically, it is atypical, but well-circumscribed sarcoma-like nodules may also be seen

Ovary and Peritoneum

Fig.  32.9. Mural nodule of anaplastic carcinoma in a mucinous cystadenomatous tumor of low malignant potential. The mural nodule was composed of anaplastic rounded tumor cells with a “rhabdoid” appearance. The anaplastic cells were positive for keratin and negative for muscle markers by immunohistochemistry.

Pseudomyxoma Peritonei Clinical ♦♦ Pseudomyxoma peritonei is the presence of abundant mucin in the peritoneal cavity. This lesion is associated with either an ovarian mucinous tumor or a gastrointestinal (usually appendiceal) mucinous tumor

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Fig. 32.10. Ovarian endometrioid adenocarcinoma. This ovarian endometrioid adenocarcinoma was focally cystic with villoglandular architecture. The villous architecture should not be mistaken for papillary serous carcinoma. In endometrioid carcinoma (in contrast to serous carcinoma), the margin of the cell groups is relatively flat, the cells are columnar, nuclear pleomorphism is not pronounced, and psammoma bodies are absent. primary with metastasis from the endometrium to ovary or the ovary to endometrium

Macroscopic

Microscopic

♦♦ Endometrioid carcinomas are cystic masses with soft, sometimes hemorrhagic or necrotic, centers. Sometimes the tumor is a nodule in the lining of an endometriotic cyst ♦♦ Endometrioid tumors of low malignant potential and benign endometrioid adenofibromas are firm fibrous tumors with a variable amount of cystic component

♦♦ Epithelial cells may or may not be present in the mucin

Microscopic

Macroscopic ♦♦ The lesion is seen as gelatinous mucin in the peritoneal cavity

Differential Diagnosis ♦♦ The primary concern is identifying the site of origin, which requires gross and histologic examination of the ovaries and appendix. Histologically similar mucinous tumor may be present in both the ovaries and appendix. In this case, (even if the appendiceal tumor is much smaller) it is thought that the appendiceal tumor should be considered the primary and that the ovarian tumor should be considered the secondary (although this remains controversial)

Endometrioid Tumors Clinical ♦♦ Endometrioid carcinomas comprise approximately 15% of all ovarian carcinomas ♦♦ Association with endometriosis is seen in approximately 40% of cases and approximately one-quarter of cases are bilateral ♦♦ Approximately 20% of endometrioid ovarian carcinomas are associated with a synchronous endometrial carcinoma. The prognosis in this situation is relatively good, and it is believed that the tumors are usually separate primaries, not a single

♦♦ Endometrial carcinomas are composed of glands resembling endometrial epithelium with varying amounts of solid architecture. Squamous differentiation is seen in about one-third of cases. Villous or villoglandular architecture is commonly seen, (Fig. 32.10) and this should not be mistaken for serous carcinoma if the other features of serous carcinoma (marked nuclear pleomorphism, scalloped cell group margins, etc.) are not seen ♦♦ Most ovarian endometrioid carcinomas are low grade (grade 1/3), which aids in their distinction from serous carcinoma ♦♦ Endometrioid tumors of low malignant potential (endometrioid borderline tumors, Fig. 32.11) are much less common than ovarian endometrioid adenocarcinomas and are usually with associated endometriosis. These tumors are composed of endometrioid glands with cytologic atypia that, similar to endometrial hyperplasia, lack confluent or invasive growth patterns. Some cases may be cystic and have a villoglandular architecture. Squamous morules may be seen in association with the epithelium and the associated stroma may be densely fibrotic. Prognosis is good (recurrence in >3% of cases)

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Fig.  32.11. Ovarian endometrioid adenofibromatous tumor of low malignant potential. This tumor shows features similar to endometrial atypical hyperplasia, including crowded but separate architecturally complex glands, nuclear stratification, and nuclear atypia.

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Fig. 32.12. Clear cell carcinoma. Ovarian clear cell carcinomas commonly have a “tubulocystic” architectural pattern and clear to pale eosinophilic cytoplasm.

♦♦ Benign endometrioid cystadenomas and adenofibromas are rare. They lack the cytologic atypia seen in endometrioid tumors of low malignant potential. They are differentiated from ovarian endometriosis by their absence of endometrialtype stroma

Differential Diagnosis ♦♦ High grade (grade 3/3) ovarian endometrioid carcinoma may resemble serous carcinoma, but endometrioid carcinoma has less pronounced nuclear pleomorphism, has round glandular lumens, may have squamous differentiation, and may be associated with endometriosis ♦♦ Metastatic colorectal adenocarcinoma may, in some cases, appear histologically similar ♦♦ Occasional cases of endometrioid carcinoma have a tubular or solid tubular pattern (“Sertoliform variant of endometrioid carcinoma”) that resembles the pattern of sex cord stromal tumors such as Sertoli cell tumor or granulosa cell tumor. Endometrioid carcinomas resembling sex cord stromal tumors, however, are inhibin-alpha negative, while sex cord stromal tumors are inhibin positive

Clear Cell Tumors Clinical ♦♦ Clear cell carcinomas comprise approximately 5% of ovarian primary malignancies ♦♦ About 60% of patients will have endometriosis, and about 25% of clear cell carcinomas arise in an endometriotic cyst ♦♦ Paraneoplastic hypercalcemia is rarely seen

Macroscopic ♦♦ These tumors are commonly large thick-walled cystic masses with nodules of tumor projecting into the cyst

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Fig. 32.13. Frozen section of ovarian clear cell carcinoma. On frozen sections, this ovarian clear cell carcinoma (same case as in Fig.  32.12) had eosinophilic, somewhat granular appearing cytoplasm and a solid architecture, mimicking a stromal tumor containing Leydig cells.

Microscopic ♦♦ Clear cell carcinomas are composed of polygonal epithelial cells with large and often irregular nuclei, which may resemble the cells of Arias-Stella reaction in gestational endometrium. The architecture is described as tubulocystic, papillary, or solid architecture. “Hobnail cells” with scant cytoplasm and hyperchromatic nuclei protruding into the lumens of the tubular structures may be seen ♦♦ The cytoplasm is clear due to the presence of glycogen (Fig. 32.12), but it must be remembered that some cases, particularly on frozen section examination, may have eosinophilic cytoplasm (Fig. 32.13). PAS (without diastase) is positive

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♦♦ Occasional cases may have prominent eosinophilic cytoplasmic globules (similar to those seen in yolk sac tumor). Some cases may be composed primarily or entirely of cells with an oxyphilic cytoplasm ♦♦ Clear cell adenofibromatous tumors of low malignant potential (borderline clear cell adenofibromatous tumors) are very rare and composed of separate round glands lined by a clear cell epithelium with notable atypia in a fibrous background. Behavior is almost always benign ♦♦ Clear cell adenofibromas are also very rare and appear similar to the low malignant potential tumors but have minimal nuclear atypia

Differential Diagnosis ♦♦ Yolk sac tumor may resemble clear cell carcinoma (and was once categorized with clear cell carcinoma as “mesonephroma”). Yolk sac tumor occurs in younger patients; it is highly malignant, alpha-fetoprotein positive, and may be associated with other germ cell tumor components ♦♦ Clear cell renal cell carcinoma metastatic to the ovary is very rare but could be a consideration if there is a history of renal neoplasia

Fig.  32.14. Brenner tumor of low malignant potential. This Brenner tumor was partially cystic with papillary structures projecting into the cyst lumen. There was a low grade nuclear pleomorphism and occasional mitotic figures.

Transitional Cell Tumors Clinical ♦♦ Benign Brenner tumors comprise approximately 2% of all ovarian neoplasms and are commonly incidental findings ♦♦ Low malignant potential and malignant Brenner tumors are extremely rare

Macroscopic ♦♦ Benign Brenner tumors are small (usually <2 cm) gray-white hard tumors, sometimes with calcification ♦♦ Low malignant potential and malignant tumors are larger and partially cystic

Microscopic ♦♦ Transitional cell tumors have an epithelium arranged in nests or papillary structures and resembles urothelium or Walthard cell rests. The epithelial cells are polygonal with oval nuclei, often with a longitudinal nuclear groove (“coffee bean nuclei”). Cytoplasm is scant to moderate in volume and generally palely eosinophilic ♦♦ Transitional cell carcinomas are not associated with a benign or low malignant potential Brenner component. Squamous differentiation may be seen. These tumors may be pure or mixed with other tumor types, such as serous carcinoma ♦♦ Malignant Brenner tumors are associated with a benign or low malignant potential Brenner component ♦♦ Low malignant potential Brenner tumors are commonly cystic with papillary structures (Fig. 32.14) with fibrovascular cores extending into the cysts. Nuclear atypia is variable ♦♦ In contrast to the malignant and low malignant potential transitional cell tumors above (all of which are very rare), benign Brenner tumors are relatively common (3–5% of all ovarian tumors). These tumors are composed of a dense fibrous stroma, which is often focally calcified, with occa-

Fig. 32.15. Benign Brenner tumor. Benign Brenner tumors are composed of nests of cells resembling urothelial cells with moderately abundant, pale eosinophilic cytoplasm. The nuclei are round to oval and often have longitudinal nuclear grooves. The surrounding stroma is fibroma-like and occasional calcifications are typical.

sional nests of transitional cells (Fig. 32.15). The nests are rounded and may have central lumens with secretion

Differential Diagnosis ♦♦ Transitional cell carcinoma of the ovary (which by definition lacks a benign Brenner component) may be impossible to distinguish from metastatic urothelial carcinoma without an appropriate patient history. It may also resemble other poorly-differentiated/undifferentiated primary carcinomas

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Squamous Cell Tumors ♦♦ Most ovarian squamous carcinomas arise in mature cystic teratomas or are seen as a component of other epithelial tumors, but pure primary ovarian squamous cell carcinomas may rarely be seen

Mixed Epithelial-Stromal Tumors Clinical ♦♦ Malignant mixed müllerian tumors (carcinosarcomas) comprise less than 1% of all ovarian malignancies

Macroscopic

may be undifferentiated or show heterologous differentiation (differentiation toward tissue not expected in the ovary, such as chondrosarcoma or rhabdomyosarcoma, Fig. 32.17). The epithelial and stromal components share genetic losses, and the stromal component may show focal keratin immunopositivity; the findings support a common clonal origin for the two components ♦♦ Chondrosarcoma is the most commonly seen heterologous component, but rhabdomyoblasts, osteoid, or lipoblasts may be seen

Differential Diagnosis

♦♦ Most present at high stage, and 90% are bilateral. The tumors are large and solid but may also be partially cystic. In some cases with heterologous differentiation, cartilage may be grossly apparent

♦♦ The differential diagnosis may include adenosarcomas, which are also rare and are composed of a benign-appearing müllerian epithelium associated with a malignant stromal component. The tumors are usually unilateral, 10-year survival is 46%, and sarcomatous overgrowth is a poor prognostic finding

Microscopic

Undifferentiated carcinomas

♦♦ The tumors have a malignant epithelial component (which may be undifferentiated, serous, or endometrioid) and a malignant stromal component (Fig. 32.16). The stromal component

Fig.  32.16. Malignant mixed müllerian tumor. These tumors have a malignant epithelial component (most often resembling a serous carcinoma, as seen on the right) and a malignant stromal component (which commonly resembles an undifferentiated sarcoma, as seen on the left) with marked nuclear pleomorphism and stromal mitoses, including atypical mitoses.

♦♦ These tumors are composed of malignant epithelial cells with a solid architecture lacking evidence of serous, mucinous, or any other differentiation. The prognosis is even worse than that of serous carcinoma

Fig. 32.17. Malignant mixed müllerian tumor with a heterologous rhabdomyosarcomatous component. This malignant mixed müllerian tumor skeletal muscle differentiation in the stromal component in the form of morphologically undifferentiated but actin and desmin positive cells, rhabdoid cells, and strap cells.

SEX CORD-STROMAL TUMORS Granulosa Cell Tumor, Adult-Type Clinical ♦♦ Over 95% of granulosa cell tumors are of adult-type and, while most occur following menopause, a small percentage of cases occur in young women or girls

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♦♦ Adult-type granulosa cell tumors may be hormonally active, usually estrogenic, but they may also be androgenic. Postmenopausal patients may have abnormal uterine bleeding or, rarely, endometrial adenocarcinoma related to hormone production by the tumor

Ovary and Peritoneum

♦♦ The tumors may be cystic and may rupture, and present with hematoperitoneum in 5–15% of cases ♦♦ Between 10 and 50% of patients develop recurrences, which may be late (20 years or more after excision of the primary tumor). Tumor rupture is a risk factor for recurrence

Macroscopic ♦♦ It is usually a unilateral encapsulated mass that, on sectioning, is grossly yellow in color

Microscopic ♦♦ Microscopically, the tumors are usually composed of rounded nests or cords of cells divided by a fibrous stroma (Fig. 32.18). The nests may have peripheral palisading. The cells have relatively uniform oval nuclei, often with longitudinal nuclear grooves. Cytoplasm is scant and palely eosinophilic ♦♦ Microfollicular, macrofollicular (resembling preovulatory follicles), and trabecular patterns may be seen. A convoluted trabecular pattern with little associated stroma has been described as the “watered silk” pattern ♦♦ Rosette-like Call-Exner bodies with central eosinophilic material may be seen in one-third to one-half of these tumors ♦♦ Inhibin-alpha is positive (Fig. 32.19). Reticulin staining surrounds cords of cells but does not surround individual cells (in contrast to thecomas)

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♦♦ Most cases in young girls result in isosexual pseudoprecocity ♦♦ Juvenile-type granulosa cell tumors may be seen in association with several congenital syndromes including Ollier disease, Maffucci syndrome, and Goldenhar syndrome ♦♦ If it is limited to the ovary in its presentation, prognosis is very good with only rare recurrences

Microscopic ♦♦ Microscopically, juvenile type granulosa cell tumors are composed of large follicle-like structures filled with fluid and solid areas (Fig. 32.20). There may be marked nuclear atypia. Oval

Differential Diagnosis ♦♦ Serous and endometrioid carcinomas, carcinoid tumor, and some metastatic carcinomas may at times show nested and trabecular patterns that may mimic granulosa cell tumor

Granulosa Cell Tumor, Juvenile Type Clinical ♦♦ Approximately 5% of granulosa cell tumors are of juvenile type, and these tumors usually occur before the age of 30

Fig.  32.18. Granulosa cell tumor (adult type) Granulosa cell tumors commonly are composed of large nests of small, relatively uniform cells with minimal cytoplasm. Rosette-like CallExner bodies may be seen and longitudinal nuclear grooves (“coffee-bean nuclei”) are apparent at high magnification.

Fig.  32.19. Granulosa cell tumor (adult type) immunohistochemical stain for inhibin. Cytoplasmic immunoreactivity for inhibin is expected in granulosa cell tumors and other sex cordstromal tumors.

Fig. 32.20. Granulosa cell tumor(juvenile type) Juvenile-type granulosa cell tumors are composed of solid areas with variable cellularity and follicle-like structures filled with fluid. Significant nuclear atypia may be seen, but the oval nuclei with longitudinal nuclear grooves typical of adult-type granulosa cell tumor are not seen.

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nuclei with longitudinal nuclear grooves characteristic of adult-type granulosa cell tumor are usually not seen

Sertoli–Leydig Cell Tumor Clinical ♦♦ Sertoli–Leydig tumors (also known as androblastoma or arrhenoblastoma) are rare, approximately 0.5% of all ovarian neoplasms ♦♦ More than one-third of patients have hormonal symptoms, most commonly virilization, but estrogen overproductionrelated symptoms may also occur ♦♦ Malignant behavior is seen in 10–30% of cases

Essentials of Anatomic Pathology, 3rd Ed.

Thecoma Clinical ♦♦ Thecomas usually occur in postmenopausal women and over half of postmenopausal patients will have abnormal uterine bleeding related to estrogen production by the tumor. Occasional (about 20%) patients may have an associated endometrial adenocarcinoma

Macroscopic ♦♦ These tumors are grossly yellow

Macroscopic ♦♦ These are solid, firm, lobulated masses, often yellow in color

Microscopic ♦♦ The tumors are composed of solid cords (Fig. 32.21), hollow tubules (Fig. 32.22), or sheets of oval, more basophilic Sertoli cells with clusters of round Leydig cells with round nuclei and abundant eosinophilic granular cytoplasm ♦♦ The tumors are classified as well-differentiated, intermediate-differentiated, and poorly-differentiated. Behavior varies by grade ♦♦ About 20% of tumors have heterologous elements such as mucinous epithelium (Fig. 32.23), cartilage, or skeletal muscle differentiation ♦♦ Inhibin-alpha is positive

Differential Diagnosis ♦♦ Poorly-differentiated Sertoli–Leydig cell tumors may have a trabecular pattern that may resemble granulosa cell tumor ♦♦ A retiform pattern with anastomosing gland-like spaces has been described and may mimic a serous tumor, yolk sac tumor, or metastatic adenocarcinoma

Fig. 32.21. Sertoli–Leydig cell tumor. The Sertoli cell component of Sertoli–Leydig cell tumors commonly has a “solid tubule” pattern.

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Fig. 32.22. Sertoli–Leydig cell tumor. The Sertoli cell component may also be seen as hollow tubules. Between the tubules, the Leydig cell component is seen as round to polygonal cells with round nuclei and abundant eosinophilic granular cytoplasm.

Fig. 32.23. Sertoli–Leydig cell tumor with heterologous mucinous differentiation. In this tumor in addition to the Sertoli cell component (basophilic spindle-shaped cells) and the Leydig cell component (clusters of eosinophilic cells) there were also glands lined by cytologically bland mucin-producing epithelium with goblet cells that resembled intestinal epithelium.

Ovary and Peritoneum

Fig.  32.24. Thecoma. This tumor is composed of luteinized stromal cells with moderately abundant, vacuolated, pale-staining cytoplasm separated by occasional collagen fibers.

Microscopic ♦♦ These tumors are composed of luteinized stromal cells with finely vacuolated cytoplasm in a background of collagen fibers (Fig. 32.24)

Differential Diagnosis ♦♦ Granulosa cell tumors may look similar, but reticulin staining is seen around individual cells in thecomas (in contrast to granulosa cell tumors)

Fibroma Clinical ♦♦ Fibromas comprise about 4% of ovarian tumors and are often small incidental tumors, but they may be large (>10 cm) and symptomatic ♦♦ Meigs syndrome is the combination of ascites and pleural effusion associated with an ovarian fibroma that resolves following excision of the tumor. This syndrome is seen only rarely (1–2% of fibromas) ♦♦ Fibromas are seen with increased frequency in patients with Gorlin syndrome (nevoid basal cell carcinoma syndrome)

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Fig. 32.25. Sclerosing stromal tumor. The tumor is variably cellular with cellular zones with stromal cells with a luteinized appearance alternating with densely collagenized zones with a banded or “keloid-like” appearance.

Fibrosarcoma Clinical ♦♦ Fibrosarcomas are rare, but they are the most common primary ovarian sarcoma

Microscopic ♦♦ Four or more mitoses per ten high power fields and significant nuclear atypia are required for this diagnosis

Sclerosing Stromal Tumor Clinical ♦♦ Sclerosing stromal tumors are benign, usually occur in young women (usually younger than 30 years), and usually hormonally inactive

Macroscopic ♦♦ These are unilateral and usually relatively small (approximately 5 cm) tumors

Microscopic

Macroscopic

♦♦ These tumors are composed of cellular pseudo-lobules composed of fibroblasts and luteinized stromal cells (Fig. 32.25) and intervening hypocellular, edematous zones

♦♦ Grossly the tumors are hard and gray-white

Differential Diagnosis

Microscopic

♦ ♦ Some fibromas or thecomas may resemble sclerosing stromal tumor. More importantly, metastatic carcinomas (especially gastric and breast) may sometimes be seen as single pale cells in fibrous background, similar to sclerosing stromal tumor. Immunohistochemical staining for keratin will resolve this differential diagnosis

♦♦ Microscopically, small oval-to-spindle-shaped cells are seen in a collagenous background. At the most, mild cytologic atypia and three mitoses per high power field are seen (see fibrosarcoma below). Inhibin expression is variable

Differential Diagnosis ♦♦ Exclusion of fibrosarcoma (see below) is the primary consideration ♦♦ Edematous fibromas may resemble massive ovarian edema or sclerosing stromal tumor

Stromal Luteoma Clinical ♦♦ Stromal luteomas are benign steroid cell tumors. Most occur in postmenopausal women and are hormonally active

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Microscopic

Differential Diagnosis

♦♦ They are composed of small nodules of luteinized stromal cells that lack crystals of Reinke (Fig. 32.26)

♦♦ Tumors without unequivocal Sertoli cell and granulosa cell differentiation should be classified as some other type of tumor or as sex cord-stromal tumors of indeterminate type

Leydig Cell Tumors Clinical ♦♦ Leydig cell tumors are rare benign steroid cell tumors. Cases occurring near the hilus of the ovary are also known as hilus cell tumors

Sex Cord Tumor with Annular Tubules Clinical

♦♦ They are usually small (<5  cm), involve the hilus of the ovary, and are yellow or brown in color

♦♦ This is a very rare tumor ♦♦ One-third of cases occur in association with Peutz-Jeghers syndrome. The Peutz-Jeghers-associated tumors are benign ♦♦ Malignant behavior is seen in approximately one-quarter of cases not associated with Peutz-Jeghers syndrome

Microscopic

Macroscopic

♦♦ They are composed of cells with abundant eosinophilic cytoplasm that characteristically have at least occasional Reinke crystals (eosinophilic rod-shaped cytoplasmic inclusions) ♦♦ Inhibin-alpha is positive

♦♦ The Peutz-Jeghers-associated cases are usually small and bilateral and might represent hamartomas (rather than neoplasms) ♦♦ The cases not associated with Peutz-Jeghers syndrome are usually large and unilateral

Macroscopic

Gynandroblastoma Clinical ♦♦ Gynandroblastoma is a very rare tumor that is usually hormonally active (virilizing) and benign

Microscopic ♦♦ These tumors are composed of a mixture of Sertoli cells forming tubules and nodules of granulosa cells that may include Call-Exner bodies

Fig.  32.26. Stromal luteoma. These tumors are benign steroid cell tumors composed of small nodules of luteinized stromal cells that lack crystals of Reinke.

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Microscopic ♦♦ The tumor is composed of Sertoli cells arranged in concentric circles around hyaline globules (Fig. 32.27) ♦♦ Inhibin is positive

Differential Diagnosis ♦♦ Granulosa cell tumors with a microfollicular pattern and gonadoblastoma may resemble sex cord tumor with annular tubules

Fig. 32.27. Sex cord stromal tumor with annular tubules. These tumors are composed of Sertoli cells arranged in concentric circles around hyaline globules.

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GERM CELL TUMORS General Information Concerning Ovarian Germ Cell Tumors ♦♦ While ovarian germ cell tumors as a group are relatively common (30% of ovarian tumors), mature cystic teratomas are the only tumors seen with great frequency. Mature cystic teratomas make up 95% of all ovarian germ cell tumors ♦♦ Among females in the first two decades of life, however, malignant germ cell tumors (tumors in this group other than mature cystic teratoma) are the most common type of malignant ovarian tumor

Dysgerminoma Clinical ♦♦ Most dysgerminomas are diagnosed before the age of 30. The tumors are usually confined to the ovary at diagnosis ♦♦ Dysgerminoma is malignant but is responsive to chemotherapy and radiotherapy and prognosis is relatively good with treatment

Macroscopic ♦♦ The tumors are large, solid multinodular masses with a pale tan or gray cut surface

Microscopic ♦♦ Dysgerminoma resembles testicular seminoma and is composed of a proliferation of primitive germ cells arranged in nests that are characteristically divided by occasional fibrous bands with lymphocytes (Fig.  32.28). Sometimes, small granulomas are also seen. The individual cells have large nuclei that are often round but often have flat sides.

The cytoplasm is usually eosinophilic and pale staining but may also be clear. The architecture is usually solid, but low intercellular cohesion may result in retraction spaces that mimic gland formation ♦♦ In some cases, syncytiotrophoblastic giant cells may be seen, but these do not, by themselves justify a diagnosis of mixed germ cell tumor ♦♦ In contrast to testicular seminoma, an isochromosome 12p cytogenetic abnormality is usually not observed

Differential Diagnosis ♦♦ Some other tumors that may have a diffuse/solid pattern in the ovary and resemble dysgerminoma include juvenile granulosa cell tumor, diffuse large B-cell lymphoma, and metastatic melanoma ♦♦ Occasionally, cord-like or tubule-like patterns may be seen in dysgerminoma that may resemble sex cord-stromal tumors or glandular neoplasms ♦♦ Immunohistochemical stains for placental-like alkaline phosphatase (PLAP), c-kit (CD117), and OCT3/4 are positive in dysgerminoma. Staining is negative for alpha-fetoprotein (in contrast to yolk sac tumor), CD30 (in contrast to embryonal carcinoma), and inhibin (in contrast to sex cord-stromal tumors)

Yolk Sac Tumor (Endodermal Sinus Tumor) Clinical ♦♦ Yolk sac tumors are malignant germ cell tumors that show evidence of differentiation into endodermal structures. Serum alpha-fetoprotein elevation and immunohistochemical expression of alpha-fetoprotein is characteristic ♦♦ Ovarian yolk sac tumors can occur in infancy and the majority occur before age 30 ♦♦ These tumors tend to metastasize early even when apparently limited to the ovary. They are responsive to modern combination chemotherapy

Macroscopic ♦♦ The tumors are usually unilateral, solid, and the cut surface is gray-yellow

Microscopic

Fig. 32.28. Dysgerminoma. The tumor most commonly is composed of nests of cells separated by bands of collagenous stroma with associated lymphocytes. The tumor cells have large, round nuclei often with flat sides and moderately abundant clear to pale eosinophilic cytoplasm.

♦♦ These tumors have a variety of histologic patterns including microcystic/reticular patten, alveolar-glandular, intestinaltype, and hepatic differentiation ♦♦ In less than 20% of cases, characteristic fibrovascular projections covered by epithelium are seen (Schiller-Duval bodies). More commonly, PAS positive eosinophilic hyaline globules are seen in association with the neoplastic epithelium (Fig. 32.29)

Differential Diagnosis ♦♦ Yolk sac tumor may at times be difficult to distinguish from primary ovarian carcinomas (especially clear cell carcinoma), dysgerminoma, or metastatic carcinomas. In addition

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♦♦ Pure ovarian nongestational choriocarcinoma is very rare, but choriocarcinoma can be seen as a component of a mixed germ cell tumor

Macroscopic ♦♦ The cut surfaces of these tumors are largely solid and hemorrhagic

Microscopic ♦♦ Choriocarcinoma is composed of a mixture of cytotrophoblast and syncytiotrophoblast, commonly associated with hemorrhage. The tumor cells immunohistochemically express beta-human chorionic gonadotropin

Differential Diagnosis Fig. 32.29. Yolk sac tumor. Malignant glandular epithelium with associated hyaline globules and small cyst-like areas with eosinophilic secretion are seen in this tumor. to alpha-fetoprotein, glypican 3 is also a useful marker for yolk sac tumor. Keratins are usually diffusely positive (in contrast to dysgerminoma that is at the most focally positive for keratin). CD30 is negative (in contrast to embryonal carcinoma which is CD30 negative) ♦♦ Clear cell carcinomas especially may resemble yolk sac tumor and both may have eosinophilic globules. Clear cell carcinomas, however, are usually seen in older women and are negative for alpha-fetoprotein and alpha 1-antitrypsin

Embryonal Carcinoma Clinical ♦♦ Pure ovarian embryonal carcinoma is extremely rare, but embryonal carcinoma may be seen as a component of a mixed germ cell tumor

Microscopic ♦♦ The tumor is histologically seen as disorganized glands and solid areas of high nuclear grade malignant epithelium. The glands commonly have long, narrow, “slit-like” lumens. The nuclei are large and irregular but often have a pale or clear appearance in the center. The cytoplasm is scant ♦♦ CD30 is positive

Differential Diagnosis ♦♦ Dysgerminoma and poorly-differentiated/undifferentiated primary and metastatic carcinomas are the usual consi­ derations

Choriocarcinoma Clinical ♦♦ Choriocarcinoma may occur as an ovarian tumor (nongestational choriocarcinoma) or related to pregnancy (gestational choriocarcinoma)

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♦♦ In rare cases, gestational and nongestational choriocarcinoma may be difficult to distinguish. Obtaining adequate history (of pregnancy, gestational trophoblastic disease, and prior tumors) and search for other germ cell tumor components (which, if present, indicate nongestational choriocarcinoma) are critical in this situation ♦♦ Pure ovarian nongestational choriocarcinoma is rare, so a pure choriocarcinoma in a woman of reproductive age should be suspected to represent gestational choriocarcinoma

Mature Cystic Teratoma (Dermoid Cyst) Clinical ♦♦ Mature cystic teratoma is benign and the only common ovarian germ cell tumor ♦♦ These tumors have a wide age distribution but usually present in premenopausal women. They may present with symptoms relating to torsion or cyst rupture

Macroscopic ♦♦ Grossly, the tumors are cystic, often filled with grayish granular keratinized debris and hair. Gross examination may identify cartilage, pigmented areas (retinal differentiation), or brain-like glial tissue. Often the cyst has a nodule at one side with more or less well-formed tooth-like structures and bone (the “Rokitansky protuberance”)

Microscopic ♦♦ These tumors are usually biphasic or triphasic, meaning that they show differentiation into tissues formed by two or three embryonic germ layers ♦♦ Microscopically, the tumors are composed of cytologically bland, highly differentiated tissues of a variety of types. Skin, hair, sebaceous glands, cartilage, adipose tissue, respiratory and gastrointestinal-type epithelium, and glial tissue are among the most common but many other recognizable tissue types may also be seen ♦♦ Rare cases of mature cystic teratoma may undergo malignant transformation with a squamous cell carcinoma being the most common malignancy to develop (80% of cases). Adenocarcinomas, sarcomas, and a large number of other tumors may also occur

Ovary and Peritoneum

Differential Diagnosis ♦♦ Exclusion of an immature teratoma component is the main concern

Monodermal Teratoma ♦♦ Monodermal teratomas are composed entirely or predominantly of a single type of tissue from one embryonic layer ♦♦ The most common type of monodermal teratoma is struma ovarii, a tumor composed of thyroid tissue (Figs. 32.30 and 32.31). Struma ovarii is an ovarian tumor that is composed predominantly (>50%) of thyroid tissue or contains hormonally functional or histologically malignant thyroid tissue. While struma ovarii is almost always benign, thyrotoxicosis is seen in 5% of cases, and rare cases of malignant struma

Fig.  32.30. Struma ovarii. This gross photo shows an ovarian tumor with a nodular, red-brown, somewhat gelatinous cut surface resembling a multinodular goiter of the thyroid.

Fig.  32.31. Struma ovarii. Microscopically, the tumor is composed of follicles filled with dense eosinophilic colloid. The lining epithelium is cuboidal and cytologically bland. “Scolloping” (the presence of clear vacuole-like spaces at the interface between the epithelium and colloid) is seen.

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ovarii (usually resembling papillary thyroid carcinoma) are seen ♦♦ Carcinoid tumors may occur in the ovary as a pure carcinoid tumor, associated with a mature cystic teratoma (Fig. 32.32), associated with a Brenner tumor, or as a strumal carcinoid (associated with struma ovarii, Fig. 32.33) ♦♦ Rarely, other tumors probably representing monodermal teratomas can be seen, including pituitary adenomas, ependymomas, and primitive neuroectodermal tumors (PNET)

Immature Teratoma ♦♦ Approximately 3% of ovarian teratomas have immature foci composed of neuroectodermal rosettes and tubules, often in

Fig.  32.32. Carcinoid tumor in association with mature cystic teratoma. This teratoma had areas of carcinoid tumor.

Fig. 32.33. Strumal carcinoid. This tumor was composed primarily of carcinoid tumor with nested and trabecular architecture. Occasional clusters of colloid containing thyroid follicles were also present.

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a background of glial tissue, and these tumors have the potential for malignant behavior ♦♦ The immature teratoma component is positive for glial fibrillary acidic protein (GFAP), neuron-specific enolase, and S-100 protein ♦♦ Immature teratoma is graded based on the extent of the immature component. Grade 1 tumors have less than one high power field with immature neuroepithelial tissue on any one slide. Grade 2 tumors have 1–3 low power (40×) fields per slide. Grade 3 tumors have immature neuroepithelium in more than three low power fields per slide. A two-tier grading system has also been proposed

Gonadoblastoma ♦♦ Gonadoblastoma is a mixed germ cell-sex cord stromal tumor composed of mixture of a dysgerminoma-like component and a sex cord component that may be similar to Sertoli cells, granulosa cells, or luteinized stromal cells (Fig. 32.34). The cells are arranged in nests with the germ cells in the middle and the stromal cell component arranged around the outside of the nest and around rounded collections of hyaline material. Calcification of the hyaline material may be prominent, producing rounded, sometimes fused calcifications ♦♦ Dysgerminoma is found in association with gonadoblastoma in a large fraction of cases. In some cases only the rounded calcifications of the gonadoblastoma remain (“burnt-out gonadoblastoma”)

Fig. 32.34. Gonadoblastoma. Gonadoblastoma is a mixed germ cell–sex cord stromal tumor composed of dysgerminoma-like cells and a sex cord component in the form of Sertoli cells, granulosa cells, or luteinized stromal cells. The cells are arranged in a nested pattern with the germ cells in the middle and the stromal cell component arranged around the outside. Collections of hyaline material and calcifications are seen. ♦♦ Most patients with gonadoblastoma have gonadal dysgenesis (phenotypically female, but with a Y chromosome), but it may also be seen with other abnormalities of sexual development or with Turner syndrome

MISCELLANEOUS TUMORS INCLUDING STROMAL NEOPLASMS, SECONDARY CARCINOMAS, AND OTHER NEOPLASMS Small Cell Carcinoma (Hypercalcemic Type) Clinical ♦♦ This is a malignant tumor with a poor prognosis (10% 5-year survival). It is associated with paraneoplastic hypercalcemia in two-thirds of cases (due to production of  parathyroid hormone-related protein) ♦♦ Patient age is usually young (10–40 years)

Macroscopic ♦♦ The tumors are unilateral and solid

Microscopic ♦♦ It is composed of cells in a diffuse pattern with scant cytoplasm and pleomorphic nuclei (Fig. 32.35). Prominent nucleoli and moderately abundant eosinophilic cytoplasm may be seen in some cases, and these features help distinguish the tumor from ovarian pulmonary-type small cell carcinoma

Differential Diagnosis ♦♦ In some cases follicle-like spaces may be present that resemble juvenile-type granulosa cell tumor, but small cell carci-

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Fig.  32.35. Small cell carcinoma, hypercalcemic type. This tumor is composed of cells in a solid pattern with very scant cytoplasm and large, pleomorphic nuclei.

Ovary and Peritoneum

noma of hypercalcemic type is EMA positive and inhibin negative ♦♦ Metastatic small cell carcinoma of pulmonary origin, dysgerminoma, lymphoma, and other “small celled” tumors must be excluded

Small Cell Carcinoma, Pulmonary Type Clinical ♦♦ This is a rare malignant tumor with a poor prognosis ♦♦ Occasionally, this tumor can be associated with another tumor type (such as a Brenner tumor or endometrioid carcinoma)

Microscopic ♦♦ This tumor resembles small cell carcinoma of the lung with moderate size nuclei, nuclear molding, and very scant cytoplasm

Differential Diagnosis ♦♦ Metastatic pulmonary small cell carcinoma must be excluded. Other tumors (including ovarian small cell carcinoma, hypercalcemic type) may also be considered

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♦♦ Myxomas are rare benign tumors composed of cytologically bland spindle cells in a background of abundant pale-staining basophilic stroma composed of hyaluronic acid ♦♦ Primary leiomyoma of the ovary is rare and often an incidental finding. Immunohistochemical staining for smooth muscle markers may be useful for distinguishing leiomyoma from the much more common ovarian fibroma

Sarcomas ♦♦ A variety of histologic types of sarcoma (including undifferentiated sarcoma) not specific to the ovary have been reported as a primary ovarian tumor. All are very rare ♦♦ Primary ovarian rhabdomyosarcoma has been reported, but the presence of a coexisting carcinoma component in the tumor (indicating a malignant mixed müllerian tumor) must be excluded

Metastatic Carcinomas Clinical

♦♦ The tumor histologically resembles hepatocellular carcinoma

♦♦ Metastatic carcinomas frequently involve the ovary and are identified in approximately one-third of women dying of cancer ♦♦ General features favoring a metastatic carcinoma over a primary ovarian carcinoma include bilaterality, the presence of small superficial tumor deposits, vascular invasion, and a desmoplastic stromal response. Obtaining adequate history, particularly concerning previous malignancies and gastrointestinal symptoms, is also critical

Differential Diagnosis

Macroscopic

♦♦ It must be distinguished from hepatoid pattern yolk sac tumor. Both are immunohistochemically positive for alphafetoprotein. Hepatoid carcinoma is not associated with other germ cell tumor components, while hepatoid pattern yolk sac tumor may be admixed with other patterns of yolk sac tumor or other germ cell tumor elements. Also, hepatoid carcinoma is usually seen in postmenopausal patients, while yolk sac tumor is usually seen in patients under 30 years of age

♦♦ Bilaterality and the presence of multiple nodules of tumor within an ovary are suggestive of metastatic disease

Hepatoid Carcinoma Clinical ♦♦ This is a very rare highly aggressive neoplasm with a poor prognosis

Microscopic

Ovarian Tumor of Probable Wolffian Origin Clinical ♦♦ This tumor may occur in the broad ligament or ovary ♦♦ A fraction of cases may have a malignant behavior

Microscopic ♦♦ It may have tubular, hollow tubular, solid, and “sieve-like” patterns

Differential Diagnosis ♦♦ The tumor is positive for some keratins (7, 19, CAM 5.2) and CD10, which may be helpful in differentiating it from Sertoli–Leydig cell tumor, which it may resemble

Benign Stromal Neoplasms ♦♦ A variety of stromal neoplasms not specific to the ovary, such as hemangiomas, may be seen as an ovarian tumor, but all are rare

Microscopic ♦♦ Krukenberg tumors are metastatic adenocarcinomas with signet-ring morphology involving the ovary (Fig.  32.36). These tumors most often originate from a diffuse-type gastric adenocarcinoma, but this morphology can also represent a metastatic colorectal, appendiceal, breast, or other adenocarcinoma. Metastatic gastric carcinoma is especially likely to be clinically mistaken for a primary ovarian carcinoma as diffuse-type gastric carcinoma may be clinically occult, may be associated with ascites, and the ovarian mass may be the first tumor identified ♦♦ Colorectal adenocarcinomas commonly involve the ovaries and may in some cases present as a unilateral or bilateral ovarian mass prior to detection of the colorectal primary. Histologic clues to the proper diagnosis include the presence of large malignant glands with necrosis of segments of the lining epithelium (“segmental necrosis”) and the presence of abundant necrotic debris with basophilic nuclear debris (“dirty necrosis,” Fig. 32.37). Some tumors may be difficult to distinguish from a primary ovarian mucinous carcinoma or mucinous tumor of low malignant potential. Immunohistochemical staining may, in some cases, be useful as colorectal carcinomas are usually CDX2+/keratin 7−, and ovarian mucinous tumors are usually CDX2−/keratin 7+, but the expression of both of these markers is variable in both of these tumor types

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Fig.  32.36. Metastatic gastric diffuse type adenocarcinoma (Krukenberg tumor). The tumor is highly cellular with round, pleomorphic cells, some of which contain mucin vacuoles, which indent the nucleus (signet ring cells).

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  32.38. Metastatic low grade appendiceal mucinous neoplasm involving the ovary. Appendiceal tumors may closely mimic a primary ovarian mucinous neoplasm.

Fig. 32.37. Metastatic colorectal adenocarcinoma involving the ovary. Features suggestive of metastatic colorectal adenocarcinoma include the presence of necrotic debris with basophilic nuclear debris in the glands (“dirty necrosis”) and columnar cell architecture with occasional goblet cells.

Fig. 32.39. Metastatic pancreatic adenocarcinoma involving the ovary. Metastatic pancreatic adenocarcinomas may involve the ovary, be cystic, and have prominent papillary architecture, mimicking a low malignant potential tumor. This ovarian mass histologically closely resembles a serous low malignant potential tumor, but a morphologically similar primary pancreatic adenocarcinoma was resected in the same operation.

so the staining pattern must be evaluated along with the patient history and gross and morphologic findings. Keratin 20 is usually positive in both colorectal adenocarcinoma and ovarian mucinous tumors so it is not especially useful in this situation ♦♦ Low grade appendiceal mucinous neoplasm metastatic to the ovary (Fig.  32.38) may be mistaken for ovarian mucinous tumors of low malignant potential or even mucinous cystadenomas. Free mucin dissecting through stroma is commonly seen in low grade appendiceal mucinous neoplasms and is a possible clue, but this may also be seen in primary ovarian mucinous tumors. A low grade mucinous ovarian

tumor received for frozen section examination should prompt the pathologist to ask the surgeon about the status of the appendix and excision and histologic examination of the appendix may be indicated ♦♦ Pancreatic adenocarcinoma may be clinically occult and rarely presents as an ovarian mass, which may be cystic and histologically mimic a primary ovarian low malignant potential tumor (Fig. 32.39) or a carcinoma ♦♦ Breast carcinoma, renal cell carcinoma, carcinoid tumor, melanoma, and sarcomas all also may metastasize to the ovary

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32-27

Lymphomas and Leukemias Clinical ♦♦ Diffuse large B-cell lymphoma (Fig.  32.40), Burkitt lymphoma, and follicular lymphomas are the most common types. Burkitt lymphoma occurs primarily in children, but may also affect adults. It may present with abdominal pain and swelling with bilateral ovarian involvement ♦♦ The ovaries may be secondarily involved by leukemia, but primary ovarian granulocytic sarcoma is extremely rare. Occasional granulocytic sarcomas are green in color (“chloroma”)

Macroscopic ♦♦ Ovarian lymphomas are bilateral in one-half of cases, but Burkitt lymphoma is almost always bilateral. The cut surface of the tumor is usually soft, solid, and gray-white in color

Microscopic Fig. 32.40. Diffuse large B-cell lymphoma involving the ovary. The histologic appearance of lymphoma may, in some cases, be difficult to distinguish from some carcinomas and stromal tumors without immunohistochemical stains.

♦♦ Either a diffuse infiltrate or nodules of lymphoid cells may be seen ♦♦ Staining with CD45 and (for B-cell neoplasms) CD20 is expected. EMA and keratins will be negative

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Part B The Peritoneum

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MESOTHELIAL LESIONS Peritonitis ♦♦ Acute peritonitis is usually bacterial or chemical, such as following a perforated viscus. Spontaneous bacterial peritonitis may also occur and risk factors include cirrhosis and immunosuppression. Peritonitis is seen histologically as a serosal fibrinopurulent exudate ♦♦ Granulomatous peritonitis can result from infections (tuberculosis, fungal infections, or parasitic infections) or from foreign body reaction (starch or talc from surgical gloves, hysterosalpingographic contrast medium, keratin from ruptured teratomas, or spillage of amnionic fluid or meconium at cesarian section)

Mesothelial Hyperplasia Clinical ♦♦ Mesothelial hyperplasia may result from chronic salpingitis, endometriosis, or adnexal tumors or cysts

Microscopic ♦♦ Significant cellular enlargement, cellular stratification, and nuclear atypia may be seen. In some cases, a papillary architecture or even psammoma bodies may be seen

Fig. 32.41. Epithelial inclusions in a pelvic lymph node. Benign glandular inclusions composed of a ciliated columnar epithelium, sometimes with associated psammoma bodies, may be seen in pelvic lymph nodes. Care must be taken to avoid over diagnosis as metastatic adenocarcinoma.

Differential Diagnosis

Differential Diagnosis

♦♦ Mesothelial hyperplasia is a potential pitfall in peritoneal fluid or pelvic washing cytology. Identification of features of  mesothelial cells such as a generally low nucleus-tocytoplasm ratio, oval nuclei, peripheral attenuation of the cytoplasm, and “scalloped” cell group margins are helpful. In problematic cases, preparation of a cell block for immunohistochemical staining is useful. The cells of mesothelial hyperplasia will usually stain for calretinin, thrombomodulin, and podoplanin and are usually negative for epithelial membrane antigen (EMA), MOC-31, and Ber-Ep4. The usual carcinomas in this differential diagnosis will usually be positive for epithelial membrane antigen, MOC-31, and Ber-Ep4 and negative for calretinin, thrombomodulin, and podoplanin. It should be remembered that no single marker appears to be perfectly reliable for the differentiation of mesothelial cells (or mesothelioma) and carcinoma

♦♦ Endosalpingiosis can potentially be mistaken for adenocarcinoma. The presence of glandular epithelium in lymph nodes or other unexpected sites is a potential pitfall and can lead to overdiagnosis of metastatic malignancy. Recognition of the cilia and bland cytology are important clues that may help avoid this error, but cilia may be difficult to identify on frozen sections

Endometriosis ♦♦ See Endometriosis in the ovary section

Endosalpingiosis Clinical ♦♦ Endosalpingioisis is a benign incidental finding

Splenosis ♦♦ Splenosis is the finding of splenic tissue implants on peritoneal surfaces following a remote history of traumatic splenic rupture

Peritoneal Inclusion Cysts ♦♦ Peritoneal inclusion cysts are benign and are usually an incidental finding. They may be solitary or multiple and are thinwalled translucent cysts with a flattened mesothelial lining ♦♦ Multilocular peritoneal inclusion cysts (also known as benign cystic mesotheliomas, Fig. 32.42) may form tumor-like masses and be associated with pelvic pain. Most patients with multilocular peritoneal inclusion cysts will have a history of abdominal surgery, pelvic inflammatory disease, and/or endometriosis. Occasional cases may recur locally

Microscopic

Well-Differentiated Papillary Mesothelioma

♦♦ It is seen microscopically as glands composed of ciliated tubal-type simple columnar epithelium in a peritoneal surface or within a pelvic or retroperitoneal lymph node (Fig. 32.41). Occasionally, associated psammoma bodies may be seen

♦♦ Well-differentiated papillary mesotheliomas are rare lesions, usually less than 2 cm in size, which are usually incidental findings. The tumors are composed of fibrovascular papillae covered by a single layer of cuboidal mesothelial cells.

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Ovary and Peritoneum

Fig. 32.42. Multilocular peritoneal inclusion cyst. The lesion is composed of multiple cyst-like structures lacking a prominent epithelial lining.

32-31

Fig.  32.44. Peritoneal malignant mesothelioma replacing the omentum. Mesothelioma may have a gross distribution of disease and a papillary histology that may be result in a misdiagnosis of an ovarian or primary peritoneal serous carcinoma.

Macroscopic ♦♦ The tumor is seen grossly as multiple nodules of tumor on a peritoneal surface

Microscopic ♦♦ The tumor cells are usually epithelioid with abundant eosinophilic cytoplasm, but sarcomatoid mesotheliomas can also occur. Papillary architecture may be seen and the tumor may be mistaken for ovarian or primary peritoneal serous carcinoma (Fig. 32.44)

Differential Diagnosis

Fig.  32.43. Peritoneal malignant mesothelioma involving the ovary. The glandular and papillary architecture may closely resemble a serous carcinoma. Behavior is usually benign, but progression to malignant mesothelioma may rarely occur

♦♦ Immunohistochemical staining is commonly necessary to distinguish mesothelioma from other malignancies, and any panel of immunohistochemical stains used for this purpose should include multiple mesothelial and epithelial markers (see the Mesothelial hyperplasia section above)

Desmoplastic Small Round Cell Tumor Clinical ♦♦ The origin of this extremely rare tumor is uncertain. It is more common in males than females; the mean age at presentation is approximately 19, and the prognosis is very poor, with more than 90% of patients dying of the tumor even with aggressive treatment

Peritoneal Malignant Mesothelioma (Diffuse Malignant Mesothelioma) Clinical

Microscopic

♦♦ Peritoneal malignant mesothelioma is less common (only 10–20% of all mesotheliomas) than pleural malignant mesothelioma. In contrast to pleural malignant mesothelioma, most cases are not related to asbestos exposure. Ascites is usually present, and ovarian involvement may occur, possibly mimicking an ovarian carcinoma (Fig. 32.43) ♦♦ These tumors have a poor prognosis, but approximately 40% of women with peritoneal malignant mesothelioma may survive for more than 4 years

♦♦ Histologically, it is composed of well-circumscribed nests of small malignant cells surrounded by a densely fibrous stroma. The tumor cells have an unusual immunophenotype with coexpression of keratin, epithelial membrane antigen, neuron-specific enolase, desmin, and vimentin ♦♦ The tumor has a characteristic t(11:22) resulting in the fusion of the EWS (Ewing sarcoma) gene and the WT1 (Wilms tumor) gene, so cytogenetic analysis may be helpful in the diagnosis

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EPITHELIAL TUMORS OF MÜLLERIAN TYPE Primary Peritoneal Carcinoma ♦♦ Primary peritoneal carcinomas are microscopically indistinguishable from ovarian carcinomas, but, by definition, the greater part of the tumor is outside the ovary and no focus of ovarian tumor is >5  mm. Serous carcinomas are

the most common subtype of primary peritoneal carcinoma. Staging, treatment, and prognosis are similar to those of ovarian carcinomas. Low grade serous carcinomas (often with abundant psammoma bodies, “psammocarcinoma”) and serous tumors of low malignant potential may also occur

MISCELLANEOUS PERITONEAL LESIONS Infarcted Appendix Epiploica ♦♦ Colonic appendices epiploicae may undergo torsion and become infarcted and calcified. These may be encountered surgically as a hard mass and may be submitted for pathologic examination. Occasionally, autoamputation may occur, and the appendix epiploica may be found free in the peritoneal space. Histologically, necrotic fat and calcification are seen

Walthard Nest ♦♦ The female pelvic peritoneum may undergo metaplastic change into any of the types of müllerian epithelium. One of the most commonly seen examples of metaplasia of the peritoneum is the presence of Walthard cell rests, which may be cystic, on the serosal surface of the fallopian tube. These small (approximately 1  mm) whitish nodules are composed of nests of benign epithelial cells that histologically resemble urothelium (Fig. 32.45)

Fig. 32.45. Walthard cell rests. Walthard cell rests, which may be cystic, may be seen in the fallopian tube serosa or elsewhere in the pelvic peritoneum.

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Tailgut Cyst (Retrorectal Cystic Hamartoma) Clinical ♦♦ Tailgut cysts are benign cystic lesions found between the rectum and sacrum. Rare cases of malignant transformation have been reported, usually as an adenocarcinoma component arising in the tailgut cyst ♦♦ Synonyms for tailgut cyst include retrorectal cystic hamartoma and epidermoid cyst

Macroscopic ♦♦ These are thin-walled cysts filled with granular keratin debris

Microscopic ♦♦ They are usually lined by a squamous epithelium (Fig. 32.46). The lining may occasionally be lined by a mucinous or ciliated glandular epithelium. The wall of the cyst is composed of fibrous connective tissue and smooth muscle

Fig.  32.46. Tailgut cyst. These benign cystic lesions occur between the rectum and sacrum. They are most commonly lined by a squamous epithelium and have fibrous tissue and smooth muscle in the wall.

Ovary and Peritoneum

32-33

Differential Diagnosis

Metastatic Tumors

♦♦ The term mature cystic teratoma should be reserved for lesions with differentiated components other than those described above for tailgut cysts. Tissue types such as glial tissue, teeth, cartilage, or peripheral nerve in a presacral cystic lesion would merit a diagnosis of teratoma and imply greater potential for recurrence

♦♦ Metastatic ovarian carcinoma is the most common carcinoma to be seen as peritoneal carcinomatosis. Endometrial, fallopian tube, and primary peritoneal carcinomas may also be seen and are histologically similar to ovarian carcinomas ♦♦ Nongynecologic carcinomas that may have peritoneal involvement include breast, colorectal, gastric, and pancreatic carcinomas

Ectopic Decidual Reaction ♦♦ Ectopic decidual reaction may be seen in the pelvic peritoneum, as well as in the ovary, fallopian tube, and pelvic lymph nodes. The stromal cells become enlarged in response to progesterone and are seen as nodules of plump, rounded cells with eosinophilic cytoplasm that may have some nuclear atypia. Associated stromal hemorrhage may be seen. This finding, especially when within a lymph node, could potentially be mistaken for malignancy

Pseudomyxoma Peritonei ♦♦ The presence of abundant intraabdominal mucin is clinically termed pseudomyxoma peritonei. This finding is most commonly associated with a low grade appendiceal mucinous neoplasm. See also Metastatic tumors in the Ovary section above

TNM CLASSIFICATION OF OVARIAN TUMORS (2010 Revision) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Tumor limited to ovaries (one or both) −− T1a: Tumor limited to one ovary; capsule intact, and no tumor on the ovarian surface. No malignant cells in ascites or peritoneal washings −− T1b: Tumor limited to both ovaries; capsules intact, and no tumor on the ovarian surface. No malignant cells in ascites or peritoneal washings −− T1c: Tumor limited to one or both ovaries with any of the following: capsule ruptured, tumor on the ovarian surface, and malignant cells in ascites or peritoneal washings −− T2: Tumor involves one or both ovaries with pelvic extension −− T2a: Extension and/or implants on uterus and/or tube(s). No malignant cells in ascites or peritoneal washings −− T2b: Extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings

−− T2c: Pelvic extension and/or implants (T2a or T2b) with malignant cells in ascites or peritoneal ­washings −− T3: Tumor involves one or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis −− T3a: Microscopic peritoneal metastasis beyond pelvis (no macroscopic tumor) −− T3b: Macroscopic peritoneal metastasis beyond pelvis 2 cm or less in greatest dimension −− T3c: Peritoneal metastasis beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastasis ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis (excludes peritoneal metastasis)

SUGGESTED READING Clement PB. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 16: Nonneoplastic lesions of the ovary. Pages 675–727. New York, NY: Springer; 2002. Clement PB. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 17: Diseases of the peritoneum. Pages 729–789. New York, NY: Springer; 2002.

Roth LM. Recent advances in the pathology and classification of ovarian sex cord-stromal tumors. Int J Gynecol Pathol 2006;25:199–215. Roth LM, Talerman A. Recent advances in the pathology and classification of ovarian germ cell tumors. Int J Gynecol Pathol 2006;25:305–320. Russell P, Robboy SJ, Anderson MC. Pathology of the Female Reproductive Tract. Robboy SJ, Anderson MC, Russel P, eds., Chapter 18: The ovaries:

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normal appearances and nonneoplastic conditions. Pages 475–526. Edinburg: Churchill Livingstone; 2002. Russell P, Robboy SJ, Anderson MC. Pathology of the Female Reproductive Tract. Robboy SJ, Anderson MC, Russel P, eds., Chapter 20: Epithelial/stromal ovarian tumors. Pages 539–605. Edinburg: Churchill Livingstone; 2002.

Essentials of Anatomic Pathology, 3rd Ed.

Talerman A. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 20: Germ cell tumors of the ovary. Pages 967–1033. New York, NY: Springer; 2002. Talerman A. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 21: Nonspecific tumors of the ovary, including mesenchymal tumors and malignant lymphoma. Pages 1035–1061. New York, NY: Springer; 2002.

Russell P, Robboy SJ, Anderson MC. Pathology of the Female Reproductive Tract. Robboy SJ, Anderson MC, Russel P, eds., Chapter 21: Sex cordstromal and steroid cell tumors of the ovaries. Pages 607–640. Edinburg: Churchill Livingstone; 2002.

Tavassoli FA, Devilee P, eds. Tumours of the Breast and Female Genital Organs. Chapter 2: Tumours of the ovary and peritoneum. Pages 113–202. Lyon, France: IARC Press; 2003.

Russell P, Robboy SJ, Anderson MC. Pathology of the Female Reproductive Tract. Robboy SJ, Anderson MC, Russel P, eds., Chapter 22: Germ cell tumors of the ovaries. Pages 641–690. Edinburg: Churchill Livingstone; 2002.

Young RH, Scully RE. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 19: Sex cord-stromal, steroid cell, and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations. Pages 905–966. New York, NY: Springer; 2002.

Seidman JD, Russel P, Kurman RJ. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 18: Surface epithelial tumors of the ovary. Pages 791–904. New York, NY: Springer; 2002.

Young RH, Scully RE. Blaustein’s Pathology of the Female Genital Tract, Fifth Edition. Kurman RJ, ed., Chapter 22: Metastatic tumors of the ovary. Pages 1063–1101. New York, NY: Springer; 2002.

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33 Placenta and Gestational Trophoblastic Disease Raymond W. Redline, md

Contents

I. Gestational Trophoblastic Disease.....33-2

Precursor Lesions.............................................33-2 Partial Hydatidiform Moles..................33-2 Complete Hydatidiform Moles.............33-3 Malignant Trophoblastic Tumors...................33-4 Choriocarcinoma....................................33-4 Placental Site Trophoblastic Tumors...............................................33-5 Epithelioid Trophoblastic Tumor.........33-6

II. Placenta.............................................33-7 Common Placental Diagnoses.........................33-7 Acute Chorioamnionitis........................33-7 Meconium Exposure: Recent Versus Prolonged..................33-9 Changes Consistent with Maternal Underperfusion/Preeclampsia.......33-11 Placental Hemorrhages..................................33-13 Intervillous Thrombus/ Fetomaternal Hemorrhage.............33-13

Retroplacental Hematoma with Intraplacental Extension/ Abruptio Placenta...........................33-14 Acute Peripheral Separation/ Marginal Abruption.......................33-14 Chronic Peripheral Separation/ Chronic Abruption.........................33-15 Fetal Large Vessel Lesions.............................33-16 Fetal Thrombotic Vasculopathy..........33-16 Chronic Thromboinflammatory Lesions.....33-17 Congenital Infection............................33-17 Villitis of Unknown Etiology...............33-18 Chronic Histiocytic Intervillositis.......33-19 Massive Perivillous Fibrin(oid) Deposition (“Maternal Floor Infarction”)......................................33-19

III. Multiple Pregnancy..........................33-20 IV. Suggested Reading...........................33-21

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_33, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Essentials of Anatomic Pathology, 3rd Ed.

GESTATIONAL TROPHOBLASTIC DISEASE (GTD) Precursor Lesions Partial Hydatidiform Moles Clinical

♦♦ Subsequent invasive mole, choriocarcinoma, and other trophoblastic tumors are rare

Gross Findings

♦♦ Partial hydatidiform moles (PM) are triploid conceptuses (three complete haploid sets of chromosomes, n = 69) with two sets derived from the father (diandric triploidy) ♦♦ Digynic triploid gestations do not show the partial molar phenotype −− Occasional cases diagnosed as PM may have other abnormal karyotypes, but these usually lack one or more of the required criteria listed below ♦♦ Trophoblast hyperplasia results from unbalanced overexpression of paternal gene products (genomic imprinting) ♦♦ PM most commonly present as, otherwise unremarkable, late first or early second trimester spontaneous abortions −− Occasionally, they first come to attention due to an ultrasound showing molar villi or an increased maternal serum human chorionic gonadotropin (hCG) level ♦♦ PM are underdiagnosed −− One of thirteen spontaneous abortions is triploid −− Two-thirds of these are diandric and one-half of these fulfill diagnostic criteria for a partial mole (see below) −− Therefore, the predicted prevalence of partial mole is approximately 1/39 spontaneous abortions ♦♦ 0.5–20% of PM have persistently elevated hCG levels after curettage (persistent GTD) requiring chemotherapy

♦♦ PM generally consist of spongy villous tissue with small 1–2  mm fluid-filled vesicles (as in hydropic abortus and complete hydatidiform mole) ♦♦ Fetal fragments or malformed fetus may be seen

Microscopic ♦♦ All of the following features must be seen to make a diagnosis of PM (Table 33.1, Fig. 33.1) −− Villous trophoblast hyperplasia (usually predominantly syncytiotrophoblast) −− Dimorphic population of large and small villi without intermediate forms −− Hydropic villi >0.5 mm −− Irregularly irregular villous contour (“coast of Norway fjord-like infoldings”) (a) Often with multicellular trophoblast inclusions within a villous stroma ♦♦ Other helpful histologic features not observed in all cases include −− Maze-like villous capillary vascular pattern in the villous stroma −− Atypical implantation site trophoblast (enlarged irregularly-shaped hyperchromatic nuclei) −− Molar villi with well-delineated central cisterns

Table 33.1. Comparison of Partial Mole, Early Complete Mole and Complete Mole Characteristics

Partial mole

Early complete mole

Complete mole

3 N

2 N

2 N

Villous p57/KIP2 positivity

+

−

−

Dimorphic villous populations

+

−

−

Dysmorphic villi

+

−

−

“Cauliflower-like” villous branching

−

+

−

Hypercellular villous stroma

−

+

−

Villous stromal karyorrhexis

−

+

−

Uniformly hydropic villi

−

−

+

Villous trophoblast hyperplasia

+

+

++

Implantation site trophoblast atypia

+

+

+

Ploidy

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either two sperms or, more commonly, a single sperm followed by endoduplication ♦♦ As in PM, trophoblast hyperplasia in CM results from an overexpression of paternally derived gene products and/or a lack of maternally derived gene products (genomic imprinting) ♦♦ CM present clinically in two distinct scenarios −− Classic presentation (>8 weeks) (a) Various combinations of the following clinical signs and symptoms Uterus large for dates Vaginal bleeding Elevated maternal hCG titers Hyperemesis Preeclampsia Thyrotoxicosis Bilateral adnexal masses (theca lutein cysts) −− Early presentation (<8 weeks) (a) Anembryonic missed abortion by ultrasound ♦♦ Clinical management −− Serial maternal serum hCG titers are measured for 1 year following diagnosis −− Metastatic workup is initiated and chemotherapy begun if levels plateau or rise −− CM requires chemotherapy in 20–30% of cases −− The risk of subsequent choriocarcinoma is much higher than for PM, approximately 1/40 without treatment ●●

●●

●●

●●

●●

●●

Fig. 33.1. Partial hydatidiform mole. −− Villous stromal karyomegaly (individual stromal cell nuclei 2–3× normal size)

Ancillary Studies ♦♦ Flow cytometry, image analysis, or fluorescence in situ hybridization (FISH) can occasionally be helpful for differentiating partial versus complete mole or partial mole versus hydropic abortus (modal DNA index = 1.5/0.3 chromosomes per cell (PM) versus 1.0 and 2.0, respectively for the other two conditions)

Differential Diagnosis ♦♦ Hydropic Abortus (HA) −− These gestations present clinically as an embryonic pregnancies or missed abortions −− They usually lack embryonic and other placental adnexal structures (yolk sac, umbilical cord, amnion) and often have an abnormal karyotype −− They lack one or more of the criteria required to diagnose PM −− Focal trophoblast hyperplasia can be seen in approximately 3% of nonmolar abortions, which can be followed up by a single maternal hCG titer to ensure return to baseline ♦♦ Complete Hydatidiform Moles (CM) −− CM have uniformly hydropic villi with central cisterns −− They lack the second population of small villi seen in PM −− Villous trophoblast hyperplasia is generally more diffuse and involves cytotrophoblast and syncytiotrophoblast equally −− P57/KIP2 immunostaining can be useful in distinguishing PM from CM (see below)

●●

Gross Findings ♦♦ Classic CM usually consists of a discohesive collection of swollen grape-like molar villi up to 5–10 mm in diameter ♦♦ Early CM is grossly unremarkable

Microscopic ♦♦ Classic (>8 weeks) CM (Fig. 33.2) −− Diffuse and circumferential villous trophoblast hyperplasia

Complete Hydatidiform Moles Clinical ♦♦ CM are diandric diploid gestations (two sets of chromosomes with both sets derived from the father) derived from fertilization of a maternal ovum lacking the female pronucleus by

Fig. 33.2. Complete hydatidiform mole.

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♦♦ HA generally lack any villous trophoblast hyperplasia or atypical implantation site trophoblast −− Unlike early CM, they show degenerative features such as hypocellular villous stroma and intervillous fibrin −− They are p57/KIP2 positive ♦♦ Nonhydropic abortions (Threatened, incomplete, complete, and elective) also lack villous trophoblast hyperplasia and atypical implantation site −− While they lack the degenerative features seen with HA, they do not show the stromal hypercellularity and canaliculi seen with early CM −− They are also P57KIP2 positive

Fig. 33.3. Early complete hydatidiform mole.

−− Involves both cytotrophoblast and syncytiotrophoblast −− Uniformly hydropic villi and many with well-defined central cisterns −− Lack of fetal vessels and nucleated red blood cells −− Frequent atypical implantation site ♦♦ Early (<8 weeks) CM (Fig. 33.3) −− Focal cytotrophoblast and syncytiotrophoblast hyperplasia of both villi and the undersurface of the chorion −− Redundant bulbous terminal villi (+ focal hydrops) −− Hypercellular myxoid villous stroma often with stromal karyorrhexis −− Labyrinthine network of villous stromal canaliculi −− Atypical implantation site −− Fetal vessels or nucleated red blood cells may be seen

Immunocytochemistry ♦♦ p57KIP2 immunostaining is negative in the nuclei of villous stromal and cytotrophoblast cells in CM −− p57/KIP2 is a paternally imprinted gene expressed only by the female genome which is lacking in diandric gestations −− Of note, the gene is not imprinted and hence is expressed in extravillous trophoblast from CM

DNA Studies ♦♦ PCR-based microsatellite analysis on microdissected maternal and fetal tissue removed from the paraffin blocks can be used to confirm diandric origin (not routinely available)

Differential Diagnosis ♦♦ PM: The differential diagnosis with CM has been discussed above −− P57/KIP2 staining is positive due to the presence of the female genome

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Malignant Trophoblastic Tumors Choriocarcinoma Clinical ♦♦ Choriocarcinoma (CC) is a rapidly growing, highly invasive malignancy with frequent metastases ♦♦ Although historically associated with a high mortality rate, CC is now generally curable with multiagent chemotherapy ♦♦ CC usually presents as a uterine tumor or in a metastatic site ♦♦ It can develop in any pregnancy at any stage ♦♦ The relative frequency of different categories of preceding pregnancies is as follows −− Hydatidiform mole (45%) −− Term pregnancy (25%) −− Spontaneous abortion (25%) −− Ectopic pregnancy (5%) ♦♦ Intraplacental choriocarcinoma is a special category of early CC detected grossly as a hemorrhagic nodule or microscopically as a hemorrhagic/necrotic lesion with sparse diagnostic foci of CC at the periphery ♦♦ Despite the early stage, these lesions may be associated with both maternal and fetal metastases ♦♦ Clinical Staging ♦♦ Elevated hCG only ♦♦ Uterine corpus involvement ♦♦ Lung metastases ♦♦ Pelvic and/or vaginal metastasis ♦♦ Distant metastasis ♦♦ Adverse prognostic factors include −− Older age −− Preceding nonmolar pregnancy −− Longer interval to preceding pregnancy −− Tumor size >5 cm −− hCG level >105 mIU/l −− Number of metastases −− Metastasis to brain, liver, or GI tract −− Previous chemotherapy

Placenta and Gestational Trophoblastic Disease

Gross Findings ♦♦ CC is a grossly hemorrhagic, ill-defined lesion within the uterovaginal wall or in the parenchyma of other organs ♦♦ Hemorrhage and necrosis are sometimes so extensive that it is difficult to detect the viable tumor

Microscopic ♦♦ CC has a biphasic pattern consisting of malignant villous cytotrophoblast and syncytiotrophoblast ♦♦ The classic architectural pattern (Fig. 33.4) consists of groups of 10–50 cytotrophoblast with scant clear cytoplasm and uniformly enlarged central nuclei with prominent nucleoli, and prominent margination of chromatin ♦♦ These clusters are surrounded by a wreath-like arcade of multinucleate syncytiotrophoblast with enlarged irregular hyperchromatic nuclei and purple cytoplasm ♦♦ The presence of extensive tumor-associated hemorrhage, necrosis, and perpendicular invasion of myometrial fibers is sometimes helpful in the absence of classic pattern described above

Immunocytochemistry ♦♦ Malignant cytotrophoblast is positive for cytokeratin only ♦♦ Malignant syncytiotrophoblast expresses cytokeratin, hCG, human placental lactogen (hPL), and placental alkaline phosphatase (PLAP)

Differential Diagnosis ♦♦ Intervillous X-cell nodules −− These lesions need to be distinguished from intraplacental CC −− They are aggregates of extravillous trophoblasts −− They lack nuclear atypia and necrosis, have dense eosinophilic cytoplasm, are surrounded by a prominent fibrinoid matrix, and express intermediate or epithelioid trophoblast markers such as inhibin A, p63, and Mel-CAM ♦♦ Placental site trophoblastic tumor (PSTT) −− These tumors are less hemorrhagic than CC in a gross exam

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−− Tumor cells have a dense eosinophilic cytoplasm and larger, more irregular and hyperchromatic nuclei −− Multinucleate cells are rare −− Tumor cells stain with intermediate trophoblast markers including hPL, inhibin A, Mel-CAM, HLA-G, and cytokeratin ♦♦ Epithelioid trophoblastic tumor (ETT) −− These tumors also lack extensive hemorrhage and necrosis −− They are composed of predominantly mononuclear cells with a clear, mildly eosinophilic cytoplasm, extracellular keratin-like pearls and with immunocytochemical features of epithelioid trophoblast such as HLA-G and p63

Placental Site Trophoblastic Tumors Clinical ♦♦ Placental site trophoblastic tumors (PSTT) are rare, generally indolent tumors composed of intermediate trophoblast usually presenting within the uterus ♦♦ They usually follow term pregnancies (95% of cases), often with a long interval (up to 15 years) ♦♦ Local invasion and distant metastasis are observed in 15–20% of cases, and these invasive tumors are often resistant to chemotherapy ♦♦ Unlike CC, PSTT generally present with a low serum hCG level, generally <2,500 mIU/ml ♦♦ The precursor lesion for PSTT is unknown −− PSTT rarely follow molar pregnancy −− Placental site nodules, commonly seen in the curettings of multiparous patients, are potential precursors ♦♦ Virtually all PSTT have a 46, XX karyotype, suggesting that they may have arisen from mosaic diandric intermediate trophoblast or as consequence of defective X inactivation in biparental intermediate trophoblast ♦♦ Since trophoblast generally manifests preferential inactivation of the paternal X chromosome, both could be associated with anomalous expression of paternal X linked genes

Gross Findings ♦♦ PSTT usually present as nodular or polypoid masses ♦♦ Occasionally it may be diffusely infiltrative ♦♦ Extensive hemorrhage or necrosis is uncommon

Microscopic

Fig. 33.4. Choriocarcinoma.

♦♦ PSTT are composed of cohesive sheets of mononuclear intermediate trophoblasts (Fig. 33.5) −− Aggregates of neoplastic cells may not only be associated with zonal necrosis but also show prominent arterial remodeling recapitulating the appearance of the normal implantation site −− Individual tumor cells are generally mononuclear, but occasionally binucleate, and have abundant eosinophilic cytoplasm −− Nuclei are enlarged with coarse clumped chromatin and prominent nucleoli

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Fig. 33.5. Placental site trophoblastic tumor (PSTT). ♦♦ Tumors with a mitotic rate >5/10 high power fields, prominent necrosis, and less dense eosinophilic cytoplasm have a worse prognosis

Immunocytochemistry ♦♦ Tumor cells have an intermediate trophoblast phenotype: keratin, hPL Inhibin A, HLA-G, and Mel-CAM positive; hCG negative, weak, or focally positive; p63 negative

Differential Diagnosis ♦♦ Placental site nodule (PSN) −− These “lesions” represent involuting/remote implantation sites (a) They are well-circumscribed aggregates of intermediate trophoblast embedded in a fibrinoid matrix and may be seen following any term pregnancy (b) Unlike PSTT, they have low cellularity and bland cytologic features (c) Immunocytochemical staining shows an epithelioid trophoblast phenotype (HLA-G, p63 positive; hPL, hCG negative) ♦♦ Exaggerated placental site −− This “lesion” is simply a normal cellular implantation site that may be encountered in any abortion specimen (spontaneous or elective) (a) In this process, the intermediate trophoblast infiltrates the decidua and myometrium as single or small groups of cells (b) Unlike PSTT, multinucleate placental site giant cells are present in the specimen (c) There is no evidence of necrosis or destructive myometrial invasion (d) This pattern is not seen following term pregnancies

Epithelioid Trophoblastic Tumor Clinical ♦♦ ETT is a rare tumor of the uterus or cervix, generally presenting with vaginal bleeding

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Fig. 33.6. Epithelioid trophoblastic tumor (ETT).

−− Extrauterine disease is not uncommon −− Preceding GTD is noted in 50% of cases ♦♦ Tumors resembling ETT can also develop from resistant nodules within a previously treated CC ♦♦ ETT is associated with an hCG level intermediate between that seen with CC and PSTT, generally <10,000 mIU/ml

Gross Findings ♦♦ ETT presents as a uterine or cervical mass, usually nodular without extensive hemorrhage or necrosis

Microscopic ♦♦ ETT are composed of cords and nests of mononuclear extravillous trophoblast with clear or eosinophilic cytoplasm (Fig. 33.6) −− The overall appearance is reminiscent of the trophoblast in the chorion laevae of the placental membranes (socalled epithelioid trophoblast) ♦♦ Tumor cell aggregates are often associated with eosinophilic, fibrillar, hyaline-like material resembling keratin ♦♦ ETT may occasionally grow along the surface of endocervical glands

Immunocytochemistry ♦♦ Tumor cells have an epithelioid trophoblast phenotype (cytokeratin, p63, HLA-G positive; hPL and hCG weak to negative)

Differential Diagnosis ♦♦ CC −− ETT are generally nonhemorrhagic and are associated with a lower hCG titer −− Tumors lack multinucleate syncytiotrophoblast −− Mononuclear tumor cells have more abundant cytoplasm than cytotrophoblast in CC ♦♦ PSTT

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−− ETT more commonly involve the cervix and lower uterine segment −− hCG titers are usually higher −− Individual tumor cells are smaller, lack strongly eosinophilic cytoplasm, and have a higher N/C ratio than intermediate trophoblast in PSTT −− Implantation site-like arterial remodeling is absent −− Immunostains for hPL are negative or focally positive

♦♦ Squamous cell carcinoma −− ETT lack positivity for human papillomavirus (HPV) and expresses cytokeratin 18 and p63 −− The overlying epithelium lacks squamous atypia ♦♦ Epithelioid leiomyosarcoma −− ETT lacks positivity for smooth muscle markers and expresses low and high molecular weight keratin filaments −− More spindled typical smooth muscle cells are absent

PLACENTA Common Placental Diagnoses Acute Chorioamnionitis Clinical ♦♦ Acute chorioamnionitis (ACA), also known as the amniotic fluid infection syndrome, is the leading cause of preterm birth ♦♦ Up to 60% of infants <1.5 kg have histologic ACA in their placentas ♦♦ ACA is also a risk factor for cerebral palsy, particularly when associated with an intense fetal inflammatory response as assessed histologically or by markedly increased cytokines in fetal circulation ♦♦ ACA is usually an ascending infection caused by organisms resident in the cervicovaginal tract −− Less commonly, organisms may spread to the placental membranes via hematogenous seeding (e.g., periodontal infections) or by transuterine contiguous spread from other pelvic organs (e.g., bladder, fallopian tube) ♦♦ Risk factors for ascending infection include cervical dilatation secondary to either incompetent cervix or preterm labor and changes in cervicovaginal flora as in bacterial vaginosis, foreign bodies (cerclage, IUD), or colonization by group B streptococci ♦♦ Causative organisms include the normal flora of the cervicovaginal tract, particularly anaerobic bacteria and Mycoplasma spp −− Less commonly, group B streptococci, E. coli, and other aerobic bacteria are implicated −− The presence of these latter organisms increases the risk of spread to the fetus (early onset sepsis) −− With foreign bodies Candida spp. become more frequent −− Rare, highly virulent causes of ACA include Listeria monocytogenes and Campylobacter fetus

♦♦ Candida ACA is characterized by yellow/white micro­ abscesses on the surface of the umbilical cord ♦♦ L. monocytogenes and C. fetus may be associated with irregular pale yellow intervillous abscesses or septic infarcts on the cut surface of the villous parenchyma

Microscopic ♦♦ The inflammatory response to infection in ACA is diffuse. −− A diagnosis of focal ACA is not recognized −− The infiltrate is composed of polymorphonuclear leukocytes (PMN) with occasional eosinophils or metamyelocytes, particularly in premature gestations −− Prolonged low-level infection may also elicit a subpopulation of vacuolated macrophages in the chorionic plate (subacute [chronic] chorioamnionitis) ♦♦ Maternal inflammatory response −− Membranes (PMN from decidual venules)/chorionic plate (PMN from intervillous space) (a) Early (Fig. 33.7): PMN in subchorionic fibrin or a diffuse band of PMNs in the chorion laevae (b) Intermediate (Fig. 33.8): PMN in chorion and amnion. (c) Late (Fig. 33.9): Necrosis and sloughing of amniocytes, PMN karyorrhexis

Gross Findings ♦♦ The fetal surface of the placenta may show grayish discoloration with haziness and blurring of the underlying chorionic plate vessels −− Severe ACA can be associated with diffuse yellow-green exudate

Fig. 33.7. Early acute subchorionitis.

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Fig. 33.8. Acute chorioamnionitis.

Fig. 33.9. Necrotizing chorioamnionitis.

Fig. 33.10. Acute umbilical phlebitis.

Fig. 33.11. Acute umbilical arteritis.

♦♦ Fetal inflammatory response −− Chorionic plate (PMN from chorionic vessels)/umbilical cord (PMN from umbilical vessels) (a) Early (Fig. 33.10): PMNs in chorionic vessels and/or umbilical vein (b) Intermediate (Fig.  33.11): PMNs in umbilical artery(ies) (c) Late (Fig.  33.12): Degenerating PMNs in Wharton jelly surrounding umbilical vessels (d) Severe fetal inflammatory response (Figs. 33.13 and 33.14): Near confluent PMN in fetal vessels wall, usually with signs of vessel wall damage or early mural thrombosis ♦♦ Candida spp −− Peripheral funisitis with neutrophilic microabscesses (Fig. 33.15) ♦♦ L. monocytogenes/C. fetus −− Acute intervillositis with intervillous abscesses (Fig. 33.16)

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Fig. 33.12. Necrotizing funisitis (acute concentric perivasculitis).

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Fig. 33.13. Severe fetal vasculitis (intense chorionic vasculitis).

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Fig. 33.16. Acute villitis and intervillositis (Listeria monocytogenes).

Special Stains and Cultures ♦♦ The following stains may be useful for specific organisms −− Candida (GMS and/or PAS) −− Group B streptococci −− L. monocytogenes (tissue gram stain) −− Anaerobes, C. fetus and other bacteria (Silver stains: Dieterle, Warthin-Starry, or Steiner) ♦♦ Bacterial and fungal cultures are generally not clinically useful

Differential Diagnosis

Fig. 33.14. Fetal vasculitis with nonocclusive chorionic vessel thrombus.

♦♦ Laminar (ischemic) necrosis: It is characterized by necrotic tissue in the decidua capsularis often accompanied by varying numbers of degenerating PMNs −− Isolated acute deciduitis without ACA is not a recognized lesion −− Most such cases are the result of ischemia secondary to maternal small vessel disease or the toxic effects of meconium ♦♦ Isolated fetal vasculitis (umbilical vein or chorionic vessels) without maternal inflammation is occasionally seen with prolonged meconium exposure ♦♦ T-cell eosinophilic vasculitis: It is a rare lesion characterized by infiltration of chorionic and major fetal stem villous vessels by these two cell types −− This lesion is idiopathic, but not believed to be infectious −− Unlike the fetal inflammatory response in ACA, the infiltrate is not polarized toward the amniotic cavity

Meconium Exposure: Recent Versus Prolonged Clinical Fig. 33.15. Peripheral funisitis (Candida spp).

♦♦ Release of meconium into the amniotic fluid is common in term infants (10–20%), but rare if ever seen prior to 34 weeks

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−− The pathophysiology is as follows −− The umbilical cord becomes transiently compressed leading to occlusion of the umbilical vein −− The resulting decrease in venous return causes a vagal intestinal vasoconstriction and reflex defecation ♦♦ Predisposing factors include all of the following: large active babies, long easily entangled umbilical cords, and decreased amniotic fluid (all findings that are common in “postdates” gestation, >42 weeks) ♦♦ The major risk for the infant is development of the meconium aspiration syndrome −− This syndrome is a chemical pneumonitis occurring in 8.6% of meconium-stained births −− It is defined as respiratory distress requiring oxygen with an abnormal chest xray −− Affected infants are at risk for extrapulmonary air leaks, persistent fetal circulation with pulmonary hypertension, and neonatal encephalopathy ♦♦ An increased interval between meconium release and delivery (prolonged meconium exposure, >6–12  h) is an additional risk factor for perinatal morbidity and mortality −− Explanations include the following (a) Meconium release before the later stages of labor often coexists with other placental findings indicative of subacute (in utero) hypoxia (b) There is a time-dependent diffusion of meconium into the vascular wall of large fetal blood vessels where it may cause vasospasm and/or structural damage (see below)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Prolonged −− Vacuolated macrophages are seen in the deep fibrous stroma of the chorionic plate, umbilical Wharton jelly, and/or on the walls of large chorionic vessels −− A distinct lesion, meconium associated peripheral vascular necrosis (Fig. 33.17), is a rare late-developing lesion characterized by extensive apoptosis of vascular smooth muscle cells (cellular dehiscence, nuclear pyknosis, and cytoplasmic eosinophilia) −− It may be seen at the periphery of umbilical or chorionic vessels and has been associated with an increased risk of neurodisability and other adverse outcomes ♦♦ Changes suggestive of subacute hypoxia may be associated with prolonged meconium exposure, including −− Increased nucleated red blood cells (NRBC) (Fig. 33.18) (a) Defined by more than 10 NRBC/10-high power (40×) fields

Gross Findings ♦♦ Recent (<6 h) −− Placental membranes are green-stained, slippery, and edematous often with separation of the amnion and chorion ♦♦ Prolonged (>6–12 h) −− Umbilical cord is often green-stained −− Chorionic plate may also be deeply stained below the amnion ♦♦ Placental findings associated with umbilical cord compression should be documented in cases with meconium staining (true knots, hypercoiling, peripheral cord insertion, tethered cord, focal attenuation or edema of the cord)

Fig. 33.17. Meconium associated peripheral vascular necrosis.

Microscopic ♦♦ Recent −− The membranes show edema of the connective tissue and variable degrees of necrosis and dehiscence of the amnionic epithelial cells −− Pigment-laden macrophages, often with prominent cytoplasmic vacuolation are seen in the amnion, chorion, and/ or decidua −− The number of macrophages roughly correlates with the amount of meconium released

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Fig. 33.18. Increased circulating fetal NRBC.

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Fig. 33.19. Villous chorangiosis. (b) Indicative of significant in utero hypoxia leading to erythropoietin release −− Villous chorangiosis/villous hypercapillarization (Fig. 33.19) (a) Defined by >10 capillaries/villus in >10 villi in several areas of the placenta (b) Indicative of capillary proliferation in response to decreased oxygen availability or excessive angiogenic growth factors

Ancillary Studies ♦♦ There are no reliable histochemical or immunohistochemical stains for meconium ♦♦ Iron stain may be used to distinguish hemosiderin from meconium pigment in selected cases

Differential Diagnosis ♦♦ Severe ACA −− Color is yellow-green rather than dark green, and the histology shows PMN infiltrates −− Chronic peripheral separation/chronic abruption −− Greenish discoloration is due to biliverdin (a hemoglobin breakdown product) and is usually accompanied by old blood clots, hemosiderin-laden macrophages, and/or circumvallate membrane insertion (see below) ♦♦ Pigment-laden macrophages upon microscopic examination in the absence of other clinical or pathologic signs of meconium, infection, or chronic abruption −− Occasional lipofuscin-laden macrophages are a normal finding in term placentas −− They usually show minimally vacuolated cytoplasm

Changes Consistent with Maternal Underperfusion/Preeclampsia Clinical ♦♦ Pathologic changes consistent with maternal underperfusion (MUP) develop secondary to inadequate remodeling of the

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uterine arterial bed resulting in decreased placental perfusion (clinical uteroplacental insufficiency) −− Affected patients are at risk for fetal growth restriction, maternal preeclampsia, abruptio placenta, and preterm delivery ♦♦ Preeclampsia is a specific maternal disorder of late pregnancy defined by recent de novo onset of hypertension and proteinuria secondary to endothelial injury caused by factors released by placental trophoblast −− Primigravidas are at increased risk −− Many individuals who develop preeclampsia have underlying genetic (increased human leukocyte antigen (HLA) sharing with father, positive family history) and/or acquired clinical risk factors (e.g., essential hypertension, obesity, hyperlipidemia, insulin resistance, coagulopathy, renal disease, connective tissue disease, enlarged placentas, and MUP) that decrease the threshold for developing disease ♦♦ The underlying pathophysiology of preeclampsia in patients with underlying MUP is believed to have two components −− Generalized dysfunction of extravillous trophoblast secondary to early endometrial hypoxia resulting in superficial placental implantation and failure of trophoblast to remodel uterine spiral arteries predisposing to underperfusion, hypoxia, and oxidative stress −− Release of increased levels of trophoblast-derived soluble VEGF-receptor and soluble endoglin into the maternal circulation where they may cause diffuse endothelial damage resulting in hypertension, glomerulopathy, edema, and coagulopathy

Gross Findings ♦♦ Placentas from patients with MUP +/− preeclampsia may have the following abnormal findings −− Placental weight less than expected for gestational age, increased fetoplacental weight ratio, thin umbilical cord (<8 mm), old and recent placental infarcts, and retroplacental hematoma consistent with abruptio placenta

Microscopic ♦♦ Membranes −− Maternal arterioles in the deciduas of patients with ­preeclampsia may show fibrinoid necrosis (“acute atherosis”) (Fig.  33.20) or mural smooth muscle hypertrophy (Fig. 33.21) −− Occlusion of small arterioles can lead to areas of microscopic decidual-chorionic infarction (“laminar necrosis”) ♦♦ Villous parenchyma −− Chronic MUP of the intervillous space leads to chronic underdevelopment of the villous tree (distal villous ­hypoplasia) (Fig.  33.22), increased syncytial knots (Fig.  33.23), villous agglutination (Fig.  33.24), and increased intervillous fibrin (Fig. 33.25) −− Total occlusion of a maternal artery results in the development of a villous infarct (Fig. 33.26)

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Fig. 33.20. Acute atherosis of decidual arterioles.

Fig. 33.23. Increased syncytial knots.

Fig. 33.21. Mural hypertrophy of decidual arterioles.

Fig. 33.24. Villous agglutination.

Fig. 33.22. Distal villous hypoplasia.

Fig. 33.25. Increased intervillous fibrin.

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Fig. 33.26. Villous infarct.

Fig. 33.27. Intervillous thrombus.

♦♦ Basal plate −− Dysfunction of extravillous trophoblast leads to superficial implantation which can be manifested histologically as excessive immature intermediate trophoblasts, large amounts of decidua containing only placental site trophoblastic giant cells, and/or failure to remodel the spiral arteries (persistent vascular smooth muscle)

−− IVT and small amounts of fetomaternal hemorrhages are common occurrences in term pregnancies −− The volume of fetomaternal hemorrhage has been positively correlated with the number and size of IVT in the placenta ♦♦ Large fetomaternal hemorrhages (greater than 40  ml) may result in hypovolemic shock or high output congestive heart failure leading to nonimmune hydrops fetalis, intrauterine fetal death, or neurodisability −− A sinusoidal fetal heart rate pattern has been described in some of these cases

Differential Diagnosis ♦♦ Perivillous fibrin plaques −− These clinically insignificant lesions mimic villous infarcts but lack collapse of the intervillous space, villous agglutination, trophoblast karyorrhexis, and PMN fragments ♦♦ Intervillous thrombi −− Unlike villous infarcts, these spherical nonbasal lesions are smooth in texture and show only focal pressure-related infarction of adjacent villi upon microscopic examination (see below)

Placental Hemorrhages Intervillous Thrombus/Fetomaternal Hemorrhage Clinical ♦♦ Intervillous thrombi (IVT) are expansile nodules of clotted blood surrounded by villous parenchyma (Fig. 33.27) −− They have been shown to contain red blood cells of presumed fetal origin and are believed to arise from the rupture of terminal villi with subsequent bleeding into maternal circulation −− However, the major component of these lesions is a mix of entrapped maternal red blood cells and fibrin triggered by the exposure to the fibrous stroma of the damaged villi ♦♦ Both flow cytometry and the Kleihauer-Betke acid elution technique have been used to measure the percentage of fetal hemoglobin-containing cells in the maternal circulation

Gross Findings ♦♦ IVT are spherical lesions surrounded by normal villous parenchyma −− They have a smooth surface on cut section −− Recent IVT are firm, glassy, and dark red, while older lesions are light red and laminated

Microscopic ♦♦ IVT are composed of recent or organizing hemorrhage in the intervillous space −− They are surrounded by and displace villi with at most minimal amounts of adjacent villous infarction −− The significance, in terms of adverse outcomes, is generally limited to cases associated with markedly increased NRBC and changes suggestive of hydrops fetalis (villous edema, cytotrophoblast proliferation, and increased Hofbauer cells)

Ancillary Studies ♦♦ Immunocytochemical staining for fetal hemoglobin has been used as an investigative technique to document the extent of fetal contribution to these lesions

Differential Diagnosis ♦♦ Villous infarct with central hemorrhage

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−− Unlike IVT, these parenchymal hemorrhages have a prominent surrounding rim of firm indurated infarcted tissue ♦♦ Retroplacental hemorrhage with intraplacental extension −− Some IVT may represent small abruptions −− These lesions are usually irregular in outline and at least focally extend to the basal plate (basal IVT) ♦♦ Massive subchorial thrombus −− These large laminated subchorionic hematomas cause significant elevation of the chorionic plate −− They are associated with very bad prognosis ♦♦ Hemorrhage into a septal cyst −− Septal cysts arise from the secretions from extravillous trophoblast entrapped within decidual infoldings in the placental parenchyma −− When the normally clear fluid is clouded by intracystic hemorrhage, they may be distinguished grossly from IVT by their fluid content and by the typical surrounding rim of extravillous trophoblast

Retroplacental Hematoma with Intraplacental Extension/Abruptio Placenta Clinical ♦♦ Placental abruptions can be separated into three clinical categories: abruption placenta, marginal abruption, and chronic abruption −− The latter two entities are discussed below −− The classic clinical criteria for abruptio placenta are vaginal bleeding, uterine rigidity, abdominal pain, hypotension, and anemia ♦♦ The pathogenesis of abruptio placenta is premature rupture of one of the major arteries supplying the intervillous space, resulting in forceful separation of the placenta from the uterus ♦♦ The underlying risk factors are as follows −− Underlying vascular structural disease (preeclampsia/ maternal uterine arteriopathy) −− Ischemia-reperfusion injury secondary to substance abuse (cocaine and smoking) −− Direct shear stress (physical trauma, intense physical labor) ♦♦ Clinicopathologic correlation is required to make a definitive diagnosis of abruption placenta −− Only half of clinical abruptio placenta are pathologically apparent, and only half of pathologic retroplacental hematomas are associated with the clinical syndrome −− However, a clinical finding of substantial retroplacental clot observed at C-section is considered as definitive evidence ♦♦ Adverse sequela of abruption placenta include acute birth asphyxia, intrauterine fetal death, and long-term neurologic impairment

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Gross Findings ♦♦ Typical findings for abruptio placenta include −− Central retroplacental hematoma indenting or rupturing into the villous parenchyma −− Concave indentation of the basal plate without retroplacental hematoma −− Irregular basal intervillous thrombus

Microscopic ♦♦ Basal plate −− Intradecidual hemorrhage, rupture through the basal plate into the intervillous space, and maternal arteriopathy (rare) ♦♦ Parenchyma −− Fresh hemorrhage into the villous stroma, and microscopic evidence of an irregular basal intervillous thrombus ♦♦ Membranes −− Large amounts of fresh, retromembranous hemorrhage suggest retroplacental bleeding at high pressure consistent with an arterial bleed (abruption placenta)

Differential Diagnosis ♦♦ Subacute abruption −− This lesion is indicative of a partial abruptio placenta but not sufficiently forceful to result in immediate delivery −− These lesions can become enlarged by a larger classic abruption placenta −− They are characterized pathologically by a retroplacental hematoma with overlying recent villous infarction ♦♦ Acute peripheral separation/marginal abruption −− These uterine venous hemorrhages are characterized by a marginal retroplacental hematoma without significant indentation or rupture of basal plate

Acute Peripheral Separation/Marginal Abruption Clinical ♦♦ Marginal abruptions are common causes of preterm delivery characterized by preterm labor with vaginal bleeding often following rupture of membranes −− However, they may be associated with precipitous delivery at any gestation ♦♦ The pathogenesis of marginal abruption is rupture of the dilated tortuous veins at the placental margin as a consequence of increased venous pressure, changes in uterine geometry (e.g., after membrane rupture), or acute inflammation (chorioamnionitis) ♦♦ The lack of correlation between the amount of marginal retroplacental hematoma and the volume of clinical hemorrhages accounts for much of the poor correlation between clinical abruptio placenta and pathologic retroplacental hemorrhages (see above)

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Gross Findings ♦♦ The classical appearance of marginal abruption is a recent marginal retroplacental hematoma without significant indentation of villous parenchyma −− Even very small hemorrhages may be clinically significant and should be sampled for histology

Microscopic ♦♦ Recent hemorrhage surrounds markedly dilated and occasionally thrombosed large marginal veins with adjacent necrotic or acutely inflamed decidua

Differential Diagnosis ♦♦ Abruptio placenta (acute or subacute) −− These arterial hemorrhages are usually centrally located and associated with indentation of the overlying parenchyma with or without signs of villous ischemia (stromal hemorrhage or infarction)

Fig. 33.28. Chronic peripheral separation (diffuse chorioamniotic hemosiderosis).

Chronic Peripheral Separation/Chronic Abruption Clinical ♦♦ The classic clinical presentation of chronic abruption is recurrent vaginal bleeding throughout pregnancy, often with preterm labor and watery vaginal discharge (due to clot retraction) ♦♦ The pathogenesis is marginal abruption without progression to delivery −− Sonographic studies have documented the sequence of peripheral blood clot pushing the placental membranes away from the margin (circumvallate membrane insertion) ♦♦ Risk factors for chronic abruption include prior history of pregnancy loss, grand multiparity, smoking, and placenta previa −− Adverse sequelae include intrauterine growth restriction (IUGR), preterm delivery, bronchopulmonary dysplasia, and long-term neurologic impairment in term births

Gross Findings ♦♦ Three features are commonly observed in cases of chronic abruption −− Old pale brown marginal blood clot −− Circumvallate membrane insertion (complete or partial) −− Greenish discoloration of the chorionic plate (biliverdin staining)

Microscopic ♦♦ The diagnostic finding in chronic abruption is focal or diffuse accumulation of hemosiderin-laden macrophages (goldbrown refractile crystals) in the membranes and chorionic plate (Fig. 33.28) ♦♦ Also typical is a ridge of old blood clot pushing the membranes away from the margin (circumvallation) (Fig. 33.29)

Ancillary Studies ♦♦ An iron stain can be used to confirm hemosiderin deposition

Fig. 33.29. Chronic peripheral separation (circumvallate membrane insertion). −− However, the pigment may be iron stain-negative in up to 30% of otherwise classic cases of chronic abruption

Differential Diagnosis ♦♦ Meconium pigment −− Meconium pigment is red-brown, nonrefractile, and associated with pronounced vacuolation of the macrophage cytoplasm −− Membranes are generally edematous and necrotic following meconium exposure, and there is no evidence of old blood clot ♦♦ Circummarginate membrane insertion −− Membranes are inserted away from the placental margin, but lack the ridge of old blood clot and/or hemosiderin deposits seen with circumvallation −− Circummargination is caused by overfolding of redundant membranes at the placental margin

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Fetal Large Vessel Lesions Fetal Thrombotic Vasculopathy Clinical ♦♦ Fetal thrombotic vasculopathy (FTV) is caused by a sustained reduction in blood flow affecting large fetal vessels in the umbilical cord, chorionic plate or major stem villi resulting in thrombosis and downstream degenerative changes in the dependent villous tree −− Reduced blood flow can be the result of primary thrombosis, extrinsic compression, or reduced perfusion secondary to cardiac insufficiency, hyperviscosity, or increased vascular resistance ♦♦ Three major risk factors are cited for the development of FTV: Chronic or recurrent umbilical cord obstruction, underlying maternal or fetal coagulopathy, and maternal diabetes −− Recent studies suggest that clinical entanglements and pathologic abnormalities of the umbilical cord are by far the most important risk factors ♦♦ FTV is a major risk factor for neonatal encephalopathy and subsequent neurodisability, particularly in term infants −− Neonatal thrombotic diathesis, coexisting fetal–neonatal thrombosis, and thromboembolic disease, particularly affecting the central nervous system (CNS) or liver are other complications −− Recent evidence suggests that a significant proportion of otherwise unexplained term stillbirths have a form of obstructive fetal vasculopathy (see below)

Fig. 33.30. Hyalinized avascular villi.

Gross Findings ♦♦ Careful gross exam will occasionally reveal thrombi in dilated or discolored chorionic plate vessels −− Segmental or arcuate regions of relative pallor may be appreciated on cut section of the villous parenchyma −− Gross abnormalities of the umbilical cord are common, including (a) Excessive length (>85 cm) (b) Hypercoiling (greater than 5 twists per 10 cm) (c) Decreased Wharton jelly (maximum cord diameter less than 8 mm) (d) Abnormal cord insertion (marginal, membranous, furcated, or tethered by an amniotic web)

Microscopic ♦♦ The defining feature of FTV is the finding of large or small groups of avascular villi (AV) with stromal hyalinization (Fig. 33.30) and/or villi with villous stromal-vascular karyorrhexis (VSK), old or recent stromal hemorrhage, and a nonspecific increase in villous Hofbauer cells (Fig. 33.31) −− VSK overlaps with an earlier entity known as hemorrhagic endovasculitis −− An average of 15 affected villi/slide is required to make the diagnosis ♦♦ Other lesions commonly associated with FTV, though not required for diagnosis, are adherent, laminated, and/or calcified

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Fig. 33.31. Villous stromal-vascular karyorrhexis. vascular thrombi (observed in 30% of cases of FTV) and fibromuscular sclerosis (gradual luminal obliteration) of intermediate-sized vessels lying between the site of obstruction and areas of downstream AV/VSK

Differential Diagnosis ♦♦ Fetal vascular involutional changes secondary to stillbirth −− These placentas show fibromuscular sclerosis and diffuse rather than segmental villous degenerative changes (AV/ VSK) due to globally reduced fetal blood flow ♦♦ Changes consequent to improper placental storage −− Freshly or incompletely fixed placentas stored for prolonged periods without refrigeration can develop changes that mimic the early phases of stillbirth (global VSK and fibromuscular sclerosis) ♦♦ Chronic villitis with obliterative fetal vasculopathy −− Large areas of AV/VSK intermixed with distal villi showing villitis of unknown etiology (VUE) (see below)

Placenta and Gestational Trophoblastic Disease

−− Stem villous vessels are narrowed or occluded secondary to a chronic lymphohistiocytic vasculitis/perivasculitis ♦♦ Maternal villous infarction −− Villous degenerative changes (AV/VSK) may be present but are accompanied by the following diagnostic features of maternal infarction (a) Collapse of the intervillous space (b) Villous agglutination (c) Abundant karyorrhectic and neutrophilic debris (d) Trophoblast necrosis ♦♦ Two other pathologic patterns associated with mechanical umbilical cord obstruction have recently been described −− Stasis-associated fetal vasculopathy in stillbirth (a) This process is defined by vascular ectasia and early thrombosis in large chorionic vessels near the cord insertion site and nondiffuse segmental areas of downstream AV/VSK (less than 15/section) −− Changes consistent with chronic/partial intermittent cord occlusion (a) This process is defined by intimal fibrin Cushions (subendothelial/intramural fibrin(oid) deposits in the walls of large fetal veins), scattered small foci of AV/ VSK (less than 15/section), and/or a significant clinical or pathologic umbilical cord problem (clinical history of cord entanglement or one of the pathologic findings described above)

Chronic Thromboinflammatory Lesions Congenital Infection Clinical ♦♦ Organisms capable of causing congenital infections are often referred to by the acronym TORCH, a mnemonic for the organisms and the serologic screening test used to assess maternal and/or fetal exposure to them −− Unless previous negative results are known, a positive IgM titer is most useful since prior maternal exposure and transplacental transfer can potentially explain a positive IgG titer (a) T = Toxoplasma gondii (b) Others (syphilis, varicella-zoster and other organisms rarely found in the United States) (c) R = Rubella virus (d) C = Cytomegalovirus (e) H = Herpes simplex virus ♦♦ TORCH infections are the result of hematogenous spread to the placenta with transplacental spread to the fetus −− They are characterized by a diffuse inflammatory response in the placenta and direct teratogenic effects on the fetus ♦♦ Fetal findings in most congenitally infected infants include hepatosplenomegaly, cytopenias, and pneumonitis −− Typical fetal findings for specific organisms are listed below (a) T. gondii: CNS calcifications, retinitis

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(b) Syphilis: Bone, skin, and mucosal membranes; GI lesions (c) Varicella zoster virus: Limb and radicular skin defects (d) Rubella virus: Congenital heart disease, cataracts, and skin rash (e) Cytomegalovirus: CNS calcifications, retinitis, hepatitis, and ascites (f) Herpes simplex virus: IUGR, microcephaly, and hepatic necrosis ♦♦ Recurrence is rare since most TORCH infections are primary and confer subsequent protective immunity to the mother

Gross Findings ♦♦ Placentas from infections by the herpes, varicella-zoster, and rubella viruses are often small for gestational age due to early placental damage and decreased growth −− Placentas from congenital syphilis, T. gondii, and sometimes cytomegalovirus can sometimes be enlarged and edematous secondary to superimposed hydrops fetalis (fetal heart failure)

Microscopic ♦♦ Two common patterns may be seen −− The first characterized by villous edema, prominent Hofbauer cells, and scant lymphocytic infiltrates (villitis) is more common with syphilis and toxoplasmosis (Fig. 33.32) −− The second characterized by diffuse lymphohistiocytic villitis, villous fibrosis, and calcification is more common with rubella and the herpesviruses (Fig. 33.33) −− Specific features for each individual organism are listed below (a) T. gondii: Umbilical cord pseudocysts and focally granulomatous villous inflammation (b) Syphilis: Necrotizing umbilical periphlebitis and proliferative stem villous periarteritis (c) Rubella virus: Viral inclusions and endothelial necrosis

Fig. 33.32. Placental syphilis.

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Fig. 33.33. Placental cytomegalovirus.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 33.34. Villitis of unknown etiology (VUE).

♦♦ Immunocytochemical stains are available for CMV, HSV, and toxoplasmosis ♦♦ Histochemical silver impregnation stains (Warthin-Starry, Dieterle, Steiner) may be useful for syphilis and other unusual bacteria

−− The basis for transepithelial migration of maternal lymphocytes, amplification of the immune response, and recurrence in subsequent pregnancies is poorly understood ♦♦ VUE is primarily associated with nonhypertensive IUGR −− Severe VUE (diffuse and/or with fetal obliterative vasculopathy) is also a recognized cause of intrauterine fetal death, recurrent reproductive failure, and cerebral palsy −− Patchy or diffuse VUE has a 20–30% recurrence risk −− Focal VUE is generally clinically insignificant

Differential Diagnosis

Gross Findings

(d) Cytomegalovirus: Viral inclusions and villous ­plasma cells (e) Herpes simplex, Varicella zoster viruses: Viral inclusions and prominent necrosis

Ancillary Studies

♦♦ Villitis of unknown etiology (see below) −− This noninfectious chronic inflammatory process affects predominantly term placentas −− Unlike congenital infections, it is predominantly lymphocytic and shows nonuniform patchy involvement of the villous tree; it lacks viral inclusions, calcifications, and villous plasma cells −− Neonates show no signs of congenital infection ♦♦ Increased villous Hofbauer cells −− This pattern is a nonspecific reaction pattern seen in many placentas, especially those showing villous immaturity or hydrops fetalis −− The key distinction is a lack of true inflammatory changes (lymphocytes, fibrosis, necrosis)

Villitis of Unknown Etiology Clinical ♦♦ VUE is a relatively common chronic inflammatory disorder observed in 3–5% of term pregnancies (Fig. 33.34) −− It is characterized by the infiltration of the fetal villous stroma by maternal T lymphocytes circulating in the intervillous space

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♦♦ VUE is difficult to identify by gross examination −− Subtle increases in the pallor and increased firmness of the parenchyma may occasionally be recognized by experienced observers

Microscopic ♦♦ The hallmark of VUE is a nonuniform chronic inflammatory process involving terminal and stem villi that includes lymphocytes −− Granulomatous and active (neutrophilic) variants are not uncommon −− Perivillous fibrin deposition can sometimes be extensive −− Decidual plasma cells are seen in about one-thirds of cases ♦♦ Focal VUE is defined by each individual focus having 10 or fewer villi −− Patchy VUE has foci with more than10 villi −− Diffuse VUE shows involvement of 5% or more of all distal villi ♦♦ Exclusively basal VUE is a distinct subtype affecting younger women and is associated with diffuse lymphoplasmacytic deciduitis and a history of other genital tract infections

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♦♦ Obliterative fetal vasculopathy is an uncommon variant of VUE, usually diffuse, characterized by major involvement of stem villi by stem vasculitis/perivasculitis, vascular occlusion, and extensive downstream avascular villi −− It is associated with cerebral palsy and other forms of neurodisabilities

Ancillary Studies ♦♦ CD3 or CD8 immunostains may be used to confirm the presence of T lymphocytes in the villous stroma ♦♦ CD20 positive B lymphocytes are sometimes seen in cases of basal VUE ♦♦ Special stains for bacteria (Gram, Steiner) should be performed if there are more than occasional neutrophils ♦♦ Immunostains for cytomegalovirus should be performed in the presence of villous plasma cells

Differential Diagnosis ♦♦ Congenital TORCH infection (see previous section) ♦♦ Increased villous Hofbauer cells −− The presence of patchy involvement and CD3 positive T lymphocytes distinguishes VUE ♦♦ Fetal thrombotic vasculopathy −− While focal VUE in the distal villous tree is sometimes seen in FTV, the presence of more diffuse VUE and/or prominent stem villitis with arterial vascular changes (obliterative fetal vasculopathy) is not consistent with this diagnosis

Chronic Histiocytic Intervillositis Clinical Aspects ♦♦ Chronic histiocytic intervillositis (CHIV) is a very rare lesion associated with spontaneous abortion and recurrent reproductive failure −− Although evidence is slight, it has been speculated that it represents an autoimmune disease or maternal alloimmune responses to oncofetal antigen

Microscopic Findings ♦♦ CHIV is characterized by diffuse infiltration of the intervillous space by a monomorphic population of CD68 positive monocyte–macrophages (Fig. 33.35) −− Accompanying features can include abundant perivillous fibrin and trophoblast necrosis −− Cases overlapping with maternal floor infarction (see below) have been reported −− CHIV lacks a significant component of VUE

Differential Diagnosis ♦♦ Placental malaria −− An unusual form of placental falciparum malaria shows similar histology but has a more polymorphous inflammatory infiltrate, greater trophoblast necrosis, and more abundant intervillous fibrin −− Malarial pigment and/or organisms are usually identifiable, and there is generally no history of recurrent reproductive failure

Fig.  33.35. Chronic histiocytic intervillositis (massive chronic intervillositis).

♦♦ Diffuse VUE with prominent chronic intervillositis −− VUE is distinguished by significant villous inflammation and a more polymorphous intervillous infiltrate (lymphocytes, monocytes, neutrophils) ♦♦ Acute villitis with intervillous abscesses −− This pattern is characterized by a predominance of neutrophils and zones of villous necrosis −− It is most commonly seen with L. monocytogenes but may be associated with other bacteria

Massive Perivillous Fibrin(oid) Deposition (“Maternal Floor Infarction”) Clinical ♦♦ Massive perivillous fibrin(oid) deposition, also known as “maternal floor infarction” (MFI), is a rare idiopathic lesion associated with a high perinatal morbidity and mortality rate and recurrent reproductive failure −− Adverse outcomes conditions associated with MFI include miscarriage, intrauterine fetal demise (IUFD), severe IUGR, preterm birth, and neurodisability ♦♦ MFI is characterized by progressive accumulation of extracellular matrix (fibrinoid) and fibrin around a substantial portion of the distal villous tree −− The strong recurrence risk (greater than 50%) suggests a strong maternal component and MFI has been associated with maternal connective tissue disease and thrombophilia in some studies −− The pathogenesis is unclear, but an aberrant response to trophoblast damage has been proposed

Gross Features ♦♦ Placentas are generally small for gestational age, though rarely will the degree of fibrinoid deposition make them large

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by the extravillous trophoblast, sometimes referred to as “X-cells”

Differential Diagnosis

Fig. 33.36. Diffuse perivillous fibrin(oid) deposition (maternal floor infarction). −− Classic MFI shows a diffuse “orange rind-like” thickening of the basal plate, usually accompanied by patchy irregular involvement of the lower two-thirds of the parenchyma −− Occasional cases lack the basal predominance −− Some observers require at least a 10% involvement in gross examination to make a diagnosis of MFI

Microscopic Findings ♦♦ Extensive fibrin and extracellular matrix material surrounds and displaces terminal villi often with at least focal acute villous degenerative changes (Fig. 33.36) −− Involvement is accentuated near and within the basal plate in the classic MFI pattern −− Areas rich in extracellular matrix and without accompanying villous degeneration often show diffuse infiltration

♦♦ Perivillous Fibrin Plaque −− These lesions, usually observed in otherwise normal term placentas, closely resemble MFI in high-power examination −− However, in contrast to MFI, they are localized discrete nodular lesions without basal predominance ♦♦ VUE with massive perivillous fibrin deposition −− Villi show lymphocytic inflammation, and the fibrin lacks extravillous trophoblast infiltration ♦♦ Increased Intervillous Fibrin −− This change associated with MUP (see above) is characterized by fibrin deposition preferentially affecting stem villi and the chorionic and basal plates −− Unlike MFI, it does not envelop large segments of the distal villous tree −− Infiltration by extravillous trophoblast may be present focally −− It is usually accompanied by other signs of MUP such as increased syncytial knots, villous agglutination, distal villous hypoplasia ♦♦ Villous Infarction −− Infarcts are localized, well-circumscribed lesions extending up from the basal plate −− Unlike the case in MFI or perivillous fibrin plaques, the villi are agglutinated, the intervillous space collapsed, and there is a uniform necrosis of the villous trophoblast −− Fibrin is minimal and extracellular matrix is absent

MULTIPLE PREGNANCY Clinical ♦♦ Monochorionic (MC) twins are derived from a single fertilized egg with separation of the inner cell mass into two embryos −− Depending on the time of cleavage, separate amnions (diamniotic MC) or a single amnionic cavity (monoamniotic MC) may be found −− Naturally-occurring MC twin placentas are always associated with monozygous (identical) twins −− However, fraternal twins with dizygous MC placentas have been reported with in vitro fertilization −− Essentially all MC twin placentas have connections between the two fetal blood supplies (anastomoses) −− Details of the vascular architecture determine the risk of twin–twin transfusion syndrome

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♦♦ Dichorionic (DC) twin placentas can be either dizygous (derived from two separate fertilized eggs) or monozygous (a single fertilized egg splitting before the separation of trophectoderm from the inner cell mass) −− These placentas rarely, if ever, have vascular anastomoses −− Dizygous (fraternal) twinning is believed to relate to ovarian function (polyovulation) and is increased with the ovulation induction agent clomiphene −− Dizygous twinning can be familial and is high among mothers of African ancestry ♦♦ Clinical syndromes associated with both MC and DC placentas −− Premature delivery, preeclampsia, and cerebral palsy

Placenta and Gestational Trophoblastic Disease

−− Discordant twin growth (greater than 25% difference in birth weights) −− Twin oligohydramnios polyhydramnios syndrome (TOPS): Asymmetric placental insufficiency resulting in worsening IUGR of the disadvantaged twin (1 small twin/1 normal twin) ♦♦ Clinical syndromes associated with MC placentas only −− Cord entanglement and IUFD (monoamniotic twins only) −− Chronic twin–twin transfusion syndrome (a) Progressive size discrepancy between twins associated with circulatory imbalance due to deep parenchymal artery to vein anastomoses unbalanced by compensatory surface anastomoses (b) This imbalance can result in congestive heart failure of either one or both the twins ♦♦ Acute twin–twin transfusion syndrome (a) Sudden circulatory imbalance leading to a loss of blood pressure in one twin is associated with a very high rate of severe CNS injury (b) This most frequently occurs following IUFD of one twin, but can also occur with spontaneous or iatrogenic (laser ablation) of vascular anastomoses that balance the two circulations

Gross findings ♦♦ Separate twin placentas are DC and require no assessment of the dividing membrane or injection studies −− Single twin placentas with a dividing membrane may be either MC or DC (a) Distinction may be easily accomplished by “peeling” the layers of the dividing membrane (2 versus 3 layers) −− Three layers = diamniotic DC (b) Placentas should be divided, weighed, and processed separately (c) Injection studies are not necessary, and the dividing membrane should be submitted for histologic confirmation −− Two layers = diamniotic MC (d) The fetal surface should be inspected for surface anastomoses (absent or rare in chronic twin–twin transfusion syndrome) (e) Air (or other) injection studies can be performed to document deep vascular anastomoses

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(f) Placentas should not be separated and sections should be submitted from each twin’s vascular territory (g) Dividing membrane should be submitted for histologic confirmation ♦♦ One placenta without dividing membrane = monoamniotic MC −− Process as described above for diamniotic MC twins (except no dividing membrane)

Microscopic ♦♦ MC dividing membranes have two layers of amnion only −− Parenchymal sections may show fetal vascular occlusive lesions related to asymmetric anastomoses or differences in villous development secondary to unequal maternal perfusion ♦♦ DC dividing membranes have two layers of amnion separated by a fused layer consisting of two chorions −− Parenchymal sections may show asymmetric histologic lesions in cases of discordant twin growth

Ancillary Studies ♦♦ Air injection studies −− Begin with the placenta from the twin with lower birth weight (or smaller umbilical cord) −− Ligate proximally and inject air into each of the two to four arteries branching from the cord insertion site (arteries travel over veins) −− Look for air appearing in the veins (or arteries) of the second twin −− If negative, repeat for arteries from the other twin

Differential Diagnosis ♦♦ MC placenta with twins of different sexes −− Consider 46,XY/45,XO with loss of a Y chromosome in one twin −− Alternatively, fusion of placentas as described above is possible ♦♦ Separate placentas with twin–twin transfusion syndrome −− Carefully inspect the region between the umbilical cords for vascular anastomoses in areas of extreme placental atrophy mimicking separation in a MC placenta −− Alternatively, consider true vascular anastomoses in DC twins that occur in some animal species and are the subject of a few case reports in humans

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Redline RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29 Suppl A:S86–S91.

Sebire NJ, Backos M, Goldin RD, Regan L. Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome. Br J Obstet Gynaecol 2002;109:570–573.

Redline RW, Wilson-Costello D. Chronic peripheral separation of placenta. The significance of diffuse chorioamnionic hemosiderosis. Am J Clin Pathol 1999;111:804–810. Redline RW, Pappin A. Fetal thrombotic vasculopathy: the clinical significance of extensive avascular villi. Hum Pathol 1995;26: 80–85. Redline RW. Clinical and pathological umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol 2004;35:1494–1498. Redline RW. Cerebral palsy in term infants: a clinicopathologic analysis of 158 medicolegal case reviews. Pediatr Dev Pathol 2008;11:456–464. Redline RW. Villitis of unknown etiology: noninfectious chronic villitis in the placenta. Hum Pathol 2007;38:1439–1446. Redline RW, Abramowsky CR. Clinical and pathologic aspects of recurrent placental villitis. Hum Pathol 1985;16:727–731. Redline RW. Invited Commentary – Maternal floor infarction and massive perivillous fibrin deposition: clinicopathologic entities in flux. Adv Anat Pathol 2002;9:372–373. Roberts JM, Gammill HS. Preeclampsia: recent insights. Hypertension 2005;46:1243–1249. Epub 2005 Oct 17. Roberts JM, Hubel CA. Is oxidative stress the link in the two-stage model of pre-eclampsia? Lancet 1999;354:788–789.

Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol 2003;102:181–192. Shanklin DR, Scott JS. Massive subchorial thrombohaematoma (Breus’ mole). Br J Obstet Gynaecol 1975;82:476–487. Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol 2001;20:31–47. Shih IM, Kurman RJ. p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations. Am J Surg Pathol 2004;28: 1177–1183. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 1998;22:1393–1403. Souter VL, Kapur RP, Nyholt DR, et al. A report of dizygous monochorionic twins. N Engl J Med 2003;349:154–158. Stanek J, Al-Ahmadie HA. Laminar necrosis of placental membranes: a histologic sign of uteroplacental hypoxia. Pediatr Dev Pathol 2005;8:34– 42. Epub 2005 Feb 8. Thaker HM, Berlin A, Tycko B, et  al. Immunohistochemistry for the imprinted gene product IPL/PHLDA2 for facilitating the differential diagnosis of complete hydatidiform mole. J Reprod Med 2004;49: 630–636.

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34 Nonneoplastic Renal Diseases Geoffrey A. Talmon, md and Donna J. Lager, md

CONTENTS

I. Glomerular Diseases..........................34-3

Morphologic Classification .............................34-3 Primary Glomerular Diseases.........................34-3 Minimal Change Disease (MCD)..........34-3 Focal Segmental Glomerulosclerosis (FSGS).................................................34-4 Membranous Nephropathy (MN).........34-4 IgA Nephropathy (IgAN).......................34-5 Membranoproliferative (Mesangiocapillary) Glomerulonephritis (MPGN)............34-6 Postinfectious Glomerulonephritis (PIGN).................................................34-7 Crescentic Glomerulonephritis.............34-8 Fibrillary Glomerulonephritis...............34-9 Secondary Glomerular Diseases.....................34-9 Diabetes Mellitus (Diabetic Nephropathy).....................34-9 Paraproteinemia...................................34-10 Systemic Lupus Erythematosus (Lupus Nephritis).............................34-13 HIV Nephropathy.................................34-13 Hereditary Systemic Disorders with Renal Involvement.....................................34-13 Fabry Disease........................................34-13 Lecithin Cholesterol Acyltransferase (LCAT) Deficiency...........................34-14 Lipoprotein Glomerulopathy...............34-16 Nail–Patella Syndrome.........................34-16 Lipodystrophy.......................................34-18 Hereditary Nephritis............................34-18

Congenital and Infantile Nephrotic Syndrome.................................34-19 Congenital Nephrotic Syndrome of the Finnish Type..........................34-19 Diffuse Mesangial Sclerosis.................34-20

II. Tubulointerstitial Diseases of the Kidney...................................34-21 Acute Infectious Pyelonephritis (Ascending or Hematogenous Infection)....................................................34-21 Chronic Pyelonephritis..................................34-21 Chronic Obstructive Pyelonephritis...................................34-21 Chronic Nonobstructive Pyelonephritis (Reflux Nephropathy)...................................34-21 Acute Tubulointerstitial Nephritis................34-22 Acute Tubular Necrosis (ATN)......................34-23 Ischemic Injury.....................................34-23 Nephrotoxic Injury...............................34-23 Oxalate Nephropathy.....................................34-23 Phosphate Nephropathy (PN).......................34-24 Light Chain Cast Nephropathy (Myeloma Kidney).....................................34-24

III. Vascular Diseases of the Kidney.......34-25 Benign Nephrosclerosis..................................34-25 Malignant Nephrosclerosis............................34-25 Renovascular Hypertension (Renal Artery Stenosis)......................................................34-25 Atherosclerosis......................................34-26

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_34, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Fibromuscular Dysplasia (FMD)........34-26 Thromboembolic Diseases.............................34-26 Cortical Infarcts....................................34-26 Renal Cholesterol Microembolism Syndrome..........................................34-27 Thrombotic Microangiopathy.............34-27 Vasculitis.........................................................34-28

Autosomal Dominant Polycystic Kidney Disease (ADPKD)......................................34-29 Autosomal Recessive Polycystic Kidney Disease (ARPKD)......................................34-30 Juvenile Nephrophthisis/Medullary Cystic Disease.............................................34-30 Acquired Renal Cystic Disease......................34-31

IV. Developmental and Cystic Diseases V. Suggested Reading...........................34-31 of the Kidney...................................34-28 Renal Dysplasia..............................................34-28

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GLOMERULAR DISEASES Morphologic Classification (Table 34.1) Primary Glomerular Diseases Minimal Change Disease (MCD) Clinical ♦♦ The most common cause of the nephrotic syndrome in children (Table 34.2) ♦♦ Mild periorbital edema, prior to the rapid onset of the nephrotic syndrome ♦♦ Proteinuria is “selective” or composed primarily of albumin ♦♦ Microscopic hematuria is rare; hypertension is unusual ♦♦ MCD in adults has been associated with various drugs (i.e., NSAIDs)

Table 34.1. Glomerular Diseases: Morphologic Classification 1. Normal glomeruli by light microscopy   (a) Minimal change disease   (b) Thin glomerular basement membrane disease   (c) Early Alport disease   (d) (Early membranous glomerulonephritis) 2. Focal/segmental lesions   (a) Focal segmental glomerulosclerosis     • Idiopathic vs. secondary   (b) Focal segmental proliferative glomerulonephritis   (c) Focal segmental necrotizing and crescentic glomerulonephritis 3. Diffuse glomerulonephritis   (a) Membranous glomerulonephritis     • Idiopathic vs. secondary   (b) Proliferative glomerulonephritis     • Mesangial proliferative glomerulonephritis    – IgA nephropathy    – Mesangial proliferative lupus nephritis     • Endocapillary proliferative glomerulonephritis    – Acute postinfectious glomerulonephritis     • Mesangiocapillary glomerulonephritis    – Membranoproliferative glomerulonephritis (MPGN)    – Diffuse proliferative lupus nephritis    – Cryoglobulinemic glomerulonephritis    – Chronic thrombotic microangiopathy

Microscopic ♦♦ Light microscopy −− The glomeruli, tubules, and interstitium appear normal (Fig. 34.1) ♦♦ Immunofluorescence microscopy −− Usually negative, mesangial IgM may occasionally be present ♦♦ Electron microscopy (Fig. 34.2) −− Diffuse effacement of the epithelial cell (podocyte) foot processes is the sole abnormality (also see Chap. 4)

Differential Diagnosis ♦♦ An early membranous lesion may look normal in light microscopy

Table 34.2. Classification of Primary Glomerulonephritis by Predominant Clinical Manifestations Nephrotic syndrome   Minimal change disease  Focal segmental glomerulosclerosis  Membranous glomerulonephritis   IgA nephropathy   Membranoproliferative GN   Acute postinfectious GN  Crescentic glomerulonephritis

Nephritic syndrome

+++++

–

++++

+

++++ +++ ++ +

+ ++ +++ ++++

+

++++

4. Crescentic glomerulonephritis   (a) Immune complex mediated crescentic glomerulonephritis   (b) Pauci-immune (ANCA-associated) crescentic glomerulonephritis   (c) Antiglomerular basement membrane antibody mediated 5. Diffuse/nodular mesangial expansion   (a) Diabetic glomerulosclerosis   (b) Light chain deposition disease   (c) Fibrillary glomerulonephritis   (d) Amyloidosis

Fig.  34.1. Minimal change disease with normal glomerulus, tubules and arteriole.

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Fig. 34.2. Electron micrograph of minimal change disease showing global podocyte foot process effacement.

♦♦ Undersampled focal segmental glomerulosclerosis (where segmental scars are not present in the biopsy) may look identical to MCD

Focal Segmental Glomerulosclerosis (FSGS) Clinical ♦♦ Focal segmental glomerulosclerosis may be primary (idiopathic) or secondary to a number of etiologic agents, including −− Unilateral renal agenesis −− Renal ablation −− Sickle cell disease −− Morbid obesity (with or without sleep apnea) −− Reflux nephropathy −− HIV nephropathy ♦♦ Idiopathic FSGS is the most common cause of nephrotic syndrome in African Americans ♦♦ Secondary FSGS usually does not present with the full nephrotic syndrome

Microscopic ♦♦ Light microscopy −− Focal and segmental glomerular sclerosis with capillary loop collapse, hyaline and lipid deposition, and often adhesion to Bowman capsule (Fig. 34.3) −− The remainder of the glomerular tuft appears normal −− Lesions begin or are more common near the corticomedullary junction ♦♦ Immunofluorescence microscopy −− May be negative −− Deposition of IgM and C3 in mesangium or in segmental sclerosis ♦♦ Electron microscopy (also see Chap. 4) −− Effacement of podocyte foot processes

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Fig. 34.3. Segmental (upper glomerulus) and global glomerulosclerosis (lower glomerulus) on silver stain. −− Podocyte denudation may be present focally as an early lesion −− Segmental sclerosis may also be seen

Differential Diagnosis ♦♦ May be secondary (see earlier) or the end result of segmental necrotizing diseases

Membranous Nephropathy (MN) Clinical ♦♦ MGN is the major cause of nephrotic syndrome in adults ♦♦ It may be primary or occur in association with a number of disorders or exposure to antigenic substances (“secondary MGN” which accounts for up to 30% of cases), such as −− Systemic lupus erythematosus −− Malignant neoplasms −− Exposure to gold and mercury −− Penicillamine, captopril, and NSAIDS −− Hepatitis B −− Various metabolic disorders ♦♦ MCD is thought to be a chronic antigen–antibody mediated disease in which the antigens are planted within the subepithelial space of the glomerular capillary loops

Microscopic ♦♦ Light microscopy (Fig. 34.4) −− The glomeruli may appear normal if the deposits are small (early disease) −− Capillary walls are thickened, with subepithelial spikes on silver stain ♦♦ Immunofluorescence microscopy −− Bright granular staining of the capillary loops with antiIgG and C3 (Fig. 34.5) ♦♦ Electron microscopy (also see Chap. 4) −− Subepithelial electron dense deposits with intervening basement membrane spikes (Fig. 34.6)

Nonneoplastic Renal Diseases

Fig.  34.4. Membranous nephropathy with subepithelial basement membrane “spikes” on silver stain.

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Fig.  34.5. Granular capillary wall staining with anti-IgG in membranous nephropathy.

−− Stage of disease correlates with incorporation of deposits into the glomerular basement membrane (GBM)

Differential Diagnosis ♦♦ As noted above, secondary causes of MGN are common (especially systemic lupus erythematosus) −− In lupus, mesangial deposits and tubuloreticular inclusions are seen ♦♦ An early lesion may be confused with minimal change disease (MCD) by light microscopy

IgA Nephropathy (IgAN) Clinical ♦♦ Most common form of primary glomerulonephritis in the world ♦♦ IgAN has a higher incidence in patients of Asian and Native American descent ♦♦ It may be related to a genetic or acquired abnormality of immune regulation leading to increased mucosal IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents ♦♦ Occurs with increased frequency in patients with −− Celiac disease −− Dermatitis herpetiformis

Fig.  34.6. Electron micrograph of subepithelial electron dense deposits and adjacent GBM spikes in membranous nephropathy. −− Liver disease ♦♦ Patients usually present with one of three syndromes −− Macroscopic hematuria concurrent with an upper respiratory infection, the so-called “synpharyngitic hematuria” −− Asymptomatic microscopic hematuria and variable proteinuria, including the nephrotic syndrome

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−− Henoch–Schonlein purpura is the systemic form of the disease process causing IgA nephropathy and occurs more frequently in children than adults (a) Patients with Henoch–Schonlein purpura manifest skin, joint, and intestinal involvement

Microscopic ♦♦ Light microscopy −− The glomeruli show varying degrees of mesangial hypercellularity (Fig. 34.7) −− Segmental proliferation, segmental sclerosis, and necrosis with crescents may be seen ♦♦ Immunofluorescence microscopy −− Mesangial deposits of IgA (dominant or codominant); IgG and C3 are variably present. (Fig. 34.8) ♦♦ Electron microscopy −− Deposits are present in the mesangium often in a “paramesangial” location (beneath the basement membrane as it covers mesangium) (Fig. 34.9)

−− Abnormal urinary sediment with nonnephrotic proteinuria −− Acute nephritis ♦♦ MPGN may be primary or associated with other systemic disorders (secondary), including −− Hepatitis B and hepatitis C infection −− Infected ventriculoatrial shunts −− Subacute bacterial endocarditis −− Schistosomiasis

Differential Diagnosis ♦♦ Mesangial deposits may also be seen in SLE (WHO class II lupus nephritis) and resolving postinfectious glomerulonephritis

Membranoproliferative (Mesangiocapillary) Glomerulonephritis (MPGN) Clinical ♦♦ Chronic progressive glomerulonephritis in older children and adults ♦♦ Circulating immune complexes have been identified in 50% of patients ♦♦ Activation of the complement system with hypocomplementemia is a hallmark of MPGN ♦♦ Patients may present with the following −− Nephrotic syndrome

Fig.  34.8. Granular mesangial staining with anti-IgA in IgA nephropathy.

Fig. 34.7. Glomerulus with mild mesangial proliferation in IgA nephropathy.

Fig.  34.9. Paramesangial electron dense deposits in IgA nephropathy.

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Fig.  34.10. Mesangial and endocapillary hypercellularirt with GBM duplication in MPGN type I.

−− Alpha 1-antitrypsin deficiency −− Chronic liver disease ♦♦ Three types of MPGN (types I–III) have been described based on morphology and clinical features −− Type II occurs mostly in children and is associated with autoantibodies to C3 convertase (“C3 nephritic factor”) −− Patients with partial lipodystrophy may develop type II MPGN

Microscopic ♦♦ All three types feature mesangial hypercellularity, matrix expansion, and mesangial interposition beneath the endothelium with formation of double contours −− Type I MPGN (Fig. 34.10) (a) Subendothelial and mesangial deposits that frequently contain C3 and immunoglobulins (b) Most cases of secondary MPGN are type I. −− Type II MPGN (dense deposit disease) (Fig. 34.11) (a) Electron-dense deposits within lamina densa of the GBM contain C3 in a linear pattern in the peripheral capillary loops with ring-like patterns in the ­mesangium −− Type III MPGN (a) Prominent mesangial, subendothelial, and subepithelial immune deposits (b) Type III is the least common form of MPGN

Postinfectious Glomerulonephritis (PIGN) Clinical ♦♦ May be caused by a number of infectious agents ♦♦ Poststreptococcal glomerulonephritis is primarily a disease of children, 6–7 years of age −− The onset is usually abrupt, with a latent period of 7–21 days between infection and the development of nephritis (“postpharyngitic hematuria”)

Fig. 34.11. Dense deposit disease (MPGN type II) with thickened, silver negative capillary wall (A). Electron micrograph of interrupted, intramembranous electron dense deposits in dense deposit disease (B). −− During epidemics, the clinical attack rate is 10–12%, but subclinical disease occurs four times more frequently than overt disease; asymptomatic contacts may have hematuria ♦♦ Common initial clinical manifestations of post-­streptococcal glomerulonephritis are −− Hematuria (microscopic or macroscopic) −− Edema −− Hypertension −− Oliguria ♦♦ The acute clinical episode of post-streptococcal glomerulonephritis is usually self-limited, and complement levels, which are usually depressed acutely, return to normal within 6 weeks ♦♦ In most patients, hematuria disappears by 6 months, but proteinuria may persist for 2 years in one-third of patients

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Fig. 34.12. Diffuse mesangial and endocapillary hypercellularity in acute postinfectious glomerulonephritis.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 34.14. Large subepithelial deposits in acute postinfectious glomerulonephritis.

Crescentic Glomerulonephritis Clinical

Fig. 34.13. Granular capillary wall and mesangial staining with anti-IgG in acute postinfectious glomerulonephritis.

Microscopic ♦♦ Light microscopy −− The glomeruli show diffuse mesangial proliferation and endocapillary hypercellularity with infiltration of neutrophils and mononuclear inflammatory cells (Fig. 34.12) −− Crescents may also be present ♦♦ Immunofluorescence microscopy −− Granular deposits of C3 and IgG along the capillary loops and in the mesangium (Fig. 34.13) ♦♦ Electron microscopy −− Large subepithelial, “hump-like” deposits as well as mesangial deposits (Fig. 34.14) −− The capillary loop deposits become less frequent after a few weeks, but the mesangial deposits persist for a longer period

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♦♦ May be −− Immune complex-mediated (SLE, IgAN, PIGN, etc.) −− Pauci-immune (ANCA-associated) – accounts for approximately 50% of cases −− Mediated by antiglomerular basement membrane antibody ♦♦ Patients with crescentic glomerulonephritis secondary to anti-glomerular basement membrane disease may also have pulmonary hemorrhage (Goodpasture disease) ♦♦ Most cases of pauci-immune glomerulonephritis are associated with small vessel vasculitidites (see later) ♦♦ The prognosis depends on the number of crescents present in the biopsy; a more diffuse crescentic process predicts a worse prognosis

Microscopic ♦♦ Light microscopy −− Disruption of the glomerular capillary loops causes extravasation of blood and cells into Bowman space, which incites proliferation of parietal epithelial cells, forming a cellular crescent (Fig. 34.15) ♦♦ Immunofluorescence microscopy −− Fibrinogen staining is seen in areas undergoing necrosis and crescent formation −− Bright linear staining of GBM for IgG in anti-glomerular basement membrane-mediated disease (Fig. 34.16) −− Negative in pauci-immune crescentic glomerulo­nephritis −− Other immune complexes are present in immune complex-mediated disease ♦♦ Electron microscopy −− Disruption of capillary wall with or without immune deposits

Nonneoplastic Renal Diseases

Fig.  34.15. Segmental glomerular necrotizing lesion (lower right) with overlying cellular crescent.

34-9

Fig.  34.17. Fibrillary glomerulonephritis with pale mesangial expansion and thickened capillary walls on silver stain.

♦♦ Immunofluorescence microscopy −− “Smudgy” mesangial and capillary wall staining for IgG and C3 are present −− If IgG subtyping is performed, IgG4 is predominant ♦♦ Electron microscopy −− There is glomerular deposition of fibrils that are thicker than amyloid fibrils and lack Congo red birefringence (Fig. 34.18) −− The 18-22 nm randomly oriented, nonbranching fibrils are present in the mesangium and at least segmentally along the capillary loop basement membranes

Secondary Glomerular Diseases Diabetes Mellitus (Diabetic Nephropathy) Clinical Fig. 34.16. Bright, linear capillary wall staining with anti-IgG in anti-GBM mediated glomerulonephritis.

Fibrillary Glomerulonephritis Clinical ♦♦ Most patients are 40–50 years of age, with a slight female predominance and a greater frequency in whites ♦♦ Most patients present with proteinuria, and occasionally the nephrotic syndrome, or with symptoms of nephritis ♦♦ Renal insufficiency is progressive, with renal failure usually occurring within 2–4 years

Microscopic ♦♦ Light microscopy −− The glomeruli show mesangial matrix expansion, variable hypercellularity, and capillary wall thickening (Fig. 34.17)

♦♦ Major cause of end-stage renal failure in the United States ♦♦ Approximately one-third of patients entering dialysis programs have lost renal function as a result of diabetes ♦♦ Patients with diabetes mellitus rarely develop clinically detectable glomerular injury before 10 years ♦♦ Nodular mesangial sclerosis (Kimmelstiel–Wilson nodule) is the quintessential lesion

Microscopic ♦♦ The histologic changes in type 1 and type 2 diabetes are identical ♦♦ Light microscopy −− Thickened tubular and glomerular basement (after 2–3 years) −− Interstitial fibrosis and expansion of mesangial regions with formation of PAS- and silver-positive mesangial nodules begins after 3–5 years; it parallels progressive loss of renal function (Fig. 34.19)

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Fig.  34.19. Diabetic glomerulosclerosis with PAS-positive mesangial nodules.

Fig. 34.18. Electron micrograph of fibrillary glomerulonephritis with mesangial electron dense deposits at low magnification (A). Electron micrograph of fibrillary glomerulonephritis with mesangial fibrils at higher magnification (B).

Fig. 34.20. Electron micrograph of diabetic glomerulosclerosis with nodular mesangial sclerosis and thickened GBM.

Paraproteinemia

Differential Diagnosis

♦♦ A group of disorders characterized by tissue damage associated with the overproduction of monoclonal immunoglobulin proteins and their components ♦♦ The renal manifestations occur as a result of the interaction of the abnormal protein with normal tissue components

♦♦ Both light chain deposition disease and amyloidosis may form mesangial nodules −− Nodules are generally PAS negative, and immunofluorescence is positive for the corresponding immunoglobulin

♦♦ Extracellular deposition of insoluble fibrillar proteins with a characteristic b-pleated sheet configuration; most proteins have an a-helical structure

♦♦ Electron microscopy −− Diffuse thickening of the capillary loop basement membranes and mesangial matrix expansion (Fig. 34.20)

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Amyloidosis

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34-11

−− Primary or AL amyloid is caused by a plasma cell dyscrasia with overproduction of a monoclonal immunoglobulin light chain, which in most patients is l light chain; overt myeloma is present in 20% of these patients −− Secondary or AA amyloid occurs in chronic infections and chronic inflammatory states, including rheumatoid arthritis, ankylosing spondylitis, tuberculosis, osteomyelitis, and intravenous drug abuse

Microscopic ♦♦ Light microscopy −− Amyloid deposits occur predominantly in glomeruli and appear as amorphous, eosinophilic nodules within the mesangium, and as thickened capillaries −− The amyloid deposits do not stain with the silver stain (nonargyrophilic), are PAS weak or negative, and show green birefringence under polarized light with the Congo red stain (Fig. 34.21) ♦♦ Electron microscopy −− The amyloid deposits are composed of nonbranching, randomly oriented, twisted fibrils that measure 8–12 mm in diameter −− Fibrils accumulate first in the mesangium and later in the subendothelial space, producing long silver-positive bundles that extend perpendicularly to the basement membrane beneath podocytes (spicules) (Fig. 34.22)

Light Chain Deposition Disease ♦♦ A systemic disease caused by overproduction of a monoclonal immunoglobulin light chain (usually k), which deposits in various organs

Microscopic ♦♦ Light microscopy −− The glomeruli contain eosinophilic mesangial nodules similar to the nodules seen in diabetic nephropathy and in amyloidosis −− Like amyloid, the mesangial nodules in light chain deposition disease are nonargyrophilic and stain weakly with PAS (Fig. 34.23) ♦♦ Immunofluorescence microscopy −− There is bright linear staining of tubular basement membranes for k light chains and less intense staining of the glomeruli; other immunoglobulins may be present rarely (Fig. 34.24) ♦♦ Electron microscopy −− Punctate granular deposits in the lamina rara interna of the glomerular basement membrane with extension into the lamina densa and lamina rara externa are less common (a) Mesangial deposits are less prominent −− The deposits are more consistently present in the tubular basement membranes and have a similar granular appearance

Cryoglobulinemic Glomerulonephritis ♦♦ Cryoglobulins are circulating immunoglobulins that precipitate on cooling and resolubilize on warming

Fig. 34.21. Pale staining glomerular amyloid deposition on silver stain (A). Arteriolar amyloid showing Congo red positivity (B). Arteriolar amyloid showing positive birefringence of Congo red stain with polarized light (C). ♦♦ Three types of cryoglobulinemia have been described −− In type I cryoglobulinemia, the immunoglobulin is a single monoclonal immunoglobulin usually without associated antibody activity

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−− In type II cryoglobulinemia, a monoclonal immunoglobulin (usually IgM-k) is directed against polyclonal immunoglobulin (usually IgG)

Essentials of Anatomic Pathology, 3rd Ed.

−− In type III cryoglobulinemia, a polyclonal immunoglobulin is directed against a polyclonal immunoglobulin

Clinical ♦♦ Type I cryoglobulinemia is most often associated with lymphoproliferative disorders such as multiple myeloma, Waldenstrom macroglobulinemia, and chronic lymphocytic leukemia ♦♦ Mixed cryoglobulinemia (types II and III) occurs in a variety of settings, including lymphoproliferative disorders, collagen-vascular diseases, and infections including Hepatitis B, C, and Epstein–Barr virus ♦♦ Several studies have demonstrated an increased incidence of hepatitis C virus infection in patients with mixed cryoglobuli­ nemia −− Antibody to hepatitis C virus has been detected in serum from 91 to 98% of patients with mixed cryoglobulinemia, and hepatitis C virus RNA in 81%

Fig. 34.22. Electron micrograph of capillary wall amyloid with subepithelial “spicules.”

Fig.  34.23. Light chain deposition disease with pale staining mesangial nodules on silver stain.

Fig. 34.24. Bright tubular basement membrane and glomerular staining for kappa light chain in light chain deposition disease.

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Microscopic ♦♦ Light microscopy −− The acute glomerular lesion of mixed cryoglobulinemia is a diffuse proliferative glomerulonephritis with prominent subendothelial and intraluminal deposits (Fig. 34.25) −− The mesangial proliferation and mesangial interposition results in a lobular architecture resembling type I membranoproliferative glomerulonephritis; infiltrating monocytes and occasional neutrophils are also present −− Renal arteritis may also be present and is found in ~30% of patients ♦♦ Immunofluorescence microscopy −− The composition of the glomerular deposits corresponds to that of the circulating cryoglobulin; mixed cryoglobulins contain IgG, IgM, C3, C1q, and C4 −− Because of the presence of a monoclonal IgM-k component, staining for these immunoglobulins is often more intense than IgG and l in type II cryoglobulinemia

Fig. 34.25. Cryoglobulinemic glomerulonephritis with mesangial and endocapillary proliferation, intraluminal cryoglobulin deposits, and mononuclear inflammatory cells.

Nonneoplastic Renal Diseases

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♦♦ The clinical presentation of HIV nephropathy is characterized by heavy proteinuria (in the nephrotic range in 90% of patients) accompanied by rapid progression to renal failure over 6–12 months ♦♦ Therapy with antiviral agents has been attempted with limited success. Immunosuppressive therapy is not generally considered safe because of the immune compromise already present in these patients

Microscopic

Fig. 34.26. Electron micrograph of curved tubular substructure of cryoglobulin.

−− Staining involves the subendothelial aspect of the glomerular capillary wall with focal globular intraluminal deposits and smaller mesangial deposits ♦♦ Electron microscopy −− The deposits are typically subendothelial. Mesangial deposits are usually smaller and less numerous. Intra­ membranous and subepithelial deposits may also be seen −− Often the deposits have a characteristic substructure with curved tubular structures, ~30 mm in diameter, that cluster in curvilinear bundles (Fig. 34.26)

Systemic Lupus Erythematosus (Lupus Nephritis) Clinical ♦♦ Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the overproduction of antibodies to endogenous antigens, usually derived from cell components; the kidneys are almost always affected, giving rise to lupus nephritis ♦♦ Lupus nephritis is classified according to a system published in 1982 under the auspices of the WHO that was revised by the International Society of Nephrology and Renal Pathology Society (ISN/RPS) in 2003

Microscopic ♦♦ There are six morphologic classes in both the WHO and ISN/ RPS schemes (Table 34.3 and Fig. 34.27) ♦♦ The degree of proliferative activity (i.e., class III vs. IV) correlates with more active renal disease and worse outcome

HIV Nephropathy Clinical ♦♦ Human immunodeficiency virus (HIV) nephropathy occurs in 5–10% of patients with HIV infection and occurs more frequently in African Americans

♦♦ Light microscopy −− Swelling and hypertrophy of podocytes with PAS + inclusion droplets (Fig. 34.28) −− Focal segmental glomerulosclerosis and global collapse of the glomerular tufts −− Microcystic, dilated tubules containing hyaline occlusive casts −− Prominent lymphocytic infiltration of the interstitium ♦♦ Electron microscopy −− Tubuloreticular inclusions are often seen in endothelial cells and interstitial leukocytes (Fig. 34.29)

Hereditary Systemic Disorders with Renal Involvement Fabry Disease Clinical ♦♦ Fabry disease (Anderson–Fabry disease, alpha-galactosidase a deficiency, angiokeratoma corporis diffusum universale) is an uncommon disorder caused by an inborn error in the catabolism of glycosphingolipids, resulting in glycosphingo­ lipidosis ♦♦ The central defect is a complete or partial deficiency of a-galactosidase A activity ♦♦ It is inherited as an X-linked disorder and is caused by a variety of mutations in the a-galactosidase gene on the long arm of the X chromosome; it has an incidence of 1:40,000 ♦♦ Diagnosis can be made in the setting of typical skin lesions (angiokeratoma corporis diffusum), corneal dystrophy, and birefringent inclusions in urinary sediment −− Confirmation of the diagnosis is made by measuring the a-galactosidase A activity in peripheral blood leukocytes ♦♦ Renal manifestations include polyuria and polydipsia with a dilute urine −− Proteinuria may be mild and insidious at onset −− Patients eventually progress to renal failure, usually by the time they reach 50 years of age ♦♦ Hemizygous males usually present with the disease as children and heterozygous females may develop a milder form −− Caucasian males with blood ABO types B or AB usually present with more severe disease ♦♦ Treatment is with enzyme replacement

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Table 34.3. Comparison of Classification Systems for Lupus Nephritis WHO classification system (1982) Class I: Normal glomeruli   • Minor glomerular abnormalities by LM   • IA: nil (by all techniques)   • IB: normal by LM but deposits present by EM or IF Class II: Mesangial lupus nephritis   • IIA: mesangial widening and/or mild hyper-cellularity (+)   • IIB: moderate hypercellularity (++) Class III: Focal and segmental proliferative lupus nephritis   • IIIA: active necrotizing lesions   • IIIB: active and sclerosing lesions   • IIIC: sclerosing lesions

Class IV: Diffuse proliferative lupus nephritis   • IVA: without segmental necrotizing lesions   • IVB: with active necrotizing lesions   • IVC: with active and sclerosing lesions   • IVD: with sclerosing lesions

Class V: Diffuse membranous lupus nephritis   • VA: pure membranous lupus nephritis   • VB: associated with lesions of class I   • VC: associated with lesions of class III   • VD: associated with lesions of class IV Class VI: Advanced sclerosing lupus nephritis   • End-stage kidney, usually lacking the specific features of lupus nephritis

Microscopic ♦♦ Light microscopy −− The glomeruli show podocyte swelling with cytoplasmic vacuolization (Fig. 34.30) −− Vacuoles are also present in the cells lining Bowman capsule, endothelial and mesangial cells, and in cells of the distal convoluted tubule and loop of Henle −− With disease progression, the glomeruli undergo segmental and global glomerulosclerosis accompanied by interstitial fibrosis and tubular atrophy ♦♦ Electron microscopy −− Numerous whorled osmiophilic structures (myelin figures and zebra bodies) are present within lysosomes in the cell cytoplasm (Fig. 34.31)

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ISN/RPS classification system (2003) Class I: Minimal mesangial lupus nephritis   • Normal glomeruli by LM, deposits by IF or IF/EM

Class II: Mesangioproliferative lupus nephritis   • Solely mesangial matrix increase or hypercellularity of any degree with mesangial immune deposits Class III: Focal lupus nephritis – <50% of glomeruli involved by endocapillary hypercellularity, crescents, and/or sclerosing lesions (scars)   • Subclassified by activity of lesion    – All lesions are active (A)    – All lesions are chronic/scars (C)    – Mixture of active and chronic lesions (A/C) Class IV: Diffuse lupus nephritis – ³50% of glomeruli involved by endocapillary hypercellularity, crescents, and/or sclerosing lesions (scars)   • Subclassified by degree of involvement of individual glomeruli and activity of lesion (as above)    – Segmental (S): ³50% of involved glomeruli are involved by endocapillary hypercellularity, crescents, and/or sclerosing lesions occupying £50% of the glomerulus    – Global (G): ³50% of involved glomeruli are involved by endocapillary hypercellularity, crescents, and/or sclerosing lesions occupying ³50% of the glomerulus    – All lesions are active (A)    – All lesions are chronic/scars (C)    – Mixture of active and chronic lesions (A/C) Class V: M  embranous lupus nephritis – subepithelial deposits by LM or IF involving >50% of capillary loops of >50% of glomeruli   • Can coexist with class III and IV Class VI: A  dvanced sclerosis lupus nephritis – >90% of glomeruli globally sclerosed with no residual active lesions ­(endocapillary hypercellularity or crescents)

−− Foot processes are generally effaced correlating with the degree of proteinuria −− Myelin figures may be seen within the epithelial cells lining Bowman capsule, endothelial cells, and tubular epithelial cells

Lecithin Cholesterol Acyltransferase (LCAT) Deficiency Clinical ♦♦ An autosomal recessive disorder that results from ­inadequate enzymatic activity of lecithin cholesterol acyltransferase, which is responsible for forming lipoprotein cholesterol esters ♦♦ Clinical features include corneal opacities, anemia, proteinuria, and premature atherosclerosis

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Fig.  34.28. Collapsing glomerulopathy with podocyte prominence in HIV nephropathy on silver stain.

Fig. 34.29. Electron micrograph of endothelial cell tubuloreticular structure in HIV nephropathy.

♦♦ There is no known treatment −− Renal transplantation is of benefit, but does not reverse the lipid abnormalities, and histologic lesions may recur by 6 months posttransplantation Fig. 34.27. Mild mesangial proliferation in class II lupus nephritis on silver stain (A). Segmental proliferation (upper left) in class III lupus nephritis on silver stain (B). Diffuse mesangial and endocapillary proliferation in class IV lupus nephritis on PAS stain (C).

♦♦ Renal involvement is common and almost all patients with renal involvement progress rapidly to chronic renal failure, usually by the fifth decade of life −− Early atherosclerotic vascular disease is a significant cause of morbidity and mortality

Microscopic ♦♦ Light microscopy −− The renal lesion is characterized by mesangial expansion and sclerosis, irregular thickening of the capillary loops with numerous bubbles or holes and foam cells (Fig. 34.32) ♦♦ Electron microscopy −− Electron-dense, lamellar structures are present within the mesangium and capillary walls and are associated with surrounding lucent spaces (Fig. 34.33) −− Podocyte foot process effacement is also present

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Fig. 34.31. Electron micrograph of Fabry disease with whorled podocyte cytoplasmic myelin figures.

Fig. 34.30. Fabry disease with vacuolated podocyte cytoplasm on silver stain (A). Fabry disease with podocyte cytoplasmic inclusions on toluidine blue stained section of plastic embedded tissue (B).

Lipoprotein Glomerulopathy Clinical ♦♦ A rare disorder caused by a mutation in the apoE gene and elevated serum levels of apolipoprotein E, inherited in an autosomal dominant fashion ♦♦ The disorder is seen primarily in those of Asian descent ♦♦ Patients usually present with proteinuria, occasionally in the nephrotic range ♦♦ Many also have mild extrarenal manifestations including hypertension, atherosclerosis, cardiovascular disease, and hepatic dysfunction ♦♦ There is no effective therapy, and the disease recurs in allografts

Microscopic ♦♦ Light microscopy −− Marked dilatation of the glomerular capillaries by a PASnegative “lipid thrombi” (Fig. 34.34)

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Fig. 34.32. LCAT deficiency with mesangial expansion and capillary wall sclerosis on silver stain. ♦♦ Electron microscopy −− The lipid thrombi contain granules and vacuoles forming concentric fingerprint-like lamellae (Fig. 34.35)

Nail–Patella Syndrome Clinical ♦♦ Nail–patella syndrome, or osteo-onychodysplasia, is a hereditary disorder characterized by the following −− Iliac horns or prominent iliac crests (80%) −− Hypoplastic or absence of patellae (60%) and patellar tendons −− Dysplasia of elbows (60–90%)

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Fig. 34.35. Electron micrograph of lipoprotein glomerulopathy showing capillary loops distended by flocculent material with indwelling, vaguely linear lamellae.

Fig. 34.33. Electron micrograph of LCAT deficiency with electron dense lamellar structures in GBM (A). Electron micrograph of LCAT deficiency with lamellar structures in GBM (higher magnification) (B).

−− Fingernail and less commonly toenail dystrophies (80–90%) −− Renal disease (50%) ♦♦ An autosomal dominant disorder with full penetrance and an incidence of approximately 1:50,000 −− The gene is located on chromosome 9 and is closely linked to the ABO blood group and adenylate cyclase loci ♦♦ Most patients with renal disease present with proteinuria, microscopic hematuria, edema, and hypertension −− An abnormal urinary sediment, impaired urinary concentrating ability, and abnormalities in urinary acidification have also been described

Microscopic

Fig.  34.34. Lipoprotein glomerulopathy with pale “lipid thrombi” in capillary loops on a Masson stain.

♦♦ Light microscopy −− The glomeruli are frequently normal in appearance but capillary loop thickening may be apparent −− Mesangial sclerosis, segmental sclerosis, tubular atrophy, and interstitial fibrosis may also be present and correlate with the degree of renal functional impairment ♦♦ Immunofluorescence microscopy −− Generally negative, but nonspecific staining for IgM, C3, or C1q may be present in sclerotic glomerular segments ♦♦ Electron microscopy −− The pathognomonic renal lesion is the finding of multiple mottled and lucent areas within the glomerular basement membrane and less commonly the mesangium (Fig. 34.36) −− These lucent areas contain clusters of collagen fibrils that are best visualized following phosphotungstic acid staining

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♦♦ The acquired forms of generalized lipodystrophy and partial lipodystrophy do not have a heritable basis −− Partial lipodystrophy most often presents in young girls between 5 and 15 years of age −− In addition to lipoatrophy and renal disease, these patients may have some of the symptoms seen in the generalized lipodystrophy group

Microscopic ♦♦ In partial lipodystrophy, the incidence of renal involvement is 15–30%, with dense deposit disease (membranoproliferative glomerulonephritis type II) occurring in 80% and type I MPGN in the remainder ♦♦ Approximately 10% of patients with dense deposit disease have partial lipodystrophy

Hereditary Nephritis ♦♦ The term hereditary nephritis encompasses a heterogeneous group of disorders that have in common microscopic hematuria but differ markedly in clinical course and outcome Fig.  34.36. Electron micrograph of a GBM in a patient with nail–patella syndrome with intramembranous collagen fibril cluster.

Lipodystrophy Clinical ♦♦ A group of uncommon disorders that is classified as to whether the condition is congenital or acquired and partial or generalized, lipodystrophy may be associated with the following −− Hyperinsulinism and insulin resistance −− Hyperlipidemia −− Hyperproteinemia −− Euthyroid hypermetabolism −− Increased basal free fatty acid levels ♦♦ Other manifestations include −− Tall stature −− Muscular hypertrophy −− Hirsutism −− Macroglossia −− Abdominal distention −− Subcutaneous nodules −− Acanthosis nigricans −− Hepatomegaly −− Cirrhosis −− Clitoral or penile enlargement −− Adenopathy −− Neurologic abnormalities ♦♦ In the congenital form, which has an autosomal recessive inheritance pattern, lipoatrophy is present at birth and diabetes mellitus develops in adolescence

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Alport Syndrome Clinical ♦♦ A hereditary disorder of basement membrane collagen that is characterized clinically by hematuria, progressive renal failure, and frequently, hearing loss and ocular abnormalities ♦♦ In most cases, the disease is inherited as an X-linked trait; absence of a family history is noted in 10–15% of patients, and these cases may represent new mutations −− The gene frequency is estimated at 1:5,000–10,000 ♦♦ The X-linked form of Alport syndrome has been shown to be caused by mutations in the gene COL4A5 on chromosome Xq22 encoding for the a5 chain of type IV collagen present in the glomerular basement membrane ♦♦ Microscopic hematuria is present from birth in affected males and has a 93% penetrance in heterozygous females ♦♦ Proteinuria is variable but may reach nephrotic range; hemizygous males inevitably progress to end-stage renal failure; heterozygous females are usually less severely affected ♦♦ Nonrenal features of Alport syndrome include −− Bilateral high-frequency hearing loss −− Ocular defects including lenticonus and retinal flecks −− Leiomyomatosis, particularly leiomyomas of the esophagus and female genital tract

Microscopic ♦♦ Light microscopy −− In the early stages of the disease, the glomeruli may appear entirely normal or may show mesangial widening −− Progression of the disease is characterized by segmental sclerosis and glomerular obsolescence, tubular atrophy, and interstitial fibrosis −− Interstitial foam cells are often present, but this is a nonspecific finding ♦♦ Immunofluorescence microscopy

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−− Direct immunofluorescence microscopy may be normal or there may be nonspecific deposition of IgM and C3 in sclerotic glomerular segments ♦♦ Electron microscopy −− The characteristic ultrastructural changes of the glomerular basement membranes include of both thickening and thinning, and in early cases, this may be the only abnormality (Fig. 34.37) −− The lamina densa is replaced by irregular lamellae and fragmented strands of lamina densa-like material −− The extent of lamellation and fragmentation of the lamina densa in the glomeruli is variable, ranging from involvement of short segments to widespread involvement in severely affected cases

Microscopic

Thin Glomerular Basement Membrane Syndrome Clinical

♦♦ The term congenital nephrotic syndrome is used to describe infants who develop nephrotic syndrome at birth or before 3 months of age ♦♦ Infantile nephrotic syndrome describes infants with a later onset of nephrotic syndrome (4–12 months of age) ♦♦ Causes of congenital and infantile nephrotic syndrome are listed in Table 34.4

♦♦ Familial thin glomerular basement membrane syndrome, or benign recurrent hematuria, is an autosomal dominant basement membrane glomerulopathy characterized by a glomerular basement membrane that is uniformly thinned to approximately half of the normal thickness ♦♦ Some cases consistent with autosomal recessive inheritance have been reported ♦♦ The overall incidence is not known; however, it is relatively common (20%) in patients with hematuria ♦♦ Patients present with continuous or intermittent microscopic hematuria usually in childhood but rarely as an adult ♦♦ Episodic gross hematuria may occur and is usually concurrent with an upper respiratory infection (“synpharyngitic hematuria”) ♦♦ A distinction must be made between thin glomerular basement membrane syndrome and Alport syndrome −− This is usually accomplished by the lack of renal insufficiency, sensorineural hearing loss, and ocular abnormalities that characterize Alport syndrome

Fig.  34.37. Electron micrograph of Alport syndrome with a lamellated and variably thickened GBM.

♦♦ Light microscopy −− The glomeruli appear normal and the tubules contain red blood cells ♦♦ Electron microscopy −− The glomerular capillary loop basement membranes show focal and segmental or diffuse thinning of the lamina densa (<200 mm in an adult, <180 mm in children 2–10 years old) (Fig. 34.38) −− The inner and outer contours of the glomerular basement membrane are smooth with no disruption or lamellation

Congenital and Infantile Nephrotic Syndrome

Congenital Nephrotic Syndrome of the Finnish Type Clinical ♦♦ Described worldwide (although the highest incidence is in Finland) with a gene frequency of 1:200 and an incidence of 1.2:10,000 live births ♦♦ Both sporadic and autosomal dominant forms occur and diagnosis is based on family history, perinatal presentation, placental size, and renal pathology ♦♦ Common clinical and gestational findings include −− Unremarkable pregnancy except for elevated alpha-fetoprotein at week 16–20 −− Premature delivery (usually 35–38 weeks) −− Small for gestational age

Fig.  34.38. Electron micrograph of thin glomerular basement membrane nephropathy with uniformly thinned GBM.

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Table 34.4. Causes of Congenital and Infantile Nephrotic Syndrome Include Congenital nephrotic syndrome

Infantile nephrotic syndrome

Primary   Finnish-type   Diffuse mesangial sclerosis   Minimal change disease  Focal segmental glomerulosclerosis   Mesangial proliferative GN   Membranous GN

Primary   Minimal change disease  Focal segmental glomerulosclerosis   Mesangial proliferative GN   Membranous GN   Diffuse mesangial sclerosis

Secondary   Drash syndrome    Diffuse mesangial    sclerosis   Membranous GN    Syphilis   Systemic lupus erythematosus   Toxoplasmosis   Nail–patella syndrome   Hemolytic uremic syndrome

Secondary   Membranous GN    Syphilis    Fanconi syndrome   Proliferative GN    Syphilis    Cytomegalovirus  Alpha 1-antitrypsin deficiency   Mercury poisoning   Drash syndrome    Diffuse mesangial sclerosis   Hemolytic uremic syndrome

−− −− −− −− −−

Breech presentation is more common Low Apgar score including asphyxia Meconium staining (more common) Large placenta, 25% greater than infant in weight Classic appearance (may be in part due to loss of thyroid binding globulin in urine)

(a) Low bridged nose (b) Wide cranial sutures (c) Large fontanelles (d) Delayed ossification (e) Flexion deformities of the extremities ♦♦ Signs of renal disease develop in the first 3 months of life and include massive proteinuria detectable at birth that is resistant to corticosteroids and immunosuppression ♦♦ The pathogenesis is not well understood but assumed to be the result of a hereditary error in glomerular basement membrane metabolism that is expressed early in gestation (16–18 weeks)

Microscopic ♦♦ Light microscopy −− The glomeruli show mesangial proliferation, dilatation of Bowman space, and presence of microcysts in the cortical tubules (Fig. 34.39) −− Scattered microglomeruli may also be found

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Fig.  34.39. Focal proximal tubule microcysts in congenital nephrotic syndrome.

♦♦ Electron microscopy −− Diffuse podocyte foot process effacement, microvillous transformation, and mesangial expansion; no immune deposits are present −− The capillary loop basement membranes show widening of the lamina rara interna and focal splitting and thinning of the lamina densa

Diffuse Mesangial Sclerosis Clinical ♦♦ Unlike congenital nephrotic syndrome of the Finnish type, diffuse mesangial sclerosis is not associated with premature birth, low birth weight, or placental enlargement ♦♦ Most patients present between 3 and 11 months of age with proteinuria, renal insufficiency, and rapid progression to end-stage renal failure, usually within 6 months of onset ♦♦ Approximately 25% of cases are associated with male psuedohermaphroditism, Wilms tumor, and nephropathy – a constellation of features referred to as the Denys– Drash syndrome which appears to be the result of a defect involving the WT1 tumor suppressor gene on chromosome 11p13

Microscopic ♦♦ Light microscopy −− The early glomerular lesion is characterized by an increase in mesangial matrix without hypercellularity −− Later, the glomerular tuft becomes an avascular sclerotic mass surrounded by a layer of podocytes, often accompanied by a dilated Bowman space −− The tubules show marked ectasia with attenuation of the epithelium and eosinophilic hyaline casts in the lumens −− A zonal distribution of lesions has been described

Nonneoplastic Renal Diseases

♦♦ Electron microscopy −− The glomeruli show podocyte damage characterized by diffuse effacement of foot processes, microvillous transformation, and pseudocyst formation

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−− The glomerular basement membranes show thickening, collapse, subendothelial and subepithelial widening, and splitting and lamellation of foci of lamina densa

TUBULOINTERSTITIAL DISEASES OF THE KIDNEY Acute Infectious Pyelonephritis (Ascending or Hematogenous Infection) ♦♦ Acute infectious pyelonephritis is rarely seen grossly except at autopsy

Macroscopic ♦♦ The kidney may be enlarged with a bulging cut surface ♦♦ Microabscesses may be present in the cortex, studding the subcapsular surface of the kidney (Fig. 34.40) ♦♦ The cut section of the kidney demonstrates pus-filled collecting ducts that extend into the underlying medulla ♦♦ The pelvicaliceal system is dilated and the renal papillae are diffusely blunted, with an inflamed mucosal lining

♦♦ Coarse U-shaped cortical and medullary scars are situated over dilated calices ♦♦ Staghorn calculi may complicate and contribute to obstruction (Fig. 34.42)

Chronic Nonobstructive Pyelonephritis (Reflux Nephropathy) ♦♦ Results from reflux of urine from the bladder into the ureter and renal pelvis

Microscopic ♦♦ There is a dense interstitial and intratubular infiltrate of acute inflammatory cells with tubular destruction (Fig. 34.41)

Chronic Pyelonephritis Chronic Obstructive Pyelonephritis ♦♦ May be caused by obstruction of the ureter by calculi (stones), tumor within the ureter, or extrinsic compression

Macroscopic ♦♦ The kidney shows pelvicaliceal dilatation and parenchymal thinning, with blunting of papillae

Fig.  34.40. Acute pyelonephritis with numerous cortical abscesses.

Fig.  34.41. Acute pyelonephritis with tubular dilatation and intraluminal neutrophils.

Fig.  34.42. Chronic pyelonephritis with calyceal blunting and calculi.

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Macroscopic ♦♦ Morphologically, it is characterized by coarse, sharply demarcated segmental scarring overlying dilated calices (Fig. 34.43) ♦♦ The kidney may be reduced in size, and process may involve one kidney ♦♦ Scarring is more prominent and extensive at the poles of the kidney

Microscopic ♦♦ Characterized by tubular atrophy, interstitial fibrosis, chronic inflammation, and periglomerular fibrosis ♦♦ Secondary focal segmental glomerulosclerosis has been associated with reflux nephropathy

Essentials of Anatomic Pathology, 3rd Ed.

−− Immune-mediated (antitubular basement membrane antibody) (a) A subtype is associated with elevated serum IgG4 levels and an increase in interstitial IgG4-positive inflammatory cells (Figs. 34.44 and 34.45) – it is associated with other IgG4-related sclerosing conditions including autoimmune pancreatitis, autoimmune cholangitis, retroperitoneal fibrosis, sialadenitis, and inflammatory pseudotumor at various sites

Microscopic ♦♦ The interstitium contains an infiltrate of mixed inflammatory cells composed predominantly of lymphocytes with admixed plasma cells and usually eosinophils (Fig. 34.46) ♦♦ Interstitial edema and tubulitis are also present

Acute Tubulointerstitial Nephritis ♦♦ An acute inflammatory disease involving the renal tubules and interstitium; glomeruli and vessels are generally spared ♦♦ Acute pyelonephritis is a form of acute tubulointerstitial nephritis; however, a number of other etiologic agents have been identified ♦♦ The most common causes of noninfectious acute interstitial nephritis include −− Drug exposure (a) Diuretics (b) Antibiotics (c) Phenytoin (d) Phenobarbital (e) Probenicid (f) Allopurinol (g) Cimetidine (h) Nonsteroidal anti-inflammatory agents −− Miscellaneous (a) Sarcoidosis (b) Lymphoma (c) Leukemia

Fig. 34.43. Reflux nephropathy with calyceal dilatation and cortical thinning at renal poles.

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Fig. 34.44. IgG4-related tubulointerstitial nephritis demonstrating marked tubular damage with abundant mononuclear cells, eosinophils, and plasma cells.

Fig. 34.45. Numerous interstitial inflammatory cells are positive for an immunoperoxidase stain for IgG4 in IgG4-related tubulointerstitial nephritis.

Nonneoplastic Renal Diseases

Fig.  34.46. Acute tubulointerstitial nephritis with interstitial edema and mixed inflammatory cell infiltrate. ♦♦ Granulomatous forms of intersititial nephritis also occur and are most commonly drug-related

Acute Tubular Necrosis (ATN) Ischemic Injury ♦♦ May complicate a number of primary disorders, many of which are associated with circulatory shock and hypovolemia ♦♦ Other conditions causing acute tubular injury include −− Extensive trauma and burns −− Pancreatitis −− Incompatible blood transfusions −− Dehydration following diarrhea, vomiting, and excessive sweating −− Rhabdomyolysis −− Septicemia −− Hemolysis ♦♦ The straight segment of the proximal tubule is most vulnerable to ischemia

Microscopic (Fig. 34.47) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Tubular dilatation Single cell necrosis with desquamation Loss of the proximal tubule brush border Pigmented (brown) casts in distal tubules Crystals in distal tubules and collecting ducts Mild interstitial edema and inflammation Accumulation of leukocytes in the vasa recta

Nephrotoxic Injury ♦♦ Defined as acute renal failure caused by a dose-dependent toxic renal injury ♦♦ Causes include −− Antimicrobials (a) Aminoglycosides (b) Tetracyclines

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Fig.  34.47. Acute tubular necrosis with tubular epithelial cell attenuation and intraluminal debris. (c) Amphotericin (d) Polymyxin (e) Cephalosporins −− Heavy metals (a) Mercury (b) Lead (c) Arsenic (d) Gold salts (e) Barium −− Miscellaneous (a) Cisplatin (b) Doxorubicin (c) Streptozocin (d) Methoxyflurane (e) Halothane (f) Heat stroke (g) Ethylene glycol (h) Carbon tetrachloride (i) Radiographic contrast agents (j) Myoglobinemia (k) Transfusion reactions (l) Snake and spider bites

Oxalate Nephropathy Clinical ♦♦ Oxalate nephropathy is often associated with calcium oxalate nephrolithiasis and is seen in the setting of elevated urine oxalate or decreased urine citrate levels ♦♦ Deposition of calcium oxalate within the kidney is caused by −− Ethylene glycol intoxication −− Crohn disease −− Small bowel bypass procedures −− Primary hyperoxaluria

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Fig.  34.48. Oxalate nephropathy with polarizable intratubular crystals.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 34.49. Intratubular calcium phosphate crystals in phosphate nephropathy highlighted by a Von Kassa stain.

♦♦ May present with acute renal failure (ethylene glycol) or chronic progressive renal insufficiency

Microscopic ♦♦ Acutely, acute tubular injury is evident with intraluminal polarizable crystals in tubules (Fig. 34.48) ♦♦ In longstanding disease, there may be variable tubular atrophy and interstitial fibrosis

Phosphate Nephropathy (PN) Clinical ♦♦ PN is associated with sodium phosphate-containing bowel cleansing agents often used in preparation for colonoscopies ♦♦ The exact incidence is unknown, but some studies suggest that up to 5% of patients show evidence of renal dysfunction after administration ♦♦ It can cause acute renal failure within hours or days after administration, or incidentally discovered azotemia weeks or months later ♦♦ PN may lead to progressive renal damage with very few patients returning to baseline renal function

Microscopic ♦♦ Basophilic, nonpolarizable calcium phosphate deposits are usually seen within tubular lumina, tubular epithelial cells, and less commonly within the interstitium. Von Kassa stains highlights the crystals (Fig. 34.49) ♦♦ Early biopsies may show acute tubular injury with varying degrees of interstitial fibrosis, and tubular atrophy becomes evident later

Light Chain Cast Nephropathy (Myeloma Kidney) ♦♦ Results from the overproduction of immunoglobulins or fragments of immunoglobulins (light chains) by a clone of malignant B-cells (plasma cells)

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Fig. 34.50. Light chain cast with associated giant cell reaction.

♦♦ Filtration of excessive light chains can cause direct toxic damage to renal tubular cells, and tubular obstruction from cast formation

Microscopic ♦♦ The term “myeloma kidney” or “cast nephropathy” refers to renal damage that occurs as a result of formation of large numbers of light chain PAS-negative casts, primarily in the distal tubules ♦♦ These casts incite a giant cell inflammatory reaction within the tubules that may cause tubular degeneration and extend into the interstitium (Fig. 34.50) ♦♦ Volume depletion predisposes to the formation of light chain casts

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VASCULAR DISEASES OF THE KIDNEY Benign Nephrosclerosis ♦♦ Estimates suggest that 15–25% of adults in the United States are hypertensive ♦♦ More than 90% of individuals with persistently elevated blood pressure are classified as having essential hypertension

Macroscopic ♦♦ The kidneys are usually normal to slightly smaller than normal and may be markedly reduced in size in long-standing cases ♦♦ The subcapsular surface is finely granular and the capsule is often adherent (Fig. 34.51) ♦♦ The cut surface reveals thinning of the cortex and v-shaped subcapsular scars

Microscopic

Fig. 34.51. Essential hypertension with finely granular cortical surface.

♦♦ The areas of scarring show varying degrees of glomerular ischemic wrinkling and hyalinization, tubular atrophy, and interstitial fibrosis ♦♦ Arterioles show hyaline deposits (hyaline arteriolosclerosis). Larger arteries display intimal thickening and subendothelial fibrosis with elastic fragmentation/reduplication and focal lipid deposits (Fig. 34.52)

Malignant Nephrosclerosis ♦♦ Malignant hypertension (papilledema in the presence of systolic and diastolic blood pressures of >220  mmHg and >120  mmHg, respectively) develops in 1–7% of hypertensive individuals ♦♦ Approximately 50% of patients with malignant hypertension have a history of essential hypertension, and only 1–2% develop the disease de novo

Fig.  34.52. Essential hypertension with segmental arteriolar hyaline deposition.

Microscopic ♦♦ The features are similar to those seen in thrombotic microangiopathy (see later) ♦♦ The glomeruli show wrinkling and duplication of the capillary loop basement membranes and fibrinoid necrosis of the vascular pole ♦♦ The blood vessels show concentric proliferative endarteritis in small arteries and arterioles (“onion-skinning,” Fig. 34.53), arteriolar necrosis, and mucoid intimal thickening of mediumsized and small arteries

Renovascular Hypertension (Renal Artery Stenosis) ♦♦ Defined as stenotic lesions of the main or segmental renal arteries inducing chronically elevated blood pressure that normalizes after correction of the stenosis ♦♦ Approximately two-thirds of renovascular hypertension in adults is due to atherosclerosis, which affects more men than women

Fig. 34.53. Malignant/accelerated hypertension with prominent concentric intimal fibrosis and luminal narrowing.

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Fig. 34.54. Atherosclerosis with large arterial plaque.

♦♦ Fibromuscular dysplasia accounts for approximately 25% of cases and is the most common cause of renovascular hypertension in young people and is found predominantly in young women

Atherosclerosis ♦♦ Atherosclerotic stenosis of the renal artery is usually located in the proximal renal artery and involves the renal artery ostia in 50% of patients

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 34.55. Medial fibroplasia form of fibromuscular dysplasia with interrupted intimal fibrosis. (a) Increased medial smooth muscle cells with little fibrosis (b) Medial dissection −− Associated with the above forms of fibromuscular dysplasia −− Adventitial fibroplasia (<1%) (a) Adventitial proliferation of fibrous connective tissue (b) May be related to retroperitoneal fibrosis

Microscopic

Thromboembolic Diseases

♦♦ The involved segments of the renal artery are narrowed by an eccentric plaque that is characterized by subendothelial intimal thickening overlying cell debris, lipid, cholesterol clefts, and foam cells (Fig. 34.54) ♦♦ Medial and adventitial fibrosis may also be present. The atherosclerotic plaque may be complicated by hemorrhage and dissection ♦♦ Calcification and osseous metaplasia may occur

♦♦ Vascular occlusion producing infarction of the renal parenchyma is relatively rare ♦♦ Thrombosis of major vessels as a consequence of trauma is more common in younger individuals; occlusion as a complication of atherosclerotic vascular disease is more often seen in older persons ♦♦ Emboli in the renal artery or one of its major branches is the most common cause of renal artery obstruction and occurs predominantly in the setting of cardiac disease and arrhythmias ♦♦ Cholesterol atheroemboli from peripheral vessels, thrombotic microangiopathy, and sickle cell disease are causes of small vessel occlusion

Fibromuscular Dysplasia (FMD) ♦♦ Patients with fibromuscular dysplasia are younger (mean age of 35 years) and are predominantly women ♦♦ FMD typically affects the distal two-thirds of the renal artery and may be bilateral ♦♦ There are intimal, medial, and adventitial forms of fibromuscular dysplasia −− Intimal fibroplasia (10%) −− Medial fibroplasia (75–80%) (a) Affects distal portion of artery (b) Aneurysmal dilatations (c) Often bilateral (d) Fibromuscular ridges alternate with a thinned media (Fig. 34.55) −− Perimedial fibroplasia (10–15%) (a) Circumferential fibrosis of the outer third of the media (b) Affects women in second and third decades (not men) −− Medial hyperplasia (1–2%)

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Cortical Infarcts ♦♦ Sudden complete occlusion of the main renal artery results in infarction of much of the renal parenchyma; occlusion of smaller renal artery branches results in necrosis of wedgeshaped segments of the renal parenchyma

Macroscopic ♦♦ The infarcted kidney appears enlarged and pale ♦♦ Regions of segmental infarction are pale, with a hyperemic border (Fig. 34.56)

Microscopic ♦♦ The infarct shows coagulation necrosis with adjacent parenchyma showing changes of acute tubular necrosis ♦♦ Hemorrhage and acute inflammation are often present at the edge of the infarct, and there may be a rind of better preserved

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Fig. 34.56. Pale, wedge-shaped cortical infarct. parenchyma, which is supplied by penetrating capsular vessels, overlying the infarct ♦♦ Within days to weeks, the infarct becomes fibrotic with eventual shrinkage of the affected parenchyma −− This area contains dense, globally sclerotic glomeruli with intervening dense fibrous tissue and characterized by tubule loss. The adjacent parenchyma may show tubular atrophy and varying degrees of glomerular sclerosis

Fig. 34.57. Cholesterol clefts in arterial atheroembolus.

Renal Cholesterol Microembolism Syndrome Clinical ♦♦ Can occur spontaneously or as a complication of aortic instrumentation in patients with diffuse atherosclerosis ♦♦ The condition may be diagnosed clinically when renal failure develops following identifiable predisposing factors and/ or when there is evidence of systemic involvement in the form of focal digital ischemia, retinal embolism, and lower extremity livedo reticularis

Microscopic ♦♦ The characteristic renal lesion in disseminated cholesterol microembolism syndrome is the finding of atheromatous material in the form of cholesterol clefts within arcuate and interlobular arteries (Fig. 34.57)

Thrombotic Microangiopathy Clinical ♦♦ Encompasses a group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombi −− Hemolytic uremic syndrome (HUS) −− Thrombotic thrombocytopenic purpura (TTP) −− Disseminated intravascular coagulation (DIC, shows fibrinolysis) −− Malignant hypertension −− Scleroderma −− Pregnancy-associated −− Therapy-associated −− Chronic transplant glomerulopathy

Fig.  34.58. Acute thrombotic microangiopathy with luminal fibrin and mesangiolytic change (A). Chronic thrombotic microangiopathy with subendothelial lucency and GBM duplication (B).

Morphologic Features (Fig. 34.58) ♦♦ Thickening of capillary walls with the formation of “double contours” ♦♦ Capillary thrombosis ♦♦ Fragmented red blood cells

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♦♦ Mesangiolysis with microaneurysm formation ♦♦ Fibrinoid change may occur in arterioles ♦♦ Mucoid intimal thickening of small and medium-sized arteries with glomerular ischemia

Vasculitis ♦♦ Vasculidites can be classified by the Chapel Hill Classification System based on the size of vessel that is predominately affected and clinical features −− Large vessel (aorta and large branches): giant cell arteritis and Takayasu arteritis −− Medium vessel (muscular arteries): polyarteritis nodosa and Kawasaki disease −− Small vessel (arterioles, capillaries, and venules): Wegener granulomatosis, Churg–Strauss syndrome, microscopic polyangiitis, leukocytoclastic vasculitis ♦♦ The kidney is most often affected by small vessel disease, typically characterized by pauci-immune necrotizing and crescentic glomerulonephritis (Fig. 34.59) ♦♦ Renal disease is often associated with other stigmata of systemic vasculitis but may be diagnosed in isolation ♦♦ Most pauci-immune crescentic glomerulonephritis is associated with a detectable level of serum anti-neutrophil cytoplasmic antibodies (ANCA) −− The antibodies may be subclassified by their staining pattern on immunofluorescence assay and the type is related to clinical syndromes: c-ANCA (cytoplasmic staining, anti-proteinase 3) and p-ANCA (perinuclear staining, anti-myeloperoxidase). Wegener granulomatosis >90% of cases (typically c-ANCA) Microscopic polyangiitis >90% (typically p-ANCA) Churg–Strauss syndrome 50–60% (typically p-ANCA) Idiopathic (isolated) >90% (c-ANCA or p-ANCA)   crescentic glomerulo-­   nephritis Polyarteritis nodosa 0–20% (often p-ANCA when   present)

Fig.  34.59. Necrotizing and crescentic glomerulonephritis in systemic vasculitis.

♦♦ Wegener granulomatosis is a necrotizing, granulomatous vasculitis that classically involves the kidney, upper, and lower respiratory tract. Other sites such as the eyes, ears, heart, nervous system, skin, and joints are less commonly affected ♦♦ Renal disease is present in most patients, usually manifesting as acute nephritic syndrome with renal functional impairments ranging from mild to overt renal failure ♦♦ Churg–Strauss syndrome is associated with asthma and peripheral eosinophilia. A prominent population of interstitial eosinophils can be present along with the necrotizing and crescentic glomerulonephritis ♦♦ Microscopic polyangiitis is not associated with the above clinical features and is often a diagnosis of exclusion ♦♦ Polyarteritis nodosa (as it is now defined) typically involves the branch points of renal, interlobar and arcuate arteries causing aneurysmal dilatation, occasionally leading to focal infarction. Necrotizing glomerulonephritis is seen uncommonly

DEVELOPMENTAL AND CYSTIC DISEASES OF THE KIDNEY Renal Dysplasia Clinical ♦♦ A developmental abnormality that results from aberrant metanephric differentiation ♦♦ Although the exact pathogenesis is unknown, possibilities include in utero urinary tract obstruction and a defect in inducer, the ampullary bud, responder tissue, or metanephric blastema ♦♦ Renal dysplasia occurs sporadically and may be associated with obstruction, multi-malformation syndromes (Meckel syndrome), chromosomal anomalies (trisomy 9 or 13), or

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♦♦

♦♦ ♦♦ ♦♦

hereditary malformation syndromes (chondrodysplasia syndromes) Unilateral multicystic renal dysplasia is the most common cause of a renal mass in childhood; bilateral lesions may present in utero or shortly after birth with oligohydramnios and Potter sequence Adults are usually asymptomatic but may have flank pain or a nonfunctioning small kidney The prognosis depends on the extent of dysplasia if bilateral, and the function of the contralateral kidney if unilateral The recurrence rate in siblings is approximately 2% but may be much greater in syndromic dysplasias

Nonneoplastic Renal Diseases

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Fig. 34.61. Renal dysplasia with architectural disarray and focal cartilage.

Fig. 34.60. Multicystic renal dysplasia.

Macroscopic ♦♦ Dysplastic kidneys may be unilateral or bilateral, large or small, reniform or irregular, and solid or cystic (Fig. 34.60)

Microscopic ♦♦ The overall architecture is disorganized. There may be primitive ducts, tubules, aberrant glomeruli, and cysts lined by flattened epithelium, all surrounded by immature mesenchymal tissue. Islands of immature cartilage may be seen, as well as relatively normal tubules and glomeruli (Fig. 34.61)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical ♦♦ The most common cystic renal disease, with an estimated frequency between 1:500 and 1:1,000 and with nearly complete penetrance ♦♦ Occurs slightly more frequently in Caucasians than in African Americans ♦♦ There is some genetic heterogeneity but approximately 85% of cases in Caucasians are associated with a defect in the PKD1 gene on chromosome 16p ♦♦ The disease course is variable, ranging from cases that are fatal in newborns to cases with minimal functional disturbance at old age; 25% of patients lack a family history ♦♦ In children, the process may be nonuniform, and the patient may appear to have a unilateral lesion early in the course ♦♦ Most patients present in the third or fourth decade with dull abdominal pain and bilaterally palpable kidneys, as well as variable renal insufficiency, gross or microscopic hematuria, hypertension, infection, and mild proteinuria

Fig. 34.62. Autosomal dominant polycystic kidney disease with irregular renal enlargement and numerous parenchymal cysts.

−− Other associated manifestations include cardiac abnormalities, congenital intracranial aneurysms (10–36%), and cysts of the liver, lungs, pancreas, and spleen ♦♦ Renal failure occurs in 50% of patients an average of 10 years after clinical detection ♦♦ Patients with ADPKD account for 10% of patients in the United States on dialysis and 6% of renal transplants

Macroscopic ♦♦ The kidneys are large, ranging from 250 to 4,000 g, and usually maintain a somewhat reniform shape ♦♦ Variable numbers of spherical, unilocular cysts are present within the cortex and medulla (Fig. 34.62) ♦♦ The calices, pelvis, and papilla are often greatly distorted

Microscopic ♦♦ Only 1–2% of the nephrons show cystic dilation of primarily the collecting tubules, proximal convoluted tubules, and Bowman space interspersed with normal or compressed renal parenchyma

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♦♦ The cysts may demonstrate focal hyperplasia of the epithelial lining and polyp formation ♦♦ Renal cell carcinoma may also occur

Autosomal Recessive Polycystic Kidney Disease (ARPKD) Clinical ♦♦ Occurs in 1/6,000–1/14,000 live births and has a 2:1 female predominance ♦♦ The pathogenesis is related to mutations in the PKHD1 gene on chromosome 6 ♦♦ The clinical presentation is variable depending on the extent and duration of disease −− Many affected newborns have severe disease with a grossly enlarged abdomen, kidneys, and signs of oligohydramnios (pulmonary hypoplasia, flattened nose, low set ears, micrognathia, hip dislocation). In the first days of life, these neonates develop fatal respiratory distress, congestive heart failure, and hypertension −− Older children and adults show a variable course with approximately 30% having an insidious onset of renal failure, which is often associated with anemia, renal osteodystrophy, growth retardation, hypertension, and congestive heart failure ♦♦ The disease is associated with hepatic ductal plate abnormalities and congenital hepatic fibrosis. There is an inverse relationship between the extent of renal cystic change and the extent of hepatic fibrosis ♦♦ Older patients have a smaller number of large cysts with marked, progressive hepatic fibrosis; although liver function is usually well maintained, severe portal hypertension, hepatosplenomegaly, and esophageal varices may develop by 5–10 years of age

Macroscopic ♦♦ The renal capsule is smooth with numerous 1–2  mm cysts visible ♦♦ On sectioning, the cysts are 1–8 mm, cylindrical, and extend radially throughout the cortex, obscuring the corticomedullary junction (Fig. 34.63) ♦♦ In older patients, the surface becomes irregular

Microscopic ♦♦ In the younger patient, the kidney is almost entirely composed of dilated terminal branches of the collecting ducts; these appear cylindrical in the cortex and round to oval within the medulla −− The cysts are lined by cuboidal epithelium, which may have foci of hyperplasia or polyp formation −− The glomeruli and proximal nephron may be compressed but are otherwise unremarkable ♦♦ In older patients, the cysts are fewer in number but are larger and are associated with tubular atrophy, interstitial fibrosis, and glomerular sclerosis

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Fig. 34.63. Autosomal recessive polycystic kidney disease with uniform renal enlargement and small, cylindrical, radially oriented cysts.

−− The hepatic lesion is diffuse but is limited to the portal triads, where there is variable fibrosis and increased numbers of irregularly shaped bile ducts

Juvenile Nephrophthisis/Medullary Cystic Disease Clinical ♦♦ Juvenile nephronophthisis and medullary cystic disease are part of a complex of progressive renal diseases affecting children and young adults characterized by nephrosclerosis, renal failure, and medullary cysts ♦♦ They often have a similar morphology and clinical picture, differing only in the pattern of inheritance (sporadic, autosomal recessive, or autosomal dominant) −− Cases in children are often called “juvenile nephrophthisis,” frequently autosomal recessive, and associated with abnormalities in several genes (NPH1–7) −− Adult cases are usually classified as “medullary cystic disease,” often autosomal dominant in inheritance, and have been linked to mutations in MCKD1 and MCKD2 genes ♦♦ Clinical presentation usually occurs between 5 and 35 years of age with anemia, polyuria, enuresis, and polydipsia secondary to the decreased concentrating ability of the tubules ♦♦ Occasionally, patients will present with associated abnormalities of the retina, skeletal, or central nervous system ♦♦ Proteinuria, hematuria, infection, stone formation, and pain are not usually present

Macroscopic ♦♦ The kidneys in medullary cystic disease are symmetrically small and firm with a finely granular surface. On sectioning, the cortex and medulla are thin and the corticomedullary junction is indistinct; the medulla contains a variable number of cysts (Fig. 34.64)

Nonneoplastic Renal Diseases

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Fig. 34.65. Acquired renal cystic disease with cortical cysts and cortical atrophy. Fig. 34.64. Medullary cystic disease with cysts near corticomedullary junction.

♦♦ The cysts form primarily from the proximal convoluted tubules and are associated with multiple small diverticula elsewhere in the tubule

Microscopic

Macroscopic

♦♦ There is severe, widespread tubular atrophy and interstitial fibrosis with diffuse thickening of the basement membranes and scattered sclerotic glomeruli ♦♦ The cysts are lined by cuboidal to flattened epithelium with surrounding fibrosis and inflammation

Acquired Renal Cystic Disease Clinical ♦♦ Affects patients on hemodialysis and peritoneal dialysis, as well as azotemic nondialyzed patients ♦♦ Cysts develop in 35–47% of patients on maintenance hemodialysis and development appears to be dependent on the duration of dialysis ♦♦ Acquired cysts occur in as many as 92% of patients who have been dialyzed more than 8 years ♦♦ Cyst formation is three to four times more common in males ♦♦ Most patients have no symptoms referable to the cysts but may present with renal bleeding or pain

♦♦ Overall, the kidneys are variable in size, but are usually of equal size in a single patient ♦♦ The kidneys contain a variable number of clear, fluidfilled cysts with some having a few large subcapsular cysts and others having numerous small cysts scattered throughout the parenchyma (Fig. 34.65) ♦♦ The cysts can be uni- or multilocular and mainly involve the cortex but can also affect the corticomedullary junction and medulla. Often there is evidence of acute or past hemorrhage

Microscopic ♦♦ The kidneys show end-stage renal disease with sclerotic glomeruli, tubular atrophy, and interstitial fibrosis ♦♦ Calcifications, hemosiderin, and arterial intimal and medial hyperplasia may also be present ♦♦ The cysts are lined by flattened to cuboidal epithelium and may contain deposits of calcium oxalate ♦♦ There is an increased incidence of renal cell carcinoma, particularly papillary renal cell carcinoma, in patients with endstage renal failure and acquired cystic disease

SUGGESTED READING Chang MY, Ong AC. Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and treatment. Nephron Physiol 2008; 108(1):1–7. Cornell LD, Chicano SL, Deshpande V, et al. Pseudotumors due to IgG4 immune complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease. Am J Surg Pathol 2007;31:1586–1597. D’Agati VD. The spectrum of focal segmental glomerulosclerosis: new insights. Curr Opin Nephrol Hypertens 2008;17(3):271–281.

de Lind van Wijngaarden RA, Hauer HA, Wolterbeek R, et al. Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: a prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol 2006;17(8):2264–2274. Fabrizi F, Colucci P, Ponticelli C, Locatelli F. Kidney and liver involvement in cryoglobulinemia. Semin Nephrol 2002;22(4):309–318. Greenberg A. Primer on Kidney Diseases. National Kidney Foundation. San Diego, CA: Academic Press; 1998.

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Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337(21): 1512–1523. Jennette JC, Olson JL, Schwartz MM, Silva FG. Heptinstall’s Pathology of the Kidney. Philadelphia PA: Lippincott, Williams, and Wilkins; 2007. Mazzucco G, De Marchi M, Monga G. Renal biopsy interpretation in Alport syndrome. Semin Diagn Pathol 2002;19(3):133–145. Narula N, Gupta S, Narula J. The primary vasculitides: a clinicopathologic correlation. Am J Clin Pathol 2005;124:S84–95. Pozzi C, Locatelli F. Kidney and liver involvement in monoclonal light chain disorders. Semin Nephrol 2002;22(4):319–330.

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Sakatsume M, Kadomura M, Sakata I, et al. Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity. Kidney Int 2001;59:1911–1918. Savige J, Rana K, Tonna S, et al. Thin basement membrane nephropathy. Kidney Int 2003;(4):1169–1178. Steinman TI, Samir AE, Cornell LD. Case 27-2008: a 64-year old man with abdominal pain, nausea, and an elevated creatinine. N Engl J Med 2008;359:951–960. Weening JJ, D’Agati VD, Scwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythmatosus revisited. J Am Soc Nephrol 2004;15:241–250.

35 Tumors of the Kidney Gregory T. MacLennan, md and Liang Cheng, md

contents

I. Renal Neoplasms in Children.............35-2 Nephrogenic Rests and Nephroblastomatosis...................................35-2 Nephroblastoma (Wilms Tumor)....................35-2 Cystic Partially Differentiated Nephroblastoma...........................................35-5 Congenital Mesoblastic Nephroma (CMN)........................................35-5 Clear Cell Sarcoma of Kidney (CCSK)..........35-7 Rhabdoid Tumor of Kidney............................35-8

II. Renal Neoplasms in Adults.................35-9 Papillary Adenoma...........................................35-9 Oncocytoma......................................................35-9 Renal Cell Carcinoma (RCC)........................35-10 Clear Cell Renal Cell Carcinoma........................................35-10 Multilocular Cystic Renal Cell Carcinoma................................35-13 Papillary Renal Cell Carcinoma.........35-14 Chromophobe Renal Cell Carcinoma........................................35-16 Collecting Duct Carcinoma.................35-17 Renal Medullary Carcinoma...............35-17

Mucinous Tubular and Spindle Cell Carcinoma................................35-19 Tubulocystic Carcinoma......................35-19 Clear Cell Papillary Renal Cell Carcinoma........................................35-20 Renal Cell Carcinoma, Unclassified....35-20 Metanephric Neoplasms................................35-20 Metanephric Adenoma.........................35-20 The Metanephric Tumor Family.........35-22 Mesenchymal Neoplasms...............................35-22 Renomedullary Interstitial Cell Tumor (Medullary Fibroma)..........35-22 Angiomyolipoma (AML)......................35-23 Juxtaglomerular Cell Tumor...............35-24 Mixed Epithelial/Renal Parenchymal Neoplasms..................................................35-25 Cystic Nephroma..................................35-25 Mixed Epithelial and Stromal Tumor................................................35-26

III. Tnm Staging of Renal Cell Carcinoma (2010 Revision) (AJCC)....................35-27 IV. Suggested Reading...........................35-27

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_35, © Springer Science+Business Media, LLC 2002, 2006, 2011

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RENAL NEOPLASMS IN CHILDREN Nephrogenic Rests and Nephroblastomatosis ♦♦ Nephrogenic rests −− Abnormally persistent foci of embryonal cells −− Identifiable in 1% of postmortem kidneys in infants −− Considered capable of developing into nephroblastoma −− Identifiable in 25–40% of kidneys harboring nephro­ blastoma −− If diffuse and multifocal, the term “nephroblastomatosis” is applicable −− If identified in a kidney harboring nephroblastoma, risk of tumor formation in opposite kidney is increased; if not found, risk in other kidney is minimal −− Subclassified into perilobar (PLNR) and intralobar (ILNR) types ♦♦ Perilobar nephrogenic rests (PLNR) −− 10× more common than ILNR in routine autopsies −− Most often multifocal −− Sharply circumscribed and no reactive changes at interface with adjacent normal renal parenchyma −− Located at the periphery of a renal lobule (Fig. 35.1) −− Lesion is comprised mostly of blastema and tubules; stroma is scant and indistinct ♦♦ Intralobar nephrogenic rests (ILNR) −− Most often unifocal −− Indistinct border and irregularly intermingled with adjacent normal kidney −− Located in central portions of renal lobule (Fig. 35.2)

Fig. 35.1. Hyperplastic perilobar nephrogenic rest immediately beneath the renal capsule. Note the absence of fibrosis at junction between the rest and the adjacent kidney. Patient status postchemotherapy for Wilms tumor, accounting for the scattered microcalcifications.

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−− Blastema, tubules, and stroma are all readily evident; stroma may predominate ♦♦ Development of malignancy (nephroblastoma) −− Risk of development of nephroblastoma in ILNR is higher than in PLNR; however, since PLNR is usually multifocal, overall risk of malignancy is the same for both conditions −− Development of nephroblastoma is characterized by spherical expansion and development of a fibrous pseudocapsule between neoplasm and normal kidney

Nephroblastoma (Wilms Tumor) Clinical ♦♦ Male to female ratio is 1:1; peak age 2–4 years; highest incidence in African Americans ♦♦ Usually occurs between 6 months and 3 years of age; rare after 3 years of age ♦♦ Comprises 85% of pediatric renal neoplasms and 5% of childhood cancers ♦♦ 5% are multicentric, 5% are bilateral, and 5% are anaplastic ♦♦ Lung metastases are common ♦♦ Associated with cryptorchidism, hypospadias, hemihypertrophy, aniridia, renal ectopia, and horseshoe kidney ♦♦ Risk factors −− Beckwith–Wiedemann (hemihypertrophy): associated with the WT2 gene; about 5% of patients develop Wilms tumor −− Wilms–aniridia–genital anomaly–retardation syndrome (WAGR): associated with the WT1 gene −− Denys–Drash syndrome (glomerulonephritis, pseudohermaphroditism, and nephroblastoma) associated with the WT1 gene

Fig.  35.2. Intralobular nephrogenic rest. Arrows indicate the nonreactive interface between the rest and normal kidney. Elements of the rest intermingle with normal kidney elements.

Tumors of the Kidney

−− Trisomy 18 −− Multicystic dysplastic kidney ♦♦ Cytogenetics: chromosome 11p13 deletion is common −− WT1 (a) Located on chromosome 11p13, a putative tumor suppressor gene (b) 30–40% of Wilms tumors show loss of heterozygosity (LOH) at 11p13 (c) Encodes 45–49  kDa protein, homologous to early growth response 1(EGR1) (d) Involved in transcription regulation with sequencespecific DNA binding −− WT2 (a) Located on chromosome 11p15.5 (b) A putative tumor suppressor gene (c) Genomic imprinting and loss of maternal allele (d) IGF2 and H19 are putative candidate genes for WT2 −− WT3 (a) Located on chromosome 16q (b) LOH is associated with cancer progression (c) LOH on chromosome 1p (d) Trisomy 18

Macroscopic ♦♦ Large (usually >5 cm) circumscribed tumor with variegated and nodular appearance; in some, extensive cyst formation punctuates solid areas ♦♦ 7% are multicentric

Microscopic ♦♦ Triphasic (Figs. 35.3 and 35.4) −− Blastema (a) Three growth patterns: nodular (organoid), serpentine, and diffuse: growth patterns have no prognostic significance

Fig. 35.3. Wilms tumor, low power.

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(b) Small densely packed cells with little cytoplasm (c) Oval to elongate nuclei, overlapping nuclei, and numerous mitotic figures −− Epithelial component (a) Abortive tubules and glomeruli (b) May show mucinous, squamous, neural, or neuroendocrine differentiation −− Stroma (a) Skeletal muscle, spindle cells, or cartilage (b) Note: cartilage in the kidney may also be seen in mesoblastic nephroma and renal cystic dysplasia ♦♦ Pushing border except diffuse blastemal pattern

Anaplasia ♦♦ One of the criteria for placing Wilms tumor under unfavorable histology category; the other is the development of a high grade sarcoma or carcinoma within nephroblastoma ♦♦ Indicates increased resistance to therapy rather than increased aggressiveness

Definition of Anaplasia (Fig. 35.5) ♦♦ Multipolar, polyploid mitotic figures - each component of the abnormal metaphase must be as large or larger than a normal metaphase ♦♦ Markedly enlarged and hyperchromatic nuclei (at least three times larger than adjacent nonneoplastic nuclei in both axes)

Focal Anaplasia ♦♦ One or only a few sharply localized regions of anaplasia within a primary tumor, the majority of areas show no significant nuclear atypia ♦♦ Anaplastic region must be circumscribed, and its perimeter must be entirely present for evaluation ♦♦ Anaplasia is confined to renal parenchyma (diagnosis is excluded if anaplasia is seen in tumor in vascular spaces)

Fig. 35.4. Wilms tumor, triphasic, composed of primitive tubules (blue arrows), blastema (red arrows), and stroma (green arrows).

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Microscopic ♦♦ Vesicular chromatin ♦♦ Distinct cherry-red nucleoli ♦♦ Hyaline eosinophilic cytoplasmic inclusions

Immunohistochemistry ♦♦ Vimentin strongly positive ♦♦ EMA focal but intensely positive

Renal Neuroblastoma Macroscopic ♦♦ Tumors are hemorrhagic and poorly circumscribed

Microscopic Fig.  35.5. Anaplasia in Wilms tumor: markedly enlarged ­hyperchromatic nuclei, and a markedly abnormal mitotic figure (red arrows).

Diffuse Anaplasia ♦♦ Anaplasia that does not meet the criteria for focal anaplasia ♦♦ Diffuse distribution throughout the primary tumor and its presence in advanced stage tumors consistently portends poor prognosis

Immunohistochemistry (Blastema) ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Vimentin positive Neuron-specific enolase (NSE) positive (focal) Cytokeratin positive (focal) Desmin positive (focal) WT1 positive

♦♦ ♦♦ ♦♦ ♦♦

Absence of distinct peritumoral fibrous capsule Organoid arrangement of tumor cells “Salt and pepper” nuclear chromatin Homer Wright rosettes

Immunohistochemistry ♦♦ Positivity for neuron-specific enolase, synaptophysin, S-100 protein, and chromogranin supportive of neuronal differentiation

Renal Synovial Sarcoma Macroscopic ♦♦ Large (mean diameter 11 cm) and variably cystic

Microscopic ♦♦ Primitive spindle cells with overlapping ovoid nuclei and scant cytoplasm ♦♦ Admixed with variably sized cystic spaces that represent trapped dilated native renal tubules and ducts

Differential Diagnosis Clear Cell Sarcoma of Kidney Macroscopic

Special Studies

♦♦ Large, centrally located, single, and circumscribed but unencapsulated

Renal Primitive Neuroectodermal Tumor (PNET) Clinical

Microscopic ♦♦ Nests or cords of epithelioid or spindled cells, nonoverlapping, separated by arborizing vascular septae of variable thickness ♦♦ Subtly infiltrative border and entrapped normal tubules at periphery

♦♦ WT1 immunostain negative ♦♦ t(X;18) translocation demonstrable

♦♦ Most patients are adolescent or young adults (range 1 month– 72 years)

Macroscopic ♦♦ Poor circumscription

Immunohistochemistry

Microscopic

♦♦ Vimentin positive; BCL2 positive ♦♦ CD34, S-100 protein, desmin, MIC2 (CD99), cytokeratin, and epithelial membrane antigen (EMA) uniformly negative

♦♦ Primitive round cells with varying degrees of rosette formation ♦♦ Nuclear chromatin is coarse, and nuclei do not overlap

Rhabdoid Tumor of Kidney Macroscopic

Immunohistochemistry

♦♦ Large, hemorrhagic, uncircumscribed, and extensively necrotic

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♦♦ CD99 positive; FLI1 positive; WT1 negative

Cytogenetics ♦♦ Characteristic translocations, especially t(11;22)(q24;q12)

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Staging Nephroblastoma (Fifth Protocol, National Wilms Tumor Study Group) ♦♦ Stage I: Limited to kidney and completely resected −− Renal capsule is intact −− Renal sinus soft tissue may be minimally infiltrated ♦♦ Stage II: Tumor infiltrates beyond kidney, but is completely resected −− Tumor extends beyond renal capsule −− Tumor infiltrates vessels within the renal sinus −− Tumor with prior open or large bore needle biopsies −− Tumor with local spillage confined to flank ♦♦ Stage III: Residual nonhematogenous tumor confined to abdomen −− Tumor in abdominal lymph nodes −− Diffuse peritoneal contamination: direct tumor growth, tumor implants, and spillage into peritoneum before or during surgery −− Gross or microscopic involvement of specimen margins −− Residual tumor in abdomen −− Tumor removed noncontiguously (piece-meal resection) ♦♦ Stage IV: Hematogenous metastases ♦♦ Stage V: Bilateral renal involvement at diagnosis (tumor in each kidney should be separately substaged)

Fig. 35.6. Cystic partially differentiated nephroblastoma resected from an 18-month-old male. The tumor consists entirely of cysts without expansile nodules of Wilms tumor.

Cystic Partially Differentiated Nephroblastoma Clinical ♦♦ Generally no symptoms, and most are detected as palpable masses ♦♦ Twice as common in males ♦♦ Occurs in children <4 years old; the great majority are <2 years old ♦♦ Clinical course is benign

Macroscopic ♦♦ Most are 5–10 cm but may be up to 18 cm in diameter ♦♦ Fibrous pseudocapsule sharply separates tumor from adjacent kidney ♦♦ Tumor is entirely composed of variably sized cysts, some of those may have papillary excrescences projecting into cystic spaces

Microscopic ♦♦ Composed of cysts separated by septa of variable thickness ♦♦ Cysts are lined by flat, cuboidal, or hobnail epithelium ♦♦ Septa contain blastema, nephroblastomatous epithelial elements, and differentiated and/or undifferentiated mesenchymal elements such as skeletal muscle, cartilage, fat, or myxoid mesenchyme (Figs. 35.6 and 35.7)

Fig.  35.7. Cystic partially differentiated nephroblastoma. The septa between the cystic spaces contain stromal tissue and immature tubules. No blastema is present.

Differential Diagnosis ♦♦ Solid expansile nodules, evident grossly or altering the rounded contour of the cysts, warrant a diagnosis of cystic nephroblastoma ♦♦ If no nephroblastomatous elements are seen in the fibrous septa, some apply the diagnostic term “cystic nephroma”; however, these lesions are viewed as different from the morphologically similar lesions that occur in adults

Congenital Mesoblastic Nephroma (CMN) Clinical ♦♦ Accounts for 2% of all pediatric renal tumors ♦♦ Most common congenital renal neoplasm

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♦♦ 90% of patients are <1 year old; median age at diagnosis is 2 months ♦♦ Presents as a palpable mass; some are found on prenatal imaging ♦♦ Recurrence rate is 5%; recurrences are usually attributable to incomplete initial resection ♦♦ Only rare instances of metastasis and tumor-related death

Cytogenetics ♦♦ Two morphologic patterns: “classic CMN” and “cellular CMN” ♦♦ Cytogenetic profile of cellular CMN (translocation t(12;15)) confirms that it is infantile fibrosarcoma arising within the kidney ♦♦ Classic CMN is viewed as infantile fibromatosis involving kidney (no translocation identified)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Cellular CMN −− Densely cellular, composed of plump spindle cells, arranged in poorly formed fascicles or in diffuse sheets −− Prominent irregular vascular spaces (“staghorn vessels”) are sometimes evident −− Abundant mitotic figures present; necrosis is frequently evident −− Despite gross circumscription, there is no pseudocapsule, and the tumor subtly infiltrates adjacent normal renal tissue (Figs. 35.10 and 35.11) −− Interface with adjacent kidney is not “interdigitating” as seen in classic type

Macroscopic ♦♦ Mean diameter is 6 cm (range 1–14 cm) ♦♦ Solitary and unilateral ♦♦ Classic CMN is indistinctly circumscribed, with a firm whorled cut surface ♦♦ Cellular CMN is soft, appears circumscribed, and often has cysts, hemorrhage, and necrosis

Microscopic ♦♦ Classic CMN −− Intersecting bundles of spindle cells resembling fibroblasts, not densely packed −− Scant collagenous background and abundant thin-walled vascular spaces −− Tongues of tumor insinuate themselves between normal adjacent renal parenchymal structures without distorting them (Figs. 35.8 and 35.9) −− Mitotic activity is inconspicuous

Fig. 35.8. Congenital mesoblastic nephroma, classic type. The tumor consists of intersecting fascicles of bland uniform spindle cells, encircling and interdigitating between native renal structures.

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Fig. 35.9. Congenital mesoblastic nephroma, classic type. The tumor irregularly infiltrates renal parenchyma at the interface between tumor and normal kidney without compressing or distorting native structures.

Fig. 35.10. Congenital mesoblastic nephroma, cellular type. The tumor is more densely cellular than its classic counterpart, and grows diffusely rather than forming intersecting fascicles. Blue arrows highlight the sharply demarcated border of the tumor.

Tumors of the Kidney

Fig.  35.11. Congenital mesoblastic nephroma, cellular type. Although the interface between the tumor and normal kidney is sharply demarcated, there is no capsule, and the tumor subtly encircles a native tubule (blue arrow).

♦♦ Mixed CMN −− Features of both classic and cellular CMN in same tumor, evident in 10–20% of cases

Immunohistochemistry ♦♦ ♦♦ ♦♦ ♦♦

Vimentin positive Actin positive (often) Desmin positive (rarely) CD34, cytokeratins, S-100 protein: all negative

Differential Diagnosis: CMN Versus Clear Cell Sarcoma of Kidney (CCSK) ♦♦ Challenging! −− Both occur at infancy −− Both are entirely mesenchymal −− Both show entrapped normal renal elements and embryonal metaplastic changes −− Features favoring CCSK over CMN (a) Age >1 year (b) Metastases (especially to bone) (c) Fine nuclear chromatin, infrequent mitotic figures, and extensive sclerosis (d) Absence of staghorn vessels (e) Entrapment of isolated nephrons (rather than groups of nephrons) (f) Negative immunostaining for desmin and actin

Clear Cell Sarcoma of Kidney (CCSK) Clinical ♦♦ Accounts for about 3% of all malignant pediatric renal neoplasms

35-7

Fig.  35.12. Clear cell sarcoma of kidney. Regularly spaced fibrovascular channels intersect cords of tumor cells.

♦♦ Twice as common in males ♦♦ Peak incidence in second year of life (ranges from 2 months–54 years) ♦♦ No associations with malformations, cytogenetic abnormalities, or syndromes ♦♦ Marked propensity for metastasis to bone (consequently, previously named “bone metastasizing renal tumor of childhood”)

Macroscopic ♦♦ Typically large (mean diameter 11  cm, mean weight 500–600 g) ♦♦ Unilateral, unicentric, soft to firm, homogeneous, and light brown or gray ♦♦ Usually confined within renal capsule; cysts are common and sometimes prominent ♦♦ Exhibits a sharply circumscribed interface with normal kidney, but has no gross capsule ♦♦ 5% involve renal vein

Microscopic (Classic Pattern) ♦♦ Epithelioid or spindled cells arranged in nests or cords ♦♦ Nests or cords are separated by regularly spaced branching small blood vessels arranged as fibrovascular septa of variable thickness (Fig 35.12) ♦♦ Cells are separated by myxoid extracellular matrix material that mimics clear cytoplasm. (Fig. 35.13) ♦♦ Cell nuclei are round to oval, with dispersed chromatin and inconspicuous or no nucleoli (Fig. 35.13) ♦♦ Mitotic activity is relatively limited ♦♦ At the interface between tumor and normal kidney, there is subtle tumor infiltration with entrapment of individual tubules and nephrons ♦♦ Many pattern variations have been described: myxoid, sclerosing, cellular, epithelioid, spindle cell, and palisading

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Fig. 35.13. Clear cell sarcoma of kidney. Tumor cells in upper right corner have minimal cytoplasm, and finely dispersed nuclear chromatin. Extracellular mucopolysaccharide matrix imparts a “clear cell” appearance to the majority of the cells in this image.

Differential Diagnosis: CCSK Versus Nephroblastoma ♦♦ Features favoring nephroblastoma −− Bilaterality and multicentricity −− Presence of heterologous cell types, such as skeletal muscle; identification of heterologous cell types excludes CCSK −− Nodularity −− Botryoid growth within renal pelvis; this finding excludes CCSK −− Tumor in renal vein −− Nephrogenic rests −− Positive immunostaining for WT1, CD56, epithelial, muscle, or neural markers ♦♦ Features favoring CCSK −− Homogeneous pale H & E staining −− Entrapment of individual nephrons at tumor periphery −− Extensive collagen deposition −− Negative immunostaining for virtually all markers except vimentin and BCL2

Rhabdoid Tumor of Kidney Clinical ♦♦ Accounts for about 2% of all pediatric renal tumors ♦♦ Highly aggressive and at least 80% of patients have metastases at the time of diagnosis ♦♦ Very lethal and notoriously chemotherapy-resistant; 80% of patients die within one year

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Fig. 35.14. Rhabdoid tumor of kidney. Tumor cells demonstrate vesicular nuclei with prominent cherry-red nucleoli and hyaline eosinophilic cytoplasmic inclusions that result in nuclear eccentricity. ♦♦ Almost all patients are <3 years old; median age is 11 months and male to female ratio is about 1.5:1 ♦♦ Identical tumors involve other sites, especially central nervous system ♦♦ Rhabdoid tumors in all sites are characterized ­cytogenetically by mutation or deletion of the INI1 tumor suppressor gene on the long arm of chromosome 22q11 ♦♦ Despite its name, the neoplasm is not of myogenic origin

Macroscopic ♦♦ Unilateral, large, unencapsulated, often with hemorrhage and necrosis, sometimes with satellite nodules representing intrarenal metastases ♦♦ Interface between tumor and kidney is indistinct

Microscopic ♦♦ Composed of diffuse sheets of monotonous discohesive large cells with −− Vesicular nuclei −− Prominent cherry-red nucleoli −− Hyaline eosinophilic cytoplasmic inclusions ­(intermediate filaments) (Fig. 35.14) ♦♦ Usually there is extensive vascular invasion ♦♦ Tumor cells often infiltrate between and around native glomeruli or tubules

Immunohistochemistry ♦♦ Vimentin strongly positive ♦♦ Intensely positive staining for EMA or cytokeratins in a few cells in a background of adjacent negatively-staining tumor cells (polyphenotypic differentiation)

Tumors of the Kidney

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RENAL NEOPLASMS IN ADULTS Papillary Adenoma Clinical ♦♦ The most common renal tubular epithelial neoplasm ♦♦ Asymptomatic, generally an incidental finding at surgery or autopsy ♦♦ Incidence: found in 10% of patients less than 40-years-old and in 40% of patients more than 70 years old ♦♦ Evident in at least 33% of kidneys with features of acquired cystic kidney disease related to prolonged dialysis ♦♦ Cytogenetics: loss of Y chromosome and combined trisomy of chromosome 7 and 17

♦♦ Cytogenetics −− Mixed populations of normal and abnormal karyotypes −− Losses of chromosomes 1 and Y, deletions from chromosome 14, and rearrangements involving c­ hromosome 11

Macroscopic ♦♦ Tan, pale yellow, or mahogany brown, and well ­circumscribed; median size is 6 cm ♦♦ Typically solitary, but multiple in about 5% of cases ♦♦ Central stellate scar in 33% and focal hemorrhage in up to 20%

Macroscopic ♦♦ Well circumscribed round or wedge-shaped, yellow or gray nodule measuring 0.1–0.5 cm ♦♦ Location: cortex, usually just beneath renal capsule ♦♦ Usually solitary, sometimes multiple and bilateral

Microscopic ♦♦ Tubular, papillary, or tubulopapillary structures (Fig. 35.15) ♦♦ “Seamless” interface with adjacent kidney (no capsule) ♦♦ Tumor cells are small with scant cytoplasm; nuclei are round or oval, sometimes grooved, with punctate chromatin and inconspicuous nucleoli (Fig. 35.16) ♦♦ Mitotic figures rare ♦♦ Some contain psammoma bodies and macrophages

Oncocytoma Clinical ♦♦ Accounts for about 5% of all resected renal epithelial neoplasms (Fig. 35.17) ♦♦ Twice as common in males; median patient age is 62 years ♦♦ Usually asymptomatic; some patients have hematuria, flank pain, or palpable mass ♦♦ Imaging studies may demonstrate central scarring ♦♦ Benign (no recorded deaths from metastatic disease) ♦♦ Cell of origin: intercalated cell of collecting duct

Fig. 35.15. Papillary adenoma. This 3 mm papillary lesion was noted in the wall of a surgically resected renal cyst.

Fig. 35.16. Papillary adenoma (higher power view of lesion in Fig. 35.15). Papillary cores lined by small dark regular cuboidal cells with uniform nuclei lacking nucleoli.

Fig.  35.17. Oncocytoma, gross specimen. Well circumscribed tan-brown lesion with focal hemorrhage and extensive central scarring.

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Fig. 35.18. Oncocytoma, composed of solid nests of oncocytic cells in a hyalinized fibrous stroma.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  35.20. Oncocytoma, All cells have abundant granular eosinophilic cytoplasm; some have round regular nuclei, and other have pleomorphic hyperchromatic nuclei. Nuclear irregularity without mitotic activity or other exclusion criteria is considered to be a degenerative change in this setting, and of no significance. vessels. These are considered permissible in an otherwise typical oncocytoma

Special Studies ♦♦ Hale colloidal iron faintly positive, mainly near luminal surface ♦♦ Positive immunostaining for most cytokeratins, EMA, and parvalbumin (Table 35.1) ♦♦ Immunostain for CK7 characteristically shows only scattered positive cells ♦♦ Immunostains for vimentin and RCC marker usually negative Fig. 35.19. Oncocytoma, with more densely packed but discrete nests of oncocytic cells and small round uniform nuclei.

Microscopic ♦♦ Cells are arranged in solid nests, tubules, or microcysts in a loose fibrous stroma (Fig. 35.18) ♦♦ Tumor is composed entirely of cells with abundant granular eosinophilic cytoplasm (Fig. 35.19) ♦♦ Nuclei are typically round to oval, £10 mm, with evenly dispersed chromatin and small central nucleoli ♦♦ Some nuclei show hyperchromasia and pleomorphism, a finding that is attributed to degenerative change in oncocytomas (Fig. 35.20) ♦♦ Findings of concern, but considered compatible with a diagnosis of oncocytoma, provided their extent is very limited, are as follows: rare mitotic figures, hemorrhage, small foci of necrosis, focal nuclear pleomorphism, extension of tumor into perinephric fat or adjacent renal parenchyma, small clusters of cells with clear cytoplasm embedded in hyalinized stroma, minute papillary projections into dilated tubules, and invasion of small, capillary-sized or even venous-type

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Ultrastructure ♦♦ Tumor cells show abundant mitochondria; other organelles are sparse

Exclusion Criteria ♦♦ Findings considered impermissible for a diagnosis of oncocytoma are as follows: areas of clear-cell or spindle-cell carcinoma, prominent papillary architecture, macroscopic or conspicuous microscopic necrosis, and significant mitotic activity, including atypical mitotic figures. Accurate assessment of these features necessitates adequate sampling of the tumor; consequently, an accurate diagnosis of an oncocytic renal neoplasm based on needle core biopsy or fine needle aspiration may not always be possible

Renal Cell Carcinoma (RCC) Clear Cell Renal Cell Carcinoma Clinical ♦♦ Male to female ratio is about 2:1; peak incidence is in the sixth and seventh decades; 23,000 new cases are diagnosed annually ♦♦ About 70% of RCC are of clear cell type

−/+f

− −

−

−

+(50%)

+(93%)

+(85%)

−

+

−

−

+/−

+

RCC marker Vimentin

+

+/−

+

+

+/−(30–45%)

+/−(20–90%)

EMA

+

+/−

Focal (5% or less)a

+

+

+

−

CK7

+

−

+/−

−

+/−

−

CK20

+

+

−

−

−/+f

−/+f

−/+f

−

+

+

−/+f

−/+f

−/+f

−

−/+f

−

−

+

−/+f

HMWCK CD117 (c-kit) AMACR

−/+f usually negative, occasionally focally positive; +/− frequently positive; AMACR alpha-methylacyl-CoA racemase (P504S); CK7 cytokeratin 7; CK20 cytokeratin 20; EMA epithelial membrane antigen; HMWCK high molecular weight cytokeratin 34bE12 a In contrast to diffuse and strong immunoreactivity for CK7 in chromophobe renal cell carcinoma, oncocytoma typically shows scattered focal positivity for CK7

Urothelial carcinoma

Collecting duct carcinoma

−/+f

Oncocytoma

− −/+f

+(63–93%)

Papillary renal cell carcinoma

Clear cell papillary renal cell carcinoma

Chromophobe renal cell carcinoma

+(81–100%)

Clear cell renal cell carcinoma

CD10

Table 35.1. Immunohistochemical Findings in Renal Epithelial Neoplasms

Tumors of the Kidney 35-11

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♦♦ Cytogenetics −− Deletion of 3p13 −− Somatic mutation or inactivation of the von Hippel– Lindau gene (tumor suppressor gene RAF-1 at 3p25) ♦♦ Arises from renal tubular epithelium and differentiates toward proximal tubular epithelium ♦♦ May present with hematogenous metastases in unusual sites ♦♦ It is the malignancy to which other cancers most commonly metastasize ♦♦ Classic triad: hematuria (40% of patients), flank pain (40%), and palpable mass (35%) ♦♦ In about 20% of patients, there is evidence of a paraneoplastic syndrome, believed to be related to the release of various proteins by tumor cells −− Polycythemia (due to erythropoietin production) −− Hypercalcemia (often seen in advanced stage) −− Hypertension (due to renin production) −− Hepatic dysfunction unrelated to metastases (Stauffer syndrome) −− Cushing syndrome (ectopic ACTH production) −− Sex hormonal imbalance (feminization, gynecomastia, or masculinization, due to release of prolactin or gonadotropin) −− Systemic amyloidosis −− Constitutional symptoms such as fever and weight loss, possibly related to release of various cytokines ♦♦ Risk factors for development of renal cell carcinoma −− Tobacco use −− Hypertension −− Obesity (especially in women) −− Acquired cystic renal disease (long-term dialysis) −− Chronic renal failure −− Tuberous sclerosis −− von Hippel–Lindau syndrome −− Familial renal cancers

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Tumor architecture is diverse – solid, alveolar, and acinar patterns are often admixed ♦♦ Tumor cells are set in a regular network of small delicate blood vessels (Fig. 35.21) ♦♦ Microcysts and macrocysts containing eosinophilic fluid may be present (Fig. 35.22) ♦♦ Many cytologic variations may be seen −− Cells with granular eosinophilic cytoplasm −− Cells with rhabdoid morphology −− Interlacing or whorled bundles of spindle cells, sometimes with marked nuclear pleomorphism (sarcomatoid change)

Fig.  35.21. Clear cell renal cell carcinoma. A prominent network of delicate blood vessels separates solid nests of cells with abundant clear cytoplasm.

Macroscopic ♦♦ Usually solitary; 4% are multicentric in same kidney, and 0.5–3.0% are bilateral ♦♦ Rounded, nodular, and often protruding from the cortical surface (bosselated) ♦♦ Well demarcated from adjacent uninvolved kidney ♦♦ Often has a pseudocapsule and typically has a “pushing” margin ♦♦ Characteristically golden yellow; the cut surface often has a variegated appearance with varying amounts of hemorrhage, necrosis, cystic change, and calcification

Microscopic ♦♦ Typically composed of cells with abundant cytoplasm that appears optically clear (due to loss of intracellular glycogen and lipids during histologic processing) and with distinct cell membranes

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Fig.  35.22. Clear cell renal cell carcinoma forming small tubules and microcysts that contain amorphous eosinophilic ­proteinaceous fluid.

Tumors of the Kidney

♦♦ Nuclear grade is second only to tumor stage in defining prognosis; grade is assigned according to the following nuclear findings −− Grade 1: Small round uniform nuclei, up to 10 µm, and nucleoli not visible (Fig. 35.23) −− Grade 2: Nuclei slightly irregular, up to 15  µm, with inconspicuous nucleoli (Fig. 35.24) −− Grade 3: Nuclei very irregular, up to 20 µm, with large prominent nucleoli (Fig. 35.25) −− Grade 4: Nuclei bizarre, spindled or multilobated, over 20 µm, with macronucleoli (Fig. 35.26)

Immunohistochemistry (Table 35.1) ♦♦ Incidence of immunoreactivity to antibodies against the following antibodies is as indicated −− Low molecular weight cytokeratins (CK8, 18, 19): frequent −− Keratins AE1/AE3 and Cam 5.2: frequent

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−− Vimentin: frequent −− High molecular weight cytokeratins (14, 34bE12): rare −− RCC marker, CD10, and EMA: occurs in the majority −− MUC1 and MUC3: occurs consistently −− Parvalbumin: no immunoreactivity

Multilocular Cystic Renal Cell Carcinoma Clinical ♦♦ Occurs in adults, with a mean age of 51 years (range 20–76), and accounts for about 5% of cases of RCC with clear cell morphology ♦♦ Male to female ratio is about 3:1 ♦♦ Prognosis is favorable after nephrectomy; there are no recorded instances of recurrence or metastasis

Fig. 35.23. Clear cell renal cell carcinoma, grade 1.

Fig. 35.25. Clear cell renal cell carcinoma, grade 3.

Fig. 35.24. Clear cell renal cell carcinoma, grade 2.

Fig. 35.26. Clear cell renal cell carcinoma, grade 4.

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Macroscopic ♦♦ Well circumscribed, with fibrous capsule ♦♦ Composed entirely of cysts containing serous or hemorrhagic fluid ♦♦ Cysts are separated by irregular septa of variable thickness ♦♦ No grossly evident solid nodules of tumor

Microscopic ♦♦ Cysts are lined by simple cuboidal and clear cells (Fig. 35.27) ♦♦ Septa consist of fibrous tissue, variable in thickness ♦♦ Septa contain aggregates of clear cells, with grade 1 nuclear characteristics (Fig. 35.28)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Small papillae may extend into the cysts ♦♦ Clear cell aggregates in septa do not form expansile nodules

Immunohistochemistry ♦♦ Clear cells within septa shows immunoreactivity to antibodies against epithelial membrane antigen and cytokeratins, but show no immunoreactivity to antibodies against macrophage markers (CD68)

Differential Diagnosis ♦♦ Extensively cystic clear cell RCC −− Contains grossly evident solid nodules of tumor or microscopically evident expansile nodules of carcinoma ♦♦ Cystic nephroma −− Cysts may be lined partially by clear cells, but no clear cell aggregates are seen within the septa ♦♦ Tubulocystic carcinoma −− Cysts are not lined by clear cells; no clear cell ­aggregates are seen within the septa

Papillary Renal Cell Carcinoma Clinical

Fig.  35.27. Multilocular cystic renal cell carcinoma. Delicate septa between the cystic spaces are lined by clear cells (blue arrows) and flat cuboidal cells.

♦♦ Male to female ratio is about 2:1; mean patient age is 50–55 years ♦♦ Accounts for 10–15% of all RCCs; it is the second most common type of renal cell carcinoma ♦♦ By definition, papillary tumors greater than 0.5 cm in diameter are considered carcinoma ♦♦ Hereditary papillary RCC is rare, and is related to a germline mutation of the c-met gene ♦♦ Cytogenetics −− Trisomy or tetrasomy 7, trisomy 17, loss of chromosome Y most commonly −− Trisomy of chromosomes 12, 16, and 20 is also ­commonly found

Macroscopic ♦♦ Well-circumscribed cortical tumor, often with a thick fibrous pseudocapsule ♦♦ Hemorrhage, necrosis, and cystic degeneration are common ♦♦ More often multiple than other types of RCC ♦♦ May contain golden-yellow areas reflecting macrophage content

Microscopic

Fig. 35.28. Multilocular cystic renal cell carcinoma. Aggregates of clear cells are present in the septa; the aggregates are noted only by microscopic examination; they are not “expansile.”

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♦♦ Tumor is composed of papillary structures and tubules in varying proportions ♦♦ Papillary cores are lined by a single cell layer that may show pseudostratification ♦♦ Fibrovascular cores may be sclerotic, edematous, or expanded by foamy or hemosiderin-laden macrophages, psammoma bodies, or cholesterol clefts ♦♦ Two morphologic variants −− Type 1: Characterized by a single layer of small dark cells with scant cytoplasm and low nuclear grade (Fig. 35.29)

Tumors of the Kidney

−− Type 2: Cells lining the papillae are large and pseudostratified, with more abundant pink cytoplasm, and of higher nuclear grade (Fig. 35.30) ♦♦ Tubules may be compacted to form “parallel arrays” (Fig. 35.31) ♦♦ Papillary stalks often contain abundant foamy macrophages (Fig. 35.32) ♦♦ Sarcomatoid change may be observed in up to 5% of cases (Figs. 35.33 and 35.34)

Immunohistochemistry ♦♦ Tumor cells are frequently immunoreactive to antibodies against pancytokeratins, CK7, and RCC marker

Fig. 35.29. Papillary renal cell carcinoma, type 1. A tumor larger than 5 mm, composed of papillary structures lined by small dark uniform cells with minimal cytoplasm and grade 1 nuclear characteristics.

Fig. 35.30. Papillary renal cell carcinoma, type 2. A tumor larger than 5  mm, composed of papillary structures lined by pseudostratified cells with abundant pink cytoplasm and high grade (grade 3) nuclear characteristics.

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♦♦ Tumor cells are usually not immunoreactive to antibodies against high molecular weight cytokeratins

Differential Diagnosis ♦♦ Papillary adenoma −− Diagnosis is based on 0.5 cm size cut-point ♦♦ Papillary urothelial carcinoma −− Fibrovascular cores are lined by multiple layers of epithelial cells ♦♦ Collecting duct carcinoma −− May have areas of papillary architecture −− The constellation of other findings that characterize collecting duct carcinoma (absence of fibrous pseudocapsule, aggressive invasion of adjacent renal parenchyma,

Fig. 35.31. Papillary renal cell carcinoma. The papillary structures are compressed, and form “parallel arrays.” Arrow indicates stromal macrophages.

Fig.  35.32. Papillary renal cell carcinoma. In this example, numerous foamy macrophages are present in the fibrovascular cores, a feature that is characteristic of this type of RCC.

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Fig. 35.33. Sarcomatoid change (spindle cell morphology) comprising part of a papillary RCC. This type of change may occur in clear cell, papillary, chromophobe, or collecting duct RCC.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 35.35. Chromophobe renal cell carcinoma, “classic cell type”: Large polygonal cells with thick distinct “plant-like” cell membranes and abundant pale or translucent flocculent pink cytoplasm.

♦♦ Commonly of low stage when detected; consequently, prognosis is relatively favorable

Macroscopic ♦♦ Typically solid, light tan or mahogany brown, and well circumscribed ♦♦ Necrosis, hemorrhage, and scarring are minimal or absent

Microscopic

Fig. 35.34. Sarcomatoid carcinoma, characterized by pleomorphic and spindle cell morphology reminiscent of sarcoma, but present in a background of papillary RCC. p­ eritumoral inflammation, and marked stromal desmoplasia) are features generally not observed in papillary RCC

Chromophobe Renal Cell Carcinoma Clinical ♦♦ Accounts for about 5% of all resected renal epithelial tumors ♦♦ Believed to originate from intercalated cells of collecting duct epithelium ♦♦ Males and females are almost equally affected; mean patient age is about 55 years ♦♦ Cytogenetics: typically, extensive loss of chromosomes (−1, −2, −6, −10, −13, −17, −21) with hypodiploid DNA index

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♦♦ Growth pattern is generally solid but sometimes limited tubule formation is evident ♦♦ Sheets of cells are intersected by fibrovascular septa, which may be thin and delicate but are often broad and hyalinized ♦♦ Tumors are composed of varying proportions of two cell types ♦♦ “Classic cell type” (Fig. 35.35) −− Large polygonal cells, with thick distinct “plant-like” cell membranes −− Tumor cells have abundant pale or translucent flocculent pink cytoplasm −− The largest tumor cells tend to aggregate adjacent to fibrovascular septa ♦♦ “Eosinophilic cell type” (Fig. 35.36) −− Smaller cells, arranged in small nests or intermingled with “classic” cells −− Cytoplasm is less abundant and is granular and more darkly eosinophilic −− Distinctive perinuclear halos are often present due to the accumulation of cytoplasmic organelles around nuclei ♦♦ In either cell type, nuclei may be round and uniform or irregular and “raisinoid” ♦♦ Sarcomatoid change may be observed in some cases; the presence of this finding markedly worsens the prognosis

Tumors of the Kidney

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−− Many clear cell RCC show positive immunostaining for vimentin; chromophobe RCC is virtually always negative for this marker −− Hale colloidal iron staining in clear cell RCC is usually absent or “clumped” as compared to the diffuse strong finely granular cytoplasmic staining seen in chromophobe RCC

Collecting Duct Carcinoma Clinical

Fig.  35.36. Chromophobe renal cell carcinoma, “eosinophilic cell type.” Cytoplasm is less abundant and is darkly eosinophilic. Blue arrow indicates a round regular nucleus with characteristic perinuclear halo; black arrow indicates a mitotic figure; green arrow indicates an irregular “raisinoid” nucleus.

Histochemical and Immunohistochemical Studies ♦♦ Hale colloidal iron stain for acid mucopolysaccharides strongly and diffusely positive ♦♦ CK7 staining is strongly and diffusely positive ♦♦ Pancytokeratin immunostaining positive ♦♦ EMA immunostaining positive ♦♦ Parvalbumin immunostaining positive ♦♦ Vimentin, CD10, and high molecular weight cytokeratin immunostaining negative

Ultrastructure ♦♦ Numerous cytoplasmic microvesicles (150–300  nm) of unknown origin

Differential Diagnosis ♦♦ Oncocytoma −− Organoid growth pattern −− Lacks the following features that may be seen in eosinophilic chromophobe RCC (a) Mitotic activity (b) Diffuse cytoplasmic staining with Hale colloidal iron (c) Few, scattered cells positive for CK7 (d) Necrosis (e) Sheet-like growth pattern (f) “Raisinoid” nuclei and perinuclear halos ♦♦ Clear cell renal cell carcinoma −− Optically clear cytoplasm is not typical of chromophobe RCC

♦♦ Accounts for less than 1% of all RCC cases ♦♦ Male to female ratio is about 2:1; mean age is about 55 years (range 13–83 years) ♦♦ Nearly one-third of patients have metastases at the time of diagnosis ♦♦ Cytogenetics: Loss of heterozygosity on multiple chromosome arms (1q, 3p, 6p, 8p,13q, 21q)

Macroscopic ♦♦ Tumors are typically gray-white and range in size from 2.5 to 12 cm, with an average of 5 cm ♦♦ When small, they are centered in the renal medulla ♦♦ Tumors exhibit irregular and grossly infiltrative borders

Microscopic ♦♦ Composed of tubular or tubulopapillary structures ♦♦ Lined by cytologic malignant cells, some may show a hobnail appearance ♦♦ Irregular angulated glands infiltrate renal parenchyma ♦♦ Infiltration is accompanied by prominent stromal ­desmoplasia, and frequently by a pronounced chronic inflammatory response at the interface between advancing tumor and normal adjacent renal parenchyma (Figs. 35.37 and 35.38) ♦♦ Intraluminal and intracytoplasmic mucin may be seen ♦♦ Dysplasia may be noted in the epithelium of adjacent collecting ducts (Fig. 35.39) ♦♦ Sarcomatoid change is common, occurring in up to 30% of cases

Immunohistochemistry ♦♦ Positive immunostaining for −− Low molecular weight keratin and pancytokeratins (usually) −− High molecular weight keratins (34bE12, CK19) (commonly) −− Ulex europaeus agglutinin-1 (UEA-1) (commonly) ♦♦ Immunostain for CD10 is negative

Renal Medullary Carcinoma Clinical ♦♦ Most often occurs in young persons with sickle cell trait, sickle cell disease, or hemoglobin sickle cell disease, but 2% of patients have no sickle cell hemoglobinopathy ♦♦ Male to female ratio is about 2:1

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Fig.  35.37. Collecting duct carcinoma. This low power view illustrates the tubular architecture of the tumor, stromal desmoplasia, and the “pushing” border, with pronounced inflammation (blue arrows) at the interface between tumor and normal kidney.

Fig. 35.38. Collecting duct carcinoma. Tumor is composed of irregular tubules in a desmoplastic stroma (blue arrows), with considerable peritumoral chronic inflammatory cell infiltrate (green arrows).

♦♦ The great majority of patients (90%) are African-American, but 5% are Caucasian and 5% are Hispanic ♦♦ Age range is 11–39 years, with a mean of 22 years ♦♦ Weight loss, hematuria, flank or abdominal pain or palpable mass are common symptoms and signs ♦♦ Often, the presenting symptoms are related to metastases ♦♦ Tumor is believed to originate in collecting duct epithelium ♦♦ Prognosis is poor: most patients die within 1 year of diagnosis, and mean survival is only about 15 weeks

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Fig. 35.39. Collecting duct carcinoma, with high grade nuclear dysplasia in some native renal tubules (blue arrows); normal tubules are indicated by green arrows.

Fig. 35.40. Renal medullary carcinoma. This type of RCC commonly demonstrates several different morphologic patterns. The malignant tubules in this example are similar to those seen in collecting duct carcinoma.

Macroscopic ♦♦ Gray-white, grossly infiltrative, and typically centered in the renal medulla

Microscopic ♦♦ A variety of architectural patterns may be present −− Reticular or yolk-sac appearance −− Adenoid cystic appearance −− Solid sheets, nests, or tubules (Fig. 35.40) ♦♦ Tumor cells may show rhabdoid morphology ♦♦ Intracytoplasmic mucin and sickled erythrocytes are evident in the great majority of cases (Fig. 35.41)

Tumors of the Kidney

Fig. 35.41. Renal medullary carcinoma. Arrows indicate ­sickled red cells in a background of poorly differentiated renal carcinoma. Patient was a 22-year-old African-American male with sickle cell trait; he died of widespread metastases 3 months after the diagnosis of renal medullary carcinoma was made.

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Fig.  35.42. Mucinous tubular and spindle cell carcinoma. Elongated tubules in a bubbly myxoid stroma consisting of abundant extracellular mucin.

♦♦ A strikingly prominent infiltrate of neutrophils may be evident within the tumor

Immunohistochemistry ♦♦ Tumor cells usually show positive immunostaining for pancytokeratins, EMA, and CEA

Mucinous Tubular and Spindle Cell Carcinoma Clinical ♦♦ Rare tumor, originally described as a subset “low grade collecting duct carcinoma” ♦♦ Generally asymptomatic, and most are found incidentally ♦♦ Male to female ratio is about 1:4; mean patient age is 53 years, with a range of 17–82 years ♦♦ Cytogenetics: Consistent losses involving chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 ♦♦ Biologic behavior is usually indolent, with only one reported case of metastasis

Fig. 35.43. Mucinous tubular and spindle cell carcinoma. Higher power view of the tumor shown in Fig.  35.42, illustrating the extremely bland nuclear characteristics of the tumor, possibly accounting for its very indolent behavior.

Macroscopic

Immunohistochemistry

♦♦ Well circumscribed, gray or light tan, and glistening cut surface

♦♦ Most express cytokeratins 18 and 19, EMA, and UEA-1; expression of Cam 5.2 and 34bE12 have also been reported ♦♦ Immunostain for CD10 is negative

Microscopic ♦♦ Tightly packed elongated tubules, arranged in parallel with some branching (Fig. 35.42) ♦♦ Abundant pale eosinophilic or basophilic extracellular mucin (Fig. 35.43) ♦♦ Collapsed tubules may impart a spindled appearance ♦♦ Tumor cells are cytologically low grade, round or oval ♦♦ Single reported case with sarcomatoid component

Tubulocystic Carcinoma Clinical ♦♦ A rare tumor, originally described as a subset of “low grade collecting duct carcinoma”; assessment of cell of origin presently under investigation ♦♦ Two-thirds of patients are asymptomatic, and the tumor is found incidentally

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♦♦ Male to female ratio is about 6:1; mean patient age is 55 years with a range of 34–81 years ♦♦ Cytogenetics: insufficient data available ♦♦ Tumor is relatively indolent; survival rate exceeds 90% ♦♦ Tumors are generally low stage when initially detected

Macroscopic ♦♦ Well circumscribed, with a mean size of 4  cm (range 1.6–17 cm) ♦♦ Spongy “bubble wrap-like” cut surface; grossly composed of innumerable cysts of variable size

Microscopic ♦♦ Cystically dilated tubules of variable size, separated by thin “spidery” septa (Fig.  35.44) and lined by a single layer of flat, cuboidal, or hobnail cells (Fig. 35.45A) ♦♦ Tumor cells usually exhibit low nuclear grade (Fig. 35.45B)

Immunohistochemistry

Essentials of Anatomic Pathology, 3rd Ed.

Renal Cell Carcinoma, Unclassified ♦♦ This category comprises 6–7% of all renal cell neoplasms ♦♦ The criteria for assignment of a renal epithelial neoplasm to this category are as follows −− Tumor is cytologically and/or architecturally ­inconsistent with any of the aforementioned types of renal cell carcinoma (Figs. 35.47 and 35.48) −− Tumor shows only sarcomatoid morphology, although immunohistochemically it is consistent with carcinoma

Metanephric Neoplasms Metanephric Adenoma Clinical ♦♦ Occurs twice as commonly in females as in males ♦♦ Mean patient age at diagnosis is 41 years, with a range between 5 and 83 years

♦♦ Tumor cells show immunoreactivity for parvalbumin, CK18, CK19, P504S, CK7, CD10, 34bE12

Clear Cell Papillary Renal Cell Carcinoma ♦♦ Occurs in patients with or without end-stage renal disease ♦♦ Mean age, 60 years; male/female ratio, 3:2 ♦♦ No evidence of tumor recurrence during mean followup of 24 months ♦♦ Mean tumor size, 2.3  cm; all stage pT1, low nuclear grade (1–2) ♦♦ Composed of cells with clear cytoplasm arranged in papillary pattern (Fig. 35.46) ♦♦ IHC: AMACR−, CA IX+, CK7+, CD10−, TFE3− ♦♦ Cytogenetics: Lack chromosome 7 gain, no loss of Y chromosome, no 3p deletion, and may have gain of chromosome 17

Fig. 35.44. Tubulocystic carcinoma, low power view, illustrating the “spider-web” appearance of the cysts and septa of which the tumor is composed.

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Fig. 35.45. Tubulocystic carcinoma. (A) The tumor bears some resemblance to multilocular cystic renal cell carcinoma, but the septa are not lined by clear cells, nor are there clear cell aggregates within the septa. (B) This illustrates low grade nuclear characteristics of the cells that typically line the septa.

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Fig.  35.48. Thyroid-like follicular carcinoma of the kidney. Until recently, it was regarded as RCC, unclassified. It is remarkable in its resemblance to thyroid follicular neoplasms. ♦♦ About half of patients have flank pain, mass, or hematuria, or are noted to have polycythemia; in the rest, the tumor is found incidentally

Macroscopic ♦♦ Tumors are typically sharply circumscribed, solid or lobulated, unencapsulated, gray, tan, or yellow ♦♦ Most are 3–6 cm in diameter, but can be as large as 15 cm ♦♦ Areas of hemorrhage are commonly seen; calcification is evident in about 20% of tumors, and cyst formation is noted in about 10% Fig. 35.46. Clear cell papillary renal cell carcinoma. The tumor is composed of papillary structures lined by clear cells with low nuclear grade (A and B).

Microscopic ♦♦ Tumors are highly cellular; they are composed of densely packed small round uniform acini in a virtually acellular stroma ♦♦ Papillary structures and glomeruloid bodies are often present (Fig. 35.49) ♦♦ Tumor forms a sharp interface with normal adjacent kidney, without a fibrous pseudocapsule ♦♦ Long angular or branching ductal structures may be present ♦♦ Psammoma bodies are common, and are sometimes abundant ♦♦ Tumor cells have scant pale or pink cytoplasm ♦♦ Cell nuclei are small, monotonous, round, smooth and darkstaining, with no or inconspicuous nucleoli

Differential Diagnosis

Fig. 35.47. Acquired cystic disease-associated renal cell carcinoma. Until recently, it was regarded as RCC, unclassified. It is distinctive by its production of abundant oxalate crystals.

♦♦ The chief entities in the differential are papillary renal cell carcinoma and nephroblastoma ♦♦ Immunostains for EMA and CK7 are negative in metanephric adenoma, and typically positive in papillary RCC; WT1 is positive in metanephric adenoma and negative in papillary RCC ♦♦ Nephroblastoma is usually triphasic, with blastema ♦♦ The presence of a fibrous pseudocapsule excludes metanephric adenoma

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Fig.  35.49. Metanephric adenoma. A very ­cellular neoplasm composed of closely packed acinar structures in an extremely paucicellular stroma. Arrows indicate “glomeruloid bodies,” often seen in this neoplasm.

Fig.  35.51. Metanephric stromal tumor demonstrating juxtaglomerular cell hyperplasia.

Fig. 35.50. Metanephric stromal tumor entrapping renal tubules (blue arrows) and glomeruli (red arrows).

Fig. 35.52. Metanephric stromal tumor demonstrating “onionskin” change around an entrapped native renal tubule.

♦♦ Tumor cells of metanephric adenoma do not exhibit nucleoli and very rarely exhibit mitotic activity; the presence of these features virtually excludes a diagnosis of metanephric adenoma

Mesenchymal Neoplasms Renomedullary Interstitial Cell Tumor (Medullary Fibroma) Clinical

The Metanephric Tumor Family ♦♦ A spectrum of tumors, all originating from metanephric blastema ♦♦ Metanephric adenoma is entirely composed of epithelial nephroblastic cells ♦♦ Metanephric stromal tumor is entirely composed of stromal elements (Figs. 35.50–35.53) ♦♦ Metanephric adenofibroma includes both epithelial and stromal elements ♦♦ Metanephric adenosarcoma – one case has been reported

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♦♦ Only very rarely causes symptoms; usually found incidentally at autopsy or surgery for another condition ♦♦ Present (and very often multiple) in 50% of autopsy kidneys ♦♦ Rarely noted in persons less than 18 years of age ♦♦ The cell of origin is thought to be a prostaglandin-­producing interstitial cell in renal medulla that regulates intrarenal blood pressure ♦♦ Tumors are not believed to cause systemic hypertension

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♦♦

♦♦ ♦♦ ♦♦

♦♦ Fig.  35.53. Metanephric stromal tumor demonstrating angio­ dysplasia.

♦♦

♦♦

♦♦ ♦♦

♦♦ ♦♦ Fig.  35.54. Renomedullary interstitial cell tumor. Stellate and spindle cells in a loose myxoid stroma.

Macroscopic ♦♦ Forms a white or gray nodule, measuring 0.1–0.5  cm in diameter, in renal medullary pyramid; only very rarely are they larger

Microscopic ♦♦ A circumscribed but unencapsulated paucicellular tumor composed of small stellate, spindled or polygonal cells in a loose background of faintly basophilic stroma (Fig. 35.54) ♦♦ Amyloid is sometimes present

Angiomyolipoma (AML) Clinical ♦♦ Angiomyolipoma is associated with several hereditary disorders −− von Recklinghausen disease

♦♦ ♦♦

−− von Hippel–Lindau syndrome −− Autosomal dominant (adult) polycystic kidney disease −− Tuberous sclerosis It occurs in 80% of patients with tuberous sclerosis (TS); the presence of multiple AML in a kidney is presumptive evidence of TS Fewer than 50% of patients with AML have the TS complex AML accounts for about 1% of all surgically excised renal tumors The mean age of patients with “sporadic” AML is about 45–55 years; in patients with TS, the diagnosis is evident by age 25–35 years of age In sporadic cases, AML is 4× more common in females; in patients with TS, males and females are almost equally affected Cell of origin: AML is considered to be a ­neoplastic (clonal) proliferation of perivascular epithelioid cells, which have no known normal counterpart Cytogenetics: AML frequently exhibits loss of ­heterozygosity (LOH) in portions of the TSC2 gene locus on chromosome 16p13 (in both sporadic and TS cases), and less often exhibits LOH in the TSC1 gene on c­ hromosome 9q34 Growth sites: renal cortex or medulla; some arise in perirenal soft tissues Symptoms −− TS patients are often asymptomatic; their tumors are detected by radiologic screening −− Patients with sporadic AML may complain of flank pain or hematuria; a mass may be palpable AML may coexist with other renal neoplasms (RCC, oncocytoma) AML is sometimes associated with lymphangioleiomyomatosis of lung In most cases, accurate radiologic diagnosis is possible (due to the fat content of the tumor) Although benign, classic AML can be life-threatening if −− Massive hemorrhage occurs −− Renal failure supervenes due to progressive loss of renal tissue −− A high grade malignancy develops within it

Macroscopic ♦♦ AML is typically intrarenal, well demarcated, ­unencapsulated, and often lobulated ♦♦ Tumor is yellow to tan-pink; hemorrhage is common and sometimes massive ♦♦ Tumors range in size from 3 to 20  cm, with a mean of 9.4 cm

Microscopic ♦♦ AML is composed of variable admixtures of mature adipose tissue, smooth muscle and abnormally formed blood vessels with variably thickened walls (Figs. 35.55 and 35.56)

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Fig.  35.55. Angiomyolipoma, composed of fat (black arrow), blood vessels (blue arrows) and smooth muscle (green arrow). ♦♦ Smooth muscle proliferations often appear to spin off perpendicularly from the outer layers of blood vessel walls, imparting a “hair-on-end” appearance ♦♦ Smooth muscle cells may be spindled or epithelioid, and may show mild degrees of nuclear atypia ♦♦ Involvement of intrarenal veins, renal vein, vena cava, and regional lymph nodes by classic AML are indicative of multifocal growth, rather than invasion or metastasis

Immunohistochemistry ♦♦ AML is characterized by coexpression of −− Melanocytic markers (HMB-45, HMB-50, CD63, MART-1/Melan A, microphthalmia transcription factor) −− Smooth muscle markers (muscle-specific actin, smooth muscle actin, desmin) ♦♦ Epithelial markers are always negative

Variant Epithelioid Angiomyolipoma (EAML) ♦♦ A potentially malignant mesenchymal neoplasm closely related to classic triphasic AML ♦♦ A member of the perivascular epithelioid cell tumor family ♦♦ Half of recorded cases have a history of tuberous sclerosis ♦♦ Tumors exhibit allelic loss of the TS2-containing region (chromosomal arm 16p) ♦♦ EAML is usually large, hemorrhagic, and locally infiltrative ♦♦ Microscopically, EAML is composed of sheets of cytologically malignant epithelioid cells, and it is easy to misdiagnose as high grade carcinoma ♦♦ The immunohistochemical profile of EAML is similar to that of classic AML ♦♦ Prognosis for EAML is not well defined; in initial reports, up to one-third of patients suffered metastasis and/or death; more recent data suggests it may be less aggressive than initially believed

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Fig. 35.56. Angiomyolipoma, demonstrating fat (black arrow), a thick-walled blood vessel (red arrow), and smooth muscle cells (blue arrow) that appear to be proliferating away from the wall of the blood vessel.

Juxtaglomerular Cell Tumor Clinical ♦♦ A benign renin-secreting tumor derived from modified smooth muscle cells of the juxtaglomerular apparatus ♦♦ Patients have refractory hypertension and high plasma renin activity; secondary hyperaldosteronism and hypokalemia is observed in some ♦♦ Patients range in age from 6 to 69 years, with a mean age of 27 years ♦♦ Occurs twice as commonly in females

Macroscopic ♦♦ Tumor is unilateral, solitary, and cortical in location ♦♦ Most tumors have a fibrous pseudocapsule and are less than 4 cm in diameter, but may be as large as 9 cm ♦♦ Tumor is solid, well circumscribed, gray-white or yellowtan, and often shows areas of hemorrhage

Microscopic ♦♦ Composed of sheets of uniform round, polygonal or spindled cells with moderate amounts of granular eosinophilic cytoplasm (Figs. 35.57 and 35.58) ♦♦ Tumor cell nuclei are uniform and round to oval, with scattered mitotic figures ♦♦ Thin and thick-walled blood vessels are common in the tumor, and are often prominent

Immunohistochemistry ♦♦ Tumor cells show immunoreactivity for renin, actin, vimentin, and CD34

Ultrastructure ♦♦ Tumor cells contain rhomboid renin-specific crystals

Tumors of the Kidney

Fig. 35.57. Juxtaglomerular cell tumor, composed of sheets of cells with smooth, round, oval or spindled nuclei and moderately abundant eosinophilic cytoplasm. A thick-walled blood vessel is also present (lower left).

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Fig.  35.59. Cystic nephroma, composed of multilocular cysts separated by fibrous septa of variable thickness.

Fig. 35.60. Cystic nephroma. Cells lining the fibrous septa may be flat, cuboidal, or “hobnail” (red arrow) in appearance. Fig.  35.58. Juxtaglomerular cell tumor. Stroma is hyalinized and focally myxoid. In some tumors (as in this case) a striking infiltrate of chronic inflammatory cells may be present (blue arrows). Note large thick-walled blood vessel.

Mixed Epithelial/Renal Parenchymal Neoplasms Cystic Nephroma Clinical ♦♦ A tumor that typically occurs in women over 30 years of age; the female to male ratio is about 8:1 ♦♦ Usually asymptomatic, and found incidentally

Macroscopic ♦♦ Most often located in upper pole ♦♦ Tumor is solitary, unilateral, encapsulated, and well demarcated from the adjacent kidney

♦♦ Tumor is composed of numerous cysts of variable size ♦♦ The adjacent renal parenchyma is compressed but is normal otherwise

Microscopic ♦♦ Tumor is composed of multilocular cysts of variable size, lined by a single layer of flat, low cuboidal, or hobnail epithelium (Fig. 35.59) ♦♦ The cytoplasm of the lining cells may be eosinophilic or clear ♦♦ The stromal septa between cysts consist of dense fibroconnective tissue that may be cellular or paucicellular (Fig. 35.60) ♦♦ It is of critical diagnostic importance that the fibrous septa do not contain elements of nephrons, elements of nephroblastoma, or nests of cells with clear cytoplasm

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Mixed Epithelial and Stromal Tumor Clinical ♦♦ Patients are adults and are predominantly female: the female to male ratio is about 8:1 ♦♦ The mean patient age is 46 years ♦♦ Some patients complain of flank pain, hematuria, or symptoms of urinary infection; at least 25% of tumors are detected incidentally

Macroscopic ♦♦ Tumor is usually centrally located, circumscribed and encapsulated ; some tumors protrude into the renal pelvis ♦♦ Tumor is composed of solid and cystic areas

Microscopic ♦♦ Tumors are complex; they are composed of a stromal component punctuated by epithelial-lined microcysts and macrocysts, which sometimes show complex branching tubules (Fig. 35.61) ♦♦ The stromal component consists of spindle cells with plump nuclei and abundant cytoplasm; stromal cellularity is markedly variable (Fig. 35.62) ♦♦ The stroma is sometimes myxoid, and may contain collagen, smooth muscle, or fat ♦♦ The epithelial cells lining the cysts may be low cuboidal, columnar, or hobnail in appearance. (Figs. 35.62 and 35.63)

Fig.  35.62. Mixed epithelial and stromal tumor of kidney. Stroma is variable, and may resemble smooth muscle or fibrous tissue. Epithelium lining the cystic space is columnar.

Fig.  35.63. Mixed epithelial and stromal tumor of kidney. Stroma resembles that of normal ovary. Epithelium lining the small tubules is flat and inconspicuous.

Immunohistochemistry

Fig.  35.61. Mixed epithelial and stromal tumor of kidney. Complex epithelial-lined papillae (blue arrow); mature fat in the stroma (black arrow).

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♦♦ The stromal spindle cells show smooth muscle differentiation, with positive immunostaining for actin and desmin; they often are immunoreactive to antibodies against estrogen and progesterone receptors ♦♦ The epithelial cells are immunoreactive to antibodies against cytokeratins and vimentin

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TNM STAGING OF RENAL CELL CARCINOMA (2010 REVISION) (AJCC) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1a: Tumor 4 cm of less in greatest dimension, limited to the kidney −− T1b: Tumor more than 4 cm but not more than 7 cm in greatest dimension limited to the kidney −− T2: Tumor more than 7 cm in greatest dimension, limited to the kidney −− T2a: Tumor more than 7 cm but less than or equal to 10 cm in greatest dimension, limited to the kidney −− T2b: Tumor more than 10 cm, limited to the kidney −− T3: Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia −− T3a: Tumor grossly extends into the renal vein or its segmental (muscle containing) branches, or tumor invades

perirenal and/or renal sinus fat but not beyond Gerota fascia −− T3b: Tumor grossly extends into the vena cava above the diaphragm −− T3c: Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava −− T4: Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Metastasis in regional lymph node(s) ♦♦ Distant Metastases (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis

SUGGESTED READING Adsay NV, Eble JN, Srigley JR, et al. Mixed epithelial and stromal tumor of the kidney. Am J Surg Pathol 2000;24:958–970. Amin MB, Amin MB, Tamboli P, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2002;26:281–291.

Brunelli M, Eble JN, Zhang S, et  al. Eosinophilic and classic chromophobe renal cell carcinomas have similar frequent losses of multiple chromosomes from among chromosomes 1, 2, 6, 10, and 17, and this pattern of genetic abnormality is not present in renal oncocytoma. Mod Pathol 2005;18:161–169.

Amin MB, Crotty TB, Tickoo SK, et al. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997;21:1–12.

Brunelli M, Eccher A, Gobbo S, et al. Loss of chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma. Mod Pathol 2008;21:1–6.

Amin MB, MacLennan GT, Paraf F, et al. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma. Am J Surg Pathol 2009;33:384–392.

Brunelli M, Gobbo S, Cossu-Rocca P, et  al. Chromosomal gains in the sarcomatoid transformation of chromophobe renal cell carcinoma. Mod Pathol 2007;20:303–309.

Amin MB, Paner GP, Alvarado-Cabrero I, et al. Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol 2008;32:1822–1834.

Cheng L, Gu J, Eble JN, et al. Molecular genetic evidence for different clonal origin of components of human renal angiomyolipomas. Am J Surg Pathol 2001;25:1231–1236.

Argani P, Beckwith JB. Metanephric stromal tumor: report of 31 cases of a distinctive pediatric renal; neoplasm. Am J Surg Pathol 2000;24:917–926. Arroyo MR, Green DM, Perlman EJ, et al. The spectrum of metanephric adenofibroma and related lesions. Am J Surg Pathol 2001;25:433–444. Brunelli M, Eble JN, Zhang S, et al. Metanephric adenoma lacks the gain of chromosomes 7 and 17 and loss of Y which are typical of papillary renal cell carcinoma and adenoma. Mod Pathol 2003;16:1060–1063. Brunelli M, Eble JN, Zhang S, et al. Gains of chromosomes 7, 17, 12, 16 and 20, and loss of Y occur early in the evolution of papillary renal cell neoplasia: a fluorescent in situ hybridization study. Mod Pathol 2003; 16:1053–1059.

Cheng L, MacLennan GT, Zhang S, et al. Evidence for polyclonal origin of multifocal clear cell renal cell carcinoma. Clin Cancer Res 2008; 14:8087–8093. Cheng L, Williamson SR, Zhang S, et al. Molecular Genetics of Renal Cell Neoplasia: Implications for Diagnosis, Prognosis and Therapy. Exp Rev Anticancer Ther 2010;10:843–864. Cheng L, Zhang S, MacLennan GT, et  al. Molecular and cytogenetic insights into the pathogenesis, classification, differential diagnosis, and prognosis of renal epithelial neoplasms. Hum Pathol 2009;40:10–29. Cheville JC, Blute ML, Zincke H, et al. Stage pT1 Conventional (clear cell) renal cell carcinoma: pathological features associated with cancer specific survival. J Urol 2001;166:453–456.

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Cossu-Rocca P, Eble JN, Delahunt B, et al. Renal mucinous tubular and spindle carcinoma lacks the gains of chromosomes 7 and 17 and losses of chromosome Y that are prevalent in papillary renal cell carcinoma. Mod Pathol 2006;19:488–493.

Gobbo S, Eble JN, MacLennan GT, et  al. Renal cell carcinomas with papillary architecture and clear cell components: the utility of immunohistochemical and cytogenetical analyses in differential diagnosis. Am J Surg Pathol 2008;32:1780–1786.

Cossu-Rocca P, Eble JN, Zhang S, et al. Interphase cytogenetic analysis with centromeric probes for chromosome 1, 2, 6, 10, and 17 in eleven tumors from a patient with bilateral renal oncocytosis. Mod Pathol 2008;21:498–504.

Gokden N, Nappi O, Swanson PE, et al. Renal cell carcinoma with rhabdoid features. Am J Surg Pathol 2000;24:1329–1338.

Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma: the seventh sickle cell nephropathy. Am J Surg Pathol 1995;19:1–11.

Halat S, Eble JN, Grignon DG, et al. Multilocular cystic renal cell carcinoma is a subtype of clear cell renal cell carcinoma. Mod Pathol 2010;23:931–936.

de Peralta-Venturina M, Moch H, Amin M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol 2001;25:275–284. Delahunt B, Eble JN, McCredie MR, et al. Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases. Hum Pathol 2001;32:590–595. Delahunt B, Kittelson JM, McCredie MR, et al. Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma, assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters. Cancer 2002;94:658–664. Delahunt B, Sika-Paotonu D, Bethwaite PB, et al. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol 2007;31:957–960. Eble JN. Angiomyolipoma of kidney. Semin Diagn Pathol 1998;15:21–40. Eble JN. Mucinous tubular and spindle cell carcinoma and post-neuroblastoma carcinoma: newly recognized entities in the renal cell carcinoma family. Pathology 2003;35:499–504. Eble JN, Bonsib S. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. Semin Diagn Pathol 1998;15:2–20. Eble JN, Bonsib SM. Extensively cystic renal neoplasms: cystic nephroma, cystic partially differentiated nephroblastoma, multilocular cystic renal cell carcinoma, and cystic hamartoma of renal pelvis. Semin Diagn Pathol 2001;15:2–20.

Grignon D, Eble JN. Papillary and metanephric adenomas of the kidney. Semin Diagn Pathol 1998;15:41–53.

Jones JD, Eble JN, Wang M, et  al. Molecular genetic evidence for the independent origin of multifocal papillary tumors in patients with papillary renal cell carcinoma. Clin Cancer Res 2005;11:7226–7233. Jones TD, Eble JN, Wang M, et al. Clonal divergence and genetic heterogeneity in clear cell renal cell carcinomas with sarcomatoid transformation. Cancer 2005;104:1195–1203. Kunju LP, Wojno K, Wolf JS, et al. Papillary renal cell carcinoma with oncocytic cells and nonoverlapping low grade nuclei: expanding the morphologic spectrum with emphasis on clinicopathologic, immunohistochemical and molecular features. Hum Pathol 2008;39:96–101. Lohse CM, Blute ML, Zincke H, et al. Comparison of standardized and nonstandardized nuclear grade of renal cell carcinoma to predict outcome among 2,042 patients. Am J Clin Pathol 2002;118:877–886. Lopez-Beltran A, Carrasco JC, Cheng L, et al. Update on the classification of renal epithelial tumors in adults. Int J Urol 2009;16:432–443. MacLennan GT, Farrow GM, Bostwick DG. Low grade collecting duct carcinoma of the kidney: report of 13 cases of low grade mucinous tubulocystic renal carcinoma of possible collecting duct origin. Urology 1997;50:679–684. MacLennan GT, Ross J, Cheng L. Cystic partially differentiated nephroblastoma. J Urol 2010;183:1585–1586. Martin SA, Mynderse LA, Lager DJ, et al. Juxtaglomerular cell tumor: a clinicopathologic study of four cases and review of the literature. Am J Clin Pathol 2001;116:854–863.

Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 1997;21: 1123–1130.

Muir TE, Cheville JC, Lager DJ. Metanephric adenoma, nephrogenic rests, and Wilms tumor. Am J Surg Pathol 2001;25:1290–1296.

Gobbo S, Eble JN, Delahunt B, et al. Renal cell neoplasia of oncocytosis has distinct morphologic, immunohistochemical and cytogenetic profiles. Am J Surg Pathol 2010;34:620–626.

Tretiakova MS, Sahoo S, Takahashi M, et al. Expression of alpha-methylacyl-CoA racemase in papillary renal cell carcinoma. Am J Surg Pathol 2004;28:69–76.

Gobbo S, Eble JN, Grignon DJ, et al. Clear cell papillary renal cell carcinoma: a distinct histopathological and molecular genetic entity. Am J Surg Pathol 2008;32:1239–1245. Gobbo S, Eble JN, Huang J, et al. Schwannoma of the kidney. Mod Pathol 2008;21:779–783.

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Sullivan PS, Rao JY, Cheng L, et al. Classical pathology versus molecular pathology in renal cell carcinoma. Curr Urol Rep 2007;8:5–11.

Wu A, Kunju LP, Cheng L, et al. Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical and molecular characteristics with an emphasis on the spectrum of Xp11.2 translocation-associated and unusual clear cell subtypes. Histopathology 2008;53:533–544.

36 Urinary Bladder Liang Cheng, md, Antonio Lopez-Beltran, md, and David G. Bostwick, md

CONTENTS



I. Congenital Anomalies........................36-3 Urachal Abnormalities.....................................36-3 Exstrophy..........................................................36-3

II. Cystitis...............................................36-3 Acute Cystitis....................................................36-3 Chronic Cystitis................................................36-4 Granulomatous Cystitis...................................36-5 Tuberculous Cystitis...............................36-5 Malakoplakia..........................................36-5 Schistosomiasis........................................36-6 Treatment-Induced Cystitis.............................36-6 Radiation Cystitis...................................36-6 BCG-Induced Granulomatous Cystitis................................................36-7 Cytoxan-Induced Hemorrhagic Cystitis................................................36-8 Postsurgical Granuloma.........................36-8 Special Variants of Cystitis..............................36-8 Interstitial Cystitis..................................36-8 Eosinophilic Cystitis...............................36-9

III. Benign Lesions and Mimics of Cancer.............................................36-10 Urothelial Hyperplasia...................................36-10 Flat Urothelial Hyperplasia.................36-10 Papillary Urothelial Hyperplasia........36-10 Metaplasia.......................................................36-11 Squamous Metaplasia..........................36-11 Nephrogenic Adenoma (Metaplasia)......................................36-11 Cystitis Glandularis.......................................36-12 Cystitis Cystica...............................................36-13

von Brunn Nests and von Brunn Nest Proliferations.............................................36-13 Florid Cystitis Glandularis............................36-13 Endometriosis.................................................36-14 Endocervicosis................................................36-15 Müllerianosis..................................................36-15 Diverticulosis...................................................36-16 Postoperative Spindle Cell Nodule................36-16 Inflammatory Myofibroblastic Tumor.........36-17 Ectopic Prostatic Tissue.................................36-19 Papillary–Polypoid Cystitis (Proliferative Cystitis)...............................36-19 Pyogenic Granuloma......................................36-20 Condyloma Acuminatum...............................36-20 Amyloidosis.....................................................36-20

IV. Neoplasms of the Bladder................36-21 Benign Urothelial Neoplasms........................36-21 Urothelial Papilloma.............................36-21 Inverted Papilloma...............................36-22 Squamous Papilloma............................36-23 Villous Adenoma...................................36-23 Flat Urothelial Lesions with Atypia..............36-24 Reactive Urothelial Atypia...................36-24 Urothelial Atypia of Unknown Significance.......................................36-24 Urothelial Dysplasia.............................36-24 Urothelial Carcinoma In Situ..............36-25 Noninvasive Papillary Urothelial Tumors....36-27 Infiltrating Urothelial Carcinoma.................36-30 Histologic Variants of Invasive Urothelial Carcinoma......................36-30 Specimen Handling and Reporting.....36-37

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_36, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Squamous Cell Carcinoma............................36-37 Adenocarcinoma.............................................36-38 Clear Cell Adenocarcinoma (Mesonephric Carcinoma)........................36-40 Sarcomatoid Carcinoma (Metaplastic Carcinoma; Carcinosarcoma)..................36-40 Small Cell Carcinoma....................................36-40

V. Soft Tissue Tumors............................36-42 Benign..............................................................36-42 Leiomyoma............................................36-42 Hemangioma.........................................36-42 Neurofibroma........................................36-42 Solitary Fibrous Tumor........................36-43 Other Benign Soft Tissue Tumors..............................................36-43

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Malignant........................................................36-43 Leiomyosarcoma...................................36-43 Rhabdomyosarcoma.............................36-44 Other Malignant Soft Tissue Tumors..............................................36-45

VI. Miscellaneous..................................36-45 Lymphoma......................................................36-45 Paraganglioma (Pheochromocytoma)..........36-46 Carcinoid.........................................................36-46 Clear Cell Myomelanocytic Tumor...............36-46

VII. TNM Classification of Bladder Cancer (2010 Revision)...................36-47 VIII. Suggested Reading...........................36-47

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CONGENITAL ANOMALIES Urachal Abnormalities Clinical ♦♦ The urachus is the vestigial remnant of the connection from the apex of the bladder to the allantois (located at the umbilicus) ♦♦ It is derived from the ventral cloaca and allantois ♦♦ Normally, the urachus closes by the 4th month of fetal life ♦♦ A spectrum of anatomic abnormalities may result in abnormal persistence or malformations in children

Pathology ♦♦ Patent urachus −− Communicating duct between the bladder and the umbilicus that allows the flow of urine and predisposes to infection −− Spontaneous closure may occur, but usually requires surgical intervention ♦♦ Urachal cyst −− Presents as a suprapubic palpable mass −− Usually occurs in the lower part of the urachus and is lined by columnar or urothelial cells ♦♦ Blind sinuses and vesicourachal diverticuli −− Refers to an external opening of the urachal duct in patients with history of chronically infected urachal cyst −− Vesicourachal diverticuli are associated with the prunebelly syndrome ♦♦ Hamartomatous polyp −− Presents as polypoid mass in the bladder near the urachus −− Composed of nests and glands of urothelial cells ♦♦ A variety of tumors may arise from urachal remnants −− This includes villous adenoma, adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and other tumors

Fig. 36.1. Exstrophy of the bladder. Extensive intestinal metaplasia is present.

Exstrophy Clinical ♦♦ A congenital malformation in which the anterior bladder wall and abdominal wall are absent ♦♦ Arises from failure of the midline to close properly in development and may be associated with other urogenital abnormalities (e.g., epispadias, bilateral inguinal hernia, bifid clitoris, vaginal stenosis) ♦♦ The exposure of the bladder mucosa to the external environment increases the risk of infection and carcinoma development (usually adenocarcinoma)

Microscopic ♦♦ Usually accompanied by some degree of bladder reversion with squamous metaplasia, cystitis glandularis, or intestinal metaplasia as associated findings (Fig. 36.1)

CYSTITIS ♦♦ Cystitis is a descriptive and often nonspecific term that refers to a variety of benign inflammatory lesions ♦♦ May be associated with proliferative and metaplastic conditions

Acute Cystitis ♦♦ Acute cystitis is characterized by predominantly neutrophilic infiltration of the lamina propria and urothelium ♦♦ It is associated with edema of lamina propria and frequent urothelial denudation ♦♦ A number of clinicopathological variants have been described

Variants ♦♦ Ulcerative cystitis

−− The urothelium is denuded and ulcerated ♦♦ Suppurative membranous cystitis −− The surface urothelium is covered by exudate and necrotic debris ♦♦ Emphysematous cystitis −− Inflammatory condition caused by infection by gas-forming bacteria such as Clostridium perfringens −− Usually limited to patients with predispositions to unusual infections, including diabetes, neurogenic bladder, and chronic urinary tract infection −− Gas-filled blebs with giant cell reaction in the lamina propria represent the main histologic finding

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♦♦ Viral cystitis −− Adenovirus, herpes simplex type 2 virus, and polyoma (Fig. 36.2) viruses have been implicated −− Patients with bladder involvement are usually immunosuppressed renal or bone marrow allograft recipients −− Maybe associated with hemorrhagic cystitis −− The identification of viral inclusions in histologic tissue sections is diagnostic −− Herpes zoster and cytomegalovirus have been rarely implicated −− No specific gross features have been described ♦♦ Fungal cystitis −− Candida albicans, Torulopsis glabrata, Aspergillus fumigatus, and Coccidioides immitis have been implicated −− Main clinical presentations are urinary tract irritative symptoms including nocturia, pain, and urgency, and frequency −− Grossly, the bladder mucosa is slightly elevated and irregular with white plaques −− Ulceration and submucosal mixed inflammation are ­frequently seen −− Typical fungal spores and hyphae are present within fibrinopurulent debris ♦♦ Actinomycosis −− Rare, a localized mass simulating a tumor may be present −− The submucosa and muscularis propria contain abundant granulation tissue and numerous abscesses −− “Sulfur granules” consisting of masses of filamentous mycelia with a peripheral array of swollen eosinophilic “clubs”

Essentials of Anatomic Pathology, 3rd Ed.

Variants ♦♦ Papillary–polypoid cystitis (proliferative papillary cystitis) −− Occurs in patients with history of indwelling catheter or vesical fistula −− Mainly seen in the dome or posterior wall of the urinary bladder −− Characterized by broad papillary projections of inflamed lamina propria with overlying hyperplastic urothelium −− The designation papillary cystitis is used when thin, finger-like papillae are present (Fig. 36.3A) −− Polypoid cystitis refers to lesions with edematous and broad-based papillae (Fig. 36.3B) −− Superficial umbrella cells are invariably present −− There is a prominent stromal edema, congestion, and inflammatory infiltrate −− See further discussion in Section “Benign Lesions and Mimics of Cancer” ♦♦ Follicular cystitis −− Typically an incidental finding −− May be associated with history of infection, biopsy, or intravesical Bacillus Calmette–Guerin (BCG) therapy

Chronic Cystitis ♦♦ Chronic inflammatory infiltrate of lamina propria is the chief characteristic together with edema and fibrosis of the lamina propria ♦♦ A number of variants have been described

Fig. 36.2. Polyoma virus infection. Nuclear viral inclusions are noted.

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Fig. 36.3. Proliferative papillary cystitis. (A) Papillary cystitis. (B) Polypoid cystitis.

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Fig. 36.5. Encrusted cystitis.

Fig. 36.4. Follicular cystitis.

−− Bladder mucosa may appear normal or have a finely nodular appearance cystoscopically −− Subepithelial lymphoid follicles with germinal centers are seen (Fig. 36.4) ♦♦ Encrusted cystitis −− Associated with infection of urea-splitting bacteria in alkalinized urine −− The ulcers are coated with calcium and phosphate salt, mononuclear cell infiltrate, and foreign body giant cell reaction (Fig. 36.5) −− May rarely extend into the muscularis propria

Granulomatous Cystitis ♦♦ Etiology −− Bacterial (a) Tuberculosis (b) Syphilis −− Fungal (a) Coccidiodomycosis (b) Histoplasmosis −− Parasitic (a) Schistosoma haematobium −− Iatrogenic (a) Post surgery or radiation (b) Post intravesical (BCG) therapy −− Malakoplakia −− Systemic granulomatous disease

−− −− −−

−−

(a) Crohn disease (b) Sarcoidosis (c) Rheumatoid disease Chronic granulomatous disease of childhood Xanthoma (with elevated serum cholesterol) Vasculitis (a) Wegener granulomatosis (b) Polyarteritis nodosa (c) Churg–Strauss syndrome Most cases remain idiopathic

Tuberculous Cystitis ♦♦ Is secondary to generalized spread from pulmonary infection by Mycobacterium tuberculosis and is often associated with renal tuberculosis ♦♦ Complications include scarring, obstruction, and fistula formation ♦♦ Histologically, presents as solitary or confluent ulcerated mucosal lesions, usually in the region of the ureteral orifices (trigone), with caseating granulomatous inflammation and fibrosis involving the lamina propria ♦♦ Frequently associated with the ulceration of the overlying mucosa ♦♦ Special stains (auramine–rhodamine or other AFB stain) demonstrate acid-fast bacilli

Malakoplakia Clinical ♦♦ “Malakoplakia” means “soft plaque” in Greek ♦♦ This benign process was first described by Michaelis and Gutmann and by von Hansemann in 1902 and 1903 ♦♦ There is a female predilection, with peak incidence in the fifth decade ♦♦ Patients typically present with symptoms of urinary tract infection

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♦♦ Represents an atypical infection by bacteria (usually Gramnegative bacteria, such as E. coli) in patients with lysosomal defects (defects in histiocyte function with impaired lysosome movement and inability of phagosomes to destroy bacteria) ♦♦ Symptoms include recurrent fever, hematuria, pyuria, urgency, pain, and weight loss ♦♦ Others organs may be involved

Macroscopic ♦♦ Multiple small yellow mucosal nodules or plaques, usually in the area of the trigone with a yellow to yellow-brown discoloration, not more than 2 cm in maximum dimension

Microscopic ♦♦ The lesion is characterized by mixed inflammatory infiltrate in the lamina propria ♦♦ Large numbers of epithelioid histiocytes (von Hansemann histiocytes) with abundant granular eosinophilic cytoplasm and intracytoplasmic inclusions (Michaelis–Gutmann bodies, 3–10 µm) are present (Fig. 36.6A) ♦♦ Michaelis–Gutmann bodies are concentrically laminated basophilic round to oval calcospherites and may be PAS+, iron+, and calcium (von Kossa stain)+, either freely in the stroma or as intracytoplasmic inclusions (Fig. 36.6B)

Electron Microscopy ♦♦ Concentrically laminated structures with a central electrondense core and radially oriented spicules ­hydroxyapatite crystals (Fig. 36.6C)

Differential Diagnosis ♦♦ Adenocarcinomas, including signet-ring cell adenocarcinoma −− Significant cytologic atypia is present −− Cytokeratin positive −− Usually lacks prominent mixed inflammatory background

Schistosomiasis Clinical ♦♦ Endemic in some parts of Africa and Southwest Asian countries, especially Egypt ♦♦ Granulomatous inflammation and fibrosis of lamina propria or muscularis propria ♦ ♦ Identification of schistosomal eggs (100 µm), ­frequently calcified in the bladder wall, is diagnostic (Fig. 36.7)

Treatment-Induced Cystitis Radiation Cystitis Clinical ♦♦ Inflammatory condition (with acute and chronic phases) associated with pelvic radiation treatment ♦♦ Patients have a previous history of radiation, not necessarily for bladder cancer, sometimes for prostate or cervical cancer ♦♦ Highly dose dependent (50% risk if receiving 70 Gy but only 5% risk with 60 Gy) ♦♦ Cystoscopy may show small papillary lesions, slight mucosal irregularities or nonspecific findings

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Fig. 36.6. Malakoplakia. (A) H&E staining. (B) PAS staining. (C) Electron microsopy.

Microscopic ♦♦ Early changes appear after 3–6 weeks and include acute cystitis and desquamation of the urothelial cells associated with hyperemia ♦♦ Later, there is epithelial hyperplasia producing a pseudoinfiltrative appearance. Nests of urothelial cells may have jagged or irregular contours

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Fig. 36.7. Schistosomiasis-associated granulomatous cystitis.

♦♦ Budding off single cells may also be seen, and the nests may show squamous differentiation, raising the suspicion of a malignant process ♦♦ These cells show mild to severe cytologic atypia with nuclear hyperchromasia; however, nucleoli are inconspicuous, the nuclear/cytoplasmic ratio is preserved or increased and mitotic figures are typically absent, features that are not characteristic of a malignant process (Fig. 36.8A) ♦♦ Other helpful features are the finding of scattered enlarged fibroblasts (Fig.  36.8B) in the lamina propria associated with nuclear hyperchromasia, hemorrhage or fibrin deposition, edema, inflammatory cells and ectatic vessels. Some vessels may show myointimal thickening and eccentric accumulation of amorphous pink material ♦♦ Acute phase occurs in <6 months (usually manifests within 6 weeks of treatment); subacute phase occurs from 6 months to 2 years after treatment; chronic phase usually takes 2–5 years to appear −− Acute phase (a) Hyperemia/congestion, petechiae (b) Marked edema with thick mucosal folds (“bullous cystitis”) (c) Mucosal erosion, denudation, and ulceration (d) Marked cellular atypia with large hyperchromatic, bizarre nuclei (e) Lamina propria edema and congestion −− Subacute phase (a) Mucosal erythema, edema, and chronic inflammation (b) Mucosal ulceration, variable atrophy, and urothelial hyperplasia −− Chronic phase (a) Thin, atrophic mucosa with or without ulceration (b) Some degree of residual epithelial atypia (c) Urothelial metaplasia and hyperplasia

Fig. 36.8. Radiation cystitis. (A) Acute phase and (B) chronic phase. (d) Fibrosis and collagen deposition in the lamina ­propria and muscularis propria with scattered atypical fibroblasts (e) Endothelial proliferation, arteriolar hyalinization, subendothelial and medial fibrosis (endarteritis obliterans) (f) Fistula formation

Differential Diagnosis ♦♦ Main entity entering differential diagnosis is carcinoma in situ (CIS), which has high nuclear cytoplasmic ratio, nuclear pleomorphism and hyperchromasia

BCG-Induced Granulomatous Cystitis Clinical ♦♦ Clinical history is critical in determining the etiology of this increasingly frequent lesion ♦♦ BCG is used to treat patients with superficial high grade bladder carcinoma or CIS ♦♦ Symptoms include dysuria, frequency, fever, and other systemic reactions (e.g., pneumonitis, hepatitis, rash, and arthralgia)

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Fig. 36.9. BCG-treatment associated granulomatous cystitis.

Microscopic ♦♦ There is erosion and ulceration of the mucosa and a sarcoidlike nonnecrotizing granuloma with giant cells (Fig. 36.9) ♦♦ Edema, congestion, and chronic inflammatory infiltrate in the lamina propria are associated features

Cytoxan-Induced Hemorrhagic Cystitis Clinical ♦♦ Occurs in up to 8% of patients treated with cyclophosphamide (Cytoxan) and is secondary to toxic metabolite acrolein (an aldehyde and oxidizing agent from tobacco and systematic inflammation) that is excreted in the urine ♦♦ May result in severe, intractable hematuria, which may require cystectomy

Fig. 36.10. Hemorrhagic cystitis. (A) Gross and (B) microscopic.

Macroscopic ♦♦ At endoscopy, there is a diffuse, severe hyperemia with edema and erosion or ulceration of the mucosa (Fig. 36.10A)

Microscopic ♦♦ Urothelial denudation/ulceration leads to regeneration with reparative urothelial changes that results in atypical urothelium covering a lamina propria with edema and extensive hemorrhage (Fig. 36.10B) ♦♦ A frequent finding is the activation of polyoma virus or adenovirus infection that should not be mistaken for malignancy

Postsurgical Granuloma Clinical ♦♦ History of prior surgery or instrumentation ♦♦ The etiology is related to immunologic recognition of altered antigen induced by the procedure (also known as necrobiotic granuloma)

Pathology ♦♦ Hemorrhage, necrosis, and mucosal irregularities are common

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♦♦ The granulomas include a central zone of fibrinoid necrosis surrounded by a peripheral rim of palisading epithelioid histiocytes (Fig. 36.11) ♦♦ Chronic inflammatory infiltrate composed of histiocytes, giant cells, lymphocytes, plasma cells, and eosinophils

Special Variants of Cystitis Interstitial Cystitis Clinical ♦♦ Uncommon inflammatory process seen in middle-aged women (30–50 years) that presents with dysuria, urgency, frequency, hematuria, or generalized pelvic pain ♦♦ The diagnosis is made clinically based on symptoms and cystoscopic examination. There is also negative testing for bacterial, fungal, or viral pathogens ♦♦ Some cases are associated with allergic and autoimmune disorder (rheumatoid arthritis, systemic lupus erythematosus, or autoimmune thyroiditis) ♦♦ Antinuclear antigen test is positive in >50% of cases

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Fig. 36.11. Postsurgical granuloma.

Macroscopic ♦♦ Scattered petechial hemorrhages ♦♦ Wedge-shaped ulceration (Hunner ulcer)

Microscopic (Fig. 36.12) ♦♦ There are two main histologic forms −− The ulcerated form (classic form; Hunner ulcer) shows scattered petechial hemorrhages, wedge-shaped ulcerations. The mucosa may be denuded or replaced by granulation tissue ♦♦ The nonulcerated form shows edema and congestion, with a mononuclear inflammatory infiltrate in the lamina propria. There are characteristic glomerulations (mucosal hemorrhage) and mucosal rupture ♦♦ Mast cell infiltration in the lamina propria and muscularis propria is common in both forms of interstitial cystitis. Perineural mononuclear infiltration is also common −− Fibrosis of the lamina propria and muscularis propria occurs frequently

Immunohistochemistry ♦♦ Discontinuous uroplakin III immunostaining in superficial (umbrella) cells of patients with interstitial cystitis and continuous immunostaining in urothelium of patients without disease has been reported

Differential Diagnosis ♦♦ Other forms of cystitis, including tuberculous cystitis and eosinophilic cystitis or nonspecific acute or chronic cystitis should be considered in the differential diagnosis

Eosinophilic Cystitis Clinical ♦♦ Inflammatory process found in women and children; seen with allergic disorders and other diseases associated with peripheral eosinophilia

Fig. 36.12. Interstitial cystitis. (A) Hunner ulcer. (B) Nonulcer form. (C) Toluidine blue stainings highlight mast cells. ♦♦ Uncommonly seen in elderly men with bladder injury or history of transurethral resection ♦♦ Symptoms include severe frequency, urgency, dysuria, and hematuria, with periods of remission and exacerbation ♦♦ Spontaneous resolution is common

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Macroscopic ♦♦ Diffuse mucosal edema and erythema or velvety yellow plaque ♦♦ Tumor-like polypoid growths that appear erythematous and may demonstrate ulceration or necrosis may be seen

Microscopic ♦♦ Mononuclear and eosinophilic infiltrate in the lamina ­propria and muscularis is the main histological finding (Fig. 36.13) ♦♦ Early disease is characterized by marked edema, congestion, and a mixed mononuclear and eosinophilic infiltrate, but in severe cases, muscle necrosis may be seen ♦♦ As the disease progresses, the inflammatory infiltrate tends to subside and varying degrees of fibrosis may be seen in the lamina propria and muscularis Fig. 36.13. Eosinophilic cystitis.

BENIGN LESIONS AND MIMICS OF CANCER Urothelial Hyperplasia ♦♦ Urothelial hyperplasia may be flat or papillary

Flat Urothelial Hyperplasia ♦♦ Flat urothelial hyperplasia is characterized by marked thickening of the mucosa usually to ten or more cell layers (Fig. 36.14) −− The nuclei may be slightly enlarged, but importantly, cytologic atypia is absent −− There is morphologic evidence of maturation from basal cells to superficial cells −− Mitotic figures are rare and limited to the basal layers

−− Tangential sectioning of suboptimally oriented biopsies may give a false impression of mucosal thickening ♦♦ The true incidence of flat hyperplasia is not known due to lack of large scale screening studies −− Flat urothelial hyperplasia may occur adjacent to low grade papillary tumors or as an isolated lesion −− When isolated, flat hyperplasia does not appear to have a premalignant potential −− In contrast, frequent genetic alterations have been identified in flat hyperplasia and concurrent papillary tumors by loss of heterozygosity analysis (LOH) and FISH analyses −− These studies suggest a link between flat hyperplasia and papillary urothelial carcinoma; but specific treatment is unwarranted in the absence of papillary urothelial carcinoma or CIS

Papillary Urothelial Hyperplasia Clinical ♦♦ This is a controversial entity with unknown clinical significance ♦♦ Some investigators consider it as a precursor to grade 1 papillary urothelial carcinoma ♦♦ Most cases of papillary urothelial hyperplasia are ­discovered incidentally on followup cystoscopy for previous papillary tumors

Microscopic

Fig. 36.14. Urothelial hyperplasia.

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♦♦ The lesion displays undulating folds of urothelium that may have increased vascularity at the base of papillary folds, but lacks well-developed fibrovascular cores of a papillary neoplasm (Fig. 36.15)

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Fig. 36.15. Papillary urothelial hyperplasia.

Fig. 36.16. Keratinizing squamous cell metaplasia.

♦♦ Although considered “hyperplastic,” papillary hyperplasia is typically surfaced by normal-appearing urothelium between four and seven cells in thickness ♦♦ Cytologically, the urothelial cells in papillary hyperplasia lack atypia and maintain nuclear polarity

Microscopic

Differential Diagnosis ♦♦ The primary differential diagnosis includes papilloma, low grade papillary neoplasm, and papillary cystitis ♦♦ In contrast to papillary neoplasms, papillary hyperplasia lacks arborization and detached papillary fronds ♦♦ Papillary hyperplasia also lacks the broad-based stalks and inflammation seen in papillary–polypoid cystitis

Metaplasia Squamous Metaplasia Clinical ♦♦ More commonly seen in men, with a male-to-female ratio of 4:1 ♦♦ Usually occurs in the setting of long-standing chronic inflammation, but may be focally present in noninflamed bladders ♦♦ Associated conditions include exstrophy, neurogenic bladder, indwelling catheter, previous surgery or biopsy, recurrent infection (e.g., schistosomiasis), and calculi ♦♦ Nonkeratinizing squamous metaplasia of the trigone in women is a normal finding secondary to estrogen stimulation and does not need to be reported ♦♦ Keratinizing squamous metaplasia is considered a putative precursor to carcinoma ♦♦ Nonkeratinizing squamous metaplasia is not associated with increased risk of carcinoma

Macroscopic ♦♦ May appear as multiple small nodular/papular mucosal lesions, or as dull white plaques ♦♦ Trigone is the region most commonly affected

♦♦ It may appear as mature or immature keratinizing squamous epithelium (Fig. 36.16)

Nephrogenic Adenoma (Metaplasia) Clinical ♦♦ Usually occurs in middle-aged men (M:F = 2:1, mean age = 41 years) ♦♦ In most cases, it is an incidental finding, but in one-third of cases, lesions are sizable and 10% are 4 cm or larger ♦♦ Frequently occurs in the setting of long-standing chronic irritation ♦♦ 20% of cases occur in children and adolescents ♦♦ 8% of patients have undergone kidney transplantation. In studies of these patients, the cells of nephrogenic adenoma derive from tubular cells of the renal transplant, and are not metaplastic proliferations of the recipient’s bladder urothelium ♦♦ Approximately 80% of the lesions occur in the bladder, with the remainder involving the urethra (15%) or ureter (5%) and, rarely, the renal pelvis ♦♦ Nephrogenic adenoma may recur, but malignant transformation has not been unequivocally documented

Macroscopic ♦♦ Papillary or polypoid small solitary yellow nodules (usually <1 cm) ♦♦ Erythematous irregular mucosa with a predilection for the trigone

Microscopic ♦♦ The lesion is composed of a well-circumscribed proliferation of small compact tubules, cysts, and delicate filiform papillae lined by columnar or cuboidal hobnail or flattened cells (Fig. 36.17) ♦♦ Cells have clear to eosinophilic cytoplasm and uniform nuclei with inconspicuous mitotic figures

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Differential Diagnosis ♦♦ Clear cell adenocarcinoma −− Usually occurs in elderly women −− The tumor is not confined to the lamina propria and has an infiltrative rather than well-circumscribed pattern of growth −− Cytologic atypia and frequent mitotic figures are seen −− Immunohistochemical stains are not helpful in this differential diagnosis due to overlapping immunohistochemical profiles ♦♦ Urothelial carcinoma with tubuloglandular pattern −− Characterized by tubules lined by multiple layers of urothelial cells rather than a single cell layer −− Cytologic atypia, infiltrative growth, frequent mitotic figures, high proliferation (Ki-67+), high p53 nuclear accumulation, lack of prominent basement membrane and architectural heterogeneity favor malignancy ♦♦ Signet-ring cell adenocarcinoma of the bladder or adenocarcinoma metastatic to the bladder −− Significant cytologic atypia and single cell infiltrates are seen −− Vacuoles positive for mucin stains and negative for glycogen

Cystitis Glandularis Clinical

Fig.  36.17. Nephrogenic adenoma. Papillae and tubules are common patterns (A). Prominent nucleoli may be seen (B). ♦♦ Intracytoplasmic vacuoles (glycogen+) may be seen, imparting a signet-ring cell appearance ♦♦ Tubules have thickened PAS+ basement membrane and may contain eosinophilic PAS+ secretions ♦♦ Often accompanied by chronic inflammation and associated with squamous metaplasia, cystitis cystica, and cystitis glandularis ♦♦ Cytologic atypia including nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli may be focally seen (atypical nephrogenic adenoma); however, these lesions are benign and do not need further treatment ♦♦ A rare variant of nephrogenic adenoma with myxoid stroma has been reported recently (fibromyxoid nephrogenic adenoma) ♦♦ The tubules of nephrogenic adenoma may occasionally be intermixed with muscle fibers of the muscularis mucosa in the bladder. This should not be mistaken for malignancy

Immunohistochemistry ♦♦ Strong positivity for wide spectrum keratin, CK7, EMA, vimentin, PAX2, and alpha-methylacyl-CoA racemase (P504S) ♦♦ TP53 and Ki-67 are typically negative

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♦♦ Cystitis glandularis is a relatively common histologic finding, most frequently seen in the trigone ♦♦ It can be divided into two subtypes: usual type and intestinal type (cystitis glandularis with intestinal metaplasia) ♦♦ Cystitis glandularis of the usual type is a common benign lesion ♦♦ Cystitis glandularis of the intestinal type (cystitis glandularis with intestinal metaplasia) is less frequent (incidence of 0.1– 0.9%) and more commonly seen in patients with exstrophy and pelvic lipomatosis −− Cystitis glandularis with intestinal metaplasia has been considered a premalignant lesion by some investigators −− A recent molecular study indicates that intestinal metaplasia in the urinary bladder is associated with significant telomere shortening relative to adjacent normal urothelial cells −− These lesions also occasionally show cytogenetic abnormalities associated with telomere shortening

Macroscopic ♦♦ On cystoscopic examination, these lesions may be seen as a nodular or polypoid growth, especially for cases of cystitis glandularis of intestinal type. These may mimick a malignant neoplasm

Microscopic ♦♦ This lesion typically evolves and imperceptibly merges with von Brunn nests, a common benign epithelial abnormality of the bladder

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Fig. 36.18. Cystitis glandularis with intestinal metaplasia.

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Fig. 36.19. Cystitis cystica.

♦♦ When those nests become cystic with central lumen formation and polarization of the inner cells, the term cystitis glandularis is used ♦♦ Cystitis glandularis, of the usual type, is composed of an inner layer of columnar to cuboidal cells surrounded by an outer layer/s of transitional cells −− Similar epithelium may be present on the surface ♦♦ The glands of cystitis glandularis of the intestinal type are lined by mucinous epithelium including goblet cells, closely resembling colonic epithelium (Fig. 36.18) −− It may be florid and associated with mucin extravasation −− The stroma may show mild edema or hyalinization and inflammatory cell infiltration

Differential Diagnosis ♦♦ Primary bladder adenocarcinoma −− The distinction between these two entities is based on growth pattern and cytology −− Adenocarcinoma often presents as advanced stage cancer with the bulk of the tumor in the serosa and muscularis propria and with less involvement of the lamina propria. The degree of cytologic atypia is substantial −− In contrast, the benign process (cystitis glandularis with intestinal metaplasia) is characterized by an orderly distribution of glands lacking cytologic atypia or mucinous cells freely floating in mucinous pools ♦♦ Endocervicosis −− This is a benign müllerian lesion composed of glands lined by endocervical-type epithelium, some of which may rupture resulting in mucin extravasation. However, if the latter is present, it is very focal and associated with a histiocytic and fibroblastic inflammatory response −− Endocervicosis is often centered in the muscularis propria rather than lamina propria

Fig. 36.20. von Brunn nest. ♦♦ These are unilocular cysts lined by single or multiple layers of cuboidal urothelial cells (Fig. 36.19) ♦♦ Acute and chronic inflammation may be present

von Brunn Nests and von Brunn Nest Proliferations ♦♦ Occur in ~85% of autopsy patients. Represent a normal variant of bladder mucosa ♦♦ Solid nests of urothelium project into the lamina propria. May contain luminal eosinophilic secretions (Fig. 36.20) ♦♦ Exuberant von Brunn nest proliferation may be observed, mimicking inverted papilloma or inverted urothelial carcinoma (Fig. 36.21)

Cystitis Cystica

Florid Cystitis Glandularis Clinical

♦♦ May appear as small (1–5  µm) yellow cysts in the lamina propria

♦♦ Usually an incidental finding. Patients may present with irritative obstructive symptoms or hematuria. No malignant potential

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Differential Diagnosis ♦♦ Adenocarcinoma is the main differential diagnosis and has significant cytologic atypia, infiltrative growth, and invasion into muscularis propria ♦♦ Endocervicosis and müllerianosis may involve both the muscularis propria and lamina propria; but the greater portion of the lesion is in the muscularis propria

Endometriosis Clinical

Fig. 36.21. Exuberant von Brunn nest proliferation.

Fig. 36.22. Florid cystits glandularis.

Macroscopic ♦♦ Nodular or polypoid lesion, with predilection for the trigone and bladder neck

Microscopic ♦♦ There is involvement of von Brunn nests by glandular metaplasia resulting in an exuberant proliferation of glands lined by columnar cells, with or without goblet cells (Fig. 36.22) ♦♦ Lesions are confined to the lamina propria and lack significant cytologic atypia, but some may be difficult to differentiate from adenocarcinoma. The situation may be further confounded by extravasation of mucin into the stroma ♦♦ Characterized by proliferations of glands in the lamina propria, some have the appearance of cystitis glandularis of the usual type ♦♦ Most glands are lined by tall columnar cells with basally located nuclei lacking cytologic atypia ♦♦ Paneth cells may be seen

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♦♦ The bladder is the organ most commonly involved by endometriosis in the urinary tract −− Approximately 1% of women with endometriosis have urinary bladder involvement −− Typically occurs in women of reproductive age −− Up to 50% have a history of pelvic surgery −− Rarely vesical endometriosis has been reported in men with prostate carcinoma treated by estrogen therapy −− Clinical manifestations include frequency, dysuria, and hematuria, and in 75% of cases these symptoms have catamenial exacerbations ♦♦ A suprapelvic mass is palpable in 50% of the patients −− Secondary and significant complications include obstruction of the ureteric orifices with secondary hydronephrosis or vesicocolic fistula −− Most commonly involves the posterior wall or trigone −− Presents as an elevated, congested and edematous area in the mucosa overlying a translucent, blue-black or redbrown area of discoloration −− On rare occasion, the appearance may mimic cystitis glandularis or an unusual gross morphology of bladder cancer

Macroscopic ♦♦ On gross examination, it may form a mass involving the bladder wall, most often secondary to muscle hypertrophy or fibrosis associated with endometriosis −− If there is no mass, a hemorrhagic punctate lesion may be observed if the glands are cystically dilated secondary to catamenial changes

Microscopic ♦♦ The lesion is composed of endometriotic glands and stroma with hemosiderin deposition (requires two of these three elements to make the diagnosis) (also see description in Chap. 37) ♦♦ The endometrial glands are typically lined by cuboidal cells with eosinophilic cytoplasm and pseudostratified nuclei that may show mitotic activity depending on the phase of the cycle ♦♦ The stroma may contain foamy histiocytes with some chronic inflammatory cells ♦♦ The endometriotic stroma may be focally absent around some of the glands, and in postmenopausal women that are

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not on estrogen replacement, the diagnosis of endometriosis may be made in the absence of endometrial stroma −− In such instances, the glands still retain their endometriotic appearance −− In some cases, the endometrial stroma may be replaced by elastotic stroma similar to that seen in radial scars of the breast ♦♦ In the urinary bladder, malignant tumors have arisen in association with endometriosis, most commonly endometrioid and clear cell adenocarcinomas

Endocervicosis Clinical ♦♦ Occurs in women of reproductive age who complain of suprapubic pain, dysuria, frequency, and hematuria with catamenial exacerbation of the symptoms ♦♦ Predilection for posterior wall or posterior dome

Microscopic ♦♦ Proliferation of endocervical-type glands, which are often cystically dilated and reactive, but lack significant cytologic atypia ♦♦ Usually involves the muscularis propria. On microscopic examination, there is a haphazard proliferation of glands throughout the bladder wall, typically centered in the muscularis propria, which may extend to the lamina propria or bladder serosa; however, the glands do not show crowding or back to back growth ♦♦ The glands have irregular sizes and shapes, and are lined by a single layer of columnar cells with abundant pale mucinous cytoplasm (mucicarmine and PASD positive). The cells have a basally located small nucleus as seen in normal endocervical glands ♦♦ Cells with a goblet-like appearance may be seen with the nucleus eccentrically compressed ♦♦ Some glands may contain ciliated cells or nonspecific cuboidal cells intercalated with the mucinous cells, and in some cases, occasional endometriotic glands may be seen (Fig. 36.23) ♦♦ Cytologic atypia is absent or mild and mitotic activity is exceptionally rare ♦♦ Extravasated mucin is associated with stromal edema, fibrosis, and a prominent inflammatory response ♦♦ May be associated with endometriotic stroma ♦♦ Primary adenocarcinoma may develop in a background of endocervicosis, in which case, there is a transition from dysplastic epithelium to frankly malignant glands

Immunohistochemistry ♦♦ Immunohistochemical stains show apical positivity of the mucinous cells for CA125 (antigen present in normal müllerian epithelia, including endocervical, endometrial, and tubal epithelium) ♦♦ Estrogen and progesterone receptors are positive ♦♦ CEA, EMA, cytokeratin, and B72.4 are also positive

Fig. 36.23. Endocervicosis (A, B).

Differential Diagnosis ♦♦ Cystitis glandularis (intestinal type), urachal remnants, and primary or secondary adenocarcinoma enter the differential diagnosis

Müllerianosis Clinical ♦♦ Occurs in women of reproductive age (37–46 years) ♦♦ Commonly located in the posterior wall of the bladder and may form a tumor-like mass (up to 3 cm)

Microscopic (Fig. 36.24) ♦♦ This entity is defined as a benign epithelial proliferation composed of an admixture of tubal, endocervical and endometrioid-type müllerian glandular epithelium outside the primary müllerian system ♦♦ Characterized by the presence of at least two of three components −− Endosalpingosis −− Endocervicosis

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involves the muscularis propria and lamina propria of the posterior wall −− Nephrogenic adenoma typically shows a tubulocystic pattern. Cilia or mucinous cells are not present. Nephrogenic adenoma does not involve the muscularis propria

Diverticulosis Clinical ♦♦ Acquired outpouching of the mucosa through the muscularis propria, usually due to increased pressure associated with bladder outlet obstruction (most commonly prostatic hyperplasia) ♦♦ Usually occurs in elderly male patients ♦♦ The diverticulum may give rise to calculi or tumor ♦♦ Tumors developing from diverticulosis are usually urothelial carcinoma, but adenocarcinoma, squamous cell carcinoma, or carcinosarcoma may be seen

Macroscopic ♦♦ Pockets of bladder mucosa projecting into (and sometimes through) the muscularis propria ♦♦ Usually located in the posterior wall, the dome, and the region of the urachus ♦♦ May contain calculi

Microscopic ♦♦ The lining is usually urothelial. Squamous metaplasia is common ♦♦ Varying degree of inflammation are seen

Postoperative Spindle Cell Nodule Clinical

Fig. 36.24. Müllerianosis. (A) Two components of müllerianosis (endocervicosis and endometriosis) are seen. (B) Endometriosis.

♦♦ Rare sequela of bladder or prostate surgery, especially transurethral resection. It usually presents weeks to months after surgery ♦♦ May be an incidental finding during routine followup or patients may present with microscopic hematuria, urinary obstruction or irritative voiding ♦♦ On cystoscopy, the lesions are typically polypoid or nodular with poorly defined margins ♦♦ These lesions may destroy and infiltrate the bladder wall mimicking a malignant tumor ♦♦ They have a benign clinical course and conservative treatment is recommended

−− Endometriosis (triad of endometrial glands, stroma, and hemosiderin-laden histiocytes) ♦♦ Müllerianosis typically involves the lamina propria and muscularis propria as a proliferation of tubules and cysts with irregular sizes and shapes lined by ciliated cells intercalated with peg cells, next to endometriotic glands with endometrial stroma, and a component of glands lined by columnar mucinous cells ♦♦ CD10+ cells in the stroma help to recognize endometriosis

Macroscopic

Differential Diagnosis

Microscopic

♦♦ The differential diagnosis includes cystitis glandularis, cystitis cystica, and nephrogenic adenoma −− Cystitis glandularis does not involve the muscularis propria, the glands are lined by the urothelium and endometriotic stroma is not seen. Müllerianosis typically

♦♦ Cellular spindle cell neoplasm with loosely arranged intersecting fascicles and myxoid vascular stroma ♦♦ Tumor cells have abundant eosinophilic cytoplasm. The nuclei are oval or spindled throughout the lesion, with one or two small nucleoli and delicate chromatin

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♦♦ Soft or firm small submucosal lesion with a gray, yellow to tan cut-surface ♦♦ Polypoid or nodular growth, typically in the same area as the previous surgery

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♦♦ Inflammatory myofibroblastic tumor (see discussion below) −− Does not have a previous history of surgery at the site where it develops −− ALK-1 positive

Inflammatory Myofibroblastic Tumor Clinical

Fig. 36.25. Postoperative spindle cell nodule.

♦♦ Mitotic activity may be brisk, up to 25/10 HPFs; however, no atypical mitosis or significant cytologic atypia is seen (Fig. 36.25) ♦♦ The tumor edge may have a pseudoinfiltrative appearance ♦♦ The spindle cells are admixed with variable number of chronic inflammatory cells in the deeper areas of the lesion, while the superficial component may be associated with acute inflammatory infiltrate due to surface ulceration ♦♦ Areas of edema, myxoid change and multiple small foci of hemorrhage are typically seen ♦♦ The cells of the postoperative spindle cell nodule are myofibroblasts by ultrastructure and by immunohistochemistry

Immunohistochemistry ♦♦ Cytokeratin and vimentin negative; smooth muscle actin often positive

Differential Diagnosis ♦♦ Sarcoma (leiomyosarcoma, fibrosarcoma) −− Sarcoma will show compact, dense cellularity as well as cytologic atypia, atypical mitotic figures, and tumor necrosis −− Clinical history of bladder surgery or procedures within the last 6–8 weeks is helpful in establishing the diagnosis ♦♦ Sarcomatoid carcinoma (especially myxoid variant) −− Biphasic tumor with identifiable epithelial elements (cytokeratin positive) −− Cytologic atypia is present ♦♦ Kaposi sarcoma −− Spindle cell proliferation of malignant endothelial cells with cytologic atypia −− Hemorrhage may results in rows or clusters of red cells within slit-like spaces associated with hemosiderin-laden macrophages and chronic inflammatory cells −− CD31 and/or CD34 immunostains are positive

♦♦ Reactive myofibroblastic proliferation in children and young adults ♦♦ Patients range in age between 30 and 50 years, although it may occur at any age and it appears to be slightly more frequent in women ♦♦ Gross hematuria is the most common presenting symptom, followed by bladder obstruction; however, some patients may be asymptomatic ♦♦ There is some uncertainty regarding the pathogenesis and malignant potential of this lesion. Some consider it as a low  grade neoplasm that may recur. Complete excision is recommended

Macroscopic ♦♦ The lesions range from pedunculated masses protruding into the bladder cavity to nodules or ulcerating masses that deeply infiltrate the bladder wall. They are solitary with a broad base ♦♦ Typically 2–5  cm in size nodular or polypoid exophytic mass

Microscopic (Fig. 36.26) ♦♦ These lesions may show two different histologic patterns −− Disorganized, loose fascicles of spindle cells with a noticeable edematous-myxoid background and a prominent vascular network composed of small capillaries (resembling nodular fasciitis) −− Cellular areas with intersecting fascicles of spindle cells and variable amounts of intercellular collagen. This pattern maybe be more commonly seen in the deeper portion of the bladder wall ♦♦ The cells are elongated with tapering eosinophilic cytoplasmic processes. Stellate cells and polygonal cells may also be seen, especially in the more myxoid areas. The nuclei are oval- to spindle-shaped with open chromatin and one or multiple nucleoli ♦♦ There is no marked cytologic atypia or nuclear pleomorphism ♦♦ Mitotic figures may be present (up to 4/10 HPFs), usually not as prominent as seen in postoperative spindle cell nodule ♦♦ There is an inflammatory infiltrate, commonly composed of eosinophils, lymphocytes and plasma cells. The latter can be quite prominent imparting an appearance reminiscent of plasma cell granuloma. Extravasation of red blood cells and focal hemorrhage are also common ♦♦ Two features worrisome for malignancy or associated with aggressive behavior −− Wall invasion reaching the outer aspect of the muscularis propria −− Presence of necrosis

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Fig. 36.26. Inflammatory myofibroblastic tumor. (A) Myxoid pattern. (B) Plasma cell predominance. (C) The tumor is well circumscribed. (D) It shows spindle cell proliferation with mixed inflammatory cell infiltrate. (E) ALK-1 immunostaining is positive. (F) FISH analysis for ALK gene break-apart rearrangement showing the native ALK region as red/green fusion signals (normal), and the breakapart ALK region as split red and green signal pattern (yellow arrows). Red signals: ALK upstream; green signals: ALK downstream.

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♦♦ These lesions are typically diploid and by electron microscopy, the cells show myofibroblastic features

Immunohistochemistry ♦♦ Cytokeratin may be positive; vimentin, EMA and desmin are positive; muscle-specific actin and smooth muscle actin are usually positive ♦♦ Anaplastic lymphoma kinase (ALK-1) positive

Differential Diagnosis ♦♦ Sarcoma (myxoid fibrosarcoma or myxoid leiomyosarcoma) −− Marked cytologic abnormalities with frequent mitotic figures, including atypical forms and more diffuse infiltrative growth −− Areas of tumor necrosis −− ALK-1 negative ♦♦ Sarcomatoid carcinoma −− More common in elderly men −− Biphasic tumor morphology with identifiable epithelial elements and cytologic atypia −− Cytokeratin is strongly positive including CK 34bE12 and CK5/6; p63 is positive in about half of the cases −− ALK-1 negative ♦♦ Postoperative spindle cell nodule −− These are more cellular and have a previous history of surgery as discussed earlier

Ectopic Prostatic Tissue Clinical ♦♦ Occurs most frequently in adolescents or young adults but can also occur in older patients, ranging in age from 30 to 84 years old ♦♦ The etiology is uncertain ♦♦ Presents with hematuria or irritative symptoms ♦♦ Mainly seen in the bladder and prostatic urethra

Microscopic ♦♦ Benign prostatic glands with overlying intact urothelium (Fig. 36.27)

Immunohistochemistry ♦♦ PSA, PSAP, and P501S are positive ♦♦ High molecular weight cytokeratin (CK 34bE12) positive in basal cells

Papillary–Polypoid Cystitis (Proliferative Cystitis) Clinical ♦♦ Also discussed in Section “Cystitis” (chronic cystitis) ♦♦ These lesions are the result of inflammation and edema in the lamina propria. They may be seen in up to 80% of patients with indwelling catheter ♦♦ Vesical fistulae, whether resulting from appendicitis, Crohn disease, diverticulitis or colorectal cancer, are also frequently

Fig. 36.27. Ectopic prostatic tissue. (A) H&E. (B) PSA immuno­ staining.

associated with proliferative cystitis. In about 50% of patients, however, obvious signs of extravesical disease may be initially absent ♦♦ On cystoscopy, the lesion frequently resembles papillary urothelial carcinoma

Macroscopic ♦♦ Most lesions are microscopic in size, but in up to 33% may reach 5 mm in largest dimension ♦♦ Papillary structures may be recognizable

Microscopic ♦♦ The term “polypoid” is used for bulbous, broad-based lesions and the term “papillary” is used for lesions with a finger-like appearance ♦♦ Distinguishing polypoid/papillary cystitis from papillary urothelial carcinoma can be challenging. In contrast to papillary urothelial carcinoma, the fronds associated with proliferative cystitis are much broader and branching is absent or minimal (Fig. 36.3)

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♦♦ There is prominent edema associated with reactive and metaplastic changes such as squamous metaplasia ♦♦ The urothelium may be hyperplastic, but it lacks cytologic atypia

Pyogenic Granuloma ♦♦ Rare examples of pyogenic granuloma have been described in the bladder ♦♦ The histology is similar to pyogenic granuloma seen at other organ sites

Condyloma Acuminatum ♦♦ Rarely occurs in the urinary bladder ♦♦ Usually coexists with condyloma of the urethra, vulva, vagina, anus, or perineum ♦♦ Male-to-female ratio = 1:2; occurs in all ages ♦♦ At cystoscopy, isolated or multiple exophytic lesions mainly in bladder neck or trigone ♦♦ Low risk HPV DNA (type 6) has been found in some cases ♦♦ Morphology is identical to those seen in other organ sites. Koilocytic atypia is present (Fig. 36.28)

Fig. 36.28. Condyloma acuminatum. Koilocytic change can be subtle (A) and human papillomavirus in situ hybridization is positive (B).

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Amyloidosis Clinical ♦♦ Primary amyloidosis of the bladder is rare and has a male predominance ♦♦ May be confused clinically with urothelial carcinoma at initial presentation, as patients are typically old (sixth to eighth decades) and have similar clinical symptoms ♦♦ On cystoscopic examination, raised, erythematous, papillary, and hemorrhagic lesions may be detected, some may be seen as yellow submucosal plaques. The lesions are often multiple ♦♦ The most commonly involved areas include the posterior, posterolateral walls, and the trigone ♦♦ Local recurrences are common, but in most cases patients do not develop systemic amyloidosis. Conservative treatment is recommended

Microscopic ♦♦ The muscularis mucosae and muscularis propria are infiltrated by extracellular proteinaceous amorphous eosinophilic deposits that may be accompanied by a minimal degree of chronic inflammation (Fig. 36.29) ♦♦ Congo red stain allows visualization of the characteristic fluorescent apple green color under polarized light

Fig. 36.29. Amyloidosis of the urinary bladder.

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NEOPLASMS OF THE BLADDER (TABLE 36.1) Benign Urothelial Neoplasms Urothelial Papilloma Clinical ♦♦ Most papillomas are solitary lesions, occurring in younger patients than carcinoma (mean age, 46 years; range, 22–89 years) ♦♦ Accounts for 1–2% of papillary urothelial neoplasms in some series ♦♦ Hematuria is the most common presenting symptom ♦♦ Urothelial papilloma may arise as a de novo neoplasm, or it may occur in patients with a clinical history of bladder cancer, as a secondary papilloma ♦♦ Urothelial papilloma may recur; however, it does not progress. Aggressive behavior has been reported in a patient with urothelial papilloma on immunosuppressive therapy secondary to a renal transplant ♦♦ The cystoscopic appearance is identical to that of low grade papillary neoplasms −− Delicate, small papillary tumor that usually is solitary

Macroscopic ♦♦ Exophytic solitary small papillary lesion (<2 cm)

Microscopic ♦♦ Urothelial papilloma is a benign exophytic neoplasm composed of a delicate fibrovascular cores lined by normalappearing urothelium (Fig. 36.30) ♦♦ Key features −− Cytologically and architecturally normal urothelium covers delicate fibrovascular stalks −− <7 layers in thickness −− Normal polarity is retained −− Mitoses are absent to rare and, if present, are located in the basal cell layer −− Lacks cytologic atypia −− Cytokeratin 20 expression is identical to that in normal urothelium (superficial “umbrella” cells only) ♦♦ The superficial (umbrella) cells are often prominent and may display increased cytoplasm, vacuolization, and degenerative nuclear atypia ♦♦ The stroma may show edema and/or lymphoid inflammatory cells ♦♦ Rarely, urothelial papilloma shows extensive multifocal involvement of the mucosa; a phenomenon referred to as diffuse papillomatosis

Molecular Pathology

Table 36.1. Classification of Urothelial Tumors Urothelial tumors   Urothelial papilloma (benign)   Inverted papilloma (benign)   Noninvasive papillary urothelial carcinoma   Invasive urothelial carcinoma    Variants     Mixed differentiation (specify percentage)      With squamous differentiation      With glandular differentiation      With trophoblastic differentiation     Nested     Microcystic     Micropapillary     Lymphoepithelioma-like     Lymphoma-like and plasmacytoid     Sarcomatoid     Clear cell (glycogen-rich)     Lipoid cell     Undifferentiated     Pleomorphic giant cell carcinoma    Urothelial carcinoma with unusual stroma reactions      With pseudosarcomatous stroma      With stromal osseous or cartilaginous metaplasia Squamous Neoplasms    Squamous cell papilloma   Squamous cell carcinoma    Variants     Verrucous squamous cell carcinoma     Basaloid squamous cell carcinoma     Schistosoma-associated squamous cell carcinoma Glandular Neoplasms   Villous adenoma   Adenocarcinoma    Urachal adenocarcinoma    Clear cell adenocarcinoma    Hepatoid adenocarcinoma Neuroendocrine tumors   Paraganglioma   Carcinoid   Large cell neuroendocrine carcinoma   Small cell carcinoma Sarcomatoid carcinoma Soft tissue tumors   Leiomyoma   Granular cell tumor   Neurofibroma   Hemangioma   Rhabdomyosarcoma   Leiomyosarcoma   Angiosarcoma   Osteosarcoma   Malignant fibrous histiocytoma

♦♦ Papillomas are diploid and show frequent FGFR3 (75%) mutation

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Immunohistochemistry ♦♦ Papilloma shows low proliferation and uncommon p53 nuclear accumulation ♦♦ Cytokeratin 20 expression is limited to the superficial (umbrella) cells in the usual expression pattern for normal urothelium

Differential Diagnosis ♦♦ Papillary urothelial neoplasm of low malignant potential and low grade papillary carcinoma enter the differential diagnosis. These tumors typically have longer slender papillae covered by urothelium with a variable degree of hyperplasia (>7 cell layers) and some degree of cytologic atypia. Urothelial papillomas show discrete papillary fronds with occasional branching but without fusion and are covered by normal urothelium

Inverted Papilloma Clinical ♦♦ Rare benign urothelial neoplasm that comprises less than 1% of urothelial tumors ♦♦ Presents with hematuria and irritative symptoms ♦♦ The male-to-female ratio is 4.5:1 and the age of patients ranges from 10–94 years ♦♦ Some cases may be multifocal ♦♦ Inverted papilloma diagnosed according to strictly defined criteria is a benign urothelial neoplasm not related to urothelial carcinoma ♦♦ Recurrence rate is 1%, most apparently due to incomplete surgical excision ♦♦ The previous reported cases of inverted papillomas that coexist with carcinoma have been questioned. The majority of those reported cases probably represent urothelial carcinoma with inverted growth according to current diagnostic criteria

Macroscopic ♦♦ Most cases are solitary nodular or sessile lesions, smaller than 3  cm, and arise in the bladder trigone/bladder neck region

Microscopic

Fig. 36.30. Urothelial papilloma. (A) Lipoid variant; (B) branching papillary architecture; (C) fibrovascular cores with fewer than seven epithelial layers.

♦♦ A recent study found FGFR3 mutations in urothelial papilloma with a frequency comparable to that of papillary urothelial neoplasia of low malignant potential and low grade papillary urothelial carcinoma

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♦♦ Inverted papilloma has a smooth surface covered by normal urothelium, and endophytic growth of urothelial cells arborizing extensively from the surface urothelium into the lamina propria but not into the muscularis propria (Fig. 36.31) ♦♦ Most cases show anastomosing cords, columns, and trabeculae of invaginated urothelium separated by thin fibrovascular septae −− Peripheral palisading of basaloid cells, thickened basement membrane, and preservation of superficial cells are characteristic of the lesion −− The lesions lack exophytic growth, significant cytologic atypia, fibrovascular cores, or infiltrative growth, features commonly present in papillary urothelial carcinoma −− Areas of glandular or squamous differentiation and microcyst formation may be seen in the central solid nests

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Fig. 36.31. Inverted papilloma. −− Trabecular, hyperplastic, and glandular subtypes have been described −− Vacuolization and foamy (xanthomatous-appearing) cytoplasmic changes have been recently reported ♦♦ Foci of nonkeratinizing squamous metaplasia and neuroendocrine differentiation have been reported −− Focal minor cytological atypia may be present but mitotic figures are not seen or very rare −− Rare cases may have focal degenerative atypia with no clinical significance

Molecular Pathology ♦♦ Recent molecular studies indicate that inverted papilloma represents a clonal proliferation characterized by frequent FGFR3 mutations

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Fig. 36.32. Squamous papilloma.

♦♦ Irritative symptoms and hematuria are common clinical symptoms ♦♦ The pathogenesis is uncertain. It is unclear whether squamous papilloma represents squamous metaplasia in a urothelial papilloma or a primary squamous proliferation ♦♦ It is a DNA-diploid lesion and is HPV-DNA negative

Microscopic ♦♦ Composed of papillary cores with overlying benign squamous epithelium (Fig. 36.32)

Immunohistochemistry

Immunohistochemistry

♦♦ Absent or minimal basal/parabasal p53 nuclear accumulation ♦♦ Epidermal growth factor immunoreactivity has also been reported

♦♦ Very low tumor cell proliferation (Ki-67) and rare p53 nuclear accumulation ♦♦ CK20 and UroVysion FISH probes are both negative

Villous Adenoma Clinical

Differential Diagnosis ♦♦ Florid proliferation of von Brunn nests rarely represents a diagnostic concern ♦♦ Low grade urothelial carcinoma has cytologic atypia, variable mitotic figures, and exophytic papillary growth ♦♦ Inverted variant of urothelial carcinoma has thicker and more irregular columns with loss of polarity and absence of  peripheral palisading basaloid cells. Cytologic atypia and mitotic figures are common in inverted urothelial carcinoma

Squamous Papilloma Clinical ♦♦ Squamous papilloma is a rare benign neoplasm seen in the bladder and urethra ♦♦ Most frequently occurs in elderly women and follows a benign clinical course without recurrence

♦♦ Benign glandular epithelial neoplasm ♦♦ Often associated with urachal adenocarcinoma, but may be seen elsewhere in the bladder

Macroscopic ♦♦ Exophytic papillary or polypoid tumor

Microscopic ♦♦ Histologically identical to villous adenoma of the colon ♦♦ Columnar mucinous cells and goblet cells lining delicate fibrovascular stalks (Fig. 36.33) ♦♦ Nuclear stratification, crowding, and nuclear hyperchromasia are characteristic

Differential Diagnosis ♦♦ Adenocarcinoma is the main differential concern but in ­contrast it has significant nuclear atypia, numerous mitotic figures, and invasion

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Flat Urothelial Lesions with Atypia (Table 36.2) Reactive Urothelial Atypia Clinical ♦♦ Often occurs in the setting of chronic irritation such as instrumentation, urolithiasis, intravesical therapy, radiation, or chemotherapy

Microscopic ♦♦ Acutely or chronically inflamed urothelium (Fig. 36.34) ♦♦ Uniformly enlarged cells with single prominent nucleoli and evenly distributed vesicular chromatin ♦♦ Mitotic figures are often seen and may be frequent

Urothelial Atypia of Unknown Significance ♦♦ A diagnostic category encompassing a spectrum of histologic abnormalities that may not be attributed to reactive or inflammatory atypia alone, but fall below the threshold for a diagnosis of dysplasia ♦♦ No adverse clinical outcome on followup ♦♦ The authors do not advocate use of this diagnostic category in surgical pathology reports

Urothelial Dysplasia Clinical Fig. 36.33. Villous adenoma. (A) Villous architecture and (B) columnar glandular cells.

♦♦ There is a male predominance (M:F = 3:1) and the mean age at diagnosis is 60 years

Table 36.2. Comparison of Reactive Atypia, Hyperplasia, Dysplasia, and Urothelial Carcinoma In Situ Characteristics

Reactive atypia

Hyperplasia

Cell layers Polarization Cytoplasm

Variable Slightly abnormal Often vacuolated

>7 Normal Homogeneous

N/C ratio

Normal or slightly increased

Normal or slightly increased

Nuclei   Size

Enlarged

  Borders   Chromatin Nucleoli Mitotic figures Umbrella cells Denudation CK20 expression

Regular/Smooth Fine/dusty Large, single Variable Present Variable Surface

a

Dysplasia

Carcinoma in situa

Variable Disordered Variable, homogeneous to granular Slightly increased

Variable Disordered Variable

Normal

Enlarged

Regular/Smooth Fine Small/absent Absent Present No Surface

Notches/creases Slight hyperchromasia Small Rare, basal Present No Variable

Enlarged with variation in size Pleomorphic Coarse Large, often multiple Prominent May be present Variable Variable

Full thickness involvement is not required for the diagnosis of urothelial carcinoma in situ

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Fig. 36.34. Reactive urothelial atypia. ♦♦ Presents with irritative/obstructive symptoms and/or hematuria ♦♦ Primary dysplasia is rare, and is a strong risk factor for the development of urothelial CIS and invasive cancer (14–19%) ♦♦ Secondary dysplasia is usually associated with concurrent or prior history of urothelial carcinoma, and represents a risk factor for recurrence and progression of urothelial carcinoma ♦♦ Grading of dysplasia is currently not recommended

Macroscopic ♦♦ Erythematous or normal-appearing mucosa

Microscopic ♦♦ Abnormal architectural and cytologic changes fall short of the diagnostic criteria for an unequivocal diagnosis of CIS/ severe dysplasia (Fig. 36.35) ♦♦ Altered polarity with preservation of superficial cells and cytoplasmic clearing is common ♦♦ Cells vary in size and shape and the nuclei show irregular granular chromatin and wrinkled nuclear membranes. There is nuclear crowding and hyperchromasia ♦♦ The long axes of nuclei may be parallel to the basement membrane ♦♦ Dysplasia typically lacks cytoplasmic vacuoles, prominent nucleoli, or atypical mitotic figures

Immunohistochemistry ♦♦ Aberrant expression of cytokeratin 20 in deeper layers of the urothelium (Fig. 36.35C) is a consistent finding ♦♦ TP53 and Ki-67 are often positive

Urothelial Carcinoma In Situ Clinical ♦♦ Occurs in the elderly (60–70 years old), with male predilection (M:F = 10:1) ♦♦ Usually associated with concurrent or prior urothelial carcinoma ♦♦ Presents with irritative/obstructive symptoms and/or hematuria

Fig.  36.35. Urothelial dysplasia. (A) Umbrella cells present; (B) hyperchromasia with variable N/C ratios; (C) aberrant expression of CK20 is noted. ♦♦ May masquerade clinically as interstitial cystitis ♦♦ At cystoscopy, there may be a nonspecific or velvety erythematous lesion with granular or cobblestone appearance, or there may be no visible lesion ♦♦ Often occurs in the regions of trigone and base of the bladder

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Macroscopic ♦♦ Erythematous and velvety lesion. Often multifocal

Microscopic (Fig. 36.36) ♦♦ Full thickness involvement is not a prerequisite for diagnosis

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The cytologic spectrum includes lesions previously designated severe dysplasia (urothelial CIS and severe dysplasia are indistinguishable histologically) and it is always high grade (grading unnecessary) ♦♦ Characterized by disorderly proliferation of malignant urothelial cells with loss of polarity and decreased cellular cohesion

Fig. 36.36. Urothelial carcinoma in situ (CIS). (A) The cells are discohesive and pleomorphic. (B) There is morphologic evidence of progression from urothelial dysplasia to CIS. Prominent vascular structures are present in the underlying mucosa. (C) There is striking different between CIS (left) and normal urothelial cells (right). (D) Clinging pattern CIS. (E) Pagetoid spread of CIS. (F) Involvement of von Brunn nest by CIS. This should not be interpreted as adenocarcinoma in situ.

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−− There is high N/C ratio, nuclear pleomorphism, hyperchromasia, irregular nuclear contours, coarsely granular chromatin, prominent nucleoli, and abnormal mitotic figures through all layers of the urothelium −− The small cell variant has hyperchromatic nuclei and inconspicuous nucleoli −− Urothelium is often denuded due to loss of cellular cohesion between dysplastic cells. The term “denuding cystitis” is often related to urothelial CIS −− In cases of denuding CIS, a few neoplastic cells may remain attached to the surface; this is known as the “clinging” pattern of CIS (Fig. 36.36D) −− Pagetoid spread and von Brunn nest involvement may be seen (Fig. 36.36E, F) −− Micropapillary variant shows pseudopapillary (without fibrovascular core) projections onto the luminal surface

Immunohistochemistry ♦♦ Aberrant expression of CK20 (increased in all layers), p53 (increased), and CD44 (decreased)

Noninvasive Papillary Urothelial Tumors Clinical ♦♦ Occurs in older adults (median age = 65 years); rare before age 50 ♦♦ More common in men (M:F = 3:1) presenting with hema­turia and irritative or obstructive symptoms ♦♦ Risk factors include smoking (fourfold higher risk), occupational exposure to certain organic compounds, especially benzidine and aromatic amines (up to 50-fold higher risk), cyclophosphamide treatment (estimated 10% absolute risk for treated patients), and prior radiation (up to fourfold higher risk) ♦♦ Some tumors are readily amenable to transurethral resection, although there is a significant risk of recurrence

Macroscopic ♦♦ Single or multiple exophytic papillary masses (Fig. 36.37)

Microscopic ♦♦ Exophytic growth pattern with thickened urothelium (>7 cell layers) ♦♦ Papillae with delicate fibrovascular cores ♦♦ Cells may appear nearly normal or show varying degrees of nuclear atypia (nuclear hyperchromasia, crowding, enlargement, pleomorphism, irregular contour, coarse granular chromatin, and prominent nucleoli) (see section “Grading”) ♦♦ Foci of squamous or glandular differentiation are often seen in high grade tumors (approximately 10% of cases) ♦♦ Small- to medium-sized tubules may be seen in otherwise typical urothelial carcinoma (tubuloglandular pattern)

Molecular Pathology ♦♦ Cytogenetic abnormalities are common in low grade noninvasive bladder carcinoma

Fig. 36.37. Gross appearance of papillary urothelial carcinoma. ♦♦ FGFR3 mutations are seen throughout the spectrum of urothelial carcinoma and the presence of FGFR3 mutation is associated with better prognosis ♦♦ TP53 mutation is more common in high grade tumors and is associated with worse prognosis ♦♦ Trisomy 7 and structural anomalies of chromosomes 1 and 11 are among other common molecular alterations ♦♦ UroVision™ FISH analysis is helpful for the diagnosis of high grade tumor recurrence in cytology specimens −− The test utilizes centromere enumeration probes for chromosome 3, 7, and 17 and a locus-specific probe for 9p21

Immunohistochemistry ♦♦ Several biomarkers are altered in noninvasive bladder carcinoma −− These include deletion of surface blood group antigen (ABO, H, Lewis), and alteration of Thomser–Friedenreich (T) antigen −− Downregulation of p21Waf1 and p27Kip1 −− Upregulation of Cyclins D1 and D3 −− High tumor cell proliferation by Ki-67 and aneuploidy by DNA ploidy analysis

Grading ♦♦ Grading remains controversial −− 1973 WHO grading system still widely used in both the pathology and urology communities −− 2004 WHO/ISUP (former 1998 ISUP/WHO) classification is not yet validated and is considered a work in progress −− Bladder cancer grading is subjective with substantial inter- and intraobserver variability −− Substantial interobserver variability still exists using the new 1998 ISUP/WHO or 2004 WHO classification systems

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−− Interobserver agreement among pathologists for the diagnosis of papillary urothelial neoplasm of low malignant potential (PUNLMP) is poor −− We recommend that both 1973 and 2004 WHO grading systems be reported −− Grading should be based on the worst area (highest grade) of the tumor

1973 WHO Grading System (Table 36.3; Fig. 36.38) ♦♦ Grade 1 −− Most cases are designated as papillary urothelial neoplasm of low malignant potential in the 2004 WHO (formerly 1998 ISUP/WHO) classification −− These tumors show a male predominance (male:female ratio = 5:1) and occur at a mean age of 65 years −− The most common symptoms are gross or microscopic hematuria −− Cystoscopically, these lesions are typically 1–2  cm in size, most often located on the lateral wall of the bladder or near the ureteric orifices, and have been described as having a “seaweed in the ocean” appearance −− There is a thickened urothelium with normal architectural arrangement of cells −− The papillae are well-formed with fibrovascular cores, intact superficial cell layer and preservation of cell polarity −− Slight nuclear enlargement, crowding, hyperchromasia, and minimal nuclear pleomorphism are present −− Mitotic figures are uncommon and basally located −− There are also cytoplasmic vacuoles and prominent nucleoli in some cells

−− Grade 1 tumors are usually diploid, and have high frequency of FGFR3 mutations −− These tumors have lower risk for recurrence and progression compared to grade 2 and grade 3 tumors ♦♦ Grade 2 −− Most are designated as low grade papillary urothelial carcinoma in the 2004 WHO classification −− There is some degree of architectural irregularity, dyscohesion, and disordered maturation with variable loss of superficial cells −− Increased nuclear atypia and mitotic figures are evident in grade 2 tumors −− Loss of cytoplasmic homogeneity and clearing are frequent −− Grade 2 tumors are at high risk of recurrence and moderate risk of stage progression and metastasis ♦♦ Grade 3 −− Designated as high grade urothelial carcinoma in the 2004 WHO (former 1998 classification) −− Characterized by loss of normal architectural arrangement of cells, marked nuclear abnormalities with frequent atypical mitotic figures −− These are typically aneuploid tumors with frequent mutations of the TP53 gene, high tumor recurrence rate, and high risk of stage progression and metastasis

2004 WHO Grading System/1998 WHO/ISUP Classification ♦♦ Papillary urothelial neoplasm of low malignant potential (PUNLMP) −− All of these tumors were considered grade 1 urothelial carcinomas by the WHO 1973 grading system

Table 36.3. Morphologic Characteristics of Urothelial Papilloma and Grade 1–3 Urothelial Tumors Characteristics

Grade 1

Cell layers Umbrella cells Polarization Cytoplasm N/C ratio

<7 Present Normal Clear/homogenous Normal

>7 Present Normal/slightly abnormal Clear/homogenous Normal or slightly increased

Variable Usually present Disordered Loss of homogeneity Slightly increased

Variable May be absent Disordered Loss of homogeneity Increased

Nuclei   Size

Normal

  Borders   Chromatin Nucleoli Necrosis Mitotic figures

Regular/smooth Fine Absent Absent Absent

Normal or slightly increased Regular/smooth Fine Small/absent Absent Rare/inconspicuous, at basal level

Enlarged with variation in size Slight variation Fine to granular Small Absent Present

Enlarged with variation in size Pleomorphic Coarse with hyperchromasia Large May be present Frequent and atypical

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Grade 3

Papilloma

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−− Histologically PUNLMP resembles the exophytic urothelial papilloma, but shows increased cellular proliferation exceeding the thickness of normal urothelium −− Cytologic atypia is minimal or absent and architectural abnormalities are minimal with preserved polarity −− Mitoses are infrequent and limited to the basal layer ♦♦ Low grade −− The male:female ratio is 2.9:1 and the mean age is 70 years (range 28–90 years) −− Most patients present with hematuria and have a single tumor in the posterior or lateral wall, but 22% of patients have two or more tumors at initial diagnosis −− Tumor recurrence, progression, and tumor-related mortality are approximately 50, 10, and 5%, respectively −− The cells lining papillary fronds show recognizable variations in architecture and cytology −− The tumor shows slender papillae with frequent branching, minimal fusion and variations in nuclear polarity, size, shape, and chromatin pattern with presence of nucleoli. Mitoses may occur at any level −− Altered expression of cytokeratin 20, CD44, p53, and p63 is frequent. Some tumors are diploid. FGFR3 mutations are seen at about the same frequency as for PUNLMP ♦♦ High grade −− Hematuria is common and the endoscopic appearance varies from papillary to nodular/solid single or multiple tumors −− In high grade tumors (all grade 3 and some grade 2, 1973 WHO scheme) the urothelium lining papillary fronds shows significant disorder with moderate-to-marked architectural and cytological atypia. Papillae frequently are fused and variations in architectural and cytological features are easily recognizable even at scanning power −− The nuclei are often pleomorphic with prominent nucleoli and altered polarity. Mitoses are frequent −− The thickness of the urothelium varies considerably. CIS is frequent in the adjacent mucosa −− Changes in cytokeratin 20, p53, p63 expression and aneuploidy are more frequent than in previous categories −− Molecular alterations in these tumors show a frequency of p53, HER2 or EGFR overexpression and p21Waf1 or p27Kip1 loss comparable to that seen in invasive cancers

Differential Diagnosis (Table 36.3) Fig. 36.38. Grading of urothelial carcinoma. (A) Grade 1. (B) Grade 2. (C) Grade 3.

−− PUNLMP is a low grade urothelial tumor with a papillary architecture. These are low-risk tumors with limited tendency to invasion and metastasis, but high risk for developing recurrent papillary urothelial carcinoma. The progression rate varies (up to 8% of cases in some series)

♦♦ Urothelial papilloma −− The urothelium lining the papillae are normal in thickness (<7 cell layers) −− There is minimal or no cytologic atypia −− Usually is a small solitary lesion (<2 cm) in patients under the age of 50 years ♦♦ Inverted papilloma −− The lesion is well circumscribed, confined within the lamina propria without muscularis propria involvement,

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and shows an endophytic growth of anastomosing cords and trabeculae of benign-looking urothelial cells with an intact urothelium on the luminal surface −− Lacks central fibrovascular cores and shows peripheral palisading of basaloid cells −− There is lack of cytologic atypia and mitoses are absent or rare ♦♦ Nephrogenic adenoma −− In particular, the papillary form presents with small papillae or tubulopapillary architecture with intervening stroma −− Single cell layer, often cuboidal −− Confined to the bladder surface or superficial lamina propria in an inflammatory stroma −− Lacks significant cytologic atypia ♦♦ Polypoid–papillary cystitis (proliferative papillary cystitis) −− Broad-based papillae with prominent inflammation and edema of the lamina propria −− Lacks cytologic atypia −− History of indwelling catheter or vesical fistula

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ ♦♦ ♦♦

♦♦

irregular nuclei. The cells often exhibit abundant eosinophilic or clear cytoplasm Mitotic figures are frequent Areas of squamous or glandular differentiation are common due to divergent differentiation Virtually the whole spectrum of bladder cancer variants may be seen accompanying otherwise typical urothelial carcinoma The presence of tumor cells in fat in transurethral resection specimens does not necessarily means extravesical extension since fat may be present in the lamina propria and in the muscularis propria

Grading ♦♦ See grading section for papillary urothelial carcinoma ♦♦ Most invasive carcinomas are of high grade

Depth of Invasion

♦♦ Islands and trabeculae of tumor cells infiltrating into the lamina propria and muscularis propria or deeper, composed of large round cells with hyperchromatic and pleomorphic

♦♦ The most important element in pathologic evaluation of urothelial cancer is the presence and extent of invasion −− In T1 carcinoma, nests, clusters, or single cells are within the papillary core or lamina propria (Fig. 36.40) −− In microinvasive carcinoma, the invasive tumor cells may acquire abundant eosinophilic cytoplasm, a feature known as paradoxical differentiation (Fig. 36.40D) −− Recognizing the level of invasion may be problematic due to tangential sectioning, thermal artifact or marked inflammatory infiltrate that obscures the neoplastic cells −− Immunohistochemistry with cytokeratin antibodies can help in difficult cases with marked inflammation or thermal artifact −− Myofibroblasts can also express cytokeratins, but it is usually weak and focal ♦♦ Reporting of muscularis mucosae invasion is not required ♦♦ Ocular measurement of the depth of invasion for pT1 tumor provides important prognostic information. The 5-year progression-free survival for patients with depth of invasion ³1.5 mm was 67%, compared to a 93% progression-free survival rate for those with depth of invasion <1.5 mm

Table 36.4. Current Prognostic Factors in Bladder Cancer Specimens

Histologic Variants of Invasive Urothelial Carcinoma (Table 36.1) Urothelial Carcinoma with Mixed Differentiation

Infiltrating Urothelial Carcinoma Clinical ♦♦ Hematuria and irritative symptoms are common clinical presentations ♦♦ Risk factors and cytogenetic abnormalities are similar to those of high grade noninvasive papillary urothelial carcinoma ♦♦ Guidelines for specimen handing and reporting of bladder specimens are listed in Tables 36.4 and 36.5

Macroscopic (Fig. 36.39) ♦♦ Nodular, papillary or ulcerative lesion with infiltrative growth

Microscopic

• Histological grade • Tumor extent (stage) • Cancer size > 3 cm in diameter • Depth of invasion (>1.5 mm) for T1 tumor • Number of tumors • Coexistent dysplasia or CIS • Tumor growth pattern • Vascular/lymphatic invasion • Lymph node involvement • Recurrence at 3-month followup cystoscopy • Molecular markers (DNA ploidy, Ki-67/MIB1, p53, RB, cadherins, p63, cyclin D1 and D3, etc.)

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♦♦ Squamous differentiation (Fig. 36.41A), defined by the presence of intercellular bridges or keratinization, occurs in 21% of urothelial carcinomas of the bladder −− Frequency increases with grade and stage −− These cases may have a less favorable response to therapy than pure urothelial carcinoma −− The diagnosis of squamous cell carcinoma is reserved for pure lesions without any associated urothelial component, including urothelial CIS −− Squamous differentiation may show basaloid or clear cell features

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Table 36.5. Practice Parameters for Handling and Reporting Bladder Specimens with Cancer General information   • Pertinent clinical information: name, medical record number, data, referring physician, relevant clinical history (past and present) Gross description   • Fresh or fixed specimen   • Nature of the specimens: biopsy, chips (TURB), partial cystectomy, radical cystectomy, cystoprostatectomy, “en bloc” resection   • Total weight of resected tissue fragments (TURB); three dimensional measurements of recognizable anatomic structures and tumors or other recognizable lesions   • Site of involvement, gross fat extension Diagnostic and prognostic information   • Histologic tumor type: urothelial, squamous, adenocarcinoma, other   • Tumor grade: use current grading schemes (WHO 2004, WHO 1973, or both)   • Extent of tumor in bladder (degree of invasion)    – No invasion    – aInvasion of the suburothelial connective tissue (provide ocular measurement for T1 tumor), muscularis propria, perivesical tissue    – Presence or absence of lymphatic/vascular invasion    – Tumor arising in a diverticulum (state whether muscularis propria is present)   • Intraepithelial abnormalities (dysplasia, CIS)    – Report focality or multifocality    – Report presence of pagetoid spread of CIS   • Ureter and urethra: report any dysplastic/neoplastic change of the mucosa, and report any invasion into adjacent suburothelial connective tissue or muscularis propria   • Extent of tumor in organs attached to the bladder   • Prostate: direct extension to the prostate, involvement of prostatic urethra, involvement of prostatic ducts with or without stromal involvement   • Seminal vesicles: report spread of carcinoma in these organs either through epithelium or by direct extension of an infiltrative tumor   • Vagina/uterus: report direct extension or metastasis to either organ   • Surgical margins    – Report status of ureteral/urethral margins    – Report perivesical margin involvement   • Lymph nodes: report presence or absence of metastasis. If metastases are present, state number and size of the largest one (<2.0 cm, 2.1–5 cm, >5 cm) Features considered optional in the final report   • Invasion of the muscularis mucosa, if present   • Genetic abnormalities   • Cytometric examination   • Morphometric examination   • p53, Ki-67   • Growth factors and receptors   • Other immunohistochemical markers

Immunohistochemistry may be useful in selected cases using either cytokeratin for suburothelial connective tissue invasion or vascular endothelial markers for vascular invasion

a

♦♦ Glandular differentiation (Fig. 36.41B), is less common than squamous differentiation −− May be present in about 6% of urothelial carcinomas of the bladder and defined as the presence of true glandular spaces within the tumor −− These may be tubular or enteric-type glands with mucin secretion. A colloid-mucinous pattern characterized by nests of cells “floating” in extracellular mucin may be present along with signet-ring cells −− The diagnosis of adenocarcinoma is reserved for pure tumors −− The clinical significance of glandular differentiation and mucin positivity in urothelial carcinoma remains uncertain

Micropapillary Variant (Fig. 36.42) ♦♦ More frequent in males (M:F = 5:1) and presents at a mean age of 67 years ♦♦ Most cases are high stage at diagnosis with a poor prognosis ♦♦ Defined by micropapillary growth with delicate filiform processes or small papillary cell clusters, resembling serous papillary carcinoma of the female genital tract ♦♦ Retraction artifact with "halo" surrounding the epithelial cluster is a common finding in these cases ♦♦ Recent studies suggest that it might be a type of glandular differentiation or a variant of adenocarcinoma

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Fig.  36.39. Gross appearance of urothelial carcinoma (A, C). (B) Papillary urothelial carcinoma with microinvasion (pT1). (D) Urothelial carcinoma with muscularis propria invasion (pT2). ♦♦ It has been suggested that greater than 50% of micropapillary component be necessary for the diagnosis of micropapillary carcinoma

Nested Variant (Fig. 36.43) ♦♦ Initially described as “deceptively benign” bladder carcinoma, it represents a highly aggressive neoplasm ♦♦ Histologically, there are irregularly distributed and compact nests of malignant cells infiltrating through the bladder wall and mimicking von Brunn nests ♦♦ Some nests have small tubular lumens ♦♦ Deeper nests often show increasing atypia, resembling conventional urothelial carcinoma ♦♦ The nests often lack intervening stroma (in contrast to von Brunn nests) ♦♦ Cells have nuclear pleomorphism and prominent nucleoli, especially in the deeper aspects where mitotic figures are also more common ♦♦ Low p27kip1 expression, high proliferation rate, and high p53 nuclear accumulation are frequent in these cases

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Fig.  36.40. Infiltrating urothelial carcinoma (pT1). (A) Single cell infiltration. (B) Retraction artifact. (C) Small nests of invasive urothelial carcinoma. (D) Paradoxical differentiation in pT1 cancer. The invading nests have a greater amount of eosinophilic cytoplasm.

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Fig. 36.41. Urothelial carcinoma with mixed differentiation. (A) Squamous differentiation. (B) Glandular differentiation.

Microcystic Variant (Fig. 36.44) ♦♦ There are few reports concerning microcystic change in urothelial carcinoma ♦♦ Typically, the cysts contain eosinophilic secretions, necrotic debris, or mucin ♦♦ These multiple small cystic spaces are lined by atypical urothelial cells ♦♦ The importance of recognizing this variant is to avoid the misdiagnosis of this cancer as cystitis cystica or cystitis glandularis

Urothelial Carcinoma with Inverted Growth (Inverted Urothelial Carcinoma) (Fig. 36.45)

Fig. 36.42. Urothelial carcinoma, micropapillary variant (A–C).

♦♦ This variant has significant nuclear pleomorphism, mitotic figures, and architectural abnormalities consistent with low or high grade urothelial carcinoma, but the morphology of this lesion at scanning power has the potential for misinterpretation as benign inverted papilloma ♦♦ Shows endophytic growth with thick and irregular anastomosing cords and trabeculae of urothelial cells with loss of polarity

♦♦ Typically lack peripheral palisading of basaloid cells (in contrast to inverted papilloma) ♦♦ Cytologic atypia and mitotic figures are common and foci of keratinization may be present ♦♦ Unless this pattern is accompanied by true destructive stromal invasion the likelihood of metastasis is very low or

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Fig. 36.45. Urothelial carcinoma, inverted variant. Fig. 36.43. Urothelial carcinoma, nested variant.

Fig. 36.46. Urothelial carcinoma, lymphoepithelioma-like variant. Fig. 36.44. Urothelial carcinoma, microcystic variant.

♦♦ ♦♦ ♦♦

♦♦

minimal, since the basement membrane is not truly breached The overlying urothelium may be dysplastic An exophytic papillary or conventional invasive component is often associated with this variant Useful features in differential diagnosis by immunohistochemistry are the high proliferation rate (Ki-67) and variable p53 accumulation similar to conventional urothelial carcinoma of the same histological grade Aberrant CK 20 is also common in carcinoma with inverted growth as are the frequent chromosome alterations seen with UroVysion FISH analysis

Lymphoepithelioma-Like Carcinoma (Fig. 36.46) ♦♦ Occurs in elderly patients at a mean age of 69 years with male predominance (M:F = 3:1)

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♦♦ Usually presents with hematuria ♦♦ Etiology is uncertain. Its association with Epstein–Barr viral infection is not established, this variant appears to be unrelated to EBV infection ♦♦ Pure tumors may respond well to chemotherapy ♦♦ Mixed tumors behave in a manner similar to other high grade urothelial carcinoma, outcome mainly determined by TNM stage ♦♦ Grossly, it presents as an infiltrating or fungating mass typically arising in the dome, posterior wall, or trigone ♦♦ A syncytial cell arrangement in sheets and nests of large round to polygonal cells with abundant basophilic or clear cytoplasm and indistinct cell borders characterizes this tumor ♦♦ Enlarged vesicular nuclei with nuclear pleomorphism, irregular nuclear membranes, coarse granular chromatin, and large prominent nucleoli are striking cellular features of this variant

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♦♦ A heavy inflammatory infiltrate composed predominantly of lymphocytes, histiocytes, and plasma cells is typically seen between the neoplastic cells. In some cases, neutrophils and eosinophils may be prominent ♦♦ Immunophenotype: pancytokeratin and CK7 are positive, and CK20 is usually negative, with a polymorphic inflammatory component

Plasmacytoid Variant (Fig. 36.47) ♦♦ This is an uncommon variant of aggressive bladder cancer ♦♦ Most patients have advanced stage cancer (>pT3); and approximately 70% have lymph node metastasis at diagnosis. The majority of patients die of cancer within a year ♦♦ The tumor may be associated with concurrent conventional high grade urothelial carcinoma, and with nested or micropapillary urothelial carcinoma ♦♦ The individual tumor cells have an eccentrically placed nucleus and abundant eosinophilic cytoplasm reminiscent of plasma cells ♦♦ Most neoplastic cells have nuclei of low to intermediate nuclear grade and there is mild nuclear pleomorphism ♦♦ Small intracytoplasmic vacuoles are usually present ♦♦ The architectural patterns of the tumor vary from solid expansile nests with noncohesive cells to mixed solid and alveolar growth. A loose discohesive architecture may be seen in some cases ♦♦ Both plasmacytoid and associated conventional urothelial carcinoma are positive for cytokeratins 7, 20, AE1/AE3, and for epithelial membrane antigen. CD138 staining is often positive in the plasmacytoid carcinoma component ♦♦ In limited samples, plasmacytoid carcinoma may be misdiagnosed as chronic cystitis or plasmacytoma, a pitfall further compounded by CD138 expression in tumor cells

Urothelial Carcinoma, Clear Cell (Glycogen-Rich) Variant (Fig. 36.48) ♦♦ The clear cell variant of urothelial carcinoma represents an extreme morphologic pattern, consisting predominantly or exclusively of cells with abundant clear cytoplasm ♦♦ Recognition of this pattern avoids confusion with clear cell adenocarcinoma of the bladder and metastatic clear cell carcinoma of the kidney and prostate ♦♦ Clear cell change is more common in poorly differentiated urothelial carcinoma ♦♦ Tumor cells are consistently positive for CK7

Urothelial Carcinoma, Lipoid Cell Variant (Fig. 36.49) ♦♦ This is a rare variant of urothelial carcinoma which exhibits transition to a cell type resembling signet-ring lipoblasts ♦♦ More frequent in elderly men (63–94 years, mean 74) and usually presenting with gross hematuria ♦♦ The majority of patients died of cancer within 4 years after the diagnosis ♦♦ The lipoid cell pattern varied from 10 to 50% of the specimen in one series

Fig. 36.47. Urothelial carcinoma, plasmacytoid variant.

Fig.  36.48. Urothelial carcinoma, clear cell (glycogen-rich) variant. ♦♦ In limited samples, it may be misdiagnosed as liposarcoma, carcinosarcoma (sarcomatoid carcinoma) or signet-ring cell adenocarcinoma ♦♦ Lipoid cell variant has an epithelial phenotype characterized by positivity for cytokeratins, in particular CK7

Undifferentiated Carcinoma ♦♦ This category contains tumors that cannot be otherwise classified and are extremely rare

Pleomorphic Giant Cell Carcinoma (Fig. 36.50) ♦♦ High grade urothelial carcinoma may appear undifferentiated, resembling giant cell carcinoma of the lung ♦♦ Rare tumor with poor prognosis ♦♦ Patients usually present with advanced stage cancer (>pT3); and 75% have had lymph node metastases at initial diagnosis ♦♦ At histology, giant, bizarre, anaplastic cells with frequent typical or atypical mitotic figures are seen

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♦♦ The architectural pattern of the tumor varies from infiltrating pleomorphic tumor with bizarre giant cells to solid expansile nests with discohesive growth ♦♦ A hypocellular desmoplastic stromal response may be seen associated with pleomorphic single cells in sclerotic stroma ♦♦ Both pleomorphic giant cell carcinoma and associated conventional urothelial carcinoma are positive for cytokeratins 7, CAM 5.2, and AE1/AE3 ♦♦ May be misdiagnosed as secondary carcinoma or sarcoma in limited samples ♦♦ The differential diagnosis also includes giant cells associated with trophoblastic differentiation, osteoclast-type giant cells in invasive urothelial carcinoma, sarcomatoid carcinoma with giant cells, and other giant cell carcinoma metastatic to the bladder

Urothelial Carcinoma with Syncytiotrophoblasts (UC with Trophoblastic Differentiation) (Fig. 36.51) ♦♦ Although controversial, the presence of syncytiotrophoblasts may be associated with a poor prognosis and most cases are of high grade and stage at diagnosis ♦♦ These tumors show human chorionic gonadotropin (hCG) immunoreactivity ♦♦ The coexpression of CK7 in some trophoblastic cells argues in favor of their urothelial origin

Urothelial Carcinoma with Unusual Stromal Reaction

Fig. 36.49. Urothelial carcinoma, lipoid cell variant(A, B).

♦♦ High grade bladder cancer may produce unusual stromal reactions, including pseudosarcomatous stroma with atypical spindled stromal cells, abundant eosinophilic cytoplasm and bizarre hyperchromatic degenerative nuclei (Fig. 36.52) ♦♦ The spindle cells are cytokeratin, EMA and CEA negative, and vimentin and smooth muscle actin positive ♦♦ Urothelial carcinoma with mature stromal osseous or cartilaginous metaplasia may be seen ♦♦ The metaplastic stroma lacks cytologic atypia

Fig. 36.50. Urothelial carcinoma, giant cell variant. ♦♦ Associated with conventional urothelial cell carcinoma, the pleomorphic giant cell component varies from 20 to 100% of the tumor specimen

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Fig. 36.51. Urothelial carcinoma with trophoblastic differentiation.

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Reporting of Cystectomy Specimens

Fig. 36.52. Urothelial carcinoma with pseudosarcomatous stroma. ♦♦ Other cases may have abundant lymphoid stroma raising the differential diagnosis of lymphoma or lymphoepitheliomalike carcinoma ♦♦ Rare cases of bladder carcinoma are associated with osteoclast-like cells that are immunoreactive for CD68

Specimen Handling and Reporting (Tables 36.4 and 36.5) Reporting of Biopsy Specimens ♦♦ It is recommended that the total weight of resected tissue fragments be reported and a minimum of 6 g or three cassettes be submitted for transurethral resection of the bladder (TURB) specimens ♦♦ In cold-cup specimens, record the number of pieces, dimensions (millimeters), and presence of papillary growth ♦♦ At microscopic evaluation, include the histopathologic type of carcinoma, histologic grade, and papillary vs. nonpapillary growth ♦♦ Presence or absence of muscularis propria (detrusor muscle) ♦♦ Invasion, including the level of invasion (lamina propria vs. muscularis propria) and extent (<1.5 vs. >1.5 mm) ♦♦ Muscularis mucosae is variably seen and its presence/ involvement is optional for reporting ♦♦ The inner vs outer half of muscularis propria invasion cannot be reliably discerned in biopsy specimens and substaging of pT2 tumors is therefore not recommended ♦♦ The term “superficial (or deep) invasion” is discouraged ♦♦ Vascular invasion should be reported when present ♦♦ The presence or absence of urothelial dysplasia and CIS should be reported ♦♦ Associated conditions (e.g., nephrogenic adenoma) should also be reported ♦♦ Ancillary studies (e.g., DNA ploidy, p53 status, chromosome markers) are optional at the present time

♦♦ Include −− Histopathologic type of carcinoma −− Histologic grade −− Papillary vs. nonpapillary growth −− Location of cancer (use anatomic landmarks) −− Tumor size −− Multifocality −− Invasion, including depth of invasion (a) Lamina propria invasion (b) Muscularis propria invasion, inner half vs. outer half −− Surgical margins (a) Urethral margins (b) Ureteral margins (c) Perivesical soft tissue margins (d) Perivesical soft tissue involvement −− Vascular invasion −− Presence or absence of urothelial dysplasia and CIS −− Lymph node status (a) Use anatomic sites, number of nodes sampled (b) Number of positive nodes (c) Largest dimension of positive nodes (d) Presence or absence of extranodal extension −− Involvement of adjacent organs including the prostate, vagina, or uterus (a) The presence or absence of stromal invasion in the prostate should be specified. −− Associated conditions (e.g., cystitis glandularis) −− Ancillary studies (e.g., DNA ploidy, p53 status, chromosome markers) are optional −− Pathologic stage

Squamous Cell Carcinoma Clinical ♦♦ Represents <5% of bladder carcinomas in Western countries and often presents with advanced cancer stage ♦♦ Risk factors may include recurrent bladder infection, diverticuli, calculi (vesical lithiasis), and indwelling catheter in patients with nonfunctioning bladder ♦♦ Some patients have a history of urethral stricture or renal transplantation ♦♦ A number of cases are associated with infection by S. haematobium, and, consequently, squamous cell carcinoma represents about 70% of bladder carcinomas in endemic countries ♦♦ Schistosomiasis-associated squamous cell carcinoma may have a better prognosis than its sporadic (nonschistosomal) counterpart

Macroscopic ♦♦ Most cases present as a solitary exophytic or infiltrative ulcerated nodular, white-tan mass with multiple small areas of necrosis

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Microscopic ♦♦ At histology, infiltrating tongues of large polygonal squamous cells with distinct cell borders, intercellular bridges, and abundant eosinophilic cytoplasm are present ♦♦ Dyskeratotic cells with nuclear pleomorphism, hyperchromasia, coarsely granular chromatin, and frequent mitotic figures are characteristically seen ♦♦ Well-differentiated neoplasms may have keratin pearls ♦♦ Most cases are associated with keratinizing squamous metaplasia that may include variable degrees of dysplasia or CIS ♦♦ Grading is of little prognostic significance ♦♦ Calcified Schistosoma eggs may be seen in Schistosomiasisassociated squamous cell carcinoma (Figs. 36.7 and 36.53)

Differential Diagnosis ♦♦ Infiltrating urothelial carcinoma may show areas of squamous differentiation −− Careful sampling of the tumor will usually show areas of typical urothelial cell differentiation −− In populations with low incidence of squamous cell carcinoma of the bladder (i.e., Western countries), tumors should be carefully sampled for evidence of urothelial features

Essentials of Anatomic Pathology, 3rd Ed.

Adenocarcinoma (Fig. 36.55) Clinical ♦♦ This is an uncommon malignant glandular neoplasm, which accounts for approximately 1–2% of bladder cancer ♦♦ It is more common in men (M:F = 2:1), with a mean age at presentation of 58 years ♦♦ Presenting symptoms are similar to other bladder carcinomas (hematuria and irritative symptoms) but also up to 25% of cases may demonstrate mucosuria ♦♦ Advanced cancer stage at presentation is the rule in most cases ♦♦ May arise from urachal elements or from metaplastic urothelium (intestinal metaplasia) ♦♦ Some may be associated with exstrophy, patent urachus, schistosomiasis, bladder augmentation, or neurogenic bladder ♦♦ May be found anywhere in the bladder, but has a predilection for the trigone and lateral wall ♦♦ Cystoscopically, it may also present as an exophytic papillary or rapidly growth infiltrative mass

Macroscopic

Variant

♦♦ Bulging intramural infiltrative or polypoid mass

♦♦ Squamous cell carcinoma, verrucous type −− This is a rare variant of squamous cell carcinoma sometimes seen in the bladder −− It is considered a low grade tumor −− At histology, it is composed of well-differentiated squamous epithelium with complex papillary and exophytic growth and invasive bulbous broad fronts associated with chronic inflammation −− Verrucous carcinoma may undergo transformation to aggressive anaplastic sarcomatoid carcinoma after radiation therapy (Fig. 36.54)

Microscopic and Histologic Variants

Fig.  36.53. Schistosoma-associated squamous cell carcinoma. Calcified Shistosoma haematobium eggs are seen.

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♦♦ Mucinous (colloid) adenocarcinoma shows islands of tumor cells suspended in mucinous lakes −− More commonly seen in tumors of urachal origin ♦♦ Signet-ring cell carcinoma has the worst prognosis; >50% of patients die of cancer within 1 year of diagnosis −− Composed of signet ring cells with intracytoplasmic mucin −− Infiltrative growth with prominent desmoplasia ♦♦ Papillary adenocarcinoma is composed of papillae lined by tall columnar cells with variable mucin production −− Some are associated with villous adenoma

Fig. 36.54. Verrucous squamous cell carcinoma.

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Fig. 36.55. Adenocarcinoma. (A) Adenocarcinoma, NOS. (B) Urachal mucinous adenocarcinoma. (C) Signet-ring cell adenoacarcinoma. (D) Hepatoid adenocarcinoma.

♦♦ Urachal adenocarcinoma −− Exclusion of adenocarcinoma from another organ is required for the diagnosis −− Usually occurs in younger patients (M > F, mean age = 50 years) −− No prognostic difference between urachal and nonurachal adenocarcinoma has been demonstrated when adjusted for stage −− By definition they are located in the dome and anterior wall, predominantly involving the muscularis propria rather than lamina propria. The overlying mucosa may be normal and intact or ulcerated with sharp demarcation of mucosa from the underlying tumor −− Intestinal metaplasia, cystitis cystica, or cystitis glandularis are absent in the dome −− May extend toward the umbilicus in the space of Retzius −− Treatment includes partial cystectomy with en bloc resection of the entire urachal-median umbilical ligament, including the umbilicus

Differential Diagnosis ♦♦ Villous adenoma −− Histologically identical to villous adenoma of the colon −− Nuclear crowding, overlapping, and atypia are seen, but there is no invasion ♦♦ Nephrogenic adenoma −− Well-circumscribed proliferation of compact tubules −− Confined to superficial lamina propria and often contains an inflammatory stroma −− Lacks significant cytologic atypia ♦♦ Cystitis glandularis −− Often coexists with von Brunn nests and cystitis cystica −− Well-circumscribed and confined to the lamina propria −− Lacks cytologic atypia −− The differential diagnosis of well-differentiated adenocarcinoma in cases of florid cystitis glandularis may be challenging

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♦♦ Müllerianosis −− Occurs in women of reproductive age (37–46 years) −− Small lesion, located in the posterior wall of the bladder with proliferation of tubules and cysts lined by endocervical-type epithelium and tubal epithelium (ciliated cells, peg cells, and intercalated cells) −− Some cases are associated with endometriosis −− Lacks cytologic atypia or prominent mucin extravasation −− Estrogen and progesterone receptors and CD10 immuno­ staining are helpful

Clear Cell Adenocarcinoma (Mesonephric Carcinoma) Clinical ♦♦ A form of adenocarcinoma with an aggressive course ♦♦ Often occurs in older patients (>35 years, mean = 58 years), with female predilection ♦♦ More commonly seen in the urethra, especially in urethral diverticulum ♦♦ Recent molecular studies suggest urothelial origin in histogenesis

Macroscopic ♦♦ Papillary or sessile infiltrative mass in the trigone and bladder neck

Microscopic ♦♦ Infiltrative growth of cysts, trabeculae, fine papillae, and tubules lined by clear cells with hobnail appearance (Fig. 36.56) ♦♦ Tubules often contain eosinophilic secretions ♦♦ Cells have a moderate amount of clear to eosinophilic cytoplasm (glycogen positive) ♦♦ Mitotic figures are frequent

Essentials of Anatomic Pathology, 3rd Ed.

Immunohistochemistry ♦♦ Cytokeratin, CK7, CK20, and EMA positive; CEA is often positive; and alpha-methylacyl-CoA racemase (P504S) negative

Differential Diagnosis ♦♦ Nephrogenic adenoma −− Occurs in younger patients with male predominance, with no predilection for the urethra −− Associated with predisposing factors such as long-standing irritative events −− Small, well circumscribed, and confined to the lamina propria −− Lacks mitotic figures or necrosis −− Immunohistochemical profile is similar to clear cell adenocarcinoma

Sarcomatoid Carcinoma (Metaplastic Carcinoma; Carcinosarcoma) Clinical ♦♦ Occurs in elderly patients (mean age of 67 years at ­presentation) with male predominance (M:F = 4:1) ♦♦ A highly aggressive tumor with a mean survival of 10 months after diagnosis in spite of aggressive treatment ♦♦ No prognostic difference for carcinosarcoma with ­heterologous elements ♦♦ Pathologic stage is the main predictor of survival ♦♦ Clinically most cases present with hematuria and irritative symptoms ♦♦ Some patients have a history of radiation therapy for unrelated causes

Macroscopic ♦♦ Polypoid or nodular mass

Microscopic (Fig. 36.57) ♦♦ At histology, there is a diffuse infiltration of malignant spindle cells through the bladder wall and in some cases there is a streaking myxoid background raising a ­differential diagnostic consideration of sarcoma or myofibroblastic proliferation ♦♦ Urothelial carcinoma is the most commonly recognized epithelial component, followed by squamous cell carcinoma ♦♦ Necrosis and hemorrhage are frequent ♦♦ Osteosarcoma, followed by chondrosarcoma, is the commonest heterologous component, but rare cases may exhibit leiomyosarcoma, and malignant fibrous ­histiocytoma (undifferentiated sarcoma)

Immunohistochemistry (See Table 36.6) Small Cell Carcinoma Clinical Fig. 36.56. Clear cell adenocarcinoma.

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♦♦ Small cell carcinoma is a malignant neuroendocrine neoplasm derived from the urothelium which histologically mimics its pulmonary counterpart

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Fig. 36.57. Sarcomatoid carcinoma (A–C). Cytokeratin staining is positive (D).

Table 36.6. Immunohistochemical Profiles of Spindle Cell Lesions of the Bladder

Postoperative spindle cell nodule Inflammatory myofibroblastic tumor Malakoplakia and caruncle Sarcomatoid carcinoma Leiomyosarcoma Lymphoepithelioma-like carcinoma

CK

SMA/MSA/desmin

EMA

Vimentin

ALK-1

−/+ −/+ − + − +

+/− +/− − + + −

− − − + − +

+ + + + + +

Not tested + – – – –

ALK1 anaplastic lymphoma kinase 1, CK cytokeratin, EMA epithelial membrane antigen, MSA muscle-specific actin, SMA smooth muscle actin

♦♦ The majority of patients present with high tumor stage and lymph node metastasis ♦♦ The prognosis of small cell carcinoma of the urinary bladder remains poor irrespective of therapy

♦♦ Electrolyte abnormalities such as hypercalcemia or hypophosphatemia, and ectopic secretion of ACTH have also been reported as paraneoplastic syndromes

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♦♦ The vesical lateral walls and the dome are the most frequent topographies but rare cases may arise in a bladder diverticulum

Macroscopic ♦♦ At gross examination, most tumors appear as a large solid, isolated, polypoid, nodular mass with or without ulceration, and the tumor may extensively infiltrate the bladder wall

Microscopic ♦♦ The diagnosis of small cell carcinoma can be made on morphologic grounds alone, even if neuroendocrine differentiation cannot be demonstrated ♦♦ The tumor cells consist of small, rather uniform cells, with nuclear molding, and scant cytoplasm ♦♦ The nuclei contain finely stippled chromatin and inconspicuous nucleoli (Fig. 36.58) ♦♦ Mitoses are present and may be frequent ♦♦ Necrosis is common and there may be DNA encrustation of blood vessel walls (Azzopardi phenomenon) ♦♦ In one of the largest series (64 cases), only 32% were pure small cell carcinoma. Most cases have areas of urothelial carcinoma in the form of flat urothelial CIS, squamous cell carcinoma, adenocarcinoma, or sarcomatoid carcinoma (Cheng et al. 2004)

Immunohistochemistry ♦♦ The immunohistochemical profile is similar to small cell carcinoma of other sites ♦♦ The majority cases are also thyroid transcription factor-1 (TTF-1) positive, therefore TTF-1 staining cannot be used to exclude lung metastasis ♦♦ Tumors are often p53 positive with a high Ki-67 labeling index ♦♦ Chromogranin A is positive in only a third of cases

Fig. 36.58. Small cell carcinoma. ♦♦ Uroplakin III and CK20 are often negative

Differential Diagnosis ♦♦ The differential diagnosis includes metastatic small cell carcinoma, lymphoma, lymphoepithelioma-like carcinoma, plasmacytoid carcinoma, and poorly differentiated ­urothelial carcinoma

SOFT TISSUE TUMORS Benign Leiomyoma (Fig. 36.59)

Microscopic

♦♦ Occurs in adults and is more frequent in females (M:F = 1:2) ♦♦ Presents with irritative, obstructive symptoms ♦♦ Grossly polypoid or pedunculated, well-circumscribed submucosal mass lacking significant cytologic atypia ♦♦ Inconspicuous mitotic figures and low proliferation rate

♦♦ Small, well-circumscribed lesion composed of dilated vascular channels ♦♦ Three types have been recognized (Cheng et al. 1999) −− Capillary (Fig. 36.60) −− Cavernous −− Arteriovenous type

Hemangioma Clinical

Neurofibroma (Fig. 36.61) Clinical

♦♦ Often occurs in young adults (<30 years) with slight male predominance ♦♦ Presents with gross hematuria and obstructive symptoms

♦♦ Usually occurs in young patients with neurofibromatosis type I ♦♦ The mean age at diagnosis is 17 years and there is a male predominance (M:F = 2.3:1)

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ovoid or elongate nuclei in an Alcian blue positive, variably collagenized matrix ♦♦ Proliferating cells are S-100 protein positive

Solitary Fibrous Tumor Clinical ♦♦ Rare, usually occurs in men ♦♦ Age at diagnosis ranges from 42 to 67 years ♦♦ May present as an incidental finding or with nonspecific urinary tract symptoms such as pelvic pressure

Macroscopic ♦♦ Well-circumscribed tumor with yellow-white cut-surface ♦♦ May present as polypoid mass with an intact mucosa ♦♦ Sizes range from 4 to 20 cm Fig. 36.59. Submucosal leiomyoma.

Microscopic ♦♦ Characterized by a proliferation of cytologically bland spindle cells in a fibrocollagenous background ♦♦ The cellular arrangement is patternless. Some cases have alternating areas of hypocellularity and hypercellularity ♦♦ Nuclei are slender with fine chromatin and a pale rim of eosinophilic cytoplasm ♦♦ Some tumors have prominent vascularity with thin-walled, branching vessels and hyalinized, thick-walled vessels

Immunohistochemistry ♦♦ All tumors display diffuse, positive immunohistochemical staining for CD34

Other Benign Soft Tissue Tumors ♦♦ Rare examples of schwannoma, granular cell tumor, and perivascular epithelioid cell tumor have been reported to occur in the bladder

Malignant Leiomyosarcoma Clinical ♦♦ Most common sarcoma of the bladder in adults, usually presenting in elderly male patients (60–70 years old)

Macroscopic ♦♦ Large bulging polypoid masses in the dome and lateral wall ♦♦ Hemorrhage and necrosis are common

Microscopic (Fig. 36.62) Fig. 36.60. Hemangioma, capillary type: (A) well-circumscribed and (B) capillary type. ♦♦ Clinical symptoms include hematuria, irritative voiding syndrome, and pelvic mass

Microscopic ♦♦ Histologically, the tumors are usually of the plexiform and diffuse type and show proliferation of spindle cells with

♦♦ Interfacing fascicles of spindle cells with blunt-ended nuclei ♦♦ Deep infiltrative growth pattern and destructive muscle invasion ♦♦ Cytologic atypia, mitotic figures, hemorrhage, and necrosis ♦♦ Inflammatory myxoid background with fine vasculature may be seen in so-called myxoid leiomyosarcoma ♦♦ Smooth muscle differentiation rather than myofibroblastic differentiation is demonstrated by immunohistochemical stains

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Fig. 36.61. Neurofibroma. Superficial, bandlike subepithelial, pseudo-Meissnerian corpuscles are prominent (A). These peudoMeissnerian corpuscles are immunoreactive for S-100 protein (B). Ganglion cells show involvement with neurofibroma (C). S-100 protein immunostaining is diffusely positive (D). −− Lacks significant cytologic atypia −− Lacks tumor necrosis −− ALK-1 positive by FISH and/or immunohistochemistry

Rhabdomyosarcoma (Fig. 36.63) Clinical ♦♦ Occurs predominantly in infants and children with male predominance ♦♦ About 20% of childhood embryonal rhabdomyosarcomas occur in the genitourinary system, and 25% of these occur in the bladder ♦♦ Predilection for trigone and prostatic urethra

Macroscopic Fig. 36.62. Leiomyosarcoma.

Immunohistochemistry (See Table 36.6) Differential Diagnosis ♦♦ Inflammatory myofibroblastic tumor −− Usually smaller with circumscribed margin

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♦♦ May present as multiple broad-based bulging polypoid grape-like masses (sarcoma botryoides)

Microscopic ♦♦ Microscopically, there are sheets and cords of primitive small cells with high N/C ratio and nuclear hyperchromasia ♦♦ Variable rhabdomyoblasts with or without cross-striations may be seen

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Fig. 36.63. Rhabdomyosarcoma. (A) The lesion has polypoid growth (botryoid subtype). (B) The cambium layer of rhabdomyoblasts immediately beneath the urothelium. (C, D) Solid sheet of rhabdomyoblasts. ♦♦ The cambium layer of rhabdomyoblasts beneath the surface in the botryoid variant is an excellent diagnostic clue (Fig. 36.63B)

Immunohistochemistry ♦♦ Desmin, muscle-specific actin, myoglobin, myogenin, and MyoD1 positive, LCA negative

Other Malignant Soft Tissue Tumors ♦♦ Rare examples of angiosarcoma

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Malignant fibrous histiocytoma (undifferentiated sarcoma) Primitive neuroectodermal tumor Malignant peripheral nerve sheath tumor Alveolar soft-part sarcoma Hemangiopericytoma Liposarcoma Chondrosarcoma Kaposi sarcoma

MISCELLANEOUS Lymphoma (Also See Chap. 15) Clinical ♦♦ There is a female predominance in primary bladder lymphoma (M:F = 1:5, mean age = 56 years) and slight male

predominance in secondary lymphoma (mean age = 50 years) ♦♦ Initial clinical symptoms are hematuria and irritative symptoms

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♦♦ Median survival of primary lymphoma is 9 years and secondary lymphoma is 6 months ♦♦ The dome and the trigone are the most common sites involved in the bladder

Microscopic ♦♦ Low grade lymphoma of the muscosa-associated lymphoid tissue (MALT) type is the most frequent category of primary bladder lymphoma −− The histology of MALT-type lymphoma is similar to that of other sites, and is characterized by centrocyte-like cells with irregular nuclear contours, clumped chromatin, and abundant pale to clear cytoplasm ♦♦ Diffuse large B-cell lymphoma is the most common type of secondary lymphoma

Paraganglioma (Pheochromocytoma) (Fig. 36.64) Clinical ♦♦ Slight female predominance (M:F = 1:1.4); usually occurs in young patients (<50 years) ♦♦ May present with hematuria and hypertension during voiding ♦♦ Cystoscopic examination shows a small (<3  cm), domeshaped nodule covered by normal mucosa, usually located in the trigone or dome

Microscopic ♦♦ Histologically similar to paraganglioma of other body sites, with intact urothelium

Immunohistochemistry ♦♦ Chromogranin A is characteristically positive ♦♦ S-100 protein highlights the sustentacular cells

Differential Diagnosis ♦♦ A bladder carcinoma with pheochromocytoma-like features has been reported and should be differentiated from paraganglioma of the bladder

Carcinoid Clinical ♦♦ Usually occurs in elderly patients (mean age, 56 years; range, 29–75 years) with slight male predominance (M:F = 1.8:1) ♦♦ Hematuria is the most common symptom at presentation ♦♦ Submucosal location with a predilection for the trigone

Microscopic ♦♦ The tumor cells have abundant eosinophilic cytoplasm and finely stippled chromatin ♦♦ Arranged in an insular, acinar, trabecular, or pseudoglandular pattern with a delicate vascular stroma

Immunohistochemistry ♦♦ Neuroendocrine markers are positive (neuron-specific enolase, chromogranin A, and synaptophysin)

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Fig. 36.64. Paraganglioma. (A) Gross appearance. (B) Typical Zellballen growth pattern is seen. (C) Sustentacular cells are highlighted by S-100 protein immunostaining.

Clear Cell Myomelanocytic Tumor Clinical ♦♦ Member of the family of perivascular epithelioid cell tumors ♦♦ One case reported arising from the muscularis propria of the urinary bladder in a 33-year-old woman. This patient has been free of the disease since the excision of the tumor 6 years ago

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Microscopic

Immunohistochemistry

♦♦ The histology of the lesion shows clear to eosinophilic, epithelioid, and spindled cells arranged in fascicles or packets with a delicate vascular stroma among the nests

♦♦ Immunohistochemically positive for HMB-45 and smooth muscle actin; and negative for S-100 protein, Melan-A, desmin, and pancytokeratin

TNM CLASSIFICATION OF BLADDER CANCER (2010 REVISION) ♦♦ Primary Tumor (T) ♦♦ Urinary Bladder −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Ta: Noninvasive papillary carcinoma −− Tis: Carcinoma in situ: “flat tumor” −− T1: Tumor invades subepithelial connective tissue −− T2: Tumor invades muscularis propria −− T2a: Tumor invades superficial muscularis propria (inner half) −− T2b: Tumor invades deep muscularis propria (outer half) −− T3: Tumor invades perivesical tissue −− T3a: Microscopically −− T3b: Macroscopically (extravesical mass) −− T4: Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall −− T4a: Tumor invades prostatic stroma, uterus, or vagina −− T4b: Tumor invades pelvic wall, abdominal wall ♦♦ Urothelial (Transitional Cell) Carcinoma of the Prostate −− Tis pu: Carcinoma in situ, involvement of the prostatic urethra −− Tis pd: Carcinoma in situ, involvement of the prostatic ducts

−− T1: Tumor invades urethral subepithelial connective tissue −− T2: Tumor invades any of the following: prostate stroma, corpus spongiosum, periurethral muscle −− T3: Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extraprostatic extension) −− T4: Tumor invades other adjacent organs (invasion of the bladder) ♦♦ Regional Lymph Nodes (N) −− NX: Lymph nodes cannot be assessed −− N0: No lymph node metastasis −− N1: Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node) −− N2: Multiple regional lymph node metastases in the true ­pelvis (hypogastric, obturator, external iliac, or presacral lymph node) −− N3: Lymph node metastasis to the common iliac lymph nodes ♦♦ Distant Metastasis (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis

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Armstrong AB, Wang M, Eble JN, MacLennan GT, Montironi R, Tan PH, Lopez-Beltran A, Zhang S, Baldridge LA, Spartz H, Cheng L. TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder. Mod Pathol 2009;22:113–118.

Amin MB, Young RH. Intraepithelial lesions of the urinary bladder with a discussion of the histogenesis of urothelial neoplasms. Semin Diagn Pathol 1997;14:84–97.

Barbisan F, Santinelli A, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M, van der Kwast T, Montironi R. Strong immunohistochemical expression of fibroblast growth factor receptor 3, superficial staining pattern of cytokeratin 20, and low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur. Cancer 2008;112:636–644.

Amin MB. Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol 2009;22 (S2): S96–S118.

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Cheng L, Montironi R, Bostwick DG. Villous adenoma of the urinary tract: a report of 23 cases including 8 with coexistent adenocarcinoma. Am J Surg Pathol 1999;23:764–771.

Bostwick DG. Natural history of early bladder cancer. J Cell Biochem (Suppl) 1992;16I:31–38.

Cheng L, Bostwick DG, Li G, et al. Conserved genetic findings in metastatic bladder cancer: a possible utility of allelic loss of chromosome 9p21 and 17p13 in diagnosis. Arch Pathol Lab Med 2001;125:1197–1199.

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Cheng L, Nascimento AG, Neuman RM, et al. Hemangioma of the urinary bladder. Cancer 1999;86:498–504.

Cheng L, Zhang S, Davidson DD, MacLennan GT, Koch MO, Montironi R, Lopez-Beltran A. Molecular determinants of tumor recurrence in the urinary bladder. Future Oncol 2009;5:843–857.

Cheng L, Neumann RM, Scherer BG, et al. Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma: a critical evaluation of the depth of muscle invasion. Cancer 1999;85:2638–2647.

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Cheng L, Scheithauer BW, Leibovich BC, et al. Neurofibroma of the urinary bladder. Cancer 1999;86:505–513. Cheng L, Weaver AL, Bostwick DG. Predicting extravesical extension of bladder carcinoma. Urology 2000;55:668–672. Cheng L, Weaver AL, Neumann RM, et  al. Substaging of T1 bladder carcinoma based on the depth of invasion as measured by micrometer: a new proposal. Cancer 1999;86:1035–1043. Cheng L, Davidson DD, MacLennan GT, Williamson SR, Zhang S, Koch MO, Montironi R, Lopez-Beltran A. The Origins of Urothelial Carcinoma. Exp Rev Anticancer Ther 2010;10:865–880. Clement PB, Young RH. Endocervicosis of the urinary bladder: a report of six cases of a benign mullerian lesion that may mimic adenocarcinoma. Am J Surg Pathol 1992;16:533–542. Eble JN, Young RH. Carcinoma of the urinary bladder: a review of its diverse morphology. Semin Diagn Pathol 1997;14:98–108. Epstein JI, Amin MB, Reuter VR, et al. The World Health Organization/ International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998;22: 1435–1448. Freeman A, Geddes N, Munson P, et  al. Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary clinicopathological study of nine cases and review of the literature. Mod Pathol 2004;17:765–771. Grignon DJ, Ro JY, Ayala AG, et al. Primary adenocarcinoma of the urinary bladder: a clinicopathologic analysis of 72 cases. Cancer 1991;67: 2165–2172. Grignon DJ, Ro JY, Ayala AG, et al. Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol 1991;95:13–20. Grignon DJ. The current classification of urothelial neoplasms. Mod Pathol 2009;22 (S2):S60–S69. Guo CC, Fine SW, Epstein JI. Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Am J Surg Pathol 2006;30:883–891. Gupta A, Wang HL, Policarpio-Nicolas ML, et al. Expression of alphamethylacyl-coenzyme a racemase in nephrogenic adenoma. Am J Surg Pathol 2004;28:1224–1229. Harnden P, Mahmond N, Southgate J. Expression of cytokeratin 20 defines urothelial papillomas of the bladder. Lancet 1999;353:974–977. Hansel DE, Nadasdy T, Epstein JI. Fibromyxoid nephrogenic adenoma: a newly recognized variant mimicking mucinous adenocarcinoma. Am J Surg Pathol 2007;31:1231–1237.

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Hodges KB, Lopez-Beltran A, Davidson DD, Montironi R, Cheng L. Urothelial dysplasia and other flat lesions of the urinary bladder: clinicopathological and molecular features. Hum Pathol 2010;41:155–162. Iczkowski KA, Shanks JH, Gadaleana V, et al. Inflammatory pseudotumor and sarcoma of urinary bladder: differential diagnosis and outcome in 38 spindle cell neoplasms. Mod Pathol 2001;14:1043–1051. Jiang J, Ulbright TM, Younger C, et al. Cytokeratin 7 and cytokeratin 20 in primary urinary bladder carcinoma and matched lymph node metastasis. Arch Pathol Lab Med 2001;125:921–923. Jimenez RE, Gheiler E, Oskanian P, et al. Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival. Am J Surg Pathol 2000;24:980–987. Jone EC, Clement PB, Young RH. Inflammatory pseudotumor of the urinary bladder. Am J Surg Pathol 1993;17:264–274. Jones TD, Carr MD, Eble JN, Wang M, Lopez-Beltran A, Cheng L. Clonal origin of lymph node metastases in bladder carcinoma. Cancer 2005;104:1901–1910. Jones TD, Kernek KM, Yang XJ, Lopez-Beltran A, MacLennan GT, Eble JN, Lin H, Pan CX, Tretiakova M, Baldridge LA, Cheng L. Thyroid transcription factor 1 expression in small cell carcinoma of the urinary bladder: an immunohistochemical profile of 44 cases. Hum Pathol 2005;36:718–723. Jones TD, Wang M, Eble JN, MacLennan GT, Lopez-Beltran A, Zhang S, Cocco A, Cheng L. Molecular evidence supporting field effect in urothelial carcinogenesis. Clin Cancer Res 2005;11:6512–6519. Jones TD, Zhang S, Lopez-Beltran A, Eble JN, Sung MT, MacLennan GT, Montironi R, Tan PH, Zheng S, Baldridge LA, Cheng L. Urothelial carcinoma with an inverted growth pattern can be distinguished from inverted papilloma by fluorescence in situ hybridization, immunohistochemistry, and morphologic analysis. Am J Surg Pathol 2007;31:1861–1867. Lacy S, Lopez-Beltran A, MacLennan GT, Foster SR, Montironi R, Cheng L. Molecular pathogenesis of urothelial carcinoma: the clinical utility of emerging new biomarkers and future molecular classification of bladder cancer. Anal Quant Cytol Histol 2009;31:5–16. Lagwinski N, Thomas A, Stephenson AJ, Campbell S, Hoschar AP, El-Gabry E, Dreicer R, Hansel DE. Squamous cell carcinoma of the bladder: a clinicopathologic analysis of 45 cases. Am J Surg Pathol 2007; 31:1777–1787. Lopez Beltran A, Bassi P, Pavone-Macaluso M, et  al. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Eur Urol 2004;45:257–266. Lopez-Beltran A, Alvarez-Kindelan J, Luque RJ, Blanca A, Quintero A, Montironi R, Cheng L, Gonzalez-Campora R, Requena MJ. Loss of heterozygosity at 9q32–33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low grade urothelial carcinoma of the bladder and their associated normal urothelium. J Pathol 2008;215:263–272. Lopez-Beltran A, Blanca A, Montironi R, Cheng L, Regueiro JC. Pleomorphic giant cell carcinoma of the urinary bladder. Hum Pathol 2009;40:1461–1466. Lopez-Beltran A, Cheng L, Andersson L, et al. Preneoplastic non-papillary lesions and conditions of the urinary bladder. Virchows Arch 2002;440:3–11. Lopez-Beltran A, Cheng L, Mazzucchelli R, Bianconi M, Blanca A, Scarpelli M, Montironi R. Morphological and molecular profiles and pathways in bladder neoplasms. Anticancer Res 2008;28:2893–2900. Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006;37: 1371–1388. Lopez-Beltran A, Cheng L. Stage pT1 bladder carcinoma: diagnostic criteria, pitfalls and prognostic significance. Pathology 2003;35:484–491.

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Mazzucchelli R, Morichetti D, Lopez-Beltran A, Cheng L, Scarpelli M, Kirkali Z, Montironi R. Neuroendocrine tumours of the urinary system and male genital organs: clinical significance. BJU Int 2009;103: 286–288. McKenney JK, Amin MB, Young RH. Urothelial (transitional cell) papilloma of the urinary bladder: a clinicopathologic study of 26 cases. Mod Pathol 2003;16:623–629. McKenney JK, Desai S, Cohen C, Amin MB. Discriminatory immunohistochemical staining of urothelial carcinoma in situ and non-neoplastic urothelium: an analysis of cytokeratin 20, p53, and CD44 antigens. Am J Surg Pathol 2001;25:1074–1078. McKenney JK, Gomez JA, Desai S, et  al. Morphologic expressions of urothelial carcinoma in situ: a detailed evaluation of its histologic patterns with emphasis on carcinoma in situ with microinvasion. Am J Surg Pathol 2001;25:356–362. Montironi R, Cheng L, Mazzucchelli R, Scarpelli M, Kirkali Z, Montorsi F, Lopez-Beltran L. Critical evaluation of the prostate from cystoprostatectomies for bladder cancer: Insights from a complete sampling with the whole mount technique. Eur Urol 2009;55:1305–1309. Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. Morphological classification and definition of benign, preneoplastic and non-invasive neoplastic lesions of the urinary bladder. Histopathology 2008;53:621–633. Montironi R, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Cheng L. 2004 World Health Organization classification of the noninvasive urothelial neoplasms: Inherent problems and clinical reflections. Eur Urol 2009;8 (Suppl):453–457. Montironi R, Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L. Morphological diagnosis of urothelial neoplasms. J Clin Pathol 2008; 61:3–10. Morton MJ, Zhang S, Lopez-Beltran A, MacLennan GT, Eble JN, Montironi R, Sung MT, Tan PH, Zheng S, Zhou H, Cheng L. Telomere shortening and chromosomal abnormalities in intestinal metaplasia of the urinary bladder. Clin Cancer Res 2007;13:6232–6236. Murphy WM, Takezawa K, Maruniak NA. Interobserver discrepancy using the 1998 World Health Organization/International Society of Urologic Pathology. Classification of urothelial neoplasms: practical choices for patient care. J Urol 2003;168:968–972. Oliva E, Young RH. Nephrogenic adenoma of the urinary tract: a review of the microscopic appearance of 80 cases with emphasis on unusual features. Mod Pathol 1995;8:722–730. Oosterhuis JW, Schapers RF, Janssen-Heijnen ML, et  al. Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems. J Clin Pathol 2002;55:900–905. Pan C, Yang XJ, Lopez-Beltran A, et al. C-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol 2005;18:320–323. Pan CC, Yu IT, Yang AH, et al. Clear cell myomelanocytic tumor of the urinary bladder. Am J Surg Pathol 2003;27:689–692. Pant-Purohit M, Lopez-Beltran A, Montironi R, MacLennan GT, Cheng L. Small cell carcinoma of the urinary bladder. Histol Histopathol 2010;25:217–221. Parker DC, Folpe AL, Bell J, et al. Potential utility of uroplakin III, thrombomodulin, high molecular weight cytokeratin, and cytokeratin 20 in noninvasive, invasive, and metastatic urothelial (transitional cell) carcinomas. Am J Surg Pathol 2003;27:1–10. Paterson RF, Ulbright TM, MacLennan GT, et  al. Molecular genetic alterations in the laser-capture microdissected stroma adjacent to bladder carcinoma. Cancer 2003;98:1830–1836.

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Samaratunga H, Khoo K. Micropapillary. Variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology 2004;45:55–64. Skinnider BF, Oliva E, Young RH, et al. Expression of alpha-methylacylCoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol 2004;28:701–705. Sung MT, Eble JN, Wang M, Tan PH, Lopez-Beltran A, Cheng L. Inverted papilloma of the urinary bladder: a molecular genetic appraisal. Mod Pathol 2006;19:1289–1294. Sung MT, Lopez-Beltran A, Eble JN, MacLennan GT, Tan PH, Montironi R, Jones TD, Ulbright TM, Blair JE, Cheng L. Divergent pathway of intestinal metaplasia and cystitis glandularis of the urinary bladder. Mod Pathol 2006;19:1395–1401. Sung MT, Maclennan GT, Lopez-Beltran A, Montironi R, Cheng L. Natural history of urothelial inverted papilloma. Cancer 2006;107:2622–2627. Sung MT, Wang M, MacLennan GT, Eble JN, Tan PH, Lopez-Beltran A, Montironi R, Harris JJ, Kuhar M, Cheng L. Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation. J Pathol 2007;211:420–430. Sung MT, Zhang S, MacLennan GT, Lopez-Beltran A, Montironi R, Wang M, Tan PH, Cheng L. Histogenesis of clear cell adenocarcinoma in the urinary tract: evidence of urothelial origin. Clin Cancer Res 2008; 14:1947–1955. Sung MT, Zhang S, Lopez-Beltran A, Montironi R, Wang M, Davidson DD, Koch MO, Cain MP, Rink RC, Cheng L. Urothelial carcinoma following augmentation cystoplasty: An aggressive variant with distinct clinicopathological characteristics and molecular genetic alterations. Histopathology 2009;55:161–173. Taylor DC, Bhagavan BS, Larsen MP, et al. Papillary urothelial hyperplasia: a precursor to papillary neoplasm. Am J Surg Pathol 1996;20: 1481–1488. Volmar KE, Chan TY, De Marzo AM, et al. Nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma. Am J Surg Pathol 2003;27: 1243–1252. Wang HL, Lu DW, Yerian LM, et  al. Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Am J Surg Pathol 2001;25:1380–1387. Wang X, MacLennan GT, Lopez-Beltran A, Cheng L. Small cell carcinoma of the urinary bladder – histogenesis, genetics, diagnosis, biomarkers, treatment, and prognosis. Appl Immunohistochem Mol Morphol 2007; 15:8–18. Wang X, MacLennan GT, Zhang S, Montironi R, Lopez-Beltran A, Tan PH, Foster S, Baldridge LA, Cheng L. Sarcomatoid carcinoma of the upper urinary tract: Clinical outcome and molecular characterization. Hum Pathol 2009;40:211–217. Yorukoglu K, Tuna B, Dikicioglu E, et  al. Reproducibility of the 1998 World Health Organization/International Society of Urologic Pathology classification of papillary urothelial neoplasms of the urinary bladder. Virchows Arch 2003;443:734–740. Young RH, Bostwick DG. Florid cystitis glandularis with mucin extravasation: a mimic of adenocarcinoma. Am J Surg Pathol 1996;20: 1462–1468. Young RH, Clement PB. Mullerianosis of the urinary bladder. Mod Pathol 1996;9:731–737. Young RH, Oliva E. Invasive transitional cell carcinomas of the urinary bladder that may be under diagnosed: a report of four cases exemplifying the homology between neoplastic and nonneoplastic transitional cell lesions. Am J Surg Pathol 1996;20:1448–1454.

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37 Renal Pelvis, Ureter, and Urethra Antonio Lopez-Beltran, md, Sean R. Williamson, md, and Liang Cheng, md

Contents

I. Congenital Anomalies........................37-2 V. Neoplasms of the Urethra..................37-8 Renal Pelvis and Ureter...................................37-2 Urethra..............................................................37-2

II. Pyelitis, Ureteritis, and Urethritis....................................37-2 III. Benign Lesions and Mimics of Cancer...........................................37-2

Fibroepithelial Polyp of the Ureter.................37-2 Ureteral Endometriosis....................................37-2 Urethral Inflammatory Polyp.........................37-3 Urethral Caruncle............................................37-3 Urethral Diverticulum.....................................37-3 Ectopic Prostatic Tissue...................................37-3 Idiopathic Retroperitoneal Fibrosis...............37-4

IV. Neoplasms of the Renal Pelvis and Ureter.........................................37-4 Benign Urothelial Neoplasms..........................37-4 Flat Urothelial Lesions with Atypia................37-4 Urothelial Carcinoma......................................37-4 Squamous Cell Carcinoma..............................37-7 Adenocarcinoma...............................................37-7

Benign Epithelial Tumors   of the Urethra...............................................37-8 Carcinoma of the Urethra...............................37-8 Urothelial Carcinoma of the Urethra.............37-9 Squamous Cell Carcinoma   of the Urethra...............................................37-9 Adenocarcinoma of the Urethra...................37-10

VI. Soft Tissue Tumors............................37-11 Renal Pelvis and Ureter.................................37-11 Urethra............................................................37-11

VII. Miscellaneous Tumors......................37-11 VIII. TNM Classification of Tumors of the Renal Pelvis and Ureter (2010 Revision)................................37-11 IX. TNM Classification of Tumors of the Urethra (2010 Revision)........37-12 X. Suggested Reading...........................37-12

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_37, © Springer Science+Business Media, LLC 2002, 2006, 2011

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CONGENITAL ANOMALIES Renal Pelvis and Ureter ♦♦ A number of congenital anomalies have been reported to occur in the renal pelvis and/or the ureter ♦♦ Double ureter is the most common anomaly, seen in approximately 0.8% of autopsies −− It is frequently associated with double renal pelvis ♦♦ Megaureter (primary or secondary to reflux) can also be seen −− It is characterized by near absence of the longitudinal muscle fibers, preponderance of circular muscle, or fibrosis of the muscle and adventitia −− In cases of renal dysplasia, the ureter is usually dysplastic (maldeveloped)

♦♦ Ureterocele (congenital dilatation of the intramural portion of the ureter) may be seen in some cases resulting in obstruction or reflux −− Childhood ureteropelvic junction obstruction is the most important cause of intrinsic ureteral obstruction

Urethra ♦♦ A number of congenital anomalies have been reported to occur in the urethra ♦♦ The most common lesions include duplication, congenital urethral polyps (usually in the prostatic urethra), and urethral valves

PYELITIS, URETERITIS, AND URETHRITIS ♦♦ Pyelitis, ureteritis, and urethritis are descriptive and often nonspecific terms that refer to a variety of benign, acute, or chronic inflammatory lesions that can be seen along the urinary tract, though they are more common in the bladder

♦♦ Morphologically similar to those seen in the urinary bladder (please refer to Chap. 36 for more details)

BENIGN LESIONS AND MIMICS OF CANCER Fibroepithelial Polyp of the Ureter Clinical ♦♦ Usually occurs in young adult men ♦♦ Clinical presentations include hematuria, intermittent flank pain, and urinary obstructive symptoms ♦♦ Polyp often occurs in the region of the verumontanum or posterior urethra but may also occur in the proximal ureter, more frequently on the left side

♦♦ Has a strong predilection for involvement of the lower third of the left ureter

Microscopic ♦♦ Composed of endometrial stroma and glands (Fig. 37.2)

Microscopic ♦♦ Polypoid projection of edematous vascular stroma with overlying atrophic or hyperplasic urothelium (Fig. 37.1) ♦♦ Chronic inflammatory cell infiltrate

Ureteral Endometriosis Clinical ♦♦ Mean age at diagnosis is 51 years ♦♦ May be asymptomatic or present with hydronephrosis and superimposed pyelonephritis ♦♦ May lead to renal failure due to silent obstruction of the ureter Fig. 37.1. Fibroepithelial polyp of the ureter.

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Fig. 37.2. Ureteral endometriosis.

Fig. 37.3. Urethral caruncle.

♦♦ Both extrinsic and intrinsic involvement by endometriosis may be encountered −− Intrinsic disease is characterized by the presence of ectopic endometrial tissue within the muscularis propria, lamina propria or ureteral lumen −− In extrinsic disease, endometrial tissue involves only the ureteral adventitia or surrounding connective tissues

♦♦ Mitotic figures are inconspicuous ♦♦ Atypical stromal cells may occasionally be present raising the suspicion of cancer; these atypical cells are cytokeratin negative ♦♦ Urothelium may show hyperplasia, metaplasia, or denudation

Immunohistochemistry ♦♦ Epithelial cells are positive for CK7, ER, and PR ♦♦ Stromal cells are positive for CD10, ER, and PR

Urethral Inflammatory Polyp ♦♦ Composed of inflamed and vascular stroma lined by normal or hyperplastic urothelium with inflammatory cells extending to the urothelium

Urethral Caruncle Clinical ♦♦ Usually occurs in postmenopausal women at a mean age of 56 years ♦♦ Typically presents as a red painful mass at the external ureteral meatus ♦♦ The etiology remains uncertain ♦♦ May be asymptomatic or present with hematuria, dysuria, and pain

Macroscopic ♦♦ Nodular or pedunculated erythematous lesion in the posterior or lateral distal urethral wall

Microscopic ♦♦ The lesion displays an exuberant proliferation of fibroblasts and endothelial cells in an inflammatory background, similar to granulation tissue (Fig. 37.3) ♦♦ Lacks significant cytologic atypia

Differential Diagnosis ♦♦ Sarcomatoid carcinoma −− Cytologic atypia and mitotic figures are prominent −− Cytokeratin positive

Urethral Diverticulum Clinical ♦♦ Usually affects women and often asymptomatic

Microscopic ♦♦ Lined by urothelium, but squamous and glandular metaplasia can be seen ♦♦ Nephrogenic adenoma or carcinoma may develop in diverticula

Ectopic Prostatic Tissue Clinical ♦♦ Occurs in adolescents or young adults and presents with hematuria or irritative symptoms ♦♦ May shed atypical cells into the urine ♦♦ Often located in the posterior portion of the prostatic urethra ♦♦ These lesions may be better classified as benign prostatic polyp

Microscopic ♦♦ Composed of benign prostatic glands with overlying intact urothelium ♦♦ PSA+, high molecular weight cytokeratin+

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Idiopathic Retroperitoneal Fibrosis Clinical ♦♦ Frequent medial deviation of the ureter on radiological examination ♦♦ The ureter is encased in firm, fibrotic tissue

Microscopic

♦♦ The lesion often shows a chronic inflammatory infiltrate with lymphocytes and plasma cells ♦♦ Occasional lymphoid follicle formation may be seen ♦♦ Stromal edema is also seen and in selected cases imparts a myxoid appearance to the lesion, raising concern for myxoid liposarcoma

♦♦ There are varying amounts of fibrosis with collagen deposition

NEOPLASMS OF THE RENAL PELVIS AND URETER ♦♦ Tumors arising in the renal pelvis and the ureter are morphologically similar to those seen in the bladder (Table 37.1) ♦♦ The incidence of these tumors ranges 0.7 to 1.1 per 100,000 and there is a male-to-female ratio of 1.7 to 1 with an increasing incidence in females ♦♦ Tumors of the ureter and renal pelvis account for 8% of all urinary tract neoplasms and are more common in older patients (mean 70 years) ♦♦ More than 90% are urothelial carcinomas ♦♦ Risk factors include tobacco smoking and occupational exposure (as for urinary bladder carcinoma), as well as additional upper urinary tract risk factors (discussed below) ♦♦ Hematuria and flank pain are the chief presenting symptoms

Benign Urothelial Neoplasms ♦♦ Benign epithelial tumors are rare in the upper urinary tract ♦♦ In this location, most benign epithelial tumors are urothelial papilloma, inverted papilloma, villous adenoma, nephrogenic adenoma, or squamous papilloma ♦♦ Most lesions are incidental findings and show similar histology to their bladder counterparts ♦♦ Synchronous inverted papilloma of the urinary bladder and the renal pelvis may occur

Flat Urothelial Lesions with Atypia ♦♦ Similar lesions to those of the urinary bladder are seen ♦♦ Refer to Chap. 36

Urothelial Carcinoma Clinical ♦♦ Carcinoma arising in the renal pelvis and calyces is twice as common as carcinoma of the ureter ♦♦ Multifocality is frequent −− Often associated with a bladder neoplasm

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Table 37.1. Histological Classification of Tumors of the Renal Pelvis and Ureter Epithelial tumors Benign   Urothelial papilloma   Inverted papilloma   Squamous cell papilloma   Nephrogenic adenoma   Villous adenoma   Others Malignant   Urothelial carcinoma   Squamous cell carcinoma   Adenocarcinoma   Small-cell carcinoma   Undifferentiated carcinoma   Others Nonepithelial tumors Benign   Fibroepithelial polyp   Leiomyoma   Fibrous histiocytoma   Neurofibroma   Hemangioma   Lipoma   Hibernoma Malignant   Leiomyosarcoma   Rhabdomyosarcoma   Fibrosarcoma   Angiosarcoma   Osteosarcoma   Malignant peripheral nerve sheath tumor (malignant schwannoma) Miscellaneous   Pheochromocytoma   Carcinoid   Lymphoma   Plasmacytoma   Wilms tumor   Choriocarcinoma   Malignant melanoma

Renal Pelvis, Ureter, and Urethra

♦♦

♦♦ ♦♦

♦♦

−− Synchronous renal cell carcinoma and urothelial carcinoma may coexist −− Bilateral synchronous or metachronous ureteral and renal pelvic carcinomas may occur Etiologic and predisposing factors additional to those of bladder malignancy include: phenacetin abuse, papillary necrosis, Balkan nephropathy, thorium containing ­radiologic contrast material, urinary tract infections, or nephrolithiasis Some tumors of the ureter are associated with hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome) Hydronephrosis and stones may be present in renal pelvic tumors while hydroureter and/or stricture may accompany ureteral neoplasms The most important prognostic factor is tumor stage −− In evaluating these specimens, it is important to avoid overstaging as pT3 tumors that invade the muscularis (pT2) but shows extension into renal tubules in a pagetoid or intramucosal pattern −− Survival for patients with pTa/pTis lesions is favorable but declines to 75% in patients with pT2 tumors

37-5

−− Survival for patients with pT3 and pT4 tumors, lymph node metastasis, or residual tumor after surgery is poor −− Ki-67 and HER2/neu overexpression might be of prognostic value and predict disease progression and cancerspecific survival

Macroscopic ♦♦ Tumors may be papillary, polypoid, nodular, ulcerative, or infiltrative (Fig. 37.4) ♦♦ Some tumors distend the entire renal pelvis while others ulcerate and infiltrate, causing thickening of the wall ♦♦ A high grade tumor may appear as an ill-defined mass that involves the renal parenchyma, mimicking a primary renal cell carcinoma

Microscopic ♦♦ These tumors mirror bladder urothelial neoplasia and therefore, occur with similar histology including noninvasive papillary carcinoma, invasive carcinoma, and carcinoma in situ ♦♦ The entire morphologic spectrum of urothelial carcinoma and its variants may be seen

Fig. 37.4. Papillary urothelial carcinoma of the renal pelvis (left) and the ureter (right).

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♦♦ Tumor types include those showing squamous and glandular differentiation, inverted growth (Fig. 37.5) or other morphologic variants (nested, microcystic, micropapillary, lymphoepithelioma-like, clear cell, and plasmacytoid) ♦♦ Sarcomatoid carcinoma (Fig. 37.6) is rare in the renal pelvis and ureter, with a poor prognosis and either homologous or heterologous elements ♦♦ Rare cases of choriocarcinoma reported in this location are thought to represent high grade urothelial carcinoma with trophoblastic differentiation

Immunohistochemistry ♦♦ Some urothelial carcinomas in this location display alphafetoprotein or cyclooxygenase-2 expression

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ P63 and high molecular weight cytokeratin (34bE12) are positive (conventional renal cell carcinomas are usually negative for these markers)

Molecular Pathology ♦♦ Urothelial carcinomas of the renal pelvis and ureter show molecular similarities to bladder carcinoma ♦♦ Microsatellite instability (MSI) is more common in upper urinary tract cancers ♦♦ Deletions on chromosome 9p and 9q may occur in more than half of upper urinary tract tumors ♦♦ Frequent deletions at 17p and TP53 gene mutations are seen in advanced carcinomas ♦♦ 20–30% of all upper urinary tract cancers demonstrate MSI and loss of the mismatch repair proteins MSH2, MLH1, or MSH6 ♦♦ Mutations in the sequences of TGFb-RII, Bax, MSH3, and MSH6 genes are found in 20–33% of cases with MSI; indicating a molecular pathway of carcinogenesis that is similar to some mismatch repair-deficient colorectal cancers ♦♦ Tumors with MSI have different clinical and histological features including −− Low tumor stage and grade −− Papillary growth −− Higher prevalence in female patients −− Often an inverted growth pattern

Grading Fig. 37.5. Urothelial carcinoma with inverted growth.

♦♦ Urothelial tumors should be graded according to the 1973 World Health Organization (WHO) classification for bladder

Fig. 37.6. Sarcomatoid carcinoma. (A) The tumor is composed of malignant spindle cells with significant cytologic atypia. The cells are positive for cytokeratin immunostaining. (B) The tumor may have a myxoid appearance (myxoid variant).

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Fig.  37.7. Papillary urothelial carcinoma, 1973 WHO grade 2 (2004 WHO low grade).

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Fig. 37.9. Signet-ring cell adenocarcinoma of the ureter.

♦♦ Pure squamous cell carcinomas are usually high grade and stage tumors that frequently invade the kidney ♦♦ Tumors usually occur in a background of ­nephrolithiasis, chronic inflammation, or squamous cell metaplasia ♦♦ Some squamous cell carcinoma may present with hypercalcemia; but are unrelated to Epstein–Barr virus infection ♦♦ Survival at 5-year followup is poor

Microscopic ♦♦ Similar to other organs; refer to Chap. 36 Fig.  37.8. Papillary urothelial carcinoma, 1973 WHO grade 3 (2004 WHO high grade). tumors; alternatively both the 1973 and 2004 WHO grading systems may be stated (Figs. 37.7 and 37.8) ♦♦ The existence of the papillary urothelial neoplasm of low malignant potential (PUNLMP) in the upper urinary tract has been recently challenged; the terminology of PUNLMP should be avoided in the diagnosis of upper urinary tract tumors

Squamous Cell Carcinoma Clinical ♦♦ Pure squamous cell carcinoma is very rare ♦♦ Squamous differentiation in urothelial carcinoma is common and may be seen in about 40% cases involving the renal pelvis and ureter

Adenocarcinoma Clinical ♦♦ Pure adenocarcinoma of the renal pelvis and ureter is rare ♦♦ These tumors can be categorized into the following types: enteric, mucinous, and signet-ring cell adenocarcinoma (Fig. 37.9) ♦♦ Glandular (intestinal) metaplasia, nephrolithiasis, and repeated infections are predisposing factors ♦♦ Most adenocarcinomas are high grade and widely invasive at presentation

Microscopic ♦♦ Similar to other organs; refer to Chap. 36 ♦♦ In the ureter, florid ureteritis glandularis may occur, raising concern for well-differentiated adenocarcinoma

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NEOPLASMS OF THE URETHRA ♦♦ This category includes epithelial and nonepithelial neoplasms of the male and female urethra, spanning from the urinary bladder to the urethral meatus, and tumors arising in the accessory glands (Cowper and Littre glands in the male as well as Skene glands in the female) (Table 37.2)

♦♦ Epithelial tumors of the urethra are three to four times more common in women than in men ♦♦ Congenital diverticulum and acquired strictures of the female urethra contribute to the female preponderance of carcinomas in the urethra

Benign Epithelial Tumors of the Urethra Table 37.2. Histological Classification of Tumors of the Urethra Epithelial tumors Benign   Squamous papilloma   Villous adenoma   Urothelial papilloma   Inverted papilloma   Others Malignant   Squamous cell carcinoma   Urothelial carcinoma   Clear cell adenocarcinoma   Non-clear cell adenocarcinoma    Enteric adenocarcinoma    Colloid (mucinous) adenocarcinoma    Signet-ring cell adenocarcinoma    Adenocarcinoma, not otherwise specified (NOS)   Adenosquamous carcinoma   Neuroendocrine carcinoma    Small cell carcinoma   Undifferentiated carcinoma   Adenoid cystic carcinoma   Germ cell tumor    Yolk sac tumor   Others

♦♦ Benign epithelial tumors are rare in the urethra of either sex ♦♦ Tumors occurring in males and females are similar ♦♦ Varieties of lesions have been reported, including squamous papilloma, villous adenoma, condyloma acuminatum (Fig. 37.10), inverted papilloma, and urothelial papilloma ♦♦ The histological features are identical to tumors described in the urinary bladder and other sites ♦♦ Villous adenoma of the urethra may be associated with tubulovillous adenoma and adenocarcinoma of the rectum

Carcinoma of the Urethra Clinical ♦♦ Tumors involving the distal urethra and meatus are most common ♦♦ The overall prognosis is relatively poor ♦♦ Tumor stage and location are important prognostic factors ♦♦ Proximal tumors have better overall survival than distal tumors −− Five-year survival was 51% for proximal tumors vs. 6% for distal tumors in females, and 50% for proximal tumors vs. 20% for distal tumors in males ♦♦ High tumor stage and the presence of lymph node metastasis are adverse prognostic parameters

Nonepithelial tumors Benign   Leiomyoma   Hemangioma   Glomangiomyoma Malignant   Malignant melanoma   Non-Hodgkin lymphoma   Plasmacytoma Tumor-like lesions   Fibroepithelial polyp   Plasmacytoma   Caruncle   Condyloma acuminatum   Nephrogenic adenoma Tumors of accessory glands Malignant  Carcinoma of Skene (female), Littre and Cowper (male) glands

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Fig. 37.10. Condyloma acuminatum in the urethra.

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Macroscopic ♦♦ Exophytic nodular, infiltrative, or papillary mass with frequent ulceration ♦♦ Urothelial tumors involving the proximal urethra exhibit macroscopic diversity with cases showing papillary growth, erythematous or white plaque-like areas (carcinoma in situ), and nodular/infiltrative growth in invasive carcinoma ♦♦ Adenocarcinomas are often large, infiltrative or expansile neoplasms which may have an exophytic surface, and appear mucinous, gelatinous, or cystic −− These tumors may occur within urethral diverticula −− Other tumors may occur in the penile urethra, bulbomembranous urethra or the prostatic urethra, which often determines the gross and histological appearance −− These tumors may grow as ulcerative, nodular, papillary, cauliflower-like, or ill-defined lesions

Microscopic ♦♦ In female patients, distal urethral and meatus tumors are most commonly squamous cell carcinomas (70%), and tumors of the proximal urethra are urothelial carcinomas (20%) or adenocarcinomas (10%) ♦♦ In the penile and bulbomembranous urethra, about 75% of cases are squamous cell carcinoma, followed by urothelial carcinomas (usually prostatic urethra and less commonly bulbomembranous and penile urethra), adenocarcinomas (usually bulbomembranous urethra) or undifferentiated carcinoma

Urothelial Carcinoma of the Urethra ♦♦ Tumors are classified as outlined in the urinary bladder and include noninvasive, papillary urothelial carcinomas, carcinoma in situ – or invasive urothelial carcinoma ♦♦ May be synchronous or metachronous to bladder neoplasia ♦♦ Tumors should be graded using the 1973 WHO grading system (alternatively using the low vs. high grade scheme as outlined in 2004 WHO grading system) ♦♦ Carcinoma in situ may involve suburethral glands, focally or extensively, and should not be mistaken as invasion ♦♦ Deeply invasive urothelial carcinomas are high grade, with or without papillary components, and characterized by irregular nests, sheets, and cords of cells accompanied by a desmoplastic and/or inflammatory response ♦♦ Tumors may exhibit squamous or glandular differentiation or unusual morphologic variations (nested, microcystic, micropapillary, clear cell, plasmacytoid) ♦♦ Coexisting small-cell or sarcomatoid carcinoma components are rarely seen ♦♦ Urothelial carcinoma may involve the prostatic urethra, exhibiting the same grade and histological spectrum described in the female urethra

Fig. 37.11. Prostatic adenocarcinoma involving the urethra.

♦♦ Features unique to prostatic urethral urothelial cancers are the frequent proclivity of high grade tumors to extend into the prostatic ducts and acini in a pagetoid fashion ♦♦ In females, differentiation from Paget disease of the vulva extending through the urethra is mandatory as is exclusion of melanoma extending to the urethra (HMB45+). Urothelial carcinomas are often CK7+/CK20+; Paget disease of the vulva is typically CK7+/CK20−. Direct extension of prostatic adenocarcinoma into the urethra must be considered in male patients (Fig.  37.11). These tumors are often categorized as prostatic ductal adenocarcinoma and are PSA and PAP positive, P63 negative ♦♦ A number of tumor-like conditions also enter the differential diagnosis, including nephrogenic adenoma (metaplasia), fibroepithelial and prostatic polyps, condyloma acuminatum, and caruncle

Squamous Cell Carcinoma of the Urethra Clinical ♦♦ Squamous cell carcinoma of the urethra is associated with HPV infection in both sexes ♦♦ High-risk human papillomavirus (HPV) 16 or 18 may be detected in up to 60% of cases in women ♦♦ In men, about 30% of squamous cell carcinomas tested positive for HPV16 ♦♦ Tumors in the bulbar urethra are usually negative for HPV ♦♦ Some HPV16 positive tumors might have a more favorable prognosis ♦♦ Low-risk HPV infection plays a crucial role in the etiology of condyloma acuminatum of the urethra ♦♦ The association of urothelial carcinoma with HPV, both in the urethra and the urinary bladder remains controversial

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Fig. 37.12. Moderately differentiated squamous cell carcinoma of the uretha. The adjacent mucosa show koilocytic atypia, ­characteristic of human papillomavirus (HPV) infection.

Microscopic ♦♦ Squamous cell carcinomas of the urethra span the range from well differentiated (including the rare verrucous carcinoma) to moderately differentiated (most common) to poorly differentiated (Fig. 37.12) ♦♦ Squamous cell carcinomas are similar in histology to those of other sites ♦♦ Squamous cell carcinomas are usually graded based on the degree of differentiation −− Well differentiated −− Moderately differentiated −− Poorly differentiated

Adenocarcinoma of the Urethra ♦♦ Adenocarcinoma of the female urethra may be seen in two forms clear: cell adenocarcinoma (approximately 40%) and non-clear cell adenocarcinoma (approximately 60%), the later frequently exhibiting similar patterns to those of the bladder (enteric, mucinous, signet-ring cell or adenocarcinoma not otherwise specified) ♦♦ Clear cell adenocarcinoma is rare in men ♦♦ Clear cell adenocarcinoma is usually characterized by histologic heterogeneity within the neoplasm, including solid, tubular, tubulocystic, or papillary patterns (Fig. 37.13) ♦♦ The cytologic features vary from low grade (resembling nephrogenic adenoma focally) to high grade (more frequently) ♦♦ Necrosis, mitotic activity, and extensive infiltrative growth are commonly observed ♦♦ Adenocarcinomas are graded based on the degree of differentiation (well differentiated, moderately differentiated, and poorly differentiated)

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Fig.  37.13. Clear cell adenocarcinoma of the urethra showing (A) papillary, (B) tubular, and (C) solid pattern. ♦♦ Bulbourethral gland carcinomas may show a mucinous, papillary, adenoid cystic, acinar, or tubular architecture ♦♦ Female periurethral gland adenocarcinomas are clear cell or mucinous and may show prostatic specific antigen immunoexpression

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SOFT TISSUE TUMORS Renal Pelvis and Ureter ♦♦ Rare examples of nonepithelial tumors and tumor-like conditions arising in the renal pelvis and/or ureter have been described including:leiomyoma, neurofibroma, fibrous histiocytoma, hemangioma, lipoma, hibernoma, and glomus tumor ♦♦ Fibroepithelial polyp is a tumor-like condition growing as an exophytic intraluminal mass of vascular connective and inflammatory cells covered by normal urothelium; rare cases may have a prominent pseudosarcomatous stroma ♦♦ Malignant soft tissue tumors include leiomyosarcoma and less frequently: rhabdomyosarcoma, osteosarcoma, fibrosarcoma, angiosarcoma, malignant peripheral nerve sheath tumor (malignant schwannoma), and Ewing sarcoma

♦♦ Gastrointestinal stromal tumor-like lesions as well as myofibroblastic proliferations may occur

Urethra ♦♦ Rare examples of soft tissue tumors arising in the urethra have been described ♦♦ Benign tumors include leiomyoma, which shows a similar morphology and immunoprofile to those of other organs. In female patients leiomyoma may show expression of estrogen receptors ♦♦ Leiomyoma may occur as a part of diffuse leiomyomatosis syndrome (esophageal and rectal leiomyoma) ♦♦ Hemangioma has also been described

MISCELLANEOUS TUMORS ♦♦ Few cases of ureteric pheochromocytoma have been reported ♦♦ Carcinoid tumors of the renal pelvis, ureter, and urethra are similarly rare and must be differentiated from metastatic disease ♦♦ Small-cell carcinoma of the renal pelvis is a rarity observed in elderly patients. These aggressive tumors usually contain foci of urothelial carcinoma and have a typical neuroendocrine immunohistochemical profile ♦♦ Renal pelvic and ureteric lymphomas are usually associated with systemic disease, while localized pelvic plasmacytoma has been reported ♦♦ Wilms tumor confined to the renal pelvis or extending into the ureter and cases of malignant melanoma of the renal pelvis may be seen rarely ♦♦ A tumor-like lesion of the renal pelvis composed of Liesegang rings has been reported recently ♦♦ Malignant melanoma has also been described in the male and female urethra, with some cases of amelanotic melanoma mimicking urethral carcinoma (Fig. 37.14) ♦♦ Primary non-Hodgkin lymphoma and plasmacytoma have also been described

Fig. 37.14. Melanoma in the urethra. Melanin pigment is apparent immediately beneath the urethral mucosa.

TNM CLASSIFICATION OF TUMORS OF THE RENAL PELVIS AND URETER (2010 REVISION) ♦♦ T: Primary Tumor −− TX Primary tumor cannot be assessed −− T0 No evidence of primary tumor −− Ta Noninvasive papillary carcinoma −− Tis Carcinoma in situ

−− T1 Tumor invades subepithelial connective tissue −− T2 Tumor invades muscularis −− T3 (Renal pelvis) Tumor invades beyond muscularis into peripelvic fat or renal parenchyma. (Ureter) Tumor invades beyond muscularis into periureteric fat

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−− T4 Tumor invades adjacent organs or through the kidney into perinephric fat ♦♦ N: Regional Lymph Nodes −− NX Regional lymph nodes cannot be assessed −− N0 No regional lymph node metastasis −− N1 Metastasis in a single lymph node 2  cm or less in greatest dimension −− N2 Metastasis in a single lymph node more than 2  cm but not more than 5  cm in greatest dimension,

or multiple lymph nodes, none more than 5 cm in greatest dimension −− N3 Metastasis in a lymph node more than 5 cm in greatest dimension ♦♦ M: Distant Metastasis −− MX Distant metastasis cannotbe assessed −− M0 No distant metastasis −− M1 Distant metastasis

TNM CLASSIFICATION OF TUMORS OF THE URETHRA (2010 REVISION) ♦♦ T: Primary Tumor −− TX Primary tumor cannot be assessed −− T0 No evidence of primary tumor −− Urethra (male and female) −− Ta Noninvasive papillary, polypoid, or verrucous carcinoma −− Tis Carcinoma in situ −− T1 Tumor invades subepithelial connective tissue −− T2 Tumor invades any of the following: corpus spongiosum, prostate, periurethral muscle −− T3 Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, anterior vagina, bladder neck −− T4 Tumor invades other adjacent organs −− Urothelial carcinoma of prostate (prostatic urethra) −− Tis pu Carcinoma in situ, involvement of prostatic urethra −− Tis pd Carcinoma in situ, involvement of prostatic ducts −− T1 Tumor invades subepithelial connective tissue

−− T2 Tumor invades any of the following: prostatic stroma, corpus spongiosum, periurethral muscle −− T3 Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extrapro­ static extension) −− T4 Tumor invades other adjacent organs (invasion of bladder) ♦♦ N: Regional Lymph Nodes −− NX Regional lymph nodes cannot be assessed −− N0 No regional lymph node metastasis −− N1 Metastasis in a single lymph node 2  cm or less in greatest dimension −− N2 Metastasis in a single lymph node more than 2 cm in greatest dimension, or multiple lymph nodes ♦♦ M: Distant Metastasis −− MX Distant metastasis cannot be assessed −− M0 No distant metastasis −− M1 Distant metastasis

SUGGESTED READING Al-Khawaja M, Tan PH, MacLennan GT, Lopez-Beltran A, Montironi R, Cheng L. Ureteral endometriosis: clinicopathological and immunohistochemical study of 7 cases. Hum Pathol 2008;39:954–959. Bonsib SM, Cheng L. Renal pelvis and ureter. In: Bostwick DG, Cheng L (eds.). Urologic Surgical Pathology. Philadelphia: Elsevier/Mosby, 2008, pp. 173–194. Cheng L, Montironi R, Bostwick DG. Villous adenoma of the urinary tract: a report of 23 cases including 8 with coexistent adenocarcinoma. Am J Surg Pathol 1999;23:764–771. Fine SW, Chan TY, Epstein JI. Inverted papillomas of the prostatic urethra. Am J Surg Pathol 2006;3:975–979. Holmang S, Johansson SL. Urothelial carcinoma of the upper urinary tract: comparison between the WHO/ISUP 1998 consensus classification and WHO 1999 classification system. Urology 2005;66:274–278.

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Holmang S, Thomsen J, Johansson SL. Micropapillary carcinoma of the renal pelvis and ureter. J Urol 2006;175:463–466. Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R. Handling and pathology reporting of specimens with carcinoma of the urinary ­bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology and the Uropathology Working Group. Virchows Arch 2004;445:103–110. Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol 2006;37: 1371–1388. Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHO classification. Eur Urol 2004;46:170–176. Lopez-Beltran A, Requena MJ, Alvarez-Kindelan J, Quintero A, Blanca A, Montironi R. Squamous differentiation in primary urothelial

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carcinoma of the urinary tract as seen by MAC387 immunohistochemistry. J Clin Pathol 2007;60:332–335. Ng KF, Chuang CK, Chang PL, Chu SH, Wallace CG, Chen TC. Absence of Epstein-Barr virus infection in squamous cell carcinoma of upper urinary tract and urinary bladder. Urology 2006;68:775–777. Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the renal pelvis: a clinicopathologic study of 130 cases. Am J Surg Pathol 2004;28:1545–1552.

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Sanchez-Ortiz R, Huang SF, Tamboli P, Prieto VG, Hester G, Pettaway CA. Melanoma of the penis, scrotum and male urethra: a 40-year single institution experience. J Urol 2005;173:1958–1965. Stein JP, Clark P, Miranda G, Cai J, Groshen S, Skinner DG. Urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. J Urol 2005;173:1163–1168. Sung MT, Maclennan GT, Lopez-Beltran A, Montironi R, Cheng L. Natural history of urothelial inverted papilloma. Cancer 2006;107: 622–2627.

Park S, Hong B, Kim CS, Ahn H. The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary tract. J Urol 2004;171:621–625.

Sung MT, Zhang S, MacLennan GT, et  al. Histogenesis of clear cell adenocarcinoma in the urinary tract: Evidence of urothelial origin. Clin Cancer Res 2008;14:1947–1955.

Perez-Montiel D, Hes O, Michal M, Suster S. Micropapillary urothelial carcinoma of the upper urinary tract: Clinicopathologic study of five cases. Am J Clin Pathol 2006;126:86–92.

Velazquez EF, Soskin A, Bock A, et  al. Epithelial abnormalities and precancerous lesions of anterior urethra in patients with penile carcinoma: a report of 89 cases. Mod Pathol 2005;18:917–923.

Perez-Montiel D, Wakely PE, Hes O, Michal M, Suster S. High grade urothelial carcinoma of the renal pelvis: clinicopathologic study of 108 cases with emphasis on unusual morphologic variants. Mod Pathol 2006;19:494–503.

Vizcaino JR, Macedo-Dias JA, Teixeira-de-Sousa JM, Silva RM, Carpenter S. Pseudotumour of renal pelvis: Liesegang rings mimicking a solid neoplasm of the renal pelvis. Histopathology 2005;47:115–117.

Reuter VE. Urethra. In: Bostwick DG, Cheng L (eds.). Urologic Surgical Pathology. Philadelphia: Elsevier/Mosby, 2008, pp. 595–614.

Wang X, MacLennan GT, Zhang S, et al. Sarcomatoid carcinoma of the upper urinary tract: clinical outcome and molecular characterization. Hum Pathol 2009;40:211–217.

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38 Prostate David G. Bostwick, md and Liang Cheng, md

Contents

I. Inflammatory Lesions.........................38-3

Acute Bacterial Prostatitis...............................38-3 Chronic Bacterial and Nonbacterial Prostatitis.....................................................38-3 Granulomatous Prostatitis..............................38-3

II. Benign Lesions and Mimics of Adenocarcinoma............................38-5 Benign Prostatic Hyperplasia and Other Forms of Hyperplasia...............38-5 Benign Prostatic Hyperplasia................38-5 Stromal Hyperplasia with Atypical Giant Cells..........................................38-5 Cribriform Hyperplasia.........................38-5 Basal Cell Proliferation..........................38-5 Atypical Adenomatous Hyperplasia........................................38-7 Postatrophic Hyperplasia.......................38-9 Sclerosing Adenosis..............................38-10 Hyperplasia of Mesonephric Remnants (Florid Mesonephric Hyperplasia).....................................38-10 Verumontanum Mucosal Gland Hyperplasia......................................38-11 Metaplasia.......................................................38-11 Squamous Metaplasia..........................38-11 Mucinous Metaplasia...........................38-11 Eosinophilic Metaplasia.......................38-12 Urothelial Metaplasia...........................38-12 Nephrogenic Adenoma.........................38-12 Atrophy...........................................................38-13 Seminal Vesicles and Ejaculatory Ducts......38-13 Senile Seminal Vesicle Amyloidosis..............38-13 Cowper Glands...............................................38-14

Paraganglia.....................................................38-14 Prostatic Urethral Polyp................................38-14 Proliferative Papillary Urethritis........38-14 Ectopic Prostatic Tissue (Benign Polyp with Prostatic-Type Epithelium).......................................38-14 Nephrogenic Adenoma.........................38-14 Benign Urothelial Papilloma................38-14 Inverted Papilloma...............................38-14

III. High Grade Prostatic Intraepithelial Neoplasia .......................................38-15 IV. Atypical Small Acinar Proliferation, Suspicious for Malignancy...............38-17 V. Malignant Tumors............................38-19 Prostatic Adenocarcinoma............................38-19 Prostatic Adenocarcinoma Variants.............38-23 Ductal (Endometrioid) Adenocarcinoma..............................38-23 Mucinous Adenocarcinoma.................38-24 Small Cell Carcinoma (High Grade Neuroendocrine Carcinoma)..........38-25 Adenocarcinoma with Neuroendocrine Differentiation......38-25 Signet-Ring Cell Carcinoma................38-25 Squamous Cell and Adenosquamous Carcinoma........................................38-26 Sarcomatoid Carcinoma (Carcinosarcoma).............................38-26 Lymphoepithelioma-Like Carcinoma........................................38-27 Cribriform Adenocarcinoma...............38-27

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_38, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Adenocarcinoma with Glomeruloid Features.............................................38-27 Atrophic Adenocarcinoma...................38-27 Adenocarcinoma with Microvacuolated Cytoplasm (Foamy Gland Carcinoma).............38-28 Pseudohyperplastic Adenocarcinoma..............................38-28 Adenoid Cystic/Basal Cell Carcinoma........................................38-28 Urothelial Carcinoma...........................38-28 Soft Tissue Tumors.........................................38-29 Rhabdomyosarcoma.............................38-29

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Leiomyosarcoma...................................38-29 Phyllodes Tumor...................................38-30 Lymphoma......................................................38-31

VI. Treatment Effects.............................38-31 Androgen Deprivation Therapy....................38-31 Radiation Therapy.........................................38-32

VII. Tnm Classification of Prostate Cancer (2010 Revision)...................38-33 VIII. Suggested Reading...........................38-33

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INFLAMMATORY LESIONS Acute Bacterial Prostatitis Clinical ♦♦ Sudden onset of fever, chills, pain, and irritative and obstructive symptoms ♦♦ Swollen, tender, and indurated on digital rectal examination ♦♦ E. coli infection accounts for 80% of cases ♦♦ Diagnosis confirmed by culture of midstream urine and/or prostatic secretions ♦♦ Transrectal ultrasonography useful for preoperative diagnosis ♦♦ Biopsy contraindicated

Microscopic ♦♦ Microabscess formation and heavy infiltrate of acute and chronic inflammatory cells (Fig. 38.1) ♦♦ Acinar destruction and epithelial cell degeneration ♦♦ Stromal hemorrhage and edema ♦♦ Abscess is a rare complication, especially in immunocompromised patients

Chronic Bacterial and Nonbacterial Prostatitis Clinical ♦♦ Chronic nonbacterial prostatitis is more common than chronic bacterial prostatitis (E. coli) ♦♦ Chlamydia trachomatis and Ureaplasma urealyticum are common etiologic agents ♦♦ Often follows an indolent clinical course with relapses and remissions

Microscopic ♦♦ Epithelial degeneration and metaplasia ♦♦ Chronic inflammation

Differential Diagnosis ♦♦ High grade prostatic intraepithelial neoplasia (HGPIN) −− Partial acinar involvement, nuclear stratification, and prominent nucleoli −− Caution is urged in diagnosing prostatic intraepithelial neoplasia (PIN) in the setting of inflammation

Granulomatous Prostatitis Clinical ♦♦ Prior history of urinary tract infection is common (Table 38.1) ♦♦ Suspicious for carcinoma on digital rectal examination ♦♦ Probably caused by blockage of prostatic ducts and stasis of secretion

Microscopic ♦♦ Specific etiology often cannot be determined from histologic examination ♦♦ Glandular disruption, epithelial degeneration, and metaplasia ♦♦ Granulomatous inflammation with or without necrosis ♦♦ Polymorphous chronic inflammation composed of multinucleated giant cells, histiocytes, lymphocytes, plasma cells, and neutrophils

Table 38.1. Etiology of Granulomatous Prostatitis Infections   Bacterial: Tuberculosis (AFB staining), syphilis   Fungal: Coccidioidomycosis, Cryptococcosis, Histoplasmosis   Parasitic: Schistosomiasis   Viral: Herpes zoster Iatrogenic   Postsurgery or radiation   Post-BCG treatment Malakoplakia Systemic granulomatous disease   Allergic   Sarcoidosis   Systemic vascular diseases    Wegner granulomatosis    Polyarteritis nodosa    Churg–Strauss vasculitis

Fig. 38.1. Acute prostatitis with microabscess formation.

Idiopathic (most common)

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Immunohistochemistry ♦♦ Prostate-specific antigen (PSA) negative, prostate acid phosphatase (PAP) negative, cytokeratin negative, CD68 positive, other macrophage markers+

Variants ♦♦ Xanthoma −− Incidental findings in elderly men −− Clusters and sheets of lipid-laden histiocytes in a nodular configuration (Fig. 38.2) −− CD68 positive, cytokeratin negative ♦♦ Xanthogranulomatous prostatitis −− Nonspecific granulomatous prostatitis −− Composed predominantly of sheets of epithelioid histiocytes (Fig. 38.3) −− Polymorphous inflammatory infiltrate −− Associated with atrophy and acinar disruption ♦♦ Malakoplakia −− Due to defective intracellular lysosomal digestion of bacteria −− Intracellular and extracellular Michaelis–Gutman bodies are characteristic of the lesion (Fig. 38.4) −− The Michaelis–Gutman bodies represent bacterial debris within phagolysosomes, highlighted by PAS and von Kossa stains ♦♦ Wegener granulomatosis −− Stellate and geographic granulomas with palisading histiocytes

Fig. 38.2. Xanthoma.

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−− Necrotizing vasculitis involving small and medium-sized vessels ♦♦ Postsurgical granulomatous prostatitis −− Occurs up to years following surgery −− Central zone of fibrinoid necrosis surrounded by peripheral palisading of epithelioid histiocytes

Fig. 38.3. Xanthogranulomatous prostatitis. Lymphocytes rim a massive monomorphous collection of macrophages with abundant clear cytoplasm. This case was initially misdiagnosed as high grade carcinoma.

Fig. 38.4. Malakoplakia. Numerous Michaelis–Gutman bodies are noted.

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BENIGN LESIONS AND MIMICS OF ADENOCARCINOMA Benign Prostatic Hyperplasia and Other Forms of Hyperplasia Benign Prostatic Hyperplasia Clinical ♦♦ Occurs in 50% or more of men >50 years ♦♦ Often presents with lower urinary tract symptoms ♦♦ Develops in transition zone, resulting from stromal and epithelial proliferation ♦♦ Etiology and pathogenesis not completely understood ♦♦ Inflammation implicated in pathogenesis of benign prostatic hyperplasia (BPH); patients with inflammation have larger prostates, higher serum PSA, and greater risk of urinary retention ♦♦ Hormonal regulation is mainly via dihydrotestosterone (DHT), derived from testosterone by the activity of 5-a-reductase ♦♦ Growth factors also play an important role in the development of BPH; epidermal growth factor (stimulatory) and transforming growth factor-b (inhibitory) alter prostatic growth

Macroscopic ♦♦ Yellow-gray rubbery to firm and bulging nodules in the transition zone and periurethral region (Fig. 38.5) ♦♦ For transurethral resection specimens, submit a minimum of six cassettes for the first 30 g of tissue and one cassette for every 10 g thereafter

Microscopic ♦♦ Epithelial and stromal hyperplasia in the transition zone and periurethral region (Fig. 38.6) ♦♦ Stromal nodules consist of fibromuscular spindle cell proliferation with thin- or thick-walled vessels and scattered lymphocytic infiltrate (mainly T-helper cells)

Fig. 38.5. Benign prostatic hyperplasia (BPH), stromal variant. Bulging from the cut surface of this adenectomy specimen is a fleshy firm stromal nodule.

♦♦ Often associated with prostatic infarct with squamous and urothelial metaplasia ♦♦ At least part of a nodule should be present for the diagnosis to be made on biopsies (uncommon) ♦♦ Multiple variants (see below) (Table 38.2)

Stromal Hyperplasia with Atypical Giant Cells ♦♦ Often occurs in the transition zone ♦♦ Benign variant of nodular hyperplasia ♦♦ Increased stromal cellularity with bizarre giant cells and nuclear degenerative changes (Fig. 38.7) ♦♦ Nuclear pleomorphism, nuclear hyperchromasia, and pyknosis ♦♦ Lacks the circumscription of leiomyoma ♦♦ No mitotic figures ♦♦ Some have applied the term prostatic stromal tumor of uncertain malignant potential, but this is discouraged as it lumps stromal hyperplasia (benign) with phyllodes tumor (malignant)

Cribriform Hyperplasia ♦♦ Often occurs in the transition zone ♦♦ Variant of nodular hyperplasia ♦♦ Cribriform pattern of acinar proliferation with intact basal cell layer (Fig. 38.8) ♦♦ Uniform cells with clear or granular cytoplasm and inconspicuous nucleoli

Basal Cell Proliferation ♦♦ Basal cells probably contain the regenerative or stem cells of the prostate ♦♦ Occurs in 6% of biopsies and 9% of transurethral resection specimens

Fig. 38.6. Benign prostatic hyperplasia (BPH). This epitheliumpredominant round nodule is typical.

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Table 38.2. Histopathological Variants of Nodular Hyperplasia Variant

Microscopic features

Usual location

Stromal hyperplasia with atypical giant cells

Stromal nodules in the setting of cellularity and nuclear atypia

Transition zone

Basal cell hyperplasia (BCH)

Proliferation of basal cells, two or more cells in thickness; may have prominent nucleoli (atypical basal cell hyperplasia) or form a nodule (basal cell adenoma)

Transition zone

Atypical adenomatous hyperplasia (AAH)

Localized proliferation of small acini in association with BPH nodule which architecturally mimics adenocarcinoma but lacks cytological features of malignancy

Transition zone

Postatrophic hyperplasia

Atrophic acini with epithelial proliferative changes; easily mistaken for adenocarcinoma due to architectural distortion

All zones

Cribriform hyperplasia

Acini with distinctive cribriform pattern, often with clear cytoplasm; easily mistaken for proliferative acini of the central zone

Transition zone

Sclerosing adenosis

Circumscribed proliferation of small acini in a dense spindle cell stroma without significant atypia; usually solitary and microscopic

Transition zone

Hyperplasia of mesonephric remnants

Rare benign lobular proliferation with colloid-like material in the lumina; may mimic nephrogenic metaplasia focally; acini do not apparently express PSA or PAP

All zones (very rare)

Verumontanum mucosal gland hyperplasia

Small benign acinar proliferation

Verumontanum

Fig. 38.7. Stromal hyperplasia with atypical giant cells.

Basal Cell Hyperplasia ♦♦ Often occurs in the transition zone ♦♦ Variant of BPH ♦♦ Proliferation of basal cells with multiple layers (³2) (Fig. 38.9) ♦♦ Often eccentrically located with partial involvement of acini, retaining the overlying columnar or cuboidal secretory cells ♦♦ Basal cells have enlarged nuclei, fine powdery chromatin, and occasional nuclear grooves

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Fig. 38.8. Cribriform hyperplasia. Note the variable size and collapsible nature of the luminal fenestrations. Unlike high grade PIN and ductal adenocarcinoma, there are no cytologic abnormalities. In this preparation, the basal cell layers at the periphery of the acini are especially prominent. ♦♦ Nuclear “bubble” artifact or intranuclear vacuole often seen in formalin-fixed tissue but not in frozen section ♦♦ Often associated with chronic inflammation

Atypical Basal Cell Hyperplasia ♦♦ Same as basal cell hyperplasia (BCH) but with prominent nucleoli (Fig. 38.10) ♦♦ Require >10% of cells displaying prominent nucleoli for diagnosis

Prostate

38-7

Basal Cell Adenoma ♦♦ Variant of BPH ♦♦ Nodule formation with BCH (Fig. 38.11) ♦♦ Well-circumscribed solid nests and aggregates of hyperplastic basal cells in a condensed fibrous stroma ♦♦ Plump nuclei, high nucleocytoplasmic ratio, and inconspicuous nucleoli ♦♦ High molecular weight cytokeratin 34bE12 positive (Table 38.3) ♦♦ PSA and PAP are patchy positive ♦♦ S-100 protein and chromogranin are often positive

Atypical Adenomatous Hyperplasia Clinical Fig. 38.9. Basal cell hyperplasia. These tight nests of basaloid cells are characteristic of BCH.

Fig. 38.10. Atypical basal cell hyperplasia. (A) The acini are set in a moderately fibrotic stroma. (B) The acini contain basal cells with prominent nucleoli.

♦♦ Usually occurs in the transition zone and is found in ~23% of prostatectomy specimens ♦♦ Multicentric in ~46% of cases

Fig.  38.11. Basal cell adenoma from a transurethral resection specimen. The lesion is well circumscribed (A). Basal cells have powdery nuclei with fine chromatin (B).

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Table 38.3. Immunohistochemical Profiles of Benign Lesions in the Prostate PSA/PAP

HMW CK

Cytokeratina

S-100 protein

SMA

Zonal predilection

Xanthoma/xanthogranulomatous prostatitis

−

−

−

−

−

Peripheral

Nephrogenic metaplasia

−

+

+

−

−

Periurethral

Postatrophic hyperplasia

+

+

+

−

−

Peripheral

Atypical basal cell hyperplasia

−/+

+

+

−/+

−

Transition

Cribriform hyperplasia

+

+

+

−

−

Transition

Sclerosing adenosis

+

+

+

+

+

Transition

Stromal hyperplasia with atypia

−

−

–

+

Transition

Hyperplasia of mesonephric remnants

−

+

+

−

−

Unknown

Verumontanum mucosal gland hyperplasia

+

+

+

−

−

Verumontanum

Seminal vesicles/ejaculatory ducts

−

+

+

−

−

Seminal vesicles

Cowper gland

−

+

+

−

−

Urogenital diaphragm

Paraganglion

−

−

−/±

±/−

−

Base ³ apex

PSA/PAP prostate-specific antigen/prostate acid phosphatase, HMW CK high molecular weight cytokeratin (34bE12), SMA smooth-muscle actin a Broad-spectrum cytokeratins

♦♦ Proposed as a putative precursor lesion, but considered by most to be benign ♦♦ The extent and zonal distribution of atypical adenomatous hyperplasia (AAH) and carcinoma share a weak but significant association ♦♦ Shares less frequent, but similar allelic imbalance with prostatic adenocarcinoma ♦♦ May be associated with a subset of low grade carcinoma arising in the transition zone ♦♦ The identification of AAH should not influence or dictate therapeutic decisions

Microscopic ♦♦ Requires most or all of the focus to be present for diagnosis of AAH on biopsy (Table 38.4) ♦♦ Well-circumscribed nodular proliferation of small acini at the periphery of BPH; sometimes involves the entire nodule (Fig. 38.12A) ♦♦ Parent gland with larger branching lumina in the central location ♦♦ Lacks diffuse nucleolar enlargement ♦♦ May contain intraluminal mucin secretions and crysta­ lloids ♦♦ Basal cell layer fragmented (Fig. 38.12B)

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♦♦ a-Methylacyl-CoA racemase (P504S) immunostaining may be focally positive

Differential Diagnosis ♦♦ Verumontanum mucosal gland hyperplasia −− Located in the posterior wall of the distal prostatic urethra −− Back-to-back arrangement of small acini with prominent corpora amylacea −− Fragmented nonlamellated orange-red concretions −− Cytoplasmic lipofuscin −− Intact basal cell layer and intimately associated with urothelial-lined ducts ♦♦ Postatrophic hyperplasia −− Lobular cluster of atrophic acini with proliferative change −− Not intimately associated with nodular hyperplasia −− Associated with adjacent atrophy with inflammation, stromal fibrosis, or smooth muscle atrophy ♦♦ Sclerosing adenosis −− Biphasic pattern with hyalinized periacinar stroma −− S-100 protein and actin positive ♦♦ Low grade small acinar prostatic adenocarcinoma −− Nucleolar enlargement −− Lacks basal cell layer

Prostate

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Table 38.4. Atypical Adenomatous Hyperplasia Vs. Well-differentiated Adenocarcinoma Carcinoma (Gleason grades 1 and 2)

Architectural and associated features

Atypical adenomatous hyperplasia

Low power

Circumscribed or limited infiltration

Circumscribed or limited infiltration

Lesion size

Variable

Variable

Gland size

Variable

Less variable

Gland shape

Variable

Less variable

Crystalloids

Infrequent (16%)

Frequent (75%)

Corpora amylacea

Frequent (32%)

Infrequent (13%)

Basophilic mucin

Infrequent

Frequent

Nuclear size variation

Less variable

Variable

Chromatin

Uniform/granular

Uniform or variable

Parachromatin clearing

Infrequent

Frequent

Nucleoli

Inconspicuous

Prominent

Nucleoli (largest)

2.5 mm (rare)

3.0 mm

Nucleoli (mean)

<1.0 mm

1.8 mm

Nucleoli > 1 mm

18%

77%

Hematoxylin and eosin stain

Inconspicuous

Absent

Antikeratin stain (high molecular weight 34bE12)

Fragmented

Virtually absent

Nuclear features

Basal cell layer

Fig. 38.12. Atypical adenomatous hyperplasia (AAH). This circumscribed cluster of small to intermediate acini was initially misdiagnosed as Gleason pattern 1 + 1 carcinoma (A); however, a fragmented basal cell layer was identified by immunostain for high molecular weight cytokeratin 34bE12 (B).

Postatrophic Hyperplasia ♦♦ Occurs in all zones with predilection for the peripheral zone (91% of cases) ♦♦ Found in up to 32% of radical prostatectomy specimens ♦♦ Lobular cluster of atrophic acini surrounding central dilated larger acini, often in a hyalinized stroma (Fig. 38.13) ♦♦ Variable acinar architectural distortion and irregularity ♦♦ Acini lined by a single layer of secretory cells with proliferative changes ♦♦ Moderate cytoplasm with luminal apocrine blebs ♦♦ Enlarged nuclei with evenly distributed fine granular chromatin and occasional enlarged nucleoli ♦♦ Fragmented or intact basal cell layer ♦♦ Often associated with adjacent inflammation

Fig. 38.13. Postatrophic hyperplasia. Irregular circumscribed aggregate of markedly atrophic distorted acini set in a fibrous stroma.

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♦♦ Distinguished from carcinoma by characteristic lobular architecture, intact or fragmented basal cell layer, inconspicuous or mildly enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy

Sclerosing Adenosis Clinical ♦♦ ♦♦ ♦♦ ♦♦

Incidental finding in 2% of transurethral resection specimens An unusual variant of BPH Occurs in transition zone, usually solitary and microscopic The only prostatic lesion with myoepithelial differentiation of basal cells ♦♦ Benign

Microscopic ♦♦ Well-circumscribed proliferation of small acini in a densely myofibroblastic stroma (Fig. 38.14A) ♦♦ Thickened basement membrane with prominent myoepithelial cells

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Acini appear to merge with adjacent pale staining cellular stroma with abundant loose ground substance ♦♦ Compressed and distorted glands imparting a pseudoinfiltrative pattern ♦♦ Occasional nuclear and nucleolar enlargement; rare cases with prominent nucleolomegaly referred to as atypical sclerosing adenosis ♦♦ Moderate amount of clear to eosinophilic cytoplasm

Electron Microscopy ♦♦ Myoepithelial differentiation with aggregates of thin filaments

Immunohistochemistry (Table 38.3) ♦♦ ♦♦ ♦♦ ♦♦

High molecular weight cytokeratin 34bE12 and p63 positive Muscle-specific actin (MSA) positive S-100 protein positive (Fig. 38.14B) Negative for a-methylacyl-CoA racemase (P504S)

Differential Diagnosis ♦♦ AAH −− Lacks densely hyalinized stroma and fragmented basal cell layer −− MSA and S-100 protein negative ♦♦ Prostatic adenocarcinoma −− Cytologic atypia with nucleomegaly and prominent nucleoli −− Lacks hyalinized stroma −− Absence of MSA, HMW cytokeratin, and S-100 protein staining

Hyperplasia of Mesonephric Remnants (Florid Mesonephric Hyperplasia) ♦♦ Occurs in all zones, mainly in the transition zone ♦♦ Rare lobular proliferation of small acini lined by single layer of cuboidal cells (Fig. 38.15)

Fig. 38.14. Sclerosing adenosis. (A) Packed circumscribed cluster of small acini of variable size set in a densely cellular stroma. (B) Intense S-100 protein immunoreactivity in the basal cells of virtually every acinus.

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Fig. 38.15. Mesonephric remnants.

Prostate

♦♦ Two growth patterns −− Closely packed small round to oval tubules lined by cuboidal hobnail cells with eosinophilic cytoplasm −− Proliferation of small acini with empty lumens or solid nests ♦♦ May have haphazard arrangement at periphery, imparting pseudoinfiltrative growth pattern ♦♦ Ectatic tubules with luminal colloid-like eosinophilic inclusions and micropapillary infoldings ♦♦ Uniform cells with occasional nuclear and nucleolar enlargement ♦♦ PSA and PAP negative; high molecular weight cytokeratin 34bE12, and p63 positive

Verumontanum Mucosal Gland Hyperplasia ♦♦ Located in the posterior wall of the midprostatic urethra ♦♦ Used as a landmark during transurethral resection of the prostate (resection is proximal) ♦♦ Recognized in 14% of radical prostatectomy specimens ♦♦ Rare in biopsies and not seen in transurethral resection specimens ♦♦ Often intimately associated with urothelium ♦♦ Multifocal lobular proliferation of closely packed small (>25) acini usually with intact basal cell layer (Fig. 38.16) ♦♦ Uniform cells with basophilic cytoplasm and lack of cytologic atypia ♦♦ Numerous corpora amylacea and distinctive orange-red nonlaminated concretions that are often fragmented ♦♦ Luminal secretory cells may contain lipofuscin pigment ♦♦ Intact basal cell layer ♦♦ PSA, PAP, and high molecular weight cytokeratin 34bE12 positive

Metaplasia (Table 38.5) Squamous Metaplasia

38-11

Table 38.5. Metaplastic Changes of the Prostate Diagnosis

Features

Squamous metaplasia

Intraductal aggregates of flattened cells with eosinophilic cytoplasm, usually at edge of infarcts

Mucinous metaplasia

Mucin-producing columnar or goblet cells in the prostate epithelium or urothelium

Eosinophilic metaplasia

Small clusters of cells with prominent cytoplasmic eosinophilic changes

Urothelial metaplasia

Urothelium within ducts and acini of the prostate; difficult to identify because of variable location of the normal urothelial–columnar junction

Nephrogenic adenoma (metaplasia)

Inflamed papillary mass of cystic or solid tubules in the urethra; rare

♦♦ Common in the region of prostatic urethra in patients with an indwelling catheter ♦♦ Syncytial aggregates of polygonal cells with abundant eosinophilic cytoplasm and hyperchromatic nuclei

Mucinous Metaplasia ♦♦ Clusters of columnar cells or goblet cells with mucin production (Fig. 38.18) ♦♦ Focal or complete involvement of acini and lack of involvement of the entire lobular unit of acini ♦♦ Negative immunostaining for PSA and PAP ♦♦ High molecular weight cytokeratin 34bE12 positive ♦♦ Mucicarmine, PAS with diastase, and alcian blue positive

♦♦ Often seen at edges of prostatic infarct and after hormonal therapy or cryotherapy (Fig. 38.17)

Fig. 38.16. Verumontanum mucosal gland hyperplasia.

Fig. 38.17. Squamous metaplasia of benign epithelium following cryosurgery.

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Fig. 38.18. Mucinous metaplasia.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 38.20. Urothelial metaplasia.

Fig. 38.19. Eosinophilic metaplasia.

Eosinophilic Metaplasia ♦♦ May represent a form of host response related to regenerative/reparative process ♦♦ Clusters of cells with prominent eosinophilic cytoplasmic granules in apical location (Fig. 38.19) ♦♦ Typically occur in small to medium-sized prostatic ducts, may also occur in acinar epithelium ♦♦ No clinical significance

Urothelial Metaplasia ♦♦ Presence of urothelium beyond the normal urothelial–columnar junction ♦♦ Stratified epithelium with streaming effect of nuclei (Fig. 38.20) ♦♦ Ovoid cells with pale cytoplasm, uniform nuclei, nuclear grooves, perinuclear halos, fine granular chromatin, and inconspicuous nucleoli ♦♦ The long axis of the cells is perpendicular to the basement membrane

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Fig. 38.21. Nephrogenic adenoma (metaplasia).

Nephrogenic Adenoma ♦♦ Suburethral location; composed of exophytic mass of small tubules or papillae with solid and cystic appearance (Fig. 38.21) ♦♦ Uniform nuclei with fine granular chromatin and inconspicuous nucleoli; rare cases have focal or extensive nucleolomegaly, referred to as atypical nephrogenic metaplasia ♦♦ Edematous and often inflamed stroma without desmoplasia ♦♦ Often associated with proliferative papillary urethritis ♦♦ Negative immunoreactivity for PSA, PAP, and CEA ♦♦ High molecular weight cytokeratin 34bE12 positive ♦♦ Positive staining for a-methylacyl-CoA racemase (P504S) (58% of cases) creates potential for misdiagnosis as adenocarcinoma ♦♦ May be neither metaplastic nor neoplastic in nature; nephrogenic metaplasia in renal transplant recipients is apparently

Prostate

derived from tubular cells of the transplant and is not a metaplastic proliferation of the recipient’s bladder urothelium.

Atrophy ♦♦ Often located in the peripheral zone ♦♦ Lobular configuration of atrophic glands with open ectatic lumina in a sclerotic stroma ♦♦ Variable acinar architectural distortion and irregularity ♦♦ Cystic dilation of acini and ducts lined by flattened attenuated epithelial cells with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli ♦♦ Basal cell layer may be fragmented ♦♦ Thought by some to be a potential precursor to adenocarcinoma, but convincing evidence is lacking

Seminal Vesicles and Ejaculatory Ducts Microscopic ♦♦ Well circumscribed ♦♦ Complex papillary folds with irregular convoluted lumens (Fig. 38.22) ♦♦ Lined by nonciliated pseudostratified columnar epithelium ♦♦ Ejaculatory ducts have large lumens with more prominent mucosal folding and prominent circumferential layer of muscular wall ♦♦ Stromal (eosinophilic) hyaline bodies −− Often seen within the muscular wall, resulting from smooth muscle degeneration −− Highlighted by Masson trichrome and PAS stain ♦♦ Bizarre smudged cells with granular refractile golden yellow lipofuscin pigment ♦♦ Enlarged nuclei with nuclear hyperchromasia, coarse granular chromatin, prominent nucleoli, and occasional nuclear halos

Fig. 38.22. Seminal vesicle. The epithelium contains scattered refractile golden brown pigment, as well as moderate aniso­ nucleosis.

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♦♦ Multinucleated giant cells with pyknotic nuclei and a lack of mitotic figures ♦♦ DNA aneuploid in 6.7% of seminal vesicles

Immunohistochemistry ♦♦ PSA and PAP negative; HMW cytokeratin 34bE12 and p63 positive

Differential Diagnosis ♦♦ Pigmented prostatic epithelium −− Scant, finely granular, yellow-brown pigment −− PSA and PAP positive ♦♦ Postatrophic hyperplasia −− Lobular arrangement of acini surrounding central dilated acini; proliferative change −− Lacks lipofuscin or cytologic atypia ♦♦ High grade PIN −− Lacks lipofuscin; displays significant nuclear pleo­ morphism ♦♦ Adenocarcinoma −− Lacks lipofuscin; displays nuclear degeneration; bizarre nuclei uncommon −− PSA and PAP positive, 34bE12 negative

Senile Seminal Vesicle Amyloidosis Clinical ♦♦ Occurs in up to 8% of men 46–60 years, 23% between age 61 and 75 years, and 40% >75 years ♦♦ Derived from secretory protein of the epithelium ♦♦ Benign; not associated with systemic amyloidosis

Microscopic ♦♦ Linear or nodular subepithelial deposition of amorphous eosinophilic amyloid (Fig. 38.23) ♦♦ Basement membrane thickening

Fig. 38.23. Senile seminal vesicle amyloidosis.

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Immunohistochemistry ♦♦ Congo red, crystal violet, toluidine blue, and PAS positive

Cowper Glands Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Located within the urogenital diaphragm; seen in apex biopsies Not present in transurethral resection specimens Equivalent to Bartholin glands of female genital tract Small paired bulbomembranous urethral glands surrounded by skeletal muscle ♦♦ Well-circumscribed small acinar proliferation (Fig. 38.24) ♦♦ Uniform cells with abundant apical mucinous cytoplasm ♦♦ Lack nuclear and nucleolar enlargement

Immunohistochemistry ♦♦ PSA negative; high molecular weight cytokeratin, mucicarmine, and PAS with diastase positive

Differential Diagnosis ♦♦ Mucinous metaplasia −− Focal involvement of a small number of acini −− Lacks skeletal muscle ♦♦ Mucinous adenocarcinoma −− Nests and clusters of epithelial cells floating in extravasated mucin pool ♦♦ Well-differentiated adenocarcinoma −− Prominent nucleoli −− PSA positive, high molecular weight cytokeratin negative

Paraganglia ♦♦ Located closer to the base than the apex of the prostate ♦♦ Usually associated with neurovascular structures ♦♦ Solid nests and organoid arrangement of closely packed polygonal cells with abundant clear cytoplasm (Fig. 38.25) ♦♦ Centrally located uniform nuclei with or without prominent nucleoli

Fig. 38.25. Intraprostate ganglionic tissue. In contrast with the benign acini (lower right), the ganglion cells are small, closely packed, and contain a light dusting of brown pigment. This focus was initially misdiagnosed as adenocarcinoma.

♦♦ PSA, PAP, and cytokeratin negative; neuroendocrine markers positive

Prostatic Urethral Polyp Proliferative Papillary Urethritis ♦♦ Papillary proliferation of urothelium with metaplastic changes and reactive atypia ♦♦ Inflammation and stromal edema

Ectopic Prostatic Tissue (Benign Polyp with Prostatic-Type Epithelium) ♦♦ Adolescents or young adults present with hematuria ♦♦ Delicate papillae with fibrovascular core and prostatic epithelial lining

Nephrogenic Adenoma ♦♦ Described elsewhere

Benign Urothelial Papilloma ♦♦ Patient <50 years with solitary lesion <2 cm in greatest dimension ♦♦ <7 cells in thickness with intact superficial (umbrella) cell layer ♦♦ No significant cytologic atypia (no more than grade 1 urothelial carcinoma)

Inverted Papilloma

Fig. 38.24. Cowper gland.

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♦♦ Patients present with hematuria and urinary obstructive symptoms ♦♦ Smooth contoured invaginated cords and columns of urothelial cells with intact overlying urothelium ♦♦ Peripheral palisading basaloid cells and thickened basement membrane ♦♦ Squamous metaplasia and microcystic change ♦♦ Scant stroma ♦♦ Lacks fibrovascular cores

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Prostate

High Grade PROSTATIC INTRAEPITHELIAL NEOPLASIA Definition

Pattern of Spread

♦♦ Precancerous end of the morphologic continuum of cellular proliferations within preexisting prostatic ducts, ductules, and acini

♦♦ Replacement of normal luminal secretory cells with preservation of the basal cell layer ♦♦ Direct invasion with disruption of the basal cell layer ♦♦ Pagetoid spread (rare)

Clinical ♦♦ Divided into low grade (formerly PIN 1) and High grade (formerly PIN 2 and 3) ♦♦ Most pathologists prefer not to report low grade PIN, recognizing the difficulty in separating this lesion from benign epithelium and reactive atypia ♦♦ PIN is genotypically and phenotypically linked to cancer ♦♦ Precedes the onset of carcinoma by 5–10 years ♦♦ Multifocal (63% of cases) and coexists with cancer in 86% of prostatectomy specimens ♦♦ Occurs in the nontransition zone (63% of cases) and all zones (36%) ♦♦ Present in up to 4.2% of transurethral resection specimens (2.8% without cancer, 10.2% with cancer) ♦♦ The volume of HGPIN increases with the pathologic stage, Gleason grade, and positive surgical margins in patients with prostate cancer ♦♦ More prevalent and extensive and occurs approximately a decade earlier in African American men than in Caucasian men ♦♦ Prevalence and extent of HGPIN are decreased after androgen deprivation therapy ♦♦ No influence on serum PSA concentration ♦♦ Occurs in up to 16% of contemporary needle biopsies ♦♦ The diagnosis of HGPIN confers a 35–50% predictive value for cancer on repeat biopsy when four to six biopsies are obtained; predictive value drops to 22–31% when ten or more biopsies are obtained ♦♦ Followup is suggested, but the interval may be 1 year or more according to some; there are no standards, and most agree that multifocal or extensive PIN requires earlier followup

Patterns of Growth ♦♦ Tufting (97% of specimens with HGPIN, most common) (Fig. 38.26A) ♦♦ Micropapillary (66%) (Fig. 38.26B) ♦♦ Flat (21%) (Fig. 38.26C) ♦♦ Cribriform (19%) (Fig. 38.26D) ♦♦ Other rare growth patterns include signet-ring cell, small cell (neuroendocrine), foamy gland (microvacuolated), hobnail (inverted), and squamous patterns

Microscopic ♦♦ Nuclear and nucleolar enlargements are the cytologic hallmark of HGPIN ♦♦ Cellular crowding, irregular spacing, nuclear stratification, and overlapping ♦♦ Partial acinar involvement may be seen ♦♦ Cells usually display cytoplasmic blebs along the luminal surface ♦♦ Disruption of the basal cell layer is highlighted by high molecular weight cytokeratin and p63 (Fig.  38.27) (Table 38.6) ♦♦ a-Methylacyl-CoA racemase (P504S) and c-myc staining positive (Fig. 38.27)

Differential Diagnosis ♦♦ Inflammatory reactive changes −− Metaplastic (eosinophilic) changes and inflammatory background ♦♦ Urothelial metaplasia −− Lacks prominent nucleoli ♦♦ Seminal vesicles and ejaculatory ducts −− Bizarre cells with lipofuscin pigment −− Nuclear hyperchromasia, nuclear pleomorphism, and degenerative changes −− PSA and PAP negative ♦♦ Cribriform hyperplasia −− Occurs in transition zone; sieve-like pattern −− Uniform cells with clear cytoplasm −− Lacks nuclear and nucleolar enlargement ♦♦ Postatrophic hyperplasia −− Lacks prominent nucleoli ♦♦ Atypical basal cell hyperplasia (ABCH) −− Small solid nests or eccentric expansion of the basal cell layers between normal columnar secretory cells and basement membrane −− The long axis of basal cells is usually parallel to the basement membrane −− Enlarged nuclei with delicate stippled chromatin, occasional nuclear grooves, and nuclear “bubble” artifact

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 38.26. Four major patterns of high grade prostatic intraepithelial neoplasia (PIN). Tufting pattern of high grade PIN (A). Small mounds of cells protrude into the lumen. This focus has a prominent basal cell layer at the periphery. Micropapillary pattern of high grade PIN (B). Elongate finger-like projections of epithelium protrude into the lumens. Flat pattern of high grade PIN (C). Cribriform pattern of high grade PIN (D).

−− Often associated with inflammatory background −− Cytokeratin 34bE12 positive ♦♦ Low grade PIN −− The epithelium lining ducts and acini are heaped up, crowded, and irregularly spaced −− Lacks prominent nucleoli and less nuclear hyper­ chromasia −− Intact basal cell layer without disruption ♦♦ Ductal (endometrioid) prostatic adenocarcinoma −− Lacks basal cell layer ♦♦ Large gland variant of Gleason pattern 3 carcinoma and cribriform variant −− More extensive involvement, infiltrative growth pattern −− Often associated with small acinar carcinoma −− Lacks circumferential basal cell layer

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Fig. 38.27. High grade PIN, triple immunostain: Brown reaction product indicates a patchy and fragmented pattern of immunoreactivity for high molecular weight cytokeratin 34bE12 in basal cell cytoplasm and p63 in basal cell nuclei; red reaction product indicates immunoreactivity for alpha-methylacyl-CoA racemase (P504S) in luminal secretory cells.

Prostate

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Table 38.6. Immunohistochemical Profiles of Preinvasive and Malignant Lesions in the Prostate PSA/PAP

HMW CK

Cytokeratina

SMA

Desmin

High grade PIN

+

+/− (Fragmented)

+

−

−

Atypical adenomatous hyperplasia

+

+/− (Fragmented)

+

−

−

Prostatic adenocarcinoma

+

−

+

−

−

Ductal adenocarcinoma

+

−

+

−

−

Mucinous adenocarcinoma

+

−

+

−

−

Small cell carcinoma

−/+

−

−/+

−

−

Signet-ring cell carcinoma

+

−

+

−

−

Squamous cell carcinoma

+/−

−

+

−

−

Sarcomatoid carcinoma

+/−

−

+

−/+

−/+

Adenoid cystic/basal cell carcinoma

−/+

+

+

−

−

Urothelial carcinoma

−

+

+

−

−

Phyllodes tumor

+

+

+

−/+

+

Leiomyosarcoma

−

−

−/+

+

+

Lymphoma

−

−

−

−

−

PSA/PAP prostate-specific antigen/prostate acid phosphatase, HMW CK high molecular weight cytokeratin (34bE12), SMA smooth-muscle actin a Broad-spectrum cytokeratins

ATYPICAL SMALL ACINAR PROLIFERATION, SUSPICIOUS FOR MALIGNANCY Clinical ♦♦ A diagnostic category encompassing a spectrum of histologic abnormalities that fall below the threshold for the diagnosis of cancer ♦♦ The incidence of atypical small acinar proliferation (ASAP) is 2.5–4% in contemporary prostate biopsies ♦♦ Predicts ~45% likelihood for cancer on repeat biopsy regardless of number of cores obtained in the first biopsy ♦♦ Many ASAP foci may represent marginally sampled cancer ♦♦ 99% of cancers were diagnosed on second and third biopsy, usually within 6 months after the ASAP diagnosis (73%) ♦♦ 41% of cancers were detected exclusively in other sites of initial ASAP lesion ♦♦ The entire prostate should be rebiopsied due to random sampling variation

Microscopic ♦♦ Lacks the full complement of requisite architectural and cytologic features of cancer (Table 38.7) ♦♦ Usually very small in size – invariably less than two dozen acini (Fig. 38.28A)

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

The focus often disappears on deeper levels Lacks unequivocal cytologic features of malignancy Enlarged nucleoli are often difficult to find Clustered growth of acini May represent partial sampling of AAH, sclerosing adenosis, or low grade cancer ♦♦ Treatment-induced atypia ♦♦ Confounding acinar atrophy and prominent inflammation in the immediate vicinity of suspicious acini, and poor histologic preparations ♦♦ Features that may be present include −− Infiltrative growth −− Variation in acinar size −− Nucleomegaly −− Nucleolar enlargement −− Microvacuolated cytoplasm −− Intraluminal proteinaceous secretions −− Luminal mucin −− Crystalloids

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Table 38.7. Reasons for the Diagnosis of Atypical Small Acinar Proliferation (ASAP) Small size of focus Small number of acini in the focus of concern (invariably fewer than two dozen acini) Small focus size, average 0.4 mm in diameter Focus present at core tip or biopsy edge, indicating that the focus is incompletely sampled Loss of focus of concern in deeper levels Conflicting morphologic findings Distortion of acini raising concern for atrophy Lack of convincing features of cancer (insufficient nucleomegaly or nucleolomegaly) Clustered growth pattern mimicking a benign process such as atypical adenomatous hyperplasia Foamy cytoplasm raising concern for foamy gland carcinoma Conflicting immunohistochemical findings Focally positive high molecular weight cytokeratin Focally positive p63 staining Negative alpha-methylacyl-CoA racemase (P504S) immunostaining Confounding findings Histologic artifacts such as thick sections or overstained nuclei Tangential cutting of adjacent high grade PIN Architectural or cytologic changes (nucleomegaly and nucleolomegaly) owing to inflammation or other lesions

Immunohistochemistry ♦♦ High molecular weight cytokeratin (34bE12) and p63 negative or equivocal (Fig. 38.28B) ♦♦ a-Methylacyl-CoA racemase (P504S) negative, weak, or equivocal

Differential Diagnosis (See “Prostatic Adenocarcinoma”) ♦♦ Prostatic adenocarcinoma −− Usually requires a minimum of three malignant acini for the diagnosis, unless (a) Prominent cytologic anaplasia was present (b) No confounding inflammation (c) Persistence of cancer on serial sections (d) The possibility of seminal vesicle/ejaculatory ducts and other mimics has been excluded

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Fig. 38.28. Atypical small acinar proliferation suspicious for but not diagnostic of malignancy. (A) The aggregate of about half a dozen small acini with variable size, shape, and spacing stands in marked contrast with the adjacent benign acini. Note cholesterol clefts and intraluminal neutrophils, raising the concern for reactive changes rather than neoplasia; (B): Same focus as (A), immunostained for high molecular weight cytokeratin 34bE12. The absence of staining in the acini of concern compounds the suspicion of malignancy. Note weak to moderate staining of basal cells in the adjacent benign acini.

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

HGPIN Atrophy and postatrophic hyperplasia Sclerosing adenosis Basal cell hyperplasia AAH

Prostate

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MALIGNANT TUMORS Prostatic Adenocarcinoma Clinical ♦♦ Most common non-skin cancer in American men ♦♦ Accounted for 192,280 newly diagnosed cancers and 27,360 cancer deaths in 2009 ♦♦ One in six men will develop clinically evident prostate cancer during his life ♦♦ Prevalence increases from 10–20% at age 50 years to ~80% at age 80 years ♦♦ Proposed risk factors include age, family history, race, dietary fat, heavy metal exposure (cadmium, zinc), vasectomy, obesity, alcohol, and HGPIN or ASAP on biopsy ♦♦ An abnormal serum PSA concentration is commonly defined as a value >2.5 ng/ml ♦♦ Up to 15% of men with cancer have normal serum PSA (<2.5 ng/ml) ♦♦ Serum PSA half-life is 2–3 days ♦♦ 70–80% of prostate cancers arise in the peripheral zone (often referred to as the posterior lobe in the older literature), 15–25% in the transition zone, and 10% in the central zone ♦♦ Prostatic carcinoma in the transition zone is usually well differentiated ♦♦ Fusions of the 5¢ untranslated end of the androgen-responsive transmembrane serene protease gene TMPRSS2 and the ETS transcription factor family members, particularly ERG, are key molecular events during initiation and progression of prostate cancer. ♦♦ TMPRSS2–ERG gene fusion is present in approximately 50% of prostate cancer ♦♦ Prostate cancer with TMPRSS2–ERG fusion may behave more aggressively than fusion-negative tumors ♦♦ Detection of TMPRSS2–ERG gene fusion may be useful for predicting cancer progression when isolated high grade PIN is identified in needle biopsies

Reporting ♦♦ Biopsy specimens −− Biopsy site −− Histopathologic type of carcinoma −− Gleason score −− Tertiary pattern −− Extent of cancer (a) Percent of specimens involved (b) Number of cores involved and total number of cores sampled −− Perineural invasion −− Extraprostatic extension (rare in biopsies) −− Associated conditions (e.g., postatrophic hyperplasia) −− Ancillary studies (e.g., DNA ploidy by digital imaging analysis) ♦♦ Transurethral resection specimens ♦♦ Weight −− 12 g, embed totally; >12 g, a minimum of six cassettes for the first 12 g, and thereafter one cassette for every 10 g; if

Macroscopic ♦♦ Yellow-white mass with a firm consistency in the peripheral zone ♦♦ Many are grossly inapparent

Gleason Grading ♦♦ Based on the degree of architectural differentiation (Figs. 38.29 and 38.30) ♦♦ The predominant grade is recorded as the primary grade, and the nondominant grade is assigned secondary grade ♦♦ When only one pattern exists (frequently encountered on biopsies), then double the grade ♦♦ Gleason score = primary grade + secondary grade ♦♦ Needle biopsy underestimates tumor grade in 33–45% cases, and overestimates grade in 4–32% cases

Fig. 38.29. Original Gleason grading diagram for prostate cancer.

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Fig. 38.30. Gleason grading of prostatic adenocarcinoma. (A): Gleason 1 + 1 = 2 adenocarcinoma on transurethral resection. At this magnification, BPH cannot be excluded. However, the acini throughout displayed enlarged nuclei and prominent nucleoli; further, the acini were negative for high molecular weight cytokeratin 34bE12; (B) Gleason pattern 2 + 2 = 4 adenocarcinoma. There is only mild to moderate variation in acinar size and shape, and the acinar contours are chiefly round and smoothly sculpted. (C) Gleason pattern 3 + 3 = 6 adenocarcinoma. There is greater variation in size, shape, and spacing of acini than in pattern 1 and 2. Note prominent nucleolomegaly; (D) Gleason pattern 4 + 4 = 8 adenocarcinoma. The malignant acini display fusion and are lined by cells with enlarged nuclei and prominent nucleoli; (E) Gleason 5 + 5 = 10 adenocarcinoma. There are sheets of cells with nuclear and nucleolar enlargement; (F) Gleason 5 + 5 = 10 adenocarcinoma. There are distorted solid nests and cords of cells with only rare abortive lumens. Note abnormal mitotic figure centrally.

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Prostate

♦♦

♦♦

♦♦ ♦♦

38-21

cancer involves <5% of tissue submitted, all remaining tissue should be examined Histopathologic type of carcinoma −− Gleason grade −− Extent of cancer (% of specimen) −− HGPIN Radical prostatectomy specimens −− Weight and size of the prostate −− Histopathologic type of carcinoma −− Gleason score −− Location of cancer (a) Bilateral versus unilateral (left or right) (b) Anterior versus posterior (c) Peripheral zone versus transition zone −− Estimated cancer volume (% of specimen) −− Extraprostatic extension (EPE) (Fig. 38.31) (a) Location and extent (b) Definition of EPE * Cancer in adipose tissue (Fig. 38.31A) * Cancer in perineural spaces of the neurovascular bundles outside the prostate (Fig. 38.31B) * Cancer in anterior muscle beyond the rounded interface between the fibromuscular stroma and skeletal muscle (Fig. 38.31C) −− Seminal vesicle invasion (Fig. 38.32) (a) Cancer in the adventitia but not in the muscular wall of the seminal vesicle does not qualify for seminal vesicle invasion −− Surgical margin status (a) Positive margins are defined as cancer cells at the inked surface (b) Sites and extent of margin involved may be used. −− Vascular/lymphatic invasion −− HGPIN −− Associated conditions (e.g., nodular hyperplasia) −− Lymph node status (a) Anatomic sites (b) Number of positive nodes (c) Size of nodal metastasis (d) Extranodal extension (we exclude this because of recent data) Ancillary studies (e.g., DNA ploidy by digital imaging analysis or flow cytometry) Pathologic stage (state which TNM classification is used)

Microscopic ♦♦ The diagnosis of cancer is made in the presence of ³3 malignant acini in most cases ♦♦ Angulated and distorted acini with an irregular haphazard arrangement and infiltrative growth pattern ♦♦ Acini vary in size, shape, and spacing, and lack basal cell layer ♦♦ Enlarged nuclei with large eccentrically located prominent nucleoli (>1 µm)

Fig. 38.31. Extraprostatic extension. (A) Cancer in the adipose tissue; (B) cancer in the perineural space of large neurovascular bundle; (C) cancer in the anterior skeletal muscle.

♦♦ The presence of multiple nucleoli is strong evidence of malignancy ♦♦ Vacuolated or microvacuolated cytoplasm

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Fig.  38.32. Seminal vesical invasion by prostatic adenocarcinoma. Lymphovascular invasion is also present.

♦♦ Collagenous micronodules are a specific finding of prostatic adenocarcinoma, correlated with mucin production by the tumor (0.6% of biopsies and 12.7% of prostatectomies) ♦♦ Extraprostatic extension and lymphovascular invasion are rare in needle biopsies and are diagnostic of prostatic adenocarcinoma ♦♦ Perineural invasion is of diagnostic value, but has no apparent clinical significance in most studies ♦♦ Complete circumferential perineural growth, intraneural and/ or ganglion invasion are usually diagnostic for cancer ♦♦ Intraluminal crystalloids and amorphous wispy basophilic acid mucin secretions are helpful, but not specific findings of cancer ♦♦ Neuroendocrine cells with large eosinophilic granules are seen focally in 10% of cases, but have no diagnostic or prognostic significance ♦♦ Necrotic debris within lumina indicates Gleason pattern 5 cancer

Immunohistochemistry (Table 38.6) ♦♦ PSA (located in endoplasmic reticulum, vesicle vacuoles, lumina cells) positive ♦♦ PAP (lysosome) positive ♦♦ Basal cell-specific cytoplasmic high molecular weight cytokeratin (34bE12) positive (Fig. 38.33) ♦♦ Basal cell-specific nuclear p63 positive (Fig. 38.33) ♦♦ a-Methylacyl-CoA racemase (P504S) positive in a granular distribution along the luminal surfaces of the neoplastic secretory cells (Fig. 38.33) ♦♦ C-myc nuclear staining for HGPIN and cancer

Differential Diagnosis ♦♦ Inflammatory reactive atypia −− Associated with inflammation and metaplasia −− Lacks nucleolar enlargement −− High molecular weight cytokeratin (34bE12) positive

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Fig. 38.33. Prostatic adenocarcinoma. (A) Gleason 3 + 3 = 6 adenocarcinoma, consisting of less than a dozen acini with hyperchromatic nuclei. (B) Triple immunostain reveals brown reaction product in benign acini but not the cancer acini (high molecular weight cytokeratin 34bE12 in basal cell cytoplasm and p63 in basal cell nuclei), and red reaction product for racemase in luminal secretory cells. (C) Another case of Gleason 3 + 3 = 6 adenocarcinoma (large acinar pattern) with immunophenotype diagnostic of malignancy (note benign acinus in top left of image for comparison).

Prostate

♦♦ Xanthoma and xanthogranulomatous prostatitis −− Sheets of foamy histiocytes −− PSA/PAP negative, cytokeratin negative, macrophage markers (CD68) positive ♦♦ Postatrophic hyperplasia (PAH) −− Lobular clusters of atrophic acini with epithelial proliferative changes −− Central large dilated atrophic acini or ducts −− Moderate cytoplasm with occasional apical cytoplasmic blebs −− Lacks diffuse nucleolar enlargement −− Background of inflammation, atrophy, and stromal fibrosis −− Intact or fragmented basal cell layer ♦♦ ABCH −− Proliferation of basal cells between normal columnar secretory cells and basement membrane −− Eccentric expansion of multiple basal cell layers −− The long axis of basal cells is often oriented parallel to the luminal surface −− Clear cytoplasm −− Enlarged nuclei with fine powdery chromatin, occasional nuclear grooves, and nuclear “bubble” artifact −− Often associated with inflammation −− High molecular weight cytokeratin (34bE12) and p63 positive ♦♦ AAH −− Lobular architecture maintained with fragmented basal cell layer −− Closely packed small acini −− Lacks cytologic features of malignancy −− Intimately associated with nodular hyperplasia with similar cytologic findings ♦♦ Seminal vesicles and ejaculatory ducts −− Circumscribed pushing border rather than haphazard arrangement −− Bizarre cells with golden-yellow lipofuscin pigment −− Nuclear hyperchromasia, nuclear pleomorphism, and degenerative changes −− Negative immunoreactivity for PSA or PAP ♦♦ Paraganglion −− Closely associated with nerves or blood vessels −− Lobular cluster of polygonal cells with abundant clear cytoplasm −− Centrally located nuclei with prominent nucleoli −− PSA, PAP, and broad spectrum cytokeratin negative; neuroendocrine markers positive ♦♦ Lesion with clear cell changes −− AAH −− Cribriform hyperplasia −− Basal cell hyperplasia

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♦♦

♦♦

♦♦

♦♦

♦♦

−− Cowper glands −− Mucinous metaplasia −− Paraganglion −− Xanthoma and xanthogranulomatous prostatitis −− Metabolic storage disease −− Sclerosing adenosis Basal cell layer disruption −− HGPIN −− Inflammatory atypia −− AAH −− Atrophy and postatrophic hyperplasia (PAH) Sclerosing adenosis −− Compressed and distorted acini in cellular fibrous stroma −− Lobular pattern is retained, and lacks cytologic atypia −− HMW cytokeratin (34bE12), p63, S-100 protein and muscle-specific antigen (MSA) positive −− Negative for a-methylacyl-CoA racemase (P504S) Hyperplasia of mesonephric remnants −− Lobular arrangement of small tubular acini −− Often contains intraluminal eosinophilic colloid-like material Nephrogenic metaplasia −− Polypoid proliferation of small tubules and papillae lined by hobnail cells −− Thickened basement membrane and intraluminal eosinophilic secretions −− Edematous stroma and cystic dilation of some tubules −− Associated with adjacent urothelium-lined ducts −− Positive a-methylacyl-CoA racemase (P504S) staining may cause diagnostic confusion Urothelial carcinoma −− Often coexisting urothelial dysplasia and carcinoma in situ −− May have history of bladder carcinoma −− Nuclear pleomorphism, eosinophilic cytoplasm −− Often associated with heavy inflammation −− PSA/PAP negative, HMW cytokeratin (34bE12) and p63 positive

Prostatic Adenocarcinoma Variants (Table 38.8) Ductal (Endometrioid) Adenocarcinoma Clinical ♦♦ Accounts for 0.8% of prostatic adenocarcinomas ♦♦ Similar clinical presentation and prognosis as conventional acinar carcinoma ♦♦ Typically occurs in elderly men with urinary obstructive symptoms ♦♦ Most cases have concurrent invasive acinar carcinoma

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♦♦ May have prominent central necrosis and frequent mitotic figures

Table 38.8. Histologic Subtypes of Prostate Cancer

Immunohistochemistry

Ductal adenocarcinoma

♦♦ PSA, PAP, a-methylacyl-CoA racemase (P504S), CEA (focal), and c-myc positive

Mucinous (colloid) adenocarcinoma Small cell carcinoma (high grade neuroendocrine carcinoma) Adenocarcinoma with neuroendocrine differentiation Signet-ring cell carcinoma Squamous cell and adenosquamous carcinoma Sarcomatoid carcinoma (carcinosarcoma) Lymphoepithelioma-like carcinoma Cribriform adenocarcinoma Adenocarcinoma with glomeruloid features Atropic adenocarcinoma Adenocarcinoma with microvacuolated cytoplasm (foamy gland carcinoma) Pseudohyperplastic adenocarcinoma Adenoid cystic/basal cell carcinoma Urothelial carcinoma

Differential Diagnosis ♦♦ Cribriform hyperplasia −− Lacks cytologic atypia, a-methylacyl-CoA racemase (P504S) positive ♦♦ HGPIN (cribriform pattern) −− Less extensive; lacks infiltrative growth ♦♦ Urothelial carcinoma −− Dysplasia and carcinoma in situ of adjacent urothelium −− PSA negative ♦♦ Large gland variant of Gleason pattern 3 adenocarcinoma ♦♦ Ectopic prostatic tissue (prostatic urethral polyp) −− Lacks cytologic atypia ♦♦ Proliferative papillary urethritis −− Lacks cytologic atypia −− PSA negative

Mucinous Adenocarcinoma Clinical ♦♦ Accounts for 0.04% of prostate carcinoma (pure mucinous pattern) ♦♦ Similar clinical presentation to typical acinar carcinoma ♦♦ Aggressive, may not respond well to radiotherapy or androgen deprivation ♦♦ Elevated serum PSA concentration and bone metastasis

Macroscopic ♦♦ Often located in peripheral zone

Microscopic Fig. 38.34. Ductal adenocarcinoma. This papillary proliferation filled the large periurethral prostatic ducts and protruded into the urethra. ♦♦ Serum PSA concentration is often normal, probably due to secretion of PSA directly into the prostatic urethra by tumor cells

Macroscopic ♦♦ Polypoid tumor located in the urethra at or near the verumontanum

Microscopic ♦♦ Considered Gleason pattern 4 (no necrosis) or 5 (with necrosis) cancer ♦♦ Cribriform and papillary proliferation of medium to largesized acini (Fig. 38.34) ♦♦ Acini lined by stratified tall columnar cells with cytologic atypia

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♦♦ Usually considered Gleason pattern 4 adenocarcinoma ♦♦ Requires 25% of tumor to contain extracellular mucin, excluding nondilated glands with mucin for diagnosis ♦♦ The presence of epithelial nests or glands in mucin pools is diagnostic (Fig. 38.35) ♦♦ May present with acinar or cribriform carcinoma with luminal distention ♦♦ Collagenous micronodules are often seen

Immunohistochemistry ♦♦ PSA+, PAP, and a-methylacyl-CoA racemase (P504S) positive

Differential Diagnosis ♦♦ Metastatic or contiguous spread of mucinous adenocarcinoma (e.g., colon cancer) −− PSA and PAP negative ♦♦ Cowper glands −− Circumscribed lobules of closely packed small uniform acini

Prostate

Fig. 38.35. Mucinous (colloid) carcinoma, with pools of mucin punctuated by floating islands and trabeculae of cancer cells.

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Fig. 38.36. Small cell carcinoma of the prostate.

−− Embedded in skeletal muscle −− Uniform cells with mucinous cytoplasm and basally located small nuclei −− PSA negative; high molecular weight cytokeratin and p63 positive

Small Cell Carcinoma (High Grade Neuroendocrine Carcinoma) Clinical ♦♦ Highly aggressive; most patients die within 2 years ♦♦ May present with paraneoplastic syndromes ♦♦ May develop after radiation therapy and hormonal therapy for acinar adenocarcinoma ♦♦ Serum PSA varies according to cancer volume and stage

Microscopic ♦♦ Considered Gleason pattern 5 adenocarcinoma (Fig. 38.36) ♦♦ Infiltrating cords and sheets of small cells with high N/C ratio and crush artifact ♦♦ Nuclear hyperchromasia, nuclear molding, and inconspicuous nucleoli ♦♦ Mixed with typical adenocarcinoma in about half of cases

Immunohistochemistry ♦♦ Neuroendocrine markers (chromogranin A, synaptophysin, serotonin) positive, PSA is usually positive, and PAP may be positive

Adenocarcinoma with Neuroendocrine Differentiation ♦♦ All adenocarcinomas have scattered cells with neuroendocrine features ♦♦ No prognostic significance for number of neuroendocrine cells other than pure small cell carcinoma (Fig. 38.37) ♦♦ Rare cancers have neuroendocrine cells with large eosinophilic granules (formerly referred to as Paneth cell-like change)

Fig. 38.37. Prostatic adenocarcinoma with neuroendocrine differentiation. These were previously designated as “Paneth celllike change” (PCLC).

Signet-Ring Cell Carcinoma Clinical ♦♦ Similar clinical presentation as typical acinar carcinoma ♦♦ High stage presentation with unfavorable prognosis

Microscopic ♦♦ Considered Gleason pattern 5 adenocarcinoma ♦♦ Requires 25% tumor with signet-ring cells for diagnosis (Fig. 38.38)

Immunohistochemistry ♦♦ PSA and PAP positive; CEA, mucin, and oil red O are usually positive

Differential Diagnosis ♦♦ Paraganglion −− Organoid nests of polygonal cells with centrally located nuclei

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Fig. 38.38. Signet-ring cell carcinoma.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 38.39. Squamous cell carcinoma in the prostate arising 10 years after radiation and hormonal therapy for high grade adenocarcinoma.

♦♦ Vacuolated smooth muscle cells or lymphocytes −− PSA and PAP negative

Squamous Cell and Adenosquamous Carcinoma Clinical ♦♦ ♦♦ ♦♦ ♦♦

Extremely rare in the prostate Account for <0.5% of cases of prostatic carcinoma Similar clinical presentation as typical acinar carcinoma Patients often have a prior history of hormonal or radiation therapy ♦♦ May be associated with schistosomiasis ♦♦ Aggressive; patients often present with osteolytic bone metastasis and are refractory to hormonal therapy ♦♦ Serum PSA may be normal even in the presence of metastasis

Macroscopic ♦♦ Often located in the periurethral region

Microscopic ♦♦ Usually High grade ♦♦ Nests and cords of malignant cells with squamous differentiation (Fig. 38.39) ♦♦ Requires the absence of acinar carcinoma and bladder involvement for diagnosis of pure squamous cell carcinoma

Immunohistochemistry ♦♦ PSA and PAP may be negative; high molecular weight cytokeratin is often positive

Differential Diagnosis ♦♦ Squamous metaplasia −− Lacks significant nuclear pleomorphism ♦♦ Metastatic squamous cell carcinoma −− PSA and PAP negative

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Fig. 38.40. Sarcomatoid carcinoma of the prostate.

Sarcomatoid Carcinoma (Carcinosarcoma) Clinical ♦♦ Often occurs in elderly patients with urinary obstructive symptoms ♦♦ Patients often have prior history of hormonal or radiation therapy ♦♦ Highly aggressive, with median survival of 12 months ♦♦ No differences in outcome for those with or without heterologous elements

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Considered Gleason pattern 5 adenocarcinoma (Fig. 38.40) Spindle cell proliferation with epithelial differentiation Nuclear pleomorphism and numerous mitotic figures Heterologous components variable, including osteosarcoma, leiomyosarcoma, etc.

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Immunohistochemistry ♦♦ PSA and PAP are sometimes positive; broad-spectrum cytokeratin positive

Differential Diagnosis ♦♦ Postoperative spindle cell nodule −− Clinical history of prior surgery −− Lacks significant nuclear pleomorphism ♦♦ Sarcoma −− Lacks evidence of epithelial differentiation

Lymphoepithelioma-Like Carcinoma ♦♦ Histologic features: islands of closely packed glands set in a dense lymphocytic stroma (Fig. 38.41) ♦♦ Very rare; unknown prognostic significance ♦♦ No association with Epstein–Barr virus

Fig. 38.42. Adenocarcinoma with glomeruloid features.

Cribriform Adenocarcinoma ♦♦ Collapsible fenestrations indicate Gleason pattern 3 cancer; near-solid rigid openings indicate Gleason pattern 4 cancer ♦♦ Main differential diagnostic consideration: extensive high grade PIN ♦♦ Used as a descriptive term – not a specific entity

Adenocarcinoma with Glomeruloid Features ♦♦ Unique Gleason grade 3 pattern consisting of a tightly cohesive tuft of cancer cells within a larger malignant acinus reminiscent of a glomerulus (Fig. 38.42)

Atrophic Adenocarcinoma ♦♦ Occurs in up to 2% of contemporary needle biopsies ♦♦ Not considered to be a specific clinicopathologic entity ♦♦ Cancer consisting of acini with dilated lumens that may be mistaken for atrophy at low power (cancer mimicking atrophy) (Fig. 38.43) ♦♦ Similar prognosis as conventional prostatic adenocarcinoma

Fig. 38.41. Lymphoepithelioma-like carcinoma of the prostate.

Fig. 38.43. Atrophic adenocarcinoma. (A) Large acini lined by flattened epithelium reminiscent of atrophy. (B) Same focus as (A) immunostained for high molecular weight cytokeratin 34bE12. The absence of staining in the acini of concern confirms the diagnosis of malignancy. Note benign acini in the upper left acting as positive internal control for the staining reaction.

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Adenocarcinoma with Microvacuolated Cytoplasm (Foamy Gland Carcinoma) ♦♦ Abundant microvacuolated cytoplasm, often with small shrunken nuclei and nucleoli (Fig. 38.44) ♦♦ May be more aggressive (unconfirmed) ♦♦ May be difficult to diagnose due to similarity to mucinous metaplasia ♦♦ Usually mixed with typical acinar adenocarcinoma

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Positive for a-methylacyl-CoA racemase (P504S) ♦♦ Uncommon, used as a descriptive term – not a specific entity

Adenoid Cystic/Basal Cell Carcinoma Clinical ♦♦ Similar clinical presentation as typical acinar carcinoma ♦♦ Considered cancer of low malignant potential ♦♦ Serum PSA concentration not elevated

Pseudohyperplastic Adenocarcinoma

Microscopic

♦♦ Resembles nodular hyperplasia (Fig. 38.45) ♦♦ Negative for basal cell markers (high molecular weight cytokeratin [34bE12] and p63)

♦♦ Irregular and infiltrating nests of basal cells in a myxoid stroma (Fig. 38.46) ♦♦ Predilection for perineural invasion ♦♦ Often coexistence of adenoid cystic pattern with rounded fenestrations and basaloid pattern with cell nests and peripheral palisading ♦♦ Elongated cells with crowding, stippled chromatin, and inconspicuous nucleoli ♦♦ May be associated with squamous differentiation and keratin production ♦♦ Two cell populations: peripheral basaloid cells and inner columnar ductal cells

Immunohistochemistry ♦♦ PSA and PAP may be positive; high molecular weight cytokeratin and p63 positive

Differential Diagnosis

Fig.  38.44. Microvacuolated (foamy gland) adenocarcinoma. The nuclei are often basally located and hyperchromatic, creating diagnostic difficulty.

♦♦ Basal cell hyperplasia/adenoma −− Solitary, well-circumscribed nodules associated with BPH −− Uniformly distributed solid nests of hyperplastic basal cells −− Condensed stroma at the periphery of nodules

Urothelial Carcinoma Clinical ♦♦ Accounts for <1% of prostate cancers

Fig. 38.45. Pseudohyperplastic adenocarcinoma. At low magnification, this focus could easily be misinterpreted as BPH. However, cytologic features and immunophenotype were diagnostic of malignancy. This focus is considered Gleason 1 + 1 = 2 adenocarcinoma.

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Fig. 38.46. Adenoid cystic/basal cell carcinoma.

Prostate

♦♦ Patients present with hematuria and urinary obstructive symptoms ♦♦ Poor prognosis, with osteolytic bone metastasis; most die within 2 years of diagnosis ♦♦ Refractory to hormonal therapy ♦♦ Serum PSA concentration is normal

Microscopic ♦♦ Marked cytologic atypia with nuclear pleomorphism and high mitotic figures (Fig. 38.47) ♦♦ Often associated with prominent stromal response and inflammatory background ♦♦ Dysplasia and carcinoma in situ common in adjacent urothelium ♦♦ Usually coexistent bladder cancer

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Table 38.9. Soft Tissue Tumors of the Prostate Benign

Malignant

Stromal hyperplasia (stromal subtype of benign nodular hyperplasia)

Rhabdomyosarcoma

Stromal hyperplasia with atypical giant cells

Leiomysarcoma

Leiomyoma

Phyllodes tumor

Postoperative spindle cell nodule

Stromal sarcoma (low grade/high grade)

Inflammatory myofibroblastic tumor

Immunohistochemistry ♦♦ CEA positive, PSA and PAP negative, high molecular weight cytokeratin (34bE12) positive and cytokeratin 20 is often positive

Differential Diagnosis ♦♦ Prostatic adenocarcinoma −− Acinar differentiation with less nuclear pleomorphism −− PSA and PAP positive, high molecular weight cytokeratin negative ♦♦ Inverted papilloma −− Complex arborizing invagination with peripheral palisading −− Lacks fibrovascular core ♦♦ HGPIN −− PSA and PAP positive

Soft Tissue Tumors (Table 38.9) Rhabdomyosarcoma ♦♦ Very rare, occurs mainly in children ♦♦ Embryonal rhabdomyosarcoma is most frequent type

Fig.  38.48. Rhabdomyosarcoma with an abundance of malignant rhabdomyoblasts. ♦♦ Sheets of immature spindle cells and occasional rhabdomyoblasts in myxoid stroma (Fig. 38.48) ♦♦ Myoglobin, MSA and desmin positive, PSA and PAP negative

Leiomyosarcoma Clinical ♦♦ Most common prostatic sarcoma in adults; accounts for 26% of all prostatic sarcomas ♦♦ Aggressive; usually recurs and results in death

Microscopic ♦♦ Similar to leiomyosarcoma of other sites ♦♦ Interlacing fascicles of spindle cells with eosinophilic cytoplasm and fusiform nuclei (Fig. 38.49) ♦♦ Necrosis, cytologic atypia, and increased number of mitotic figures

Immunohistochemistry Fig. 38.47. Urothelial (transitional cell) carcinoma of the prostate.

♦♦ Smooth muscle-specific actin and desmin positive

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Fig. 38.49. Leiomyosarcoma of the prostate.

Differential Diagnosis ♦♦ Symplastic leiomyoma −− Multinuclear giant cells and bizarre cells with nuclear degeneration −− Mitotic figures inconspicuous ♦♦ Stromal hyperplasia with atypical giant cells −− Bizarre hyperchromatic nuclei with inconspicuous nucleoli, rarely vacuolated −− No mitotic figures or necrosis ♦♦ Postoperative spindle cell nodule −− Small size of lesion −− Fascicles of relative uniform spindle cells in a myxoid stroma −− Cells with abundant cytoplasm −− Enlarged nuclei with fine granular chromatin and prominent nucleoli −− Mitotic figures may be frequent −− Lacks atypical mitotic figures and nuclear pleo­ morphism −− Prominent vasculature and associated with inflammation ♦♦ Blue nevi −− Pigmented dendritic bipolar cells in fibrous stroma

Phyllodes Tumor Clinical ♦♦ ♦♦ ♦♦ ♦♦

Patients usually present with urinary obstructive symptoms Potentially aggressive and often recurrent May dedifferentiate after recurrence (stromal overgrowth) Histogenesis is uncertain

Macroscopic ♦♦ Cystic and spongy tumor with prostatic enlargement, similar to BPH

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Fig. 38.50. Phyllodes tumor. Leaf-like projections with a benign proliferation of epithelium and stroma.

Microscopic ♦♦ Biphasic growth of stromal and epithelial components ♦♦ Interlacing fascicles of spindle cells with leaf-like projections into duct-like spaces (Fig. 38.50) ♦♦ Increased stromal cellularity and overgrowth with compressed, elongated channels ♦♦ Uniform nuclei with inconspicuous nucleoli ♦♦ Grading is not reliable for predicting recurrence ♦♦ May undergo sarcomatous transformation after recurrence (stromal overgrowth)

Immunohistochemistry ♦♦ Stroma: actin and vimentin positive, desmin and S-100 protein negative ♦♦ Luminal epithelial cells: PSA, PAP, and keratin positive

Differential Diagnosis ♦♦ Stromal hyperplasia with atypical giant cells −− Increased stromal cellularity and nuclear atypia −− Bizarre cells with nuclear degenerative change −− Associated with BPH ♦♦ Nodular hyperplasia with fibroadenoma-like areas −− Cystically dilated acini associated with hyperplastic epithelium ♦♦ Multilocular prostatic cystadenoma −− Epithelial cell-lined cyst in a fibrous stroma −− Lacks stromal cellularity ♦♦ Leiomyosarcoma −− Lacks biphasic growth pattern of phyllodes tumor ♦♦ Seminal vesicle cyst (lateral location) and müllerian duct cyst (midline location) −− Unilocular cyst −− No stromal cellularity −− PSA and PAP negative

Prostate

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Lymphoma Clinical ♦♦ Occurs in elderly patients presenting with urinary obstructive symptoms ♦♦ Secondary involvement more common than primary involvement (55% vs. 35%) ♦♦ Poor prognosis (median survival = 23–28 months) regardless of age, histologic type, treatment, clinical stage at presentation, or type of involvement (primary vs. secondary) ♦♦ Criteria for the diagnosis of primary lymphoma −− Absence of hematopoietic involvement (spleen, lymph nodes, peripheral blood, or liver) within 1 month prior to diagnosis −− Limited to the prostate and adjacent soft tissue

Macroscopic ♦♦ Diffusely enlarged with firm to rubbery consistency

Fig. 38.51. Small lymphocytic lymphoma involving the prostate.

Microscopic ♦♦ Diffuse large cell and small lymphocytic lymphoma are the two most common types ♦♦ Diffuse irregular infiltrates of monotonous lymphocytes (Fig. 38.51) ♦♦ Preservation of acini

Differential Diagnosis ♦♦ Granulomatous prostatitis −− Acinar destruction with polymorphous inflammatory infiltrate

TREATMENT EFFECTS Androgen Deprivation Therapy Benign ♦♦ Acinar atrophy and distortion ♦♦ Decreased ratio of acini to stroma, with stromal fibrosis and hyalinization (Fig. 38.52) ♦♦ ABCH, squamous metaplasia, and urothelial metaplasia ♦♦ Acinar rupture with preservation of basal cell layer ♦♦ Cytoplasmic vacuolization and nuclear shrinkage

Differential Diagnosis ♦♦ Clear cell change may be seen in the following lesions −− AAH

Cancer ♦♦ Linear arrays and ragged infiltrate of malignant acini with cytoplasmic vacuolization, nuclear pyknosis, and hyperchromasia (Fig. 38.53) ♦♦ Nucleoli may be inconspicuous ♦♦ Malignant glands are often dilated, with atrophic features and a hemangiopericytoma-like pattern ♦♦ Lacks basal cell layer ♦♦ Reduced incidence and extent of HGPIN

Immunohistochemistry ♦♦ PSA positive, PAP positive, HMW cytokeratin (34bE12) and p63 negative, racemase (P504S) positive (cancer) (Fig. 38.53)

Fig.  38.52. After hormonal treatment, benign prostatic tissue shows acinar destruction, stromal fibrosis, mucin pools, and calcifications.

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Fig. 38.54. Radiation change of the benign prostatic epithelium initially misdiagnosed as adenocarcinoma. There are marked nuclear abnormalities, including variation in size and shape and hyperchromasia. −− −− −− −− −− −− −− −−

Cribriform hyperplasia Basal cell hyperplasia Cowper glands Mucinous metaplasia Paraganglion Xanthoma and xanthogranulomatous prostatitis Metabolic storage disease Sclerosing adenosis

Radiation Therapy Benign ♦♦ Lobular and acinar atrophy, decreased acini to stroma ratio, stromal edema, and fibrosis ♦♦ ABCH (Fig. 38.54), squamous and transitional cell metaplasia ♦♦ Acinar rupture with extravasation, dystrophic calcification ♦♦ Vascular myointimal proliferation ♦♦ Cytoplasmic clearing with nuclear pyknosis

Cancer

Fig.  38.53. Androgen deprivation therapy-treated adenocarcinoma. (A) Needle biopsy contains numerous minute nests of malignant cells with small nuclei and abundant clear cytoplasm. These nests stand in contrast with the large adjacent atrophic acini. (B) Brown staining indicated PSA immunoreactivity in the cytoplasm of most of the malignant cells, confirming prostatic epithelial origin. (C) Immunostain for high molecular weight cytokeratin 34bE12 reveals an absence of staining in the malignant acini. Benign acini are positive.

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♦♦ Linear arrays and ragged infiltrate of malignant acini with cytoplasmic vacuolization, nuclear pyknosis, and hyperchromasia (Fig. 38.55) ♦♦ Nucleoli may be inconspicuous ♦♦ Lacks basal cell layer ♦♦ Reduced incidence and extent of HGPIN ♦♦ Grading of salvage prostatectomy specimens is predictive of survival

Immunohistochemistry ♦♦ PSA positive, PAP positive, HMW cytokeratin (34bE12) and p63 negative, racemase (P504S) positive (cancer) (Fig. 38.55)

Prostate

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Fig. 38.55. Prostatic adenocarcinoma after radiation therapy (A and B). Individual cancer cells may be difficult to distinguish from atypical basal cells. Immunostaining for PIN4 were helpful for the diagnosis; high molecular weight cytokeratin 34bE12 (brown, cytoplasmic), P504/racemase (red), and p63 (brown, nuclear).

TNM CLASSIFICATION OF PROSTATE CANCER (2010 REVISION) ♦♦ Primary Tumor (T) −− TX: Primary cancer cannot be evaluated −− T0: No evidence of primary tumor −− T1: Clinically inapparent tumor neither palpable nor visible by imaging −− T1a: Tumor incidental histologic finding in 5% or less of tissue resected −− T1b: Tumor incidental histologic findings in more than 5% of tissue resected −− T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA) −− T2: Tumor confined within prostate −− T2a: Tumor involves one-half of lobe or less −− T2b: Tumor involves more than one-half of one lobe, but not both lobes −− T2c: Tumor involves both lobes −− T3: Tumor extends through the prostate capsule −− T3a: Extracapsular extension (unilateral or bilateral) −− T3b: Tumor invades seminal vesicle(s)

−− T4: Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall ♦♦ Regional Lymph Nodes (N) Clinical −− NX: Regional lymph nodes were not assessed −− N0: No regional lymph node metastasis −− N1: Metastasis in regional lymph node(s) Pathologic −− pNX: Reginal nodes not sampled −− pN0: No positive regional nodes −− pN1: Metastases in regional node(s) ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis −− M1a: Nonregional lymph node(s) −− M1b: Bone(s) −− M1c: Other site(s) with or without bone disease

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Cheng L, Bostwick DG. Atypical sclerosing adenosis of the prostate: a rare mimic of adenocarcinoma. Histopathology 2010;56:627–631.

Cheng L, Slezak J, Bergstralh EJ, et al. Preoperative prediction of surgical margin status in prostate cancer patients treated by radical prostectomy. J Clin Oncol 2000;18:2862–2868.

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Egan AJM, Lopez-Beltran A, Bostwick DG. Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol 1997;21:931–935.

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Eichelberger LE, Cheng L. Does pT2b prostate carcinoma exist? Critical appraisal of the 2002 TNM classification of prostate carcinoma. Cancer 2004;100:2573–2576. Eichelberger LE, Koch MO, Eble JN, Ulbright TM, Juliar BE, Cheng L. Maximum tumor diameter is an independent predictor of prostate-­specific antigen recurrence in prostate cancer. Mod Pathol 2005;18:886–890. Eichelberger L, Koch MO, Daggy J, et  al. Predicting tumor volume in radical prostatectomy specimens from prostate cancer patients. Am J Clin Pathol 2003;120:386–391.

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Emerson RE, Koch MO, Daggy JK, Cheng L. Closest distance between tumor and resection margin in radical prostatectomy specimens: lack of prognostic significance. Am J Surg Pathol 2005;29: 225–229. Emerson RE, Koch MO, Jones TD, Daggy JK, Juliar BE, Cheng L. The influence of extent of surgical margin positivity on prostate specific antigen recurrence. J Clin Pathol 2005;58:1028–1032. Epstein JI, Allsbrook WC, Jr., Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 2005;29:1228–1242. Evans AJ, Henry PC, Van der Kwast TH, et al. Interobserver variability between expert urologic pathologists for extraprostatic extension and surgical margin status in radical prostatectomy specimens. Am J Surg Pathol 2008;32:1503–1512. Galosi AB, Mazzucchelli R, Scarpelli M, et al. Solitary fibrous tumour of the prostate identified on needle biopsy. Eur Urol 2009;564:567. Grignon DJ. Unusual subtypes of prostate cancer. Mod Pathol 2004; 17:316-327. Hansel DE, Epstein JI. Sarcomatoid carcinoma of the prostate: a study of 42 cases. Am J Surg Pathol 2006;30:1316–1321. Hansel DE, Herawi M, Montgomery E, Epstein JI. Spindle cell lesions of the adult prostate. Mod Pathol 2007;20:148–158. Hattab EM, Koch MO, Eble JN, Lin H, Cheng L. Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma. J Urol 2006;175:1695–1699. Hong H, Koch MO, Foster RS, et al. Anatomic distribution of periprostatic adipose tissue: a mapping study of 100 radical prostatectomy specimens. Cancer 2003;97:1639–1643.

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Montironi R, Cheng L, Mazzucchelli R, Lopez-Beltran A. Pathological definition and difficulties in assessing positive margins in radical prostatectomy specimens. BJU Int 2009;103:286–288. Montironi R, Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M. High grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate. Nat Clin Pract Urol 2007;4:321–332. Montironi R, Cheng L, Lopez-Beltran A, Mazzucchelli R, Scarpelli M, Kirkali Z, Montorsi. Joint appraisal of the radical prostatectomy specimens by the urologist and uropathologist. Eur Urol (in press). Montironi R, Cheng L, Lopez-Beltran A, Scarpelli M, Mazzucchelli R, Mikuz G, Kirkali A, Montorsi F. Original Gleason System versus 2005 ISUP Modified Gleason System. Eur Urol (in press). Montironi R, Cheng L, Lopez-Beltran A, et al. Decision support systems for morphology-based diagnosis and prognosis of prostate neoplasms: a methodological approach. Cancer 2009;115(S13):3068–3077. Montironi R, Cheng L, Lopez-Beltran A, et al. Stage pT0 in radical prostatectomy with no residual carcinoma and with a previous positive biopsy conveys a wrong message to clinicians and patients: Why is cancer not present in the radical prostatectomy specimen? Eur Urol 2009;56: 272–274. Montironi R, Cheng L, Mazzucchelli R, et al. Critical pathological evaluation of the prostate from cystoprostatectomies for bladder cancer: insights from a complete sampling with the whole mount technique. Eur Urol 2009;55:1305–1309. Montironi R, Cheng L, Scarpelli M, et  al. Pathological reflection on European Urology: extended, saturation, and systematic prostate biopsies. Eur Urol 2008;53:1111–1114. Montironi R, Mazzucchelli R, Scarpelli M, et  al. Prostate carcinoma II: prognostic factors in prostate needle biopsies. BJU Int 2006;97:492–497.

Hossain D, Meiers I, Qian J, MacLennan GT, Bostwick DG. Prostatic stromal hyperplasia with atypia: follow-up study of 18 cases. Arch Pathol Lab Med 2008;132:1729–1733.

Montironi R, Mazzucchelli R, Scarpelli M, et al. Prostate carcinoma I: prognostic factors in radical prostatectomy specimens and pelvic lymph nodes. BJU Int 2006;97:485–491.

Iczkowski KA, Bostwick DG. Criteria for biopsy diagnosis of minimal volume prostatic adenocarcinoma: analytic comparison with nondiagnostic but suspicious atypical small acinar proliferation. Arch Pathol Lab Med 2000;124:98–107.

Montironi R, Scattoni V, Mazzucchelli R, et al. Atypical foci suspicious but not diagnostic of malignancy in prostate needle biopsies (also referred to as “atypical small acinar proliferation suspicious for but not diagnostic of malignancy”). Eur Urol 2006;50:666–674.

Iczkowski KA, Ferguson KL, Grier DD, et al. Adenoid cystic/basal cell carcinoma of the prostate: clinicopathologic findings in 19 cases. Am J Surg Pathol 2003;27:1523–1529.

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39 Testis and Testicular Adnexa Kenneth A. Iczkowski, md and Thomas M. Ulbright, md

Contents

I. Nonneoplastic Lesions of Testis..........39-3 Congenital Abnormalities................................39-3 Cryptorchidism.......................................39-3 Anorchidism............................................39-3 Polyorchidism..........................................39-3 Adrenal Cortical Rests...........................39-4 Splenic–Gonadal Fusion........................39-4 Acquired Abnormalities..................................39-4 Testicular Torsion and Infarct...............39-4 Varicocele................................................39-4 Infections and Inflammatory Conditions of Testis and Epididymis.........39-5 Viral Orchidoepididymitis.....................39-5 Bacterial Orchidoepididymitis..............39-5 Granulomatous Orchidoepididymitis.............39-5 Mycobacterial Orchidoepididymitis.....39-5 Fungal Orchidoepididymitis..................39-6 Syphilitic Orchidoepididymitis..............39-6 Leprosy....................................................39-6 Sarcoidosis...............................................39-6 Malakoplakia..........................................39-6 Idiopathic Granulomatous Orchitis......39-7 Infertility...........................................................39-7 Normal or Nearly Normal......................39-7 Hypospermatogenesis.............................39-7 Aspermatogenesis...................................39-8 Early Maturation Arrest........................39-8 Late Maturation Arrest.........................39-9 Tubular Hyalinization (Evaluable in Biopsy Only)...............39-9

II. Neoplasms of Testis..........................39-10 Gross Processing of an Orchiectomy Specimen....................................................39-10

Germ Cell Tumors..........................................39-10 Cell of Origin.........................................39-10 Risk of Germ Cell Tumors...................39-10 Ancillary Stains.....................................39-10 Staging...................................................39-10 Treatment..............................................39-10 Intratubular Germ Cell Neoplasia, Unclassified....................39-12 Seminoma..............................................39-13 Spermatocytic Seminoma....................39-15 Embryonal Carcinoma.........................39-16 Yolk Sac Tumor (Endodermal Sinus Tumor)....................................39-17 Teratoma................................................39-18 Dermoid Cyst........................................39-19 Epidermoid Cyst...................................39-19 Choriocarcinoma..................................39-19 Mixed Germ Cell Tumor......................39-19 Regressed Tumor..................................39-19 Sex Cord-Stromal Tumors.............................39-20 Leydig Cell Tumor................................39-20 Sertoli Cell Tumor, Typical Type........39-21 Sclerosing Sertoli Cell Tumor..............39-22 Large-Cell Calcifying Sertoli Cell Tumor........................................39-22 Granulosa Cell Tumor, Adult Type.....39-22 Granulosa Cell Tumor, Juvenile Type....................................39-22 Mixed Germ Cell and Sex Cord-Stromal Tumor................................39-23 Gonadoblastoma...................................39-23 Testicular Hilum: “Tumor” of Adrenogenital Syndrome......................39-23 Rete Testis: Adenocarcinoma........................39-23

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_39, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Essentials of Anatomic Pathology, 3rd Ed.

Hematopoietic Neoplasms.............................39-24 Lymphoma and Plasmacytoma...........39-24 Leukemia...............................................39-24 Vascular Lesions: Capillary Hemangioma....................................39-24

III. Lesions of Epididymis and Tunics.....39-25 Sperm Granuloma..........................................39-25 Adenomatoid Tumor......................................39-25 Papillary Cystadenoma..................................39-26 Hydrocele and Well-Differentiated Papillary Mesothelioma............................39-26 Malignant Mesothelioma...............................39-26 Tumors Homologous to Ovarian Tumors.....39-26

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IV. Lesions of Spermatic Cord...............39-26 Nodular Fibrous Periorchitis........................39-26 Vasitis Nodosa.................................................39-27 Proliferative Funiculitis.................................39-27 Paratesticular Sarcoma......................................................39-28 Rhabdomyosarcoma.............................39-28 Liposarcoma..........................................39-28 Leiomyosarcoma...................................39-28

V. TNM Classification of Testicular Tumors (2010 Revision)...................39-28 VI. Suggested Reading...........................39-28

Testis and Testicular Adnexa

39-3

NONNEOPLASTIC LESIONS OF TESTIS Congenital Abnormalities Cryptorchidism Clinical ♦♦ In this condition, one or both testes fail to descend into the scrotum. Location can be in the upper scrotum, inguinal canal, or within the abdomen. The condition is bilateral in 18% of patients; family history of cryptorchid testis will be found in 14% −− The cause is unknown but may relate to hormonal abnormalities, mechanical impairment to descent, or unidentified intrinsic abnormality in the testis (a) Complications include infertility and the development of germ cell tumors. Infertility is the most frequent complication; 9% of infertile males have cryptorchid testes. Other complications include torsion and infarction. Only 16–25% of patients with bilateral cryptorchid testes are fertile but fertility improves to 25–81% if only one testicle is undescended. If orchidopexy (restoration of testicle to the scrotum) is performed before 4 years of age, fertility is often maintained in the undescended testicle −− Germ cell tumors are 4–10 times more likely in a cryptorchid testis. Orchidopexy does not decrease the risk of a germ cell tumor, but allows for regular testicular exam

Macroscopic ♦♦ Testes may be of normal size or small

Microscopic (Fig. 39.1) ♦♦ The histologic appearance of cryptorchid testis varies with age, testicular position, and prior hormonal therapy. Human chorionic gonadotropin or gonadotropin releasing hormone [GnRH] is sometimes used as a hormonal means to bring the testicle into the scrotum

Fig. 39.1. Cryptorchid testis in 13-year-old boy. Tubules have no germ cells and show aspermatogenesis. Right side of field has a Sertoli cell nodule.

♦♦ The prepubertal testis often shows a Sertoli cell nodule (Pick adenoma) comprised of a circumscribed collection of small tubules lined by fetal-type Sertoli cells; the testis usually contains germ cells but in decreased numbers. Following puberty, changes become more pronounced and include tunica propria thickening, reduced tubular diameter, tubular sclerosis, interstitial fibrosis, and more prominent Leydig cell clusters

Anorchidism Clinical ♦♦ This rare condition is due to the absence of both testicles. It can only be distinguished clinically from cryptorchidism ♦♦ Unilateral anorchidism (vanishing testis syndrome) occurs in 1 in 5,000 males; bilateral testes are absent in 1 in 20,000 males. The gonad may disappear due to many causes, including intrinsic gonadal disorder, infection, trauma, torsion, infarction or atrophy resulting from the overproduction of androgens

Macroscopic ♦♦ All that remains may be epididymis, vas, or a “fibrous nubbin.” If a vas deferens is identified, then an ipsilateral testicle had to exist during gestation

Microscopic (Fig. 39.2) ♦♦ The fibrous nubbin consists of dense collagen, siderophages, and dystrophic calcification

Polyorchidism Clinical ♦♦ This is the very unusual (<80 reported cases) presence of more than two testicles. Patients present with a scrotal mass that may be confused with a testicular tumor

Fig. 39.2. Congenital anorchia caused by in utero infarction. All that remains is a zone of dense fibrous tissue with dystrophic calcifications and siderophages.

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39-4

Macroscopic ♦♦ The extra testis may have its own epididymis and a vas deferens that joins other vas distally, or the testis may share a common epididymis with another testicle

Microscopic ♦♦ The spermatogenic function of supernumary testis varies: the testis may be normal, or have hypospermatogenesis

Adrenal Cortical Rests Clinical ♦♦ This clinically insignificant finding, identified in 4–15% of individuals, is usually an incidental finding. Adrenal cortical tissue may be in the testis, adjacent spermatic cord, or epididymis

Macroscopic ♦♦ Encapsulated nodules of adrenal cortical tissue measuring a few millimeters are found in the spermatic cord, epididymis, rete testis, or tunica albuginea, and rarely within testis

Microscopic ♦♦ Adrenocortical tissue is found that typically exhibits usual zonation of the adrenal tissue seen in normal cortex. Adrenal medullary tissue is not present

Splenic–Gonadal Fusion Clinical ♦♦ Patients present with a scrotal or inguinal mass consisting of fused spleen and testis. It occurs in two forms: continuous fusion has a cord connecting the spleen to the fused splenic tissue/testis; discontinuous fusion has no cord. Approximately one-third of patients with the continuous form have severe congenital defects of extremities. Enlargement occurs in conditions associated with splenomegaly

Macroscopic ♦♦ The splenic tissue is attached to the testicle, typically a discrete mass as large as 12 cm. In the continuous type, small aggregates of splenic tissue may be found along the length of the cord, or the entire cord may be composed of splenic tissue. Grossly, the tissue is normal spleen

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Prompt intervention is necessary to prevent infarction. Detorsion should be performed within 6–8  h of torsion to prevent the loss of the testicle. Infarction is almost certain if torsion is not corrected within 24  h. Detorsion may be attempted manually, but it may require surgical intervention (orchidopexy) ♦♦ The diagnosis is usually evident by history and exam, but Doppler studies or nuclear-based perfusion scans may be useful to show decreased blood flow in torsion (vs. increased blood flow in epididymitis/ inflammatory conditions)

Macroscopic ♦♦ Gross examination reveals a swollen, blood-filled testicle

Microscopic (Fig. 39.3) ♦♦ Up to 6 h after torsion, the testis shows venous congestion and interstitial hemorrhage. At 9  h, neutrophils marginate from the capillaries and severe interstitial hemorrhage is present. After 1–2 days, hemorrhagic infarction develops. Trauma can cause infarction in adults

Varicocele Clinical ♦♦ Varicocele is thought to be the result of insufficient venous valves. It results from abnormal dilatation and tortuosity to veins of the pampiniform plexus of spermatic cord. Varicocele primarily involves the left side (90% of cases), or may be bilateral (10%) It is associated with infertility, and a number of hypotheses have been posited regarding this association, including endocrinologic insufficiency, venous stasis, resulting in a buildup of toxic metabolites and decreased oxygenation, and increased temperature due to blood flow ♦♦ Ligation of the left spermatic vein may correct varicocoele and fertility. Fertility returns in up to 55% of patients undergoing ligation

Macroscopic ♦♦ Rarely seen by pathologists, the lesion consists of tortuous and dilated veins of the pampiniform plexus

Microscopic ♦♦ Histologic appearance is that of normal spleen and testis

Acquired Abnormalities Testicular Torsion and Infarct Clinical ♦♦ Torsion is twisting of the spermatic cord, usually within the tunica vaginalis. The twisting obstructs veins and the testicle becomes hemorrhagic. Eventually, the arterial flow is interrupted and infarction occurs. Predisposing conditions include absence of scrotal ligaments, shortened attachment of peritoneal ligaments, incomplete descent, and testicular atrophy. Torsion mostly occurs in children and young adults who present with marked testicular pain. It may develop after physical activity

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Fig. 39.3. Infarct of testis in a 75-year-old man with testicular trauma. Orchiectomy 4 weeks later shows shadow outlines of tubules. Inset (left) has necrotic cell debris filling tubular lumen.

Testis and Testicular Adnexa

Microscopic (Fig. 39.4) ♦♦ Multiple channels of dilated spermatic vein are often surrounded by fibrosis. Testicular biopsy shows hypospermatogenesis (see below) with germ cell sloughing and Leydig cell hyperplasia. Histologic changes may revert to normal after spermatic vein ligation

Infections and Inflammatory Conditions of Testis and Epididymis Viral Orchidoepididymitis Clinical ♦♦ Mumps is the most common viral etiology of orchidoepididymitis. Next in frequency are Coxsackie B, influenza, EBV, echovirus, adenovirus, varicella, vaccinia, rubella, and dengue. AIDS may involve the testicle and is characterized by a lymphocytic infiltrate ♦♦ Usually, viral orchitis occurs as a complication of up to 35% of adult mumps. It is infrequent in children. Men with unilateral involvement usually maintain fertility. However, it is bilateral in 25% of cases, and this bilateral involvement often leads to infertility. Testicular involvement typically becomes evident in 4–6 days after parotid involvement

Macroscopic ♦♦ Testis appears normal at the early stage, but if involvement is severe, atrophic changes develop

Microscopic ♦♦ Changes are multifocal and characterized by lymphocytic and neutrophilic infiltrates of seminiferous tubules and interstitium. There is loss of germ cells; ultimately, tubular sclerosis and interstitial fibrosis develop

Bacterial Orchidoepididymitis Clinical ♦♦ In younger men, acute and chronic bacterial orchitis is most often attributable to Chlamydia trachomatis, and Neisseria gonorrhea, representing common causes of male infertility (see below). In older men, Escherichia coli from associated

Fig. 39.4. Varicocele shows dilated venous channels.

39-5

urinary tract infection is the most common etiologic agent. Other responsible agents seeding from other sites via lymphatics or blood are Klebsiella sp., Streptococci, Staphylococci, Pneumococci, Salmonella enteritidis, and Actinomyces israeli ♦♦ Brucellosis involves the testicle and epididymis in 20% of all cases. Brucellosis is characterized by a testicular mass with constitutional symptoms (undulating fever, malaise, headache, and sweats). Complications include an abscess with involvement of the scrotum and scrotal sinus formation

Macroscopic (Fig. 39.5) ♦♦ Testicle is swollen and may contain an abscess

Microscopic ♦♦ Polymorphonuclear leukocyte inflammatory infiltrate involving interstitium and seminiferous tubules, progressing to abscess. Brucellosis causes an infiltrate of lymphocytes and histiocytes with occasional granulomas present

Granulomatous Orchidoepididymitis Mycobacterial Orchidoepididymitis Clinical ♦♦ Testicular involvement by Mycobacterium tuberculosis is always secondary to infection elsewhere in the body. In adults, tuberculous orchitis typically occurs as an descending infection from other sites in the genitourinary tract. Renal tuberculosis results in bladder and prostatic involvement, with subsequent spread to the epididymis and testicle. Most patients are adults. In children, involvement usually occurs by hematogenous spread from the lung. Patients may have constitutional symptoms but usually present with only testicular swelling and pain

Macroscopic (Fig. 39.6) ♦♦ Testicle may be enlarged with multiple soft, nodular, white caseating granulomas that typically are a few millimeters in size or may coalesce. Fistulae may extend to the scrotum

Fig. 39.5. Testis from a 14-year-old boy with severe acute and chronic orchidoepididymitis. There is testicular swelling with a pale, yellow cut surface caused by a purulent exudate.

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Essentials of Anatomic Pathology, 3rd Ed.

obliterative endarteritis and destructive inflammation; over time, the testes become fibrotic −− Acquired (or tertiary) syphilis has two histologic patterns: interstitial orchitis and gummatous orchitis. Interstitial orchitis is identical to that seen in congenital syphilis, and ultimately leads to small fibrotic testes. Gummatous orchitis is characterized by coagulative necrosis with a peripheral zone of fibrous tissue containing lymphocytes, plasma cells, and occasional giant cells. Both gummas and interstitial orchitis may occur in the same testicle. Spirochetes may be seen with special silver stains (Warthin–Starry, Dieterle) Fig.  39.6. Tuberculous orchitis and epididymitis. Both organs are expanded by numerous yellow nodules.

Microscopic ♦♦ Necrotizing and nonnecrotizing granulomatous inflammation is present. Granulomas contain histiocytes, giant cells, and lymphocytes in a fibrotic stroma that surrounds necrotic material. The inflammatory process is destructive of testicular parenchyma

Fungal Orchidoepididymitis Clinical ♦♦ Rarely, fungal infections involving the genitourinary tract may occur in immunocompromised patients. Fungal organisms that can cause orchitis include Blastomyces hominis, Coccidioidomyces immitis, Histoplasma capsulatum, Cryptococcus neoformans, and Trichophyton mentagraphytes

Macroscopic ♦♦ Necrotic granulomas and abscesses are present

Microscopic ♦♦ Histologic features are identical to those of fungal infections occurring elsewhere in the body. Necrotizing and nonnecrotizing granulomas and neutrophilic microabscesses are present. Organisms may be identified using special stains, such as methenamine silver or periodic acid-Schiff stains

Syphilitic Orchidoepididymitis Clinical ♦♦ Congenital and acquired forms occur. In congenital syphilis, testicular enlargement is present at birth. In the acquired form, the testes are involved in tertiary syphilis

Leprosy Clinical ♦♦ Leprosy is a very rare cause of infertility in the USA, but more frequent in other parts of the world. The testes are involved because the low temperature within the scrotum facilitates the growth of bacillus

Macroscopic ♦♦ The gross appearance of testes is dependent on the stage of infection. In early stage, testes may look normal but in later stages, testes are small and fibrotic

Microscopic ♦♦ Three phases of testicular leprosy −− Early phase: a vascular phase characterized by lepra cells containing numerous organisms within blood vessel walls and testicular interstitium −− This is followed by an interstitial phase with obliterative endarteritis, interstitial fibrosis, and lepra cells −− Finally, there is obliterative phase characterized by a loss of testicular parenchyma and replacement by fibrous tissue

Sarcoidosis Clinical ♦♦ Sarcoidosis is a systemic granulomatous disease of unknown cause, and involves the genitourinary system in 0.2% of all cases. Only a few cases involving the testes have been reported and these tend to be unilateral

Macroscopic ♦♦ Small nodules may be present

Microscopic

Macroscopic

♦♦ Nonnecrotizing granulomas are present, identical to sarcoid granulomas elsewhere in the body. Histologically, must exclude a granulomatous reaction due to seminoma, mycobacterial infection, or idiopathic granulomatous orchitis

♦♦ In infants, the testes are enlarged; over time, the testes become fibrotic and small. In adults, the testes are soft, yellow, and necrotic. Gummas may be present

Malakoplakia Clinical

Microscopic ♦♦ The testes involved by congenital syphilis exhibit interstitial inflammation with abundant plasma cells. Arteries show

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♦♦ This unusual form of bacterial infection most commonly affects the bladder in middle-aged women. However, in men, the testes are involved in 12% of cases of genitourinary malakoplakia. Patients have a defect in the capacity of their

Testis and Testicular Adnexa

mononuclear cells to kill phagocytized bacteria. Inflammation is histiocytic and forms masses. Infection is due to coliform bacteria such as E. coli (most common), Proteus vulgaris, Klebsiella pneumonia, and others

Macroscopic ♦♦ The testes are enlarged, with yellow, soft parenchyma

Microscopic ♦♦ There are aggregates of histiocytes with abundant, foamy, slightly granular cytoplasm. Some of the histiocytes contain Michaelis–Gutmann bodies that are intracytoplasmic calcific concretions with target-like appearance. These cause tubular destruction

Idiopathic Granulomatous Orchitis Clinical ♦♦ Clinically and pathologically this is a granulomatous inflammatory disorder of older males. Hypotheses for etiology include infection or autoimmune orchitis. The lesion presents as a unilateral tender testicular mass mimicking a tumor. Rare cases have been bilateral; 66% of patients who have symptoms have a urinary tract infection

Macroscopic ♦♦ The testis is enlarged and nodular, with white to yellow homogeneous parenchyma with areas of necrosis. Grossly, it resembles lymphoma, a leukemic infiltrate, or malakoplakia

Microscopic (Fig. 39.7) ♦♦ Inflammation may primarily involve tubules (tubular orchitis) or interstitium (interstitial orchitis). In tubular orchitis, inflammatory cells (plasma cells and lymphocytes) ring seminiferous tubules, and there is a loss of germ cells: epithelioid histiocytes with or without giant cells populate the tubules; inflammation is associated with vascular thrombosis and vasculitis. In interstitial orchitis, inflammation is interstitial. In both forms, a loss of tubules and fibrosis occur as a result of inflammation

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Infertility ♦♦ In men who are azoospermic (no sperm) or oligospermic (decreased sperm), open testicular biopsy has been the standard method to assess spermatogenesis. However, fine-needle aspiration cytology, a less invasive method, has been shown to correlate with biopsy in 94% of cases, its only limitation being that tubular basement membrane status is not assessed (Meng et al. 2001). By either approach, the pathologist can recognize six diagnostic patterns −− Normal or nearly normal −− Hypospermatogenesis −− Aspermatogenesis −− Early maturation arrest −− Late maturation arrest −− Tubular hyalinization (evaluable in biopsy only)

Normal or Nearly Normal ♦♦ This pattern is due to excurrent duct obstruction (blockage of ducts leading away from testis)

Clinical ♦♦ Approximately 10% of biopsied infertile patients have normal histology. Patients have azoospermia, normal-sized testicles, and normal spermatogenesis on a testicular biopsy. Sperm motility may be impaired. Obstruction can be the result of congenital atresia of vas deferens or epididymis, cystic fibrosis, or acquired by infection or surgical ligation (vasectomy) −− Young syndrome is a lesion at the junction of head and body of epididymis in which the ductus epididymidis is blocked by thick fluid. Patients also have sinusitis and bronchiectasis as in children with cystic fibrosis

Macroscopic ♦♦ No alterations are seen

Microscopic (Fig. 39.8) ♦♦ Spermatogenesis is normal for many years following obstruction. Epididymis has ability to store, and phagocytize sperm and sperm products at a rate that matches sperm production −− Testicular biopsy shows active spermatogenesis. After vasovasostomy (reversal of vasectomy), there may be some germinal cell disorganization and sloughing, variable amounts of tunica propria thickening, and occasional interstitial fibrosis. Vasitis nodosa may be seen

Hypospermatogenesis Clinical

Fig. 39.7. Idiopathic granulomatous orchitis with collections of epithelioid histiocytes filling seminiferous tubules and a chronic inflammatory infiltrate in the interstitium.

♦♦ This is the second most common cause of testicular infertility. Patients are potent and have normal secondary sexual characteristics but are oligospermic. Germ cells and developing forms are present in normal proportions, but overall numbers are markedly decreased −− It is usually idiopathic, but can be related to androgen receptor responsiveness defect (Reifenstein syndrome), the after-effect of cryptorchidism in formerly ­cryptorchid

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 39.10. Sertoli cell-only syndrome. The tubule is lined entirely by uniform, columnar Sertoli cells. Germ cells are absent. Fig. 39.8. Normal testis. Tubular profile shows spermatogonia at the periphery with maturation progression toward the lumen of primary spermatocytes, spermatids, and spermatozoa.

Clinical ♦♦ Patients are potent, with normal secondary sexual characteristics, but azoospermic. Follicle-stimulating hormone levels are always high as a result of the absence of spermatogenesis. Most cases are idiopathic but chemotherapeutic agents and radiation can cause similar changes, and these may be reversible

Macroscopic ♦♦ No alterations are usually present, although occasionally, the testes are smaller than normal

Microscopic (Fig. 39.10) ♦♦ Seminiferous tubules show a moderate decrease in diameter and are devoid of germ cells. Only Sertoli cells remain. In a few cases, some tubules show spermatogenesis, so the diagnosis is germ cell aplasia with focal spermatogenesis ♦♦ This pattern also prevails in the following entities Fig. 39.9. Hypospermatogenesis. Primary spermatocytes, spermatids, and spermatozoa can be found but in reduced numbers. Courtesy of Dr. W. M. Murphy, Leesburg, FL. patients after ordidopexy, or exposure to toxins, excess heat, varicocele, or hormonal dysfunction including hypothyroidism

Macroscopic ♦♦ No alterations are evident

Microscopic (Fig. 39.9) ♦♦ There is overall thinning of the germinal epithelium with proportional hypoplasia of spermatogonia, primary spermatocytes, spermatids, and spermatozoa (sperm with tail). There may be diffuse Leydig cell hyperplasia

Aspermatogenesis ♦♦ This is most often the result of the Sertoli cell-only syndrome (absence/aplasia of germ cells). The condition is usually idiopathic

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−− Androgen insensitivity (testicular feminization) syndrome: a phenotypic female but genetic male with normal male testosterone levels. Testes are present in the abdomen, inguinal canal, or labia majora and are removed after puberty to prevent tumors. The size of the testes varies. In most cases, tubules have Sertoli cells only (Fig. 39.11) −− Cryptorchid testes may present with this pattern, although early maturation arrest is more common ♦♦ Hypogonadotropic hypogonadism: this pattern occurs with greatly increased numbers of Sertoli cells −− Hypergonadotropic hypogonadism, chemotherapy, radiotherapy, or estrogens can cause a Sertoli cell-only picture ♦♦ Mixed atrophy: a variant in which some testicular lobules have aspermatogenesis with Sertoli cells only while others have normal tubules with spermatogenesis

Early Maturation Arrest Clinical ♦♦ Also called premeiotic or “complete” maturation arrest, this is the most common cause of testicular infertility.

Testis and Testicular Adnexa

Fig. 39.11. Androgen insensitivity (testicular feminization) syndrome. Seminiferous tubules contain only small, fetal-type Sertoli cells, surrounded by Leydig cells. In one-third of patients, spermatogonia are present.

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Fig. 39.13. Tubular hyalinization with Leydig cell prominence, a pattern seen in Klinefelter syndrome and postpubertal cryptorchid testes.

Late Maturation Arrest Clinical ♦♦ In some patients with oligospermia or azoospermia, this pattern is seen; also called postmeiotic or “incomplete” maturation arrest

Macroscopic ♦♦ No alterations are evident

Microscopic ♦♦ There are primary spermatocytes and spermatids but absent or markedly decreased spermatozoa (sperm with tail)

Fig.  39.12. Early maturation arrest. Only spermatogonia and primary spermatocytes are seen, some with mitotic figures (lower left). The lumen is devoid of spermatids or spermatozoa. Courtesy of Dr. W. M. Murphy, Leesburg, FL.

Patients are potent, with normal secondary sexual characteristics, but they are oligospermic or azoospermic. The cause is usually idiopathic but cryptorchidism, alcoholism, exposure to toxins and postpubertal gonadotropin deficiency can result in a similar pattern. In adulthood, cryptorchid testes most often show this pattern, but may also show aspermatogenesis

Macroscopic ♦♦ No alterations are evident

Microscopic (Fig. 39.12) ♦♦ Spermatogonia and primary spermatocytes are present, but no spermatids or spermatozoa (sperm with tail). Biopsy shows <17 spermatogonia per tubular profile

Tubular Hyalinization (Evaluable in Biopsy Only) Clinical ♦♦ Klinefelter syndrome and other karyotypic abnormalities cause dysgenetic hyalinization. It is the result of an abnormal number of X chromosomes, commonly with genotype of 47, XXY and primary gonadal insufficiency. Approximately 1 in 1,000 newborns are affected. Males have a eunuchoid phenotype with tall stature, incomplete virilization (poorly developed secondary sex characteristics), gynecomastia, and mental retardation; phenotypic and testicular changes become evident at puberty. They have an increased incidence of breast cancer and extragonadal germ cell tumors of the mediastinum

Macroscopic ♦♦ The testes are usually small and firm (<2.5  cm in greatest dimension)

Microscopic (Fig. 39.13) ♦♦ The testes show progressive failure of spermatogenesis with a loss of germ cells and Sertoli cells. The tunica of tubules thickens and eventually all that remains are hyalinized empty tubules lacking elastic fibers. Leydig cell clusters become

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more prominent. It is debatable whether this represents Leydig cell hyperplasia or prominence of Leydig cells as a result of testicular volume loss ♦♦ Other causes of tubular hyalinization −− Hormonal deficit, hypopituitarism of pre- or postpubertal onset −− Estrogen excess (endogenous, from cirrhosis or estrogenproducing tumor of adrenal, exogenous causes, as prostate cancer therapy) −− Androgen excess, either endogenous from adrenogenital syndrome or an androgen-producing tumor, or exogenous

−− Glucocorticoid excess, either endogenous from Cushing syndrome or exogenous from steroid therapy −− Hypothyroidism −− Ischemia due to torsion or to severe atherosclerosis ♦♦ Postobstructive change results in a mosaic of normal and hyalinized tubules. This is usually secondary to varicocele of pampiniform plexus or disorders involving dilatation of rete testis. It follows infection (mumps or Coxsackie B orchitis), and can be due to physical and chemical agents (lead, carbon disulfide, radiation, chemotherapy, or Addison disease)

NEOPLASMS OF TESTIS Gross Processing of an Orchiectomy Specimen (See Table 39.1) ♦♦ Because the testicular tunica albuginea is impermeable to fixative, placing it directly into fixative will cause autolysis. Instead, the testis should be at least bisected prior to fixation. Even in normal testis, fixation artifact can create areas that resemble tumor (Fig. 39.14) ♦♦ A margin section of spermatic cord should be sampled first before the tumor is sampled to avoid contamination of tumor on the knife blade. About one block should be submitted per centimeter of greatest dimension of tumor, plus one section to include the testicular hilum. This is because extratesticular extension is present in 16% of cases and occurs at the hilum in 91% of these (Dry and Renshaw 1999)

Germ Cell Tumors Cell of Origin ♦♦ The precursor of invasive germ cell tumors is intratubular germ cell neoplasia, unclassified type (IGCNU); differentiated forms of intratubular germ cell tumors are also seen, most commonly intratubular seminoma or intratubular embryonal carcinoma ♦♦ Owing to the rarity of intratubular embryonal carcinoma in association with germ cell tumors, it is hypothesized that seminomas arise from IGCNU; but nonseminomatous germ cell tumors too can arise from IGCNU ♦♦ IGCNU does not give rise to spermatocytic seminoma, or to the pediatric forms of yolk sac tumor or teratoma ♦♦ Seminoma cells and IGCNU are identical morphologically, and share many other features, including karyotypic abnormalities, high DNA content, ultrastructure, and immunohistochemical profiles

Risk of Germ Cell Tumors ♦♦ Certain conditions increase the risk of germ cell tumors in men −− Cryptorchidism (about 4×), history of a prior testicular tumor, first degree relative with a germ cell tumor, gonadal dysgenesis, and androgen insensitivity syndrome. Patients

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with history of cryptorchidism may get 1–3 biopsies bilaterally at age 18 for early detection of IGCNU

Ancillary Stains ♦♦ See Table 39.2.

Staging ♦♦ The TNM staging systems for testicular germ cell tumors is shown at the end of the chapter ♦♦ The hilum should be sampled in all orchiectomies with tumor

Treatment Seminoma ♦♦ Clinical stage I tumors and nonbulky stage II tumors are usually treated by radical orchiectomy and radiation to ipsilateral para-aortic and pelvic lymph nodes ♦♦ Some patients with a stage I tumor may be treated by radical orchiectomy alone, with careful followup ♦♦ Cure rate is 95% for stage I tumors and nearly 90% for stage II tumors ♦♦ In patients with bulky stage II seminoma and more advanced stages, orchiectomy and chemotherapy are performed, with survival rates of 80%

Nonseminomatous Germ Cell Tumors ♦♦ Stage I −− Treatment option A is radical orchiectomy and retroperitoneal lymph node dissection. The cure rate is 90–95% and the relapse rate is 5–10%. Treatment option B is radical orchiectomy and surveillance with a cure rate of 60–70% and relapse rate is 30–40%. Chemotherapy, however, salvages almost all of these relapses ♦♦ Stage II −− If nonbulky, orchiectomy, lymph node dissection, and chemotherapy are used with a cure rate of 90% −− If bulky, orchiectomy, chemotherapy, and resection of residual masses are used with a cure rate of 70–80% ♦♦ In stage I tumors, a large percentage of embryonal carcinoma (>40%), lymphovascular invasion, and presence of

May have focal necrosis, but has squared off nuclei, clear cytoplasm, fibrovascular septa, with lymphocytes, CD30−, CK AE1/3−, SOX2−, c-kit+

Microcystic pattern has edema in spaces, but cysts are lined by cytologic seminoma cells (not flat cells); AFP−, CK AE1/3−, OCT3/4+

Squared off nuclei, usually no tubules, inhibin−, OCT3/4+

Intertubular pattern exists but has square nuclei, fibrovascular septa; possibly granulomas, lacks plasmacytoid chromatin; unilateral; CD20−, CD45−, OCT3/4+

Yolk sac tumor

Sertoli cell tumor

Lymphoma

Seminoma

Embryonal carcinoma

Seminoma

Correct diagnosis→: Findings that rule out: Few lymphocytes or granulomas; form glands or papillae; CD30+, SOX2+, c-kit mostly −

Embryonal carcinoma

Focal microcysts lined by flat cells, hyaline globules, bandlike basement membrane deposits, OCT3/4−

More variable nuclei, focal microcysts lined by flat cells, hyaline globules, bandlike basement membrane deposits; more than just borderline elevation of serum AFP; CK AE1/3+, AFP+, OCT3/4−, GPC3+

Yolk sac tumor

Lymphoma Both may have intertubular growth; lack square nuclei; have plasmacytoid chromatin; no IGCNU; often bilateral; CD20+, CD45+, OCT3/4−

Sertoli cell   tumor Usually forms tubules; can have clear cells but smaller nuclei, inconspicuous nucleoli; no IGCNU; inhibin+/−, OCT3/4−, PLAP−

Table 39.1. Morphologic Differential Diagnosis of Germ Cell Tumors

Testis and Testicular Adnexa 39-11

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Fig.  39.14. Incomplete fixation resulting in pseudohyperchromasia of the central portion of a benign testicular specimen.

Fig. 39.15. Intratubular germ cell neoplasia, unclassified (IGCNU). Neoplastic germ cells show abundant clear cytoplasm and atypical nuclei with prominent nucleoli. There is no spermatogenesis.

Table 39.2. Immunohistochemical Profiles of Testicular Germ Cell Tumorsc Tumor

OCT3/4

CD117 (c-kit)

+

+b

Spermatocytic seminoma

−

Embryonal carcinoma Yolk sac tumor

Seminomac c

Cytokeratin

Vimentin

PLAP

N-Cda

-/+

+

+

−

+b

-/+

-

-

−

+

−

+

-

+

−

−

−

+

+

+

+

Teratoma

−

−

+

+

±

−/+

Choriocarcinoma

−

−

+

-

±

−

c

N-Cd, N-cadherin Only membranous staining is true positivity for c-kit. c-kit is reactive in 40% of spermatocytic seminomas (Kraggerud et al. 1999) c Newer immunostains include D2-40, a membranous stain that strongly stains seminoma but rarely, and weakly stains embryonal carcinoma. AP-2g is a nuclear transcription factor strongly expressed by both seminoma and embryonal carcinoma. Recently, stem cell marker SALL4 has been demonstrated as sensitive and specific for seminoma, embryonal carcinoma, and yolk sac tumor, being particularly useful for metastatic yolk cell tumor (Cao et al. 2009) a

b

choriocarcinoma are features that put the patient at an increased risk of relapse

Intratubular Germ Cell Neoplasia, Unclassified Clinical ♦♦ Intratubular germ cell neoplasia is the precursor for invasive tumor. IGCNU almost always accompanies invasive germ cell tumors, except in testes with spermatocytic seminoma or pediatric tumors. Most patients (>70%) with IGCNU develop an invasive germ cell tumor within 7 years ♦♦ Two 3-mm testicular biopsies will identify the majority of patients with IGCNU. IGCNU is identified in 1% of all testicular biopsies performed for infertility, and in 4–5% of con-

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tralateral testes after diagnosis of germ cell tumor. Treatment is orchiectomy in unilateral cases and bilateral orchiectomy or radiation in bilateral cases

Macroscopic ♦♦ Testis is normal or atrophic

Microscopic (Figs. 39.15 and 39.16) ♦♦ The seminiferous tubules have cells with nuclear enlargement, prominent nucleoli, thick nuclear membranes, and decreased absence of spermatogenesis. IGCNU can involve some tubules while adjacent tubules are nonneoplastic (Fig. 39.16). Cells are confined to basal aspect of tubules ♦♦ When cells distend and fill tubules, this is termed intratubular seminoma (Fig. 39.17)

Testis and Testicular Adnexa

Fig. 39.16. IGCNU. Note patchy involvement.

Fig.  39.17. Intratubular seminoma. Tubules are distended by cell morphologically identical to IGCNU cells.

Histochemistry ♦♦ Cells are glycogen positive. OCT3/4 (OCT4) is a most effective nuclear stain for IGCNU and is negative in nonneoplastic spermatocytes and spermatogonia. IGCNU is also uniformly positive for D2-40, c-kit, and placental alkaline phosphatase (PLAP) in a cytoplasmic and membranous staining pattern. Only rarely normal spermatocytes are PLAP+ and spermatogonia are PLAP−

Cytogenetics ♦♦ DNA content is triploid or hypotetraploid

Seminoma Clinical ♦♦ Seminoma is the most common germ cell tumor, accounting for 50% of all germ cell tumors. It is most common in middle age men (mean age at diagnosis, 40 years) and rare in children and the elderly. Patients present with a painless testicular mass, but up to 15% may have a normal exam

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Fig.  39.18. Seminoma. The tumor cells have clear cytoplasm, well-defined cytoplasmic membranes and polygonal, “boxy” nuclei with one or more prominent nucleoli.

Fig.  39.19. Classic seminoma. Interconnected tumor nests are partially separated by fibrous septa that contain lymphocytes. ♦♦ 30% of patients have metastases at presentation, but only 3% have symptoms related to metastases. The serum a-fetoprotein is normal. In 10% of patients with Stage I seminoma, b-human chorionic gonadotropin is elevated – usually mildly. Increased lymphocytes mean a better prognosis

Macroscopic ♦♦ The tumor is circumscribed, lobular gray-white and fleshy. The cut surface bulges. Hemorrhagic foci may represent syncytiotrophoblasts

Microscopic (Fig. 39.18) ♦♦ Cells have round nuclei, often with squared-off ­contours, with one to several nucleoli and clear to slightly ­eosinophilic cytoplasm. Cell borders are well defined. Architecturally, tumor cells are arranged in solid nests separated by fibrous septa that have a lymphoid infiltrate (Fig. 39.19). There may be vascular invasion. A granulomatous infiltrate is present in 50% of all cases (Fig. 39.20)

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Fig.  39.20. Seminoma. This tumor contains loosely cohesive clusters of epithelioid histiocytes as well as a prominent lymphocytic infiltrate.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 39.22. Fixation artifact in seminoma.

Fig. 39.21. Seminoma with syncytiotrophoblast cells. −− Syncytiotrophoblasts are present in up to 20% of all cases (Fig. 39.21) −− Anaplastic seminoma was defined as seminoma with increased mitotic activity. Behavior is no different than other seminomas, and the use of the term “anaplastic” has been discontinued −− As with benign testis (Fig.  39.11a), uneven fixation of testicular tumor can produce areas resembling ‘something else’ (Fig. 39.22) −− Patterns (a) Sheet-like (Figs.  39.23 and 39.24) with minimal stromal trabeculae (b) Cord-like (Fig. 39.25) (c) Rim of viable tumor cells (Fig. 39.26) or nodules of necrosis and scarring (Fig. 39.27); this is sometimes the result of radiation (d) Microcystic: usually has irregular spaces with edema (Fig. 39.28) (e) Plasmacytoid: has more abundant cytoplasm and atypia

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Fig. 39.23. Solid pattern of seminoma.

Fig. 39.24. Entirely solid pattern of seminoma.

Testis and Testicular Adnexa

Fig. 39.25. Trabecular pattern of seminoma.

Fig. 39.26. In seminoma, tumor cells may show punctate cytoplasmic reactivity for cytokeratin AE1/3 (shown here) or other cytokeratin cocktails. (f) Intertubular: interstitial growth of tumor with preservation of tubules. This pattern can occur at the periphery of the tumor or throughout. Cord-like and tubular growth patterns like Sertoli cell tumor, can predominate in rare cases

Differential Diagnosis ♦♦ Includes sex-cord stromal tumors (clear cytoplasm is lipid not glycogen) −− The solid pattern of embryonal carcinoma: a search will often reveal glands, and it is c-kit negative, CD30 positive, and SOX2 positive −− The solid pattern of yolk sac tumor: flatter cellular profiles would be seen and there are usually other yolk sac tumor patterns −− Metastatic adenocarcinoma (particularly renal cell) −− Orchitis (differential diagnosis is with intertubular pattern of seminoma, which always has some ­lymphocyte infiltrate)

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Fig. 39.27. “Burnt-out” seminoma. An entirely necrotic tumor (proved to be seminoma by preserved immunoreactivity) is surrounded by fibrosis and atrophic parenchyma.

Fig. 39.28. Seminoma with microcystic spaces. −− Lymphoma: often bilateral, negative for germ cell markers, positive for LCA

Histochemistry (See Table 39.2) ♦♦ Cytoplasm contains glycogen. Cell nuclei are positive for OCT3/4, NANOG, or AP-2g. Cytoplasmic membranous staining is observed with c-kit (CD117) and PLAP (Fig. 39.29). The profile of reactivity is identical to IGCNU ♦♦ Seminoma contains cytokeratins, although only 36% of cases are positive. Moreover, this reactivity is almost always confined to <10% of tumor cells and signal is often punctate and perinuclear (Cheville et al. 2000). Some cases are CK7 positive, but all are CK20 negative ♦♦ EMA and CD30 are negative

Spermatocytic Seminoma Clinical ♦♦ Recent research shows that spermatocytic seminoma is quite different from seminoma, with contrasting morphologic, cytogenetic, and clinical features. It occurs only in the testis and represents up to 2% of germ cell tumors. 9% are bilateral. There is a right-side predilection

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Fig.  39.29. Seminoma with strong cytoplasmic reactivity for placental alkaline phosphatase (PLAP).

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  39.31. Embryonal carcinoma. A gland-like structure is formed by cells with markedly pleomorphic nuclei. Nuclei are more crowded and vesicular and nucleoli more prominent than in seminoma; the cytoplasm is granular. and microcysts are present. Nests and pseudoglandular structures are also identified. Mitotic figures and apoptosis may be frequent. Lymphoid and granulomatous infiltrates are scant to absent

Histochemistry ♦♦ Cells are negative for glycogen and for virtually all relevant markers: PLAP, vimentin, muscle marker, cytokeratin, a-fetoprotein, human chorionic gonadotropin, EMA, and CEA. CD117 (c-kit) may be positive

Cytogenetics ♦♦ DNA content is variable, often polyploid Fig.  39.30. Spermatocytic seminoma. Note the polymorphous cell population. Most cells are intermediate cells with stippled (“spireme”) chromatin, but small and giant cells are also seen. Edema separates the tumor nests.

♦♦ Patient average age is in the 50s and they present with a testicular mass. It very rarely metastasizes and therefore is almost always cured by orchiectomy −− Unusual cases may be associated with sarcoma: either rhabdomyosarcoma or undifferentiated sarcoma

Macroscopic ♦♦ The tumors are multinodular and often have a yellow-gray, edematous to gelatinous appearance. Hemorrhage and cysts are common

Microscopic (Fig. 39.30) ♦♦ Nuclei are round, unlike the squared off nuclei in ­seminoma. There is a three cell-type population: small cells, intermediate cells, and large cells with “spireme” filamentous chromatin patterns. Some of these cells may be multinucleate giant cells. Cells are arranged in sheets

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Embryonal Carcinoma Clinical ♦♦ Embyonal carcinoma is a common component of mixed germ cell tumor but considerably less common as a pure tumor. Most men present in their 20–30s with a testicular mass and it is very rare in children and older men. 40% of patients have metastasis at presentation but only 10% of patients have symptoms related to metastases. Serum AFP is normal, and b-hCG is elevated in 60% of cases

Macroscopic ♦♦ Fleshy gray-white tumor, often with prominent necrosis and hemorrhage

Microscopic (Fig. 39.31) ♦♦ Cells of embryonal carcinoma are large with vesicular nuclei, prominent nucleoli, and indistinct cell borders ♦♦ Patterns: Solid (most common), glandular, papillary. A rim of viable cells may surround necrotic areas, particularly after chemotherapy (Fig. 39.32) ♦♦ In mixed germ cell tumors, there may be intimate admixture with a yolk sac tumor. This presents as double-layered cells: ribbons of embryonal carcinoma plus flattened neoplastic cells that are yolk sac tumor (AFP+)

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Fig. 39.32. Embryonal carcinoma with necrosis.

Fig. 39.34. Yolk sac tumor, microcystic pattern. Cells have elongated cytoplasmic processes. The hyaline globules (center right) in a cystic space are characteristic.

Fig. 39.33. CD30 patchy reactivity in embryonal carcinoma.

Fig. 39.35. Yolk sac tumor with endodermal sinus (center) and microcystic patterns.

Immunohistochemistry (See Table 39.2) ♦♦ Tumor cells are CD30 +, a finding unique to embryonal carcinoma among the germ cell tumors. Staining is characteristically patchy, with some cells negative (Fig. 39.33). CD30 is useful in distinguishing the solid pattern of embryonal carcinoma from seminoma. Tumor is also OCT3/4 +, PLAP patchy +, cytokeratin +, CD117/c-kit−, and EMA−

Differential Diagnosis ♦♦ Some patterns of embryonal carcinoma resemble yolk sac tumor, but OCT3/4 and CD30 are negative in the latter

Yolk Sac Tumor (Endodermal Sinus Tumor) Clinical ♦♦ In children, yolk sac tumor is the most common germ cell tumor (and most common testicular tumor), where it occurs in pure form. The majority of cases are diagnosed before 24 months with a mean age of 18 months. In adults, it is unusual

in pure form, but is found in approximately 50% of mixed germ cell tumors ♦♦ Both children and adults have elevated serum AFP. In children, orchiectomy alone results in a cure rate of 90%. Both adults and children present with a testicular mass

Macroscopic ♦♦ Masses are white to tan, with frequent myxoid and cystic change

Microscopic ♦♦ Numerous patterns occur that are rarely single and typically multiple, a significant aid in diagnosis −− Microcystic is the most common (Fig. 39.34) −− Others: endodermal sinus pattern (Fig.  39.35), papillary, solid, glandular, macrocystic (Fig. 39.36), alveolar, myxoid, sarcomatoid, polyvesicular-vitelline, hepatoid, parietal ♦♦ Other characteristics include intracellular hyaline globules; pink extracellular bands of basement membrane material between cells in most cases; and Schiller–Duval bodies

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Fig.  39.36. Yolk sac tumor with macrocystic and microcystic patterns.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 39.37. Teratoma in mixed germ cell tumor. Embryonal carcinoma at left. Nest of keratinizing squamous cells at right is an element of teratoma.

(­ central vessel rimmed by loose connective tissue that in turn is lined by malignant epithelium, all within a cystic space) in endodermal sinus pattern (Fig. 39.35)

Immunohistochemistry (See Table 39.2) ♦♦ AFP + (focal or patchy), cytokeratin+, glypican-3+, PLAP+/−, EMA−, CD 30−, CD99−. Rarely, tumor is positive for liver marker Hep Par1

Differential Diagnosis ♦♦ Solid yolk sac tumor may be confused with seminoma but shows greater pleomorphism, generally lacks lymphocytes, and is OCT3/4 negative and often AFP and glypican-3 positive

Teratoma Clinical ♦♦ In children, teratoma is the second most common germ cell tumor. It occurs in its pure form with a mean age at diagnosis of 13 months. Metastases do not occur ♦♦ In adults, teratoma occurs as a component of a mixed germ cell tumor and is identified in >50% of mixed tumors. It is treated like a nonseminomatous germ cell tumor. Metastases do occur, even in pure teratomas, and these may be either teratoma or other germ cell tumor types. Both adults and children present with a testicular mass

Macroscopic ♦♦ In mixed germ cell tumors, the teratomatous component is often solid and cystic

Microscopic ♦♦ Mature teratoma is composed of somatic-type tissues that can include enteric-type glands, muscle, and squamous epithelium (Fig.  39.37). Respiratory epithelium and cartilage are other possible findings. Atypia may be seen. Immature teratoma contains immature neuroectodermal elements, blastema, or cellular stroma. Prognostic ­significance of immature elements is negligible (unlike with immature teratoma of ovary)

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Fig.  39.38. Overgrowth of embryonic-type neuroectodermal elements (surrounding a remaining tubule) represents a primitive neuroectodermal tumor (PNET). ♦♦ Adult cases are associated with IGCNU. Pediatric cases are not −− Teratoma can give rise to carcinoma, such as adenocarcinoma and squamous cell carcinoma, or sarcoma, such as rhabdomyosarcoma, Wilms-like tumor, or primitive neuroectodermal tumor (PNET). The clinical significance of development of sarcoma or carcinoma is not known (a) Two monodermal forms are carcinoid tumor and PNET: Carcinoid tumors can be associated with other teratomatous elements (15% of cases). They have a good prognosis, with 10–14% developing metastases. Carcinoid syndrome occurs rarely. They usually are not associated with IGCNU (b) The overgrowth of immature neural elements in a teratoma may result in PNET (Fig. 39.38), which may behave aggressively. The PNET usually ­resembles central nervous system PNETs rather than peripheral PNETs

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Dermoid Cyst Clinical ♦♦ Because of benign outcome after orchiectomy, this belongs to a separate category from mature teratoma (Ulbright and Srigley 2001)

Microscopic ♦♦ Dermoid cyst is composed of mature skin with adnexal structures and smooth muscle bundles in the wall (like arrector pili) and hair; may have ciliated epithelium, intestinal mucosa, or bone. Unlike in mature teratoma, they lack atypia or associated IGCNU

Epidermoid Cyst Clinical ♦♦ The outcome is benign after orchiectomy, although they may have loss of heterozygosity on some of the same chromosomes as in malignant germ cell tumors (Younger et  al. 2003)

Fig. 39.39. Choriocarcinoma showing a classic biphasic pattern and associated hemorrhage.

Microscopic ♦♦ Epidermoid cyst has a keratin-filled squamous lining. Like dermoid cyst, there is no cytologic atypia or associated IGCNU. Unlike dermoid cyst, it lacks adnexal structures or heterologous elements

Choriocarcinoma Clinical ♦♦ The pure form is very unusual (<1% of germ cell tumors) but it is a component of 10% of mixed germ cell tumors. Many patients present with symptoms related to metastases to the brain or lungs. The serum b-hCG is elevated, and the cross-reactivity of this with other hormones may lead to gynecomastia and thyrotoxicosis. Patients have a poorer prognosis than with other germ cell tumors, but the tumor is sensitive to chemotherapy. Children do not develop choriocarcinoma

Macroscopic ♦♦ The tumor is hemorrhagic and necrotic

Microscopic (Fig. 39.39) ♦♦ The tumor contains multinucleated syncytiotrophoblastic cells and mononuclear cytotrophoblast or intermediate trophoblast. Both elements need to be present for diagnosis of choriocarcinoma. Often a peripheral rim of cells remains viable and contains the diagnostic cell types

Immunohistochemistry (See Table 39.2) ♦♦ Human chorionic gonadotropin (hCG) is the strongest in syncytiotrophoblast but also stains cytotrophoblast. Also positive are: cytokeratin AE1/3, CEA, inhibin, human placental lactogen, and PLAP

Differential Diagnosis ♦♦ Degenerate cells of embryonal carcinoma mimic choriocarcinoma. Embryonal carcinoma lacks the hemorrhage of choriocarcinoma and the b-hCG reactivity

Fig. 39.40. Mixed germ cell tumor with components of embryonal carcinoma and yolk sac tumor.

Mixed Germ Cell Tumor ♦♦ Comprising 33% of all germ cell tumors, mixed tumors are composed of two or more germ cell tumor types, often seminoma and nonseminomatous components. Embryonal carcinoma with yolk sac tumor is shown (Fig. 39.40). AFP and b-hCG are often elevated

Regressed Tumor ♦♦ Germ cell tumors can regress. Microscopically, replacement of the testis by viable and necrotic fibrovascular tissue can preclude typing of preexisting tumor (Fig. 39.41), although sometimes immunostains of any remnant of necrotic tumor may permit a precise diagnosis (Miller et al. 2009). Scar tissue is nodular or stellate with chronic inflammation, prominent vessels, and ghost outlines of tubules. The differential diagnosis is scar due to trauma or vascular disease ♦♦ IGCNU with a scar is diagnostic of regressed germ cell tumor ♦♦ Nodules of hyperplastic Leydig cells and microliths in tubules may occur peripheral to the scar of a regressed germ cell tumor

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Fig. 39.41. Regressed germ cell tumor in 36-year old. Testis is replaced by fibrovascular tissue (left) and coagulative necrosis (right).

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 39.43. Leydig cell tumor. Cells have eosinophilic cytoplasm and round nuclei with conspicuous central nucleoli. There is prominent microvasculature. Unlike in seminoma, cells are not nested, and there are no lymphocytic infiltrates or granulomas.

Macroscopic ♦♦ Leydig cells impart a yellow to yellow-tan color; tumor is solid and lobulated. Malignant tumors tend to be larger (>5 cm) than benign tumors. Necrosis can be seen in malignant tumors. Bilateral in 3% of cases

Microscopic

Fig.  39.42. Coarse intratubular calcifications correspond to regression of intratubular embryonal carcinoma. ♦♦ Coarse intratubular calcification is evidence of a regressed embryonal carcinoma (Fig. 39.42)

Sex Cord-Stromal Tumors Leydig Cell Tumor Clinical ♦♦ Normal Leydig cells produce testosterone and are located in the interstitium of the testis. Leydig cell tumors comprise 3–5% of testicular neoplasms. They occur both in adults (majority: 80%) and children. Children present with endocrinologic symptoms (virilization, gynecomastia) while adults present with a testicular mass and some (10–30%) have gynecomastia. In children, Leydig cell tumor is benign but in adults, up to 10% are malignant ♦♦ Benign tumors are treated by orchiectomy; malignant tumors need orchiectomy and retroperitoneal lymph node dissection. Tumors do not respond to radiation, thus the differential diagnosis with seminoma is crucial

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♦♦ Neoplastic Leydig cells vary in size but usually have round nuclei, single prominent nucleoli, and abundant eosinophilic cytoplasm (Fig.  39.43) or abundant clear cytoplasm. Edematous or fibrous stroma intervenes. Reinke crystals are present in 40% of cases, and lipochrome can be abundant in some cases ♦♦ Patterns: solid, pseudoglandular, and trabecular ♦♦ Electron microscopy shows mitochondria with tubular cristae. Rarely, adipose differentiation or spindle cell growth is noted ♦♦ Malignant features include large size (>5  cm), increased mitotic activity (>5/10 hpf), necrosis, angiolymphatic invasion, and invasion of surrounding structures, such as tunica, epididymis, and spermatic cord. Malignant behavior is not always predictable from the histology ♦♦ Differential diagnosis includes testicular tumor of adrenogenital syndrome (see below) which is bilateral, dark brown grossly, lacks Reinke crystals, usually has a more prominent fibrous stroma, and is less often immunoreactive with inhibin-a ♦♦ Nelson syndrome. The high ACTH levels produced by a pituitary adenoma released from cortisol suppression after bilateral adrenalectomy can cause steroid cell hyperplasia. This is multifocal rather than forming a single mass, does not efface seminiferous tubules and lacks Reinke crystals

Histochemistry ♦♦ The clear cytoplasm is lipid, not glycogen. Inhibin-a is reactive (Iczkowski et  al. 1998) in most cases. Most cases are positive for MelanA, calretinin, and CD99. Reactivity is

Testis and Testicular Adnexa

variable with cytokeratins, and tumor rarely reacts with S-100 protein, chromogranin, synaptophysin, and estrogen and progesterone receptors

Sertoli Cell Tumor, Typical Type Clinical ♦♦ Sertoli cells are located within seminiferous tubules, and they are necessary for spermatogenesis. Sertoli cell tumors account for <1% of testicular tumors. They occur both in children (15% of cases) and in middle-aged adults, and can be malignant (10% of cases) in both. Malignant cases may be misinterpreted as seminoma (Henley et  al. 2002) owing to solid growth and cytoplasmic clarity. Patients present with a testicular mass, and estrogen production by the tumor can result in gynecomastia and impotence. The treatment is orchiectomy

Macroscopic ♦♦ Tumors are well circumscribed, solid pale yellow, or white to gray masses. Large size and necrosis are worrisome features for malignancy

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Electron Microscopy ♦♦ Charcot–Böttcher filaments (perinuclear aggregates of intermediate filaments) are pathognomonic of Sertoli cells or Sertoli cell differentiation

Differential Diagnosis ♦♦ Distinction from seminoma depends on lower grade nuclei, less frequent mitotic figures, presence of lipid rather than glycogen, OCT3/4 negativity, and often, inhibin-a positivity ♦♦ The androgen insensitivity syndrome, or testicular feminization, causes most patients to be phenotypic females. Proliferations of Sertoli cells occur that are either hamartomas or adenomas (with basement membrane deposits) ♦♦ The cryptorchid (more frequently) and noncryptorchid testis may contain nonneoplastic Sertoli cell nodules that have centralized basement membrane deposits in the tubular lumina, and often have some admixed germ cells (Fig. 39.46). These are typically microscopic rather than macroscopic lesions

Microscopic ♦♦ Tumors are typically composed of solid and hollow tubules containing Sertoli cells (Fig. 39.44). In some cases the cells may be arranged in cords (Fig. 39.45), solid nests, and sheets. The nuclei are polygonal and round to slightly angulated. The cytoplasm varies from clear to pale to eosinophilic ♦♦ Malignant behavior can be difficult to predict. Features worrisome for malignancy are similar to those seen in Leydig cell tumors

Histochemistry ♦♦ Inhibin-a (Iczkowski et al. 1998) is a positive marker, but tumors are less consistently reactive than Leydig cell tumor (47% of cases in combined series). Tumor can be positive for synaptophysin, chromogranin, S-100 protein, CD99, and with cytokeratin AE1/3 and CAM5.2 in 60–100% of cases

Fig.  39.44. Sertoli cell tumor showing both solid and hollow tubules.

Fig. 39.45. Sertoli cell tumor. Tumor cells form closely packed cords. Tumor cell nuclei are small and uniform.

Fig. 39.46. Sertoli cell nodule (tubular adenoma). This nodule is composed of tubules lined by immature Sertoli cells with small, dense nuclei and focal central basement membrane deposits. This is a nonneoplastic lesion.

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Fig. 39.47. Sclerosing Sertoli cell tumor. Tumor cells still have a cordlike arrangement, but the stroma is dense and acellular, unlike typical Sertoli cell tumor.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 39.48. Large cell calcifying Sertoli cell tumor. The tumor forms cords of eosinophilic cells with nearby calcifications.

Immunohistochemistry Sclerosing Sertoli Cell Tumor Clinical ♦♦ Rare variant of Sertoli cell tumor. Patients present with a testicular mass and without endocrinologic symptoms. No malignant cases have been reported

Macroscopic ♦♦ Similar to a typical Sertoli cell tumor

Microscopic ♦♦ Cords, nests, and tubules of Sertoli cells are present within an abundant fibrous stroma (Fig. 39.47)

Large-Cell Calcifying Sertoli Cell Tumor Clinical ♦♦ This is a rare variant of Sertoli cell tumor, with 60 cases reported. Patients are usually young, with mean age of about 25 years. 40% are bilateral. Tumor may be sporadic, or part of the Carney syndrome and, more rarely, in patients with Peutz–Jeghers syndrome. In patients with syndromes, the tumor tends to be multifocal ♦♦ Malignant tumors (17% of cases) occur, and usually are sporadic type (only one malignant tumor has been reported associated with Carney syndrome)

Macroscopic ♦♦ Benign tumors are small (usually <2 cm), tan-yellow, gritty nodules confined to the testicle. Malignant tumors are larger and may have areas of necrosis

Microscopic (Fig. 39.48) ♦♦ Tumor cells are arranged in sheets, small nests, and cords, and have abundant cytoplasm. Stroma characteristically has a neutrophil infiltrate and is myxoid to fibrous. Calcifications, including psammomatous calcifications, are  present. Malignant tumors are large and may show extratesticular spread, increased mitotic activity, necrosis, or angiolymphatic invasion

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♦♦ S-100+, inhibin+, EMA−, and cytokeratins are variable (usually negative to weak staining)

Electron Microscopy ♦♦ Charcot–Böttcher filaments present in some cases

Granulosa Cell Tumor, Adult Type Clinical ♦♦ Testicular granulosa cell tumor is much less common than in the ovary. Average patient age is 42 years and 20% of the men have gynecomastia. Four patients have been reported with metastasis, of whom two died

Macroscopic ♦♦ The mass is lobulated, firm, and uniformly yellow-gray

Microscopic ♦♦ Granulosa cell tumor is microfollicular, trabecular, or solid with a few larger cysts. Call–Exner bodies may be seen. Cells have scant cytoplasm and angular pale nuclei. They may have nuclear grooves

Granulosa Cell Tumor, Juvenile Type Clinical ♦♦ This is a rare sex cord-stromal tumor that is most common in infants under 5 months. It may occur in the setting of gonadal dysgenesis. Infants present with a testicular mass. No malignant cases have been reported. It is debated whether the tumor is of Sertoli cell origin

Macroscopic ♦♦ Tumors are small, solid to cystic, and typically tan-yellow

Microscopic (Fig. 39.49) ♦♦ Lobular arrangements of large follicles lined by stratified polygonal cells, diffuse patterns, and microcystic foci are seen in variable combinations. An intervening fibrous stroma is noted in some cases. Follicles may contain a faintly staining mucicarmine positive secretion

Testis and Testicular Adnexa

Fig. 39.49. Juvenile granulosa cell tumor. Multiple follicles with central, fluid-containing cysts are associated with a spindle cell stroma.

Mixed Germ Cell and Sex Cord-Stromal Tumor Gonadoblastoma Clinical ♦♦ This unique mixture of seminoma-like cells and sex cord cells occur in dysgenetic gonads in patients with intersex syndrome (80% are phenotypically female; 20% phenotypically male). Patients may have ambiguous genitalia. Patient karyotype is most commonly 46XY or 45X/46XY. Gonadoblastoma is premalignant, and can progress to invasive germ cell tumor, usually seminoma. The risk is elevated in the bilateral gonads. Treatment is gonadectomy

Macroscopic ♦♦ Tumors are solid yellow to tan in dysgenetic gonads; in males, testes are cryptorchid, and often contain female components (involution of müllerian structures does not occur)

Microscopic (Fig. 39.50) ♦♦ The tumor is composed of multiple round nests of seminoma-like cells, with admixed sex cord (Sertoli-like) cells. Nests of seminoma-like cells are surrounded by peripheral palisading of small, dark Sertoli-like cells. Irregular deposits of eosinophilic basement membrane material may be present within the nests, similar to those seen in Sertoli cell adenoma and Sertoli cell nodule, which, however, lack the seminoma-like cells

Testicular Hilum: “Tumor” of Adrenogenital Syndrome Clinical ♦♦ Testicular hilum: “tumor” of adrenogenital syndrome (TTAGS) is a benign mass. It occurs in many patients who have adrenogenital syndrome, a salt-losing disorder

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Fig. 39.50. Gonadoblastoma. The predominant cell type is seminoma like with clear cytoplasm. A few small, dark Sertoli-like or sex cord cells are also present. There are deposits of hyaline basement membrane material. (21-hydroxylase deficiency) that is untreated or not sufficiently treated. It is a nodular hyperplasia of steroid cells caused by the highly elevated ACTH levels that occur in this disorder. The “tumor” masses become evident in childhood or adulthood. A key finding is synchronous bilateral testicular involvement ♦♦ Serum ACTH, androstenedione, and 17-hydroxyprogesterone are increased. Tumor responds to administration of corticosteroids to reduce the high ACTH level

Macroscopic ♦♦ Originates in testicular hilum and may extend to parenchyma. Dark brown to green tissue with septa, size up to 10 cm

Microscopic ♦♦ Proliferation of large cells with abundant eosinophilic cytoplasm, resembling Leydig cells. Lipochrome pigment may be prominent. Stroma may be hyalinized. Tumor may originate from steroid cell rests −− Differential diagnostic consideration is Leydig cell tumor. The bilaterality and dark brown color favor TTAGS. Leydig cell tumor may have crystals of Reinke, which are not present in TTAGS. TTAGS has coarse fibrous tissue septa surrounding lesional cell lobules, whereas septa are usually less prominent in Leydig cell tumor

Rete Testis: Adenocarcinoma Clinical ♦♦ Patients are usually elders and have a painful testis. About 25% have hydrocele. Prognosis is poor

Macroscopic ♦♦ The mass is white, tan or yellow

Microscopic ♦♦ Plugs of tumor grow in dilated rete channels and also infiltrate the stroma of the rete testis. Spindled configurations of

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Fig. 39.51. Diffuse large cell lymphoma expands testis, with a cream-colored cut surface. Lymphoma is the most common testicular neoplasm in elderly men. Courtesy of Dr. W. M. Murphy, Leesburg, FL. the tumor cells with slit-like luminal spaces are relatively rare. Adenocarcinoma may be mimicked by metastasis, which should be excluded on clinical grounds or confirmed by specific immunostaining (such as PSA)

Hematopoietic Neoplasms Lymphoma and Plasmacytoma (See Chapter 15) Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  39.52. Capillary hemangioma. The tumor forms slit-like lumina as it grows between tubules.

are often positive and OCT3/4 is negative. The differential diagnosis with anaplastic large cell lymphoma is more difficult because both are CD30 positive. However, the latter will again be negative for OCT3/4, PLAP, cytokeratins, and will not be accompanied by IGCNU

Leukemia (See Chapter 17) Clinical

♦♦ Testicular lymphoma is most often the result of secondary spread; occasionally, primary lymphoma may also occur. Most are of nongerminal center B-cell type. Plasmacytoma also occurs in testes, and is also usually due to secondary spread in a patient with multiple myeloma. Most men are in their 60s – older than for seminoma. Involvement is bilateral in 20% of all cases. Survival is stage-dependent

♦♦ Testes are a sanctuary site for leukemia, and 50% of patients who die with leukemia have leukemia cells in the testis at autopsy. It is often bilateral ♦♦ Testicular biopsies may be positive for leukemia when the patient is in clinical remission. Acute lymphoblastic leukemia is particularly prone to testicular relapse, which predicts a systemic relapse

Macroscopic

Macroscopic

♦♦ Tumor is white to tan and fleshy (Fig. 39.51)

♦♦ Testes may be normal to enlarged, with a mass

Microscopic

Microscopic

♦♦ Tumor frequently has an interstitial growth pattern with sparing of seminiferous tubules. In adults, most lymphomas are diffuse large cell type with a B-cell phenotype. Tumors may have immunoblastic features. In children, small noncleaved lymphoma is most common and follicular lymphoma represents a higher proportion of cases than in adults. Plasmacytomas are composed of plasma cells that vary in their amount of atypia

♦♦ Leukemia has an interstitial growth, like a lymphoma. Morphologic features are dependent on the type of leukemia

Differential Diagnosis ♦♦ The differential diagnosis with seminoma may be difficult on routine sections because lymphoma cells may have clear cytoplasm and prominent nucleoli. Immunostains for LCA

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Vascular Lesions: Capillary Hemangioma Clinical ♦♦ These may be associated with a history of trauma and present as mass lesions (Iczkowski et al. 1998)

Microscopic ♦♦ There are tiny vascular spaces (Fig.  39.52), positive for CD34, factor VIII, and other endothelial markers

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LESIONS OF EPIDIDYMIS AND TUNICS Sperm Granuloma Clinical ♦♦ Sperm granuloma commonly occurs in patients after vasectomy. Patients present with pain and swelling of upper pole of epididymis, or lesion is asymptomatic

Macroscopic ♦♦ Lesion forms a solitary yellow nodule, measuring up to a few centimeters

Microscopic

gioma and angiosarcoma. Tumors may contain signet-ringlike cells, similar to signet ring adenocarcinoma

Immunohistochemistry ♦♦ The cells are mesothelial and strongly react with cytokeratins AE1/3, CK7, CAM5.2, calretinin, and vimentin. Lack of reactivity for vascular markers rules out hemangioma and angiosarcoma. Low miB-1 proliferation index and lack of cytokeratin 20 reactivity rule out gastrointestinal and other primary origins. Notably, tumor cells can be reactive with germ cell marker D2-40, a diagnostic pitfall (Kuroda et al. 2007)

♦♦ Exuberant foreign body giant cell reaction to extravasated sperm. Necrosis occurs in early stages (Fig. 39.53). Fibrotic tissue surrounds granuloma in later stages

Adenomatoid Tumor Clinical ♦♦ A nodule typically involves the epididymis; and may also be identified in tunica albuginea and spermatic cord. These lesions are benign, cured by complete excision. Rare cases have been described in the adrenal. They also occur in the uterus and fallopian tube

Macroscopic ♦♦ A circumscribed white-tan nodule involves epididymis, spermatic cord, or tunica (Fig. 39.54) but may extend into rete testis and testis

Microscopic ♦♦ Nests and tubules of vacuolated epithelioid cells occupy a fibrous or fibromuscular stroma (Fig.  39.55). Epithelioid cells have bland nuclear features. The cells may be flattened and have an endothelial appearance, mimicking heman-

Fig.  39.54. Adenomatoid tumor. This example is larger than most, almost the size of the bisected testis. Note its circumscription and gray-tan color. Courtesy of Dr. W. M. Murphy, Leesburg, FL.

Fig.  39.53. Sperm granuloma of epididymis. Numerous extravasated sperm are being engulfed by macrophages (spermiophages) and foreign body giant cells are present. Courtesy of Dr. W. M. Murphy, Leesburg, FL.

Fig. 39.55. Adenomatoid tumor. The tumor forms tubules and cords of cells with eosinophilic, frequently vacuolated cytoplasm.

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Papillary Cystadenoma Clinical ♦♦ This is a benign lesion cured by excision. von Hippel–Lindau syndrome is associated with it (cerebellar hemangioblastoma, retinal angioma, spinal cord hemangioma, cysts of skin, lung, pancreas, kidney, renal cell carcinoma, pancreatic endocrine tumors, and pheochromocytoma)

Macroscopic ♦♦ Epididymis has a cyst; papillary excrescences arise within a cyst wall

Microscopic

a relationship with asbestos exposure similar to pleural and peritoneal mesothelioma. Patients present with mass, hydrocoele, or hernia sac. Treatment is radical orchiectomy with high resection of spermatic cord. Long-term survival is 50%

Macroscopic ♦♦ Solid and cystic masses line hydrocoele sac; necrosis may be present in larger masses

Microscopic ♦♦ Identical to mesotheliomas at other locations with epithelioid (75% of cases) and biphasic types

Immunohistochemistry

♦♦ Papillae lined by columnar ciliated cells, like efferent ductules. Cytoplasm is clear to vacuolated, with PAS-positive secretions

♦♦ Tumors are positive for calretinin CK5/6, pan-cytokeratin, and other mesothelial markers (but less commonly for thrombomodulin) while negative for CEA

Hydrocele and Well-Differentiated Papillary Mesothelioma

Tumors Homologous to Ovarian Tumors

Clinical ♦♦ Hydrocele is the most common cause of scrotal swelling and can become infected (vaginalitis) or hemorrhagic (hematocele). It represents accumulation of fluid within a dilated tunica vaginalis. Well-differentiated papillary mesothelioma occurs in young men who present with hydocele. If no stromal invasion is present, the lesion is clinically benign, although some cases of invasive mesothelioma have areas identical to well-differentiated papillary mesothelioma

Macroscopic ♦♦ Hydrocele forms thin membranous sac. Papillary mesothelioma has papillary excrescences present within tunica vaginalis which forms hydrocele sac

Microscopic ♦♦ Hydrocele lined by flat mesothelium. Papillary mesothelioma has papillae lined by one or two layers of bland mesothelial cells. Cytoplasm is clear to eosinophilic. Reactivity with calretinin excludes serous borderline tumor (see below)

Malignant Mesothelioma Clinical ♦♦ This is a rare malignant lesion of testicular mesothelium of tunica vaginalis; it rarely involves epididymis or spermatic cord. It may be seen in men with asbestos exposure, suggesting

Clinical ♦♦ Tumors that appear of Mullerian origin or homologous with ovarian epithelial neoplasms occur in paratesticular region. The group includes mucinous and serous cystadenoma, serous borderline tumor, serous and mucinous cystadenocarcinoma, endometrioid carcinoma, and Brenner tumor. They may present as incidental finding at inguinal herniorrhaphy. The most common subtype, serous borderline tumor of the paratestis (McClure et  al. 2001), presents as a testicular mass/hydrocele. No recurrences of serous borderline tumor are reported after resection

Macroscopic ♦♦ Serous borderline tumor ranges from 1 to 6  cm. It usually arises from the visceral layer of the tunica vaginalis covering the tunica albuginea, although occasionally from the parietal tunica vaginalis

Microscopic ♦♦ Paratesticular serous borderline tumor is identical to that of the ovary. It is cystic, with numerous broad, intracystic papillae lined by stratified columnar cells with only minimal atypia. Estrogen and progesterone reactivity, may be seen, consistent with Mullerian origin. The tumor also stains for cytokeratin 7 but not cytokeratin 20 or calretinin. Differential diagnosis includes adenomatoid tumor (positive for calretinin, negative for hormone receptors) and malignant mesothelioma (calretinin positive, higher MIB-1 activity)

LESIONS OF SPERMATIC CORD Nodular Fibrous Periorchitis Clinical ♦♦ This benign fibrous lesion of spermatic cord may also involve the tunica or epididymis. It is also known as inflammatory pseudotumor or fibrous pseudotumor. Patients present with a

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testicular mass mimicking a neoplasm; wide range of patient ages. Patients may also have a hydrocoele

Macroscopic ♦♦ A nodular or diffuse thickening is noted in the tunica, spermatic cord, or epididymis

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Microscopic ♦♦ The appearance (Fig.  39.56) is similar to inflammatory pseudotumors in other sites. There is active inflammation in a stroma ranging from loose to densely collagenized

Vasitis Nodosa (Fig. 39.57) Clinical ♦♦ This is usually observed after vasectomy or vasovasostomy

Macroscopic ♦♦ The blind end of a transected vas deferens contains a nodule

Microscopic ♦♦ This is a proliferative reaction of vas epithelium producing sperm-containing ductules, which communicate with the central lumen of the vas deferens, extend into the muscularis and periadventitial fibroadipose tissue. Associated with chronic inflammation, possibly sperm granuloma (see above) ♦♦ Intramuscular location resembles invasive adenocarcinoma, but the presence of sperm, chronic inflammation, and lack of atypia are key

Fig. 39.56. Nodular fibrous periorchitis. Inset: The mass arises in the dartos smooth muscle bundles; no testis or epididymis is present. Main picture: Fibroblasts have a loose, “tissue culture’ appearance. Some hemosiderin deposits are at the left and hemorrhage is at the right.

Proliferative Funiculitis

Macroscopic

Clinical

♦♦ The spermatic cord is thickened in either a nodular or diffuse manner

♦♦ This benign spermatic cord lesion affects a wide range of patient ages. Mimicking a neoplasm, it presents as a swelling in the inguinal area. The etiology may relate to ischemia or torsion. It may also be an incidental finding at inguinal herniorrhaphy

Microscopic ♦♦ This pseudosarcomatous myofibroblastic proliferation is similar to inflammatory pseudotumor and plasma cell granuloma. There is a fasciitis-like pattern featuring chronic

Fig. 39.57. Vasitis Nodosa. Left: Ductular epithelial infoldings of the vas deferens infiltrate into the smooth muscle wall. Right: Despite this infiltrative appearance, the presence of lymphohistocytic inflammation and extravasated sperm in the ductules support a benign diagnosis.

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inflammation and usually plasma cells in a loose stroma. The lesion is usually positive for smooth muscle actin. The differential diagnosis includes aggressive fibromatosis (desmoid tumor), which is locally invasive, and has long fascicles of uniform spindles in parallel arrays. Also one needs to rule out sarcoma, which metastasizes

Paratesticular Sarcoma Rhabdomyosarcoma Clinical ♦♦ This is the most common sarcoma of the paratesticular region in children, usually occurring before the age of 10 years. Patients present with a large scrotal mass in the tunics, spermatic cord, or epididymis. Effective therapy (radical orchiectomy, radiation and chemotherapy) has resulted in survivals in over 80% of cases

Macroscopic ♦♦ A large gray-white mass forms in the scrotum; site of origin is often impossible to locate

Microscopic ♦♦ Embryonal rhabdomyosarcoma is the most common subtype in the paratesticular region, with a disproportionate number having a spindle cell pattern. Alveolar and pleomorphic rhabdomyosarcoma are less commonly seen

Liposarcoma ♦♦ This is the most common paratesticular sarcoma in adults. It is most often well differentiated (sclerosing), but may show dedifferentiation. In high grade sarcomas, the areas of welldifferentiated liposarcoma should be sought with thorough sampling. Treatment is radical orchiectomy. 23% develop recurrence after surgery; 10% develop metastases (those with dedifferentiation or de novo high grade morphology)

Leiomyosarcoma ♦♦ The majority are low grade lesions but high grade lesions behave aggressively. Tumor occurs in adults, and most often involves testicular tunica or spermatic cord (Fisher et  al. 2001). After radical orchiectomy there is long-term survival in 67%

TNM Classification of Testicular Tumors (2010 Revision) Testis ♦♦ Primary Tumor (T) −− Tx: Unknown status of testis −− T0: No apparent primary (includes scars) −− Tis: Intratubular neoplasia; no invasion −− T1: Tumor confined to testicle, without vascular invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis −− T2: Tumor extending through the tunica albuginea with involvement of tunica vaginalis or the presence of angiolymphatic invasion −− T3: Spermatic cord involvement −− T4: Scrotal involvement ♦♦ Regional Lymph Nodes (N) −− Nx: Nodal status unknown

−− N1: Single lymph node involved, <2 cm −− N2: Single node, 2–5 cm or multiple nodes <5 cm −− N3: Any nodes >5 cm ♦♦ Distant Metastasis (M) −− Mx: Status of metastases unknown −− M0: No distant metastases −− M1: Distant metastases ♦♦ Serum Markers (S) −− SX: marker studies not performed −− S1: LDH 1.5 times “normal” (upper limit of normal for assay) and hCG <5,000 mIm/mL, and AFP <1,000 mg/mL −− S2: LDH 1.5–10 times “normal” or hCG 5,000– 50,000 mIm/mL, or AFP 1,000–10,000 mg/mL −− S3: LDH 10 times “normal” or hCG >50,000 mIm/mL, or AFP >10,000 mg/mL

SUGGESTED READING Nonneoplastic Testis Cendron M, Huff DS, Keating MA, et al. Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent. J Urol 1993;149: 570–573.

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Giwercman A, Muller J, Skakkebaek NE. Cryptorchidism and testicular neoplasia. Horm Res 1988;30: 157–163. Iczkowski KA, Kiviat J, Cheville JC, Bostwick DG. Multifocal capillary microangioma of the testis. J Urol Pathol 1997;7: 113–119.

Testis and Testicular Adnexa

Ishikawa S, Mizushima M, Furuta M, et al. Leydig cell hyperplasia and the maintenance of bone volume: bone histomorphometry and testicular histopathology in 29 male leprosy autopsy cases. Int J Lepr Other Mycobact Dis 2000;68: 258–266. Jarow JP, Budin RE, Dym M, et al. Quantitative pathologic changes in the human testis after vasectomy. a controlled study. N Engl J Med 1985;313: 1252–1256. Kogan J, Tennenbaum S, Gill B, et al. Efficacy of orchiopexy by patient age 1 year for cryptorchidism. J Urol 1990;144: 508–509. McLachlan RI, Rajpert-De Meyts E, Hoei-Hansen CE, de Kretser DM, Skakkebaek NE. Histological evaluation of the human testis--approaches to optimizing the clinical value of the assessment: mini review. Hum Reprod 2007;22: 2–16.

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Jones TD, Ulbright TM, Eble JN, Baldridge LA, Cheng L. OCT3/4 staining in testicular tumors: a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol 2004;28: 935–940. Jones TD, Ulbright TM, Eble JN, Cheng L. OCT3/4: A sensitive and specific biomarker for intratubular germ cell neoplasia of the testis. Clin Cancer Res 2004;10: 8544–8547. Kernek KM, Brunelli M, Ulbright TM, et al. Fluorescence in situ hybridization analysis of chromosome 12p in paraffin-embedded tissue is useful for establishing germ cell origin of metastatic tumors. Mod Pathol 2004;17: 1309–1313. Kernek KM, Ulbright TM, Zhang S, et al. Identical allelic loss in mature teratoma and different histologic components of malignant mixed germ cell tumors of the testis. Am J Pathol 2003;163: 2477–2484.

Meng MV, Cha I, Ljung B-M, Turek PJ. Testicular fine-needle aspiration in infertile men: correlation of cytologic pattern with biopsy histology. Am J Surg Pathol 2001;25: 71–79.

Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. a clinicopathologic analysis of 40 cases and review of the literature. Am J Surg Pathol 1985;9:177–192.

Nistal M, Paniagua R. Non neoplastic diseases of the testis. In: Bostwick DG, Cheng L, eds. Urologic Surgical Pathology. 2nd ed. St. Louis: Mosby; 2008.

Kraggerud SM, Berner A, Bryne M, et al. Spermatocytic seminoma as compared to classical seminoma: an immunohistochemical and DNA flow cytometric study. APMIS 1999; 107: 297–302.

Nistal M, Paniagua R, Diez-Pardo JA. Histologic classification of undescended testes. Hum Pathol 1980;11: 666–673. Resiman EM, Colquitt LA, Childers J, et  al. Brucella orchitis: a rare cause of testicular enlargement. J Urol 1990;143: 821–822

Manivel JC, Jessurun J, Wick MR, et al. Placental alkaline phosphatase immunoreactivity in testicular germ cell tumors. Am J Surg Pathol 1987;11: 21–29.

Shulman A, Shohat B, Gillis D, et  al. Mumps orchitis among soldiers: frequency, effect on sperm quality, and sperm antibodies. Fertil Steril 1992;57: 1344–1346.

Miller JS, Lee TK, Epstein JI, Ulbright TM. The utility of microscopic findings and immunohistochemistry in the classification of necrotic ­testicular tumors: A study of 11 cases Am J Surg Pathol 2009;33: 1293–1298.

Singer AJ, Gavrell GH, Leidich RB, et al. Genitourinary involvement of systemic sarcoidosis confined to the testicle. Urology 1990;35: 422–444.

Moul JW, McCarthy WF, Fernandez EB, et al. Percentage of embryonal carcinoma and vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer. Cancer Res 1994;54: 362–364.

Takihara M, Sakatoku J, Cockett ATK. The pathophysiology of varicocele in male infertility. Fertil Steril 1991;55: 861–868.

Neoplastic Testis Brandli DW, Ulbright TM, Foster RS, et al. Stroma adjacent to metastatic mature teratoma after chemotherapy for testicular germ cell tumor is derived from the same progenitor cells as the teratoma. Cancer Res 2003;63: 6063–6068. Burke AP, Mostofi FK. Intratubular malignant germ cells in testicular biopsies: clinical course and identification by staining for placental alkaline phosphatase. Mod Pathol 1988;1: 475–479. Burke AP, Mostofi FK. Placental alkaline phosphatase immunohistochemistry of intratubular malignant germ cells, and associated germ cell tumors. Hum Pathol 1988;19: 663–670. Cao D, Li J, Guo CC, Allan RW, et al. SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol 2009;33: 1065–1077. Cheng L, Sung M-T, Cossu-Rocca P, et al. OCT3/4: biological functions and clinical applications as a marker of germ cell neoplasia. J Pathol 2007;211: 1–9. Cheville JC, Rao S, Iczkowski KA, et al. Cytokeratin expression in seminoma of the human testis. Am J Clin Pathol 2000; 113: 583–588. Dry SM, Renshaw AA. Extratesticular extension of germ cell tumors preferentially occurs at the hilum. Am J Clin Pathol 1999;111: 534–538. Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumors of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol 2002;26: 541–550. Iczkowski KA, Bostwick DG, Cheville JC. Immunohistochemical profile of Sertoli and Leydig cell testicular tumors. Mod Pathol 1998;11: 774–779. Iczkowski, KA, Butler, SL, Shanks JH, Hossain D, Schall A, Meiers I, Zhou M, Torkko KC, Kim SJ, McLennan GT. Trials of new germ cell immunohistochemical stains in 93 extragonadal and metastatic tumors. Hum Pathol 2007;29: 275–281.

Niehans GA, Manivel JC, Copland GT, et al. Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer 1988;62: 1113–1123. Shanks JH, Iczkowski KA. Non-germ cell tumours of the testis. Curr Diagn Pathol 2002;8: 83–93. Sogani PC, Fair WR. Surveillance alone in the treatment of clinical Stage I nonseminomatous germ cell tumor of the testis. Semin Urol 1988;6: 53–56. Tetu B, Ro JY, Ayala AG. Large cell calcifying Sertoli cell tumor of the testis: a clinicopathologic, immunohistochemical, and ultrastructural study of two cases. Am J Clin Pathol 1991;96: 717–722. Ulbright TM. The most common, clinically significant misdiagnoses in testicular tumor pathology, and how to avoid them. Adv Anat Pathol 2008;15: 18–27. Ulbright TM, Emerson RE. Neoplasms of the testis. Chapter 13. In: Bostwick DG, Cheng L, eds. Urologic Surgical Pathology. 2nd ed. St. Louis: Mosby; 2008. Ulbright TM, Srigley JR. Dermoid cyst: a study of five postpubertal cases including a pilomatrixoma-like variant, with evidence supporting its separate classification from mature testicular teratomas. Am J Surg Pathol 2001;25: 788–793. Ulbright TM, Henley JD, Cummings OW, Foster RS, Cheng L. Cystic trophoblastic tumors: a non-aggressive lesions in post-chemotherapy resections of patients with testicular germ cell tumors. Am J Surg Pathol 2004;28: 1212–1216. Wilkins BS, Williamson JM, O’Brien CJ. Morphological and immunohis­ tochemical study of testicular lymphomas. Histopathology 1989;15:147–156. Young RH. Testicular tumors – some new and a few perennial problems. Arch Pathol Lab Med 2008;132: 548–564. Younger C, Ulbright TM, Zhang S, et al. Molecular evidence supporting the neoplastic nature of some epidermoid cysts of the testis. Arch Pathol Lab Med 2003;127: 858–860. Zuckman MH, Williams G, Levin HS. Mitosis counting in seminoma: an exercise of questionable significance. Hum Pathol 1988;19: 329–335.

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Zukerberg LR, Young RH, Scully RE. Sclerosing Sertoli cell tumor of the testis: a report of 10 cases. Am J Surg Pathol 1991;159: 829–834.

Kuroda N, Toi M, Hiroi M, Lee GH. Diagnostic pitfall of D2-40 in adenomatoid tumour. Histopathology 2007;51:719–721.

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McClure RF, Keeney GL, Sebo TJ, Cheville JC. Serous borderline tumor of the paratestis: a report of seven cases. Am J Surg Pathol 2001;25: 373–378.

Fisher C, Goldblum JR, Epstein JI, Montgomery E. Leiomyosarcoma of the paratesticular region: a clinicopathologic study. Am J Surg Pathol 2001;25: 1143–1149.

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Waisman J. Malakoplakia outside the urinary tract. Arch Pathol Lab Med 2007;131: 1512–1513.

40 The Penis Alcides Chaux, md, Gustavo Ayala, md, and Antonio L. Cubilla, md

Contents

I. Anatomy and Histology.....................40-2

II. Congenital Anomalies........................40-4

Hypospadias......................................................40-4 Epispadias.........................................................40-4 Aphalia..............................................................40-4 Micropenis (Hypoplasia).................................40-4 Other Congenital Malformations...................40-4

Warty (Condylomatous) Carcinoma............40-19 Papillary, Not Otherwise Specified Carcinoma..................................................40-21 Sarcomatoid Carcinoma................................40-21 Pseudoglandular Carcinoma.........................40-22 Pseudohyperplastic Carcinoma....................40-24 Carcinoma Cuniculatum...............................40-24 Adenosquamous Carcinoma.........................40-26 Mixed Carcinomas.........................................40-27

III. Benign Tumors and Tumor-Like Conditions.........................................40-5 VI. Other Malignant Epithelial Condyloma Acuminatum.................................40-5 Tumors.............................................40-28 Giant Condyloma.............................................40-5 Penile Cysts.......................................................40-6 Epidermal Inclusion Cyst......................40-6 Mucinous Cyst........................................40-7 Median Raphe Cyst................................40-7 Other Rare Cysts....................................40-7 Verruciform Xanthoma...................................40-7 Peyronie Disease...............................................40-8 Papillomatosis of Glans Corona......................40-8 Lipogranuloma.................................................40-8 Penile Melanosis–Lentiginosis.........................40-9

IV. Precursor Lesions and Precancerous Conditions.........................................40-9 Squamous Hyperplasia....................................40-9 Penile Intraepithelial Neoplasia....................40-10 Lichen Sclerosus.............................................40-11

Clear Cell Carcinoma....................................40-28 Paget Disease...................................................40-28 Malignant Melanoma.....................................40-29

VII. Nonepithelial Tumors.......................40-29 Benign Mesenchymal Tumors.......................40-29 Granular Cell Tumor...........................40-29 Angiokeratoma.....................................40-29 Epithelioid Hemangioma.....................40-29 Myointimoma........................................40-30 Malignant Mesenchymal Tumors.................40-30 Vascular Tumors...................................40-30 Leiomyosarcoma...................................40-30 Other Primary Sarcomas.....................40-30 Malignant Lymphoma...................................40-30

VIII. Secondary Tumors............................40-30

V. Squamous Cell Carcinoma...............40-13 IX. TNM Staging System (2010 Revision)................................40-31 Squamous Cell Carcinoma, Usual Type.......40-15 Basaloid Carcinoma.......................................40-17 Verrucous Carcinoma....................................40-17

X. Suggested Readings..........................40-32

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_40, © Springer Science+Business Media, LLC 2002, 2006, 2011

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ANATOMY AND HISTOLOGY Gross Features ♦♦ The penis is divided in a distal portion, which includes the glans, the coronal sulcus and the foreskin, and a proximal portion, named the penile shaft. Hidden in the pubic area is the root of the penis. Most of the primary tumors, either benign or malignant, affect the distal penis ♦♦ The glans is the most distal cone-shaped region of the penis formed by corpus spongiosum and covered by a squamous mucosa. The distal (penile) urethra opens up in the meatus urethralis, a ventrally located slit-like orifice in the glans. The glans corona is the wider region of the glans and separates it from the coronal sulcus, which is a cul-de-sac region between the glans and the foreskin ♦♦ The foreskin extends up and covers the glans. It presents an inner (mucosal) surface in direct contact with the glans mucosa and an outer (cutaneous) surface which is in continuity with the skin of the shaft. The line in which the inner and outer surfaces reach each other forms the preputial ring. The frenulum connects the foreskin to the ventral portion of the glans corona ♦♦ Three types of foreskin are described: in the long-type the foreskin completely covers the glans; in the middle-type the preputial ring is located between the meatus urethralis and the glans corona, covering partially the glans; in the short-type the glans remains practically uncovered and the preputial ring is located at the level of the glans corona ♦♦ The penile shaft is covered by skin with an underlying loose connective tissue, the penile (Buck) fascia. The penile erectile tissues are distributed in two dorsal columns of corpora cavernosa and one ventral column of corpus spongiosum. A dense connective tissue, the tunica albuginea, encases both corpora cavernosa. The corpora cavernosa ends up approximately at the level of the glans corona and the corpus spongiosum expands to form the glans

Microscopic Features ♦♦ The glans, coronal sulcus and inner surface of the foreskin are covered by a nonkeratinizing squamous epithelium with

♦♦

♦♦

♦♦

♦♦

an underlying lamina propria (Fig.  40.1A). In the glans, beneath the lamina propria, it is located the corpus spongiosum, a specialized erectile tissue composed of irregular vascular spaces with a fibroelastic intervening stroma (Fig. 40.1B) In the penile shaft, besides the ventrally located corpus spongiosum, the two dorsally located corpora cavernosa extend through its entire length. Corpora cavernosa also correspond to a specialized erectile tissue, similar to corpus spongiosum. However, vascular spaces in corpus cavernosum are more densely packed with less intervening stroma (Fig.  40.1C, bottom). The dense connective tissue of the tunica albuginea separates the corpora cavernosa from the outer penile fascia proximally and from the corpus spongiosum of the glans distally (Fig. 40.1C, top). The distal urethra transverses the corpus spongiosum of the shaft and the glans through its entire length, opening up in the meatus urethralis (Fig. 40.1D) The penile (Buck) fascia corresponds to a loose connective tissue which extends from the penile root to the coronal sulcus. Along this penile fascia important arteries and veins transverse the penile shaft. The shaft is covered by skin, with adnexal structures and pilosebaceous units In the foreskin, beneath the lamina propria there is the dartos, recognized by smooth-muscle bundles. The outer surface of the foreskin is covered by skin with its dermis and epidermis. Since the connective tissues of the lamina propria and the dermis are similar, distinction between the inner and the outer surface is made comparing the morphological features of the covering epithelia The epithelium–stroma interface in the foreskin inner squamous mucosa is more regular and flat and the basal layer is not pigmented (Fig. 40.1E). When compared with the squamous mucosa the epidermis shows more irregular rete ridges and a pigmented basal layer (Fig. 40.1F). Also, adnexal structures, such as sebaceous glands, and Meissner corpuscles are only seen in the outer surface of the foreskin

Fig. 40.1. Histology of the penis. (A) Glans: a 6–7 cells thick layer of nonkeratinized squamous epithelium covers the glans. Underneath, the connective tissue of lamina propria separates the epithelial surface from the corpus spongiosum, a specialized form of erectile tissue. (B) Corpus spongiosum: is recognized by the presence of irregular and wide-spaced vascular channels immersed in a dense fibroelastic stroma. (C) Corpus cavernosum: formed by less irregular and more densely packed vascular spaces with less intervening stroma when compared with corpus spongiosum. At the top of the image it is noted the dense

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Fig. 40.1. (continued) connective tissue of the tunica albuginea. (D) Transverse section through the corpus spongiosum of the shaft showing the irregular lumen of the penile urethra lined by a stratified cylindrical epithelium. Beneath, a lamina propria surrounds the urethral epithelium. Some of the vascular spaces of the corpus spongiosum are also noted. (E) The foreskin inner mucosa is formed by a nonkeratinized squamous epithelium similar to that covering the glans and the coronal sulcus. Note the almost flat epithelial base and the absence of pigmented keratinocytes. (F) The foreskin outer surface is covered by a slightly keratinized squamous epithelium. Note the irregular rete ridges of the basal epithelium and the easily recognized pigmentation of the basal cells.

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CONGENITAL ANOMALIES Hypospadias

Aphalia

♦♦ Hypospadias is the most common congenital anomaly of the male external genitalia with an incidence of 3–5/1,000 male births. It is characterized by an incomplete fusion of the urethral folds with abnormal opening of the urethra along the ventral aspect of the penis ♦♦ Most of the time the urethral opening takes place near glans, along the shaft or near the penile base in the form of slits of variable length. Extension to the scrotal raphe is exceptional. In rare cases the urethral folds fusion completely fails and the distal urethra remains open through its entire length, from the scrotal raphe to the meatus urethralis ♦♦ Other anomalies found associated with hypospadias include absence of the foreskin, cryptorchidism, inguinal hernias and chordee. The term chordee makes reference to a bending of the penis, congenital in hypospadias, and caused by a distal misdevelopment of the penile fascia. Strictures could develop as a consequence of hypospadias with the consequent impaired ejaculation and secondary infertility

♦♦ Aphalia, also named penile agenesis, is a rare condition detected in 1/10,000,000 male births and caused by a failure in the embryologic development of the genital tubercle ♦♦ Scrotal sacs are present but no penile shaft is observed. Aphalia tends to be associated with other malformations of the urogenital tract, such as cryptorchidism, imperforate anus, renal agenesis and other renal malformations, and with musculoskeletal and cardiopulmonary defects

Epispadias ♦♦ Epispadias is a very rare abnormality with an incidence of 1/30,000 male births. It is characterized by the opening of the penile urethra at the dorsal aspect of the penis, caused by a misplaced development of the genital tubercle which forms in the region of the urorectal septum instead of the cranial margin of the cloacal membrane ♦♦ As a consequence of this displacement a portion of the cloacal membrane is located cranially to the genital tubercle; when this membrane ruptures the urogenital sinus outlet extends through the dorsal surface of the penis. Most of the cases of epispadias are associated with bladder exstrophy in which the lower portion of the abdominal wall fails to close around the cloacal membrane with the subsequent exposure of the bladder mucosa to the outside ♦♦ Other associated abnormalities include cryptorchidism, renal agenesis and ectopic kidney. Urethral opening may be constricted, and the location may impair normal ejaculation and subsequent insemination, resulting in infertility

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Micropenis (Hypoplasia) ♦♦ Hypoplasia of the penis implies the presence of a small penis with a size of two or more standard deviations bellow the mean adjusted by age. The length of the penis should be measured along the dorsal surface of the shaft from the pubis to the tip of the glans and with the penis stretched to resistance. In these cases, the ratio of the penile shaft length to its circumference is normal ♦♦ Penile hypoplasia is usually associated with endocrine abnormalities causing insufficient androgen stimulation for growth of the external genitalia. Primary hypogonadism explains most of the cases; hypothalamic and pituitary dysfunction the remainder. In some cases no endocrine abnormality is detected and the cause remains unknown

Other Congenital Malformations ♦♦ In webbed penis, a very common anomaly, the penis is normal but the skin of the scrotal sacs extends to the penile ventral surface and hides it. Concealed penis makes reference to the presence of an otherwise normally developed penis but hidden under the adipose tissue of the suprapubic area, scrotum, perineum, or thigh. The asymmetric development of one corpus cavernosum, either hypoplasia or hypertrophy, can cause a congenital lateral curvature of the penis. Areas of fibrosis affecting the erectile tissues can produce torsions of the penile shaft ♦♦ The presence of a double penis (diphallus) is consequence of the division of the genital tubercle in two, with the subsequent penile duplication and it is associated with other congenital anomalies, including hypospadias, renal agenesis, imperforate anus, cardiac defects, and others

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BENIGN TUMORS AND TUMOR-LIKE CONDITIONS Condyloma Acuminatum General Features ♦♦ Condyloma acuminatum is a human papillomavirus (HPV) related lesion affecting the anogenital area of sexually active young and middle-age males. Most commonly it is caused by serotypes 6 and 11 although others can also be involved

verrucous carcinomas. Most of the cases are associated with HPV infection by low risk serotypes, with a predominance of HPV-6 ♦♦ Affected males are older than those with condyloma acuminatum but younger than those with warty carcinomas

Macroscopic

♦♦ The most common anatomical site affected is the glans; the foreskin, the meatus urethralis or the distal urethra are other frequently involved sites. The lesion usually is multicentric and clinically depicts a typical cauliflower-like papillary appearance. The size is variable, ranging from unapparent millimetric lesions to tumors larger enough to cause clinical concern about their nature

♦♦ The lesion preferentially affects the foreskin and coronal sulcus, with secondary glans involvement in some cases, and it is larger than the condyloma acuminatum, with an average size of 5–10 cm ♦♦ Giant condyloma is clinically similar to condyloma acuminatum although the gross aspect is more exophytic and verruciform and the tumoral base presents a pushing and burrowing pattern of growth

Microscopic

Microscopic

♦♦ The histological picture is characteristic with variable degrees of papillomatosis, acanthosis, parakeratosis and hyperkeratosis, and prominent fibrovascular cores (Fig. 40.2A). The hallmark of the lesion is the koilocyte, a superficially located and conspicuous polygonal cell with wrinkled nuclei, clear perinuclear halos and frequent binucleation (Fig. 40.2B). The interface between the lesion and the stroma is always sharp and well defined

♦♦ The histological picture is also similar to condyloma acuminatum but the papillomatosis is more exuberant and the endophytic expansion of the papillae into the subjacent tissue is clearly evident (Fig. 40.3A, B) ♦♦ “Atypical giant condyloma” is the denomination given to a giant condyloma with more cytological atypias than those expected for this lesion but not fulfilling the morphological criteria of warty carcinomas (Fig. 40.3C, D)

Macroscopic

Giant Condyloma General Features ♦♦ Also known as “Buschke–Löwenstein tumor” giant condyloma is a very rare and benign HPV-related verruciform tumor, which can sometimes be confused with warty or

Differential Diagnosis ♦♦ The differential diagnoses include mainly warty carcinomas and other verruciform tumors, such as verrucous and papillary carcinomas (Table 40.1). Warty carcinomas are characterized by more or less prominent cytological atypia and a jagged and infiltrative tumoral base, both features absent in

Fig.  40.2. Condyloma acuminatum. (A) Papillomatosis, acanthosis, and slight parakeratosis are typical features of condyloma acuminatum. Koilocytes are recognized at the surface of the papillae. Note the broad and flat interface between tumor and stroma. (B) Koilocytes are easily found at the tip of the papillae. The presence of fibrovascular cores is a constant feature. There is no cytological atypia.

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Fig. 40.3. Giant condyloma. (A) In giant condyloma the morphological features are similar to condyloma acuminatum but papillomatosis is more prominent and complex and there is a bulbous pushing extension into underlying tissues. (B) No cytological atypias are recognized and the tumor-stroma interface is broad. A chronic stromal reaction is seen. (C, D) The presence of epithelial atypia located at the base of the papillae in an otherwise usual giant condyloma defines the lesion as an “atypical condyloma.” giant condyloma. In verrucous carcinoma the fibrovascular cores are unapparent and in papillary carcinomas the tumoral base is jagged and irregular; neither of these two aforementioned variants exhibit koilocytic changes ♦♦ In some cases foci of malignant transformation could appear in an otherwise benign giant condyloma. In most of these circumstances the malignant component exhibit the aspect of a squamous cell carcinoma of the usual type and, more rarely, of the warty or basaloid type ♦♦ HPV detection and serotypificaion could help in problematic cases for distinguishing a giant condyloma from a warty carcinoma, as well as immunohistochemical surrogates, such as p16INK4a expression, the later negative in condylomas

Penile Cysts General Features ♦♦ Penile cysts are widely distributed and can affect practically any anatomical location. Clinically their aspect is very

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s­ imilar with the presence of a slowly growing painless mass. The most common type of penile cyst is the epidermal inclusion cyst

Epidermal Inclusion Cyst ♦♦ They are similar to those occurring elsewhere. The etiology is unknown but in some cases they are associated with hypospadias, phimosis, or penile-enlargement surgical procedures. Usually they are found in young boys and elderly men ♦♦ They are preferentially located at the coronal sulcus, near the frenulum, the foreskin and, less frequently, the shaft. Most of them do not exceed 1.0 cm in maximum diameter ♦♦ Histologically, epidermal inclusion cysts are lined by a nonatypical keratinized squamous epithelium surrounding the cyst cavity. Keratin debris fills up the cyst cavity. Keratinization pattern is orthokeratotic with the presence of a more or less evident granular layer. Skin adnexa are absent

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Table 40.1. Differential Diagnosis in Penile Verruciform Carcinomas Giant condyloma

Feature

Verrucous carcinoma

Warty carcinoma

Papillary, NOS Carcinoma carcinoma cuniculatum

Papillae

Arborizing, condylomatous, non undulating, rounded

Long and undulating, condylomatous, complex

Straight

Variably complex

Straight

Fibrovascular cores

Prominent

Prominent

Rare

Variably present

Rare

Tumoral base

Regular, broad and pushing

Rounded or irregular and jagged

Regular, broad and pushing

Irregular and jagged

Regular, broad and pushing

Histological grade

1–2

1–2

1

1–2

1–2

Koilocytosis

Present at surface, rarely diffuse but not pleomorphic

Prominent and diffuse, pleomorphic

Absent

Absent

Absent

Growth pattern

Exophytic

Predominantly exophytic with a variable endophytic component

Exophytic

Predominantly exophytic with an endophytic component

Exoendophytic

Nodal metastases

No

Yes

No

Yes

No

HPV-related

Yes

Yes

No

No

No

Mucinous Cyst ♦♦ These cysts arise from ectopic urethral mucosa and are lined by a columnar stratified epithelium with mucinous cells. Preferentially located at the glans or foreskin, they have been described as paraurethral or perimeatal cysts

Median Raphe Cyst ♦♦ Median raphe cysts are caused by a developmental failure in the closure of the urethral folds and, hence, are always located at the ventral midline of the penis, from near the meatus urethralis to the scrotal median raphe. They usually do not communicate with the urethra. When located near the meatus urethralis they are referred as “parameatal cysts ” ♦♦ Clinically median raphe cysts manifest as uni or multilocular painless lesions, although in occasions they can be associated with local discomfort, dysuria or even dyspareunia. Sometimes they are traumatized and manifest as painful nodules or ulcerated areas ♦♦ Histologically the epithelial lining is variegated and can be urothelial-like, nonkeratinized squamous, pseudostratified columnar, mucinous, or apocrine-like. No epithelial atypias should be present

Other Rare Cysts ♦♦ Dermoid cysts have been occasionally reported at the penis and their aspect is identical to that observed elsewhere in the body. The clinical aspect is similar to other penile cysts. Histologically, the cyst is lining by a stratified squamous epithelium with adnexal structures such as sebaceous glands and hair follicles

♦♦ Lymphatic cysts can also be observed at the penis but they are exceedingly rare. The histological picture is identical to similar cysts elsewhere

Verruciform Xanthoma General Features ♦♦ Verruciform xanthomas are rare verrucoid penile lesions similar to their oral counterparts. They are the consequence of inflammatory conditions which produce epithelial damage and lipid release into the lamina propria; these lipids are then engulfed by cells of the immune system ♦♦ Several studies have failed in identifying a causal relationship between verruciform xanthoma and HPV infection

Macroscopic ♦♦ The aspect is very similar to a verruciform penile tumor, with which it can be confused, especially with warty and verrucous carcinomas

Microscopic ♦♦ The verrucoid lesion is composed of a papillary squamous hyperplasia with papillomatosis, acanthosis, hyperkeratosis, and parakeratosis. Beneath the hyperplasic epithelium there is a characteristic dermal infiltrate composed mainly of lipid-laden histiocytes (“foamy cells”) filling up most of the dermal papillae. Neutrophiles are detected in some cases

Differential Diagnosis ♦♦ The main differential diagnosis is with verruciform penile carcinomas. The presence of epithelial atypias and the

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absence of the characteristic foamy cells infiltrate are indicative of a neoplastic process

Peyronie Disease General Features ♦♦ Peyronie disease is a variant of superficial fibromatosis, which affects primarily the tunica albuginea and secondarily extends to the corpora cavernosa. It is very frequent, affecting 1–4% of the males ♦♦ The etiology is unknown, although it has been reported in association with coital trauma, urethral instrumentation, usage of beta-blockers, autoimmune disease, and carcinoid syndrome ♦♦ It has been established that an alteration and reduction in the elastic fibers content of the tunica albuginea is the main pathogenic event; this process secondarily induces similar changes in the erectile tissues of the corpora cavernosa ♦♦ The disease has a progression phase usually of months of duration and then stabilizes. A minority of the cases present spontaneous regression

Clinical ♦♦ Most of the patients are in their fifties. The disease is rare before 20-year-old. Clinically, a penile curvature, more evident during erection, is observed. In some cases, painful erection and dyspareunia are referred ♦♦ The palpation of the shaft discloses the presence of multiples areas of induration, most common over the dorsal aspect of the penis

Essentials of Anatomic Pathology, 3rd Ed.

Papillomatosis of Glans Corona General Features ♦♦ This is a very common condition present in about onequartet of sexually active males and characterized by the presence of multiple small papules preferentially located at the level of the glans corona. Also named “penile papules” and “hirsutoid papilloma,” it has been linked to an excessive sexual activity

Macroscopic ♦♦ This condition has a preference for the dorsal aspect of the glans corona where it presents as multiple painless small papules orderly distributed in two or three columns. The papules are homogeneous in size and shape with a pearly gray surface. In some cases they can extend to cover most of the glans. Similar lesions have been rarely observed in the foreskin

Microscopic ♦♦ Histologically the papillae are covered by a nonatypical hyperplasic epithelium over a loose lamina propria. The picture is similar to that offered by an angiofibroma, although the lesion is not neoplastic

Differential Diagnosis

Macroscopic

♦♦ Clinically this condition can be confused with condylomas, although the macroscopic features are very characteristic. The anatomical location and the regularity of the papules are very suggestive of hirsutoid papillomas. The differential diagnosis on histological grounds is straight­ forward

♦♦ The main alterations are observed at the level of the tunica albuginea in the form of a dense and irregular thickening of this anatomical structure and the presence of several fibrotic nodules in the dermis and penile fascia

Lipogranuloma General Features

Microscopic ♦♦ The hallmark of the disease is the presence of extensive foci of sclerosis centered in the tunica albuginea and extending to the corpora cavernosa in most of the cases. In the sclerotic areas spindle cells, corresponding mainly to fibroblasts and myofibroblasts, are recognized ♦♦ Other histological findings include perivascular lymphocytic infiltrates, alterations in the erectile vasculature and calcification/ossification in some cases

Differential Diagnosis ♦♦ Peyronie disease should be distinguished from penile sarcomas and penile metastases. The clinical picture and imaging findings can be similar in these cases ♦♦ Ultrasound-guided fine needle aspiration can render a more accurate diagnosis in difficult cases. The previous or concurrent history of malignancy is present in most of the patients with penile metastases ♦♦ The self-injection of pharmacological substances such as papaverine hydrochloride and phentolamine mesylate can produce secondary fibrosis of the tunica albuginea clinically similar to Peyronie disease. Proper anamnesis is essential in these cases

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♦♦ Penile lipogranuloma makes reference to an inflammatory reaction secondary to the local injection of foreign lipidic substances into the penis, such as Vaseline, paraffin, silicone, or wax ♦♦ Most of the time the lesion affects exclusively the penis, although in some cases there is extension to adjacent sites, especially the scrotum

Macroscopic ♦♦ Beyond the more or less distorted aspect of the organ, sometimes suggesting a neoplasia, no specific gross abnormalities are characteristic of this condition. Areas simulating cysts can occasionally be observed

Microscopic ♦♦ Penile lipogranuloma is characterized by the presence of a more or less sclerotic stroma with a prominent inflammatory infiltrate and abundant foreign body-type multinucleated giant cells. Sclerosis can sometimes be very prominent and so the designation of “sclerosing lipogranuloma” is appropriate in these cases ♦♦ The inflammatory cells surround vacuoles and cyst-like spaces of variable size which correspond to the areas of lipidic injection

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Differential Diagnosis

Macroscopic

♦♦ The histological picture can be roughly similar to an adenomatoid tumor or a lymphangioma. However, vacuoles in adenomatoid tumor are more homogeneous in size and shape and do not content lipids. The vacuole-like spaces of lymphangioma are lined by endothelium while the cyst-like areas of lipogranuloma there is no epithelial lining ♦♦ Sclerosing liposarcoma should also be ruled out. The presence of foreign body-type giant cells, the more prominent inflammatory infiltrate and the absence of lipoblasts is indicative of a penile lipogranuloma

♦♦ Penile melanosis usually manifests as a large, single, pigmented macula with irregular borders while penile lentiginosis is characterized by the presence of multiple hyperpigmented small- to medium-size lesions with uniform or variegated pigmentation

Microscopic ♦♦ The histological picture is similar in both entities. Melanocytic hyperplasia with more or less prominent hyperpigmentation of basal layers in an otherwise normal epidermis is the typical finding. Stromal melanophages can occasionally be seen, especially in penile lentiginosis

Penile Melanosis–Lentiginosis General Features

Differential Diagnosis

♦♦ Penile melanosis and penile lentiginosis are nonneoplastic hyperpigmented lesions that can clinically be confused with benign and malignant melanocytic proliferations. They are usually found in the glans, the shaft or in both

♦♦ These hyperpigmented lesions should be distinguished from acral malignant melanoma. The diagnosis is made by histological examination of the lesion. The presence of atypia indicates a malignant proliferation

PRECURSOR LESIONS AND PRECANCEROUS CONDITIONS Squamous Hyperplasia General Features ♦♦ Squamous hyperplasia is defined as any nonatypical thickening of the epithelia covering the glans, coronal sulcus or foreskin. Although it is more a reaction pattern than a specific entity its frequent association with areas of penile intraepithelial neoplasia (PeIN) and penile carcinoma suggests a precancerous role ♦♦ Squamous hyperplasia is especially associated with low grade variants of squamous cell carcinomas (SCC) such as usual, papillary and verrucous carcinomas, and rarely with HPV-related tumors (basaloid and warty carcinomas). Its association with areas of PeIN of the differentiated type is also common and it can coexist with several penile dermatoses

Clinical ♦♦ Squamous hyperplasia is usually found in continuity with an in situ or invasive penile SCC, although it can also be identified adjacent or even distant from the primary lesion. The clinical picture is very similar to that presented by PeIN

Macroscopic ♦♦ The typical aspect is that of whitish areas with irregular borders. Sometimes a slightly raised and pearly appearance is observed

Microscopic ♦♦ Squamous hyperplasia is characterized by acanthosis and hyperkeratosis with normal epithelial maturation and no cytological atypias (Fig.  40.4A). Parakeratosis is usually absent and koilocytic changes are not seen. Is not unusual the concomitant presence of lichen sclerosus

♦♦ Four patterns of growth can be identified: (a) Flat: the interface between the epithelium and the stroma is linear; this is the most common subtype. (b) Papillary: the interface between epithelium and stroma is jagged and irregular and low hyperkeratotic papillae are evident. (c) Pseudoepitheliomatous: very unusual pattern characterized by a downward proliferation of epithelial rete ridges that appear detached from the overlying acanthotic epithelium; the epithelial nests are regular and peripheral palisading is observed, with no evident stromal reaction. (d) Verrucous o verrucoid: prominent acanthosis with hyperkeratosis, hypergranulosis and slight papillomatosis; it is commonly found adjacent to verrucous carcinomas. In up one-quarter of the cases mixed patterns are observed

Differential Diagnosis ♦♦ Squamous hyperplasia should be distinguished from differentiated PeIN and from low grade keratinizing SCC variants. The presence of cytological atypia, even minimal, and altered epithelial maturation should prompt the diagnosis of PeIN; parakeratosis, a rare finding in squamous hyperplasia, is usually easily found in these cases. Positivity for p53 and Ki-67 above the basal layer is indicative of a intraepithelial squamous neoplasia ♦♦ Pseudohyperplastic SCC can be confused with squamous hyperplasia, especially with the pseudoepitheliomatous pattern. However, epithelial nests in pseudohyperplastic SCC are more irregular, peripheral palisading is not evident, there is usually a marked stroma reaction and, although minimal, there is cytological atypia ♦♦ Distinguishing verrucous carcinoma from verrucoid squamous hyperplasia can sometimes be difficult, especially in small biopsies. The presence of cytological atypia and

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Fig. 40.4. Precursor lesions. (A) Squamous hyperplasia: there is marked epithelial thickening with acanthosis and hyperkeratosis but with preserved maturation and no cytological atypias. (B) Differentiated PeIN: there is acanthosis and parakeratosis with easily recognized atypical epithelial cells. Although distorted there is a tendency for epithelial maturation with basaloid cells in the lower one-half and polygonal squamoid cells in the upper one-half of the epithelium. Cytoplasm retains the typical eosinophilia of keratinized cells. (C) Differentiated PeIN: similar changes but there are marked epithelial atypia. (D) Basaloid PeIN: a small- to intermediate-size monotonous population of basaloid cells replaces the entire thickness of the epithelium. There is no tendency for epithelial maturation and the cytoplasm is more basophilic when compared with atypical cells of differentiated PeIN. Note the flat surface with parakeratosis.

stromal reaction are indicative of a neoplastic process. Grossly, verrucous carcinomas are more prominent, larger and exophytic than areas of squamous hyperplasia. The clinical aspect of the lesion can aid in problematic cases ♦♦ Other verruciform tumors, such as papillary and warty SCC, can also sometimes enter in the differential diagnosis. Evident papillomatosis, prominent fibrovascular cores, and koilocytosis are indicative of a warty carcinoma. In papillary SCC, which can be confused with papillary squamous hyperplasia, the papillae are longer and the fibrovascular cores are more prominent. In both verruciform SCC cytological atypias are recognized

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Penile Intraepithelial Neoplasia General Features ♦♦ The term “penile intraepithelial neoplasia” (PeIN) refers to the presence of any degree of cytological atypia and altered epithelial maturation in the squamous epithelium lining the glans, coronal sulcus, or foreskin. The cytological alterations can be subtle or can occupy most or the entire epithelial thickness. In all cases, no evidence of extension beyond the basal lamina is observed ♦♦ The terminology regarding PeIN grading and subtyping is confusing. It can be classified into PeIN I, II, or III or into low and high grade PeIN

The Penis

♦♦ PeIN is classified into differentiated (“simplex”), warty, basaloid, and warty-basaloid types. The histological picture, anatomical location, and associated carcinomas are different in one subtype and in the other ♦♦ The terms “erythroplasia of Queyrat” and “Bowen disease,” both indicating a basaloid PeIN, the first in the glans and the latter in the penile shaft, add confusion to the terminology and should be avoided ♦♦ Foci of PeIN are frequently found in association with penile carcinomas, either merging with the invasive component or adjacent to it. However, PeIN can also be detected as a single lesion during clinical examination for other conditions or during peniscopy

Clinical ♦♦ When not associated with an invasive penile carcinoma differentiated PeIN tends to be localized in the foreskin of males older than those with PeIN showing warty and/or basaloid features. The lesion can be clinically evident or become noted after peniscopy. The clinical aspect is very similar to squamous hyperplasia ♦♦ The preferred anatomical location of PeIN with warty and/or basaloid features is the glans, although it can affect any anatomical compartment. As single lesions, these types of PeINs are more frequently observed than differentiated PeIN, although when an invasive component is present the latter is more prevalent. Affected patients are younger than those presenting differentiated PeIN

Macroscopic ♦♦ Differentiated PeIN presents as a single whitish macula, plaque, or slightly raised geographical lesion. When associated with a penile carcinoma it is usually found at the periphery of the tumor or in adjacent areas ♦♦ The gross picture of PeIN with warty and/or basaloid features presenting as a single lesion is more variegated, with whitish, brownish or erythematous maculae, plaques or papules with a granular or velvety surface. Its presence in invasive carcinomas is difficult to establish

Microscopic ♦♦ Differentiated PeIN is characterized by hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, and elongated rete ridges associated with altered epithelial maturation and more or less extended epithelial atypia (Fig. 40.4B). Nuclear pleomorphism, coarse chromatin and evident nucleolus are cytological features usually found in the epithelial cells. The atypical changes can be limited to the lower one-third of the epithelium or extend through most or all of it (Fig. 40.4C). Differentiated PeIN is also frequently found in association with lichen sclerosus ♦♦ In basaloid PeIN the epithelium is replaced by a monotonous proliferation of blue cells of small to intermediate size with scant basophilic cytoplasm (Fig.  40.4D). Apoptosis and a high mitotic rate are common findings. Parakeratosis and isolated koilocytes are seen in some cases. A papillary pattern of growth is unusual and in most of the cases the surface is flat ♦♦ In warty PeIN the surface shows a characteristic spiky aspect, with conspicuous koilocytosis and atypical parakeratosis.

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Cellular pleomorphism is more evident than in basaloid PeIN ♦♦ In some cases a mixed warty-basaloid PeIN is observed. Both components can be found in different adjacent areas of the same lesion or can be form a superimposed pattern in which the upper third of the epithelium shows warty features while in the lower half the basaloid component predominates. A mixed differentiated, warty and/or basaloid PeIN is also occasionally observed ♦♦ Differentiated PeIN tend to be associated with non-HPVrelated keratinizing variants of penile carcinoma such as usual, papillary and verrucous SCC, while PeIN with warty and/or basaloid features is mostly found with HPV-related tumors such as warty and basaloid carcinomas. When the PeIN pattern is mixed the invasive component habitually shows mixed features

Differential Diagnosis ♦♦ Differentiated PeIN should be distinguished from squamous hyperplasia. The presence of epithelial maturation and absence of cytological atypia are indicative of a hyperplasic process. Parakeratosis is a constant feature of differentiated PeIN and very rare or inconspicuous in squamous hyperplasia. Immunohistochemistry for p53 and Ki-67 can aid also in the differential diagnosis ♦♦ Basaloid PeIN should be distinguished from urothelial carcinoma in situ of the distal urethra. Immunohistochemical urothelial markers, such as ­uroplakin-III, thrombomodulin, and cytokeratins 7 and 20, are helpful in difficult cases. Over expression of p16INK4a are characteristic of basaloid PeIN and absent in urothelial carcinomas ♦♦ Warty PeIN can be confused with condyloma acuminatum. The presence of cytological atypias and the identification of high risk HPV (16 and 18) are indicative of PeIN. Over expression of p16INK4a, consistently absent in condylomata, can also be helpful

Lichen Sclerosus General Features ♦♦ Also known as “balanitis xerotica obliterans” lichen sclerosus is a chronic inflammatory and sclerotic condition affecting mainly the penis and vulva. Its frequent association with differentiated PeIN and with special variants of SCC, especially those HPV-unrelated, strongly suggests a precancerous role ♦♦ The etiology is known but several conditions, such as autoimmune diseases and immunologic disregulations, are associated with this disease. HLA haplotypes, especially DQ7 but also DR7, DQ8, DQ9, and DR4, are frequently present in patients with lichen sclerosus

Clinical ♦♦ Lichen sclerosus has a predilection for the foreskin and the glans and is frequently found in cases of phimosis

Macroscopic ♦♦ The typical aspect is that of irregular whitish atrophic areas located in the foreskin or in the perimeatal area of the glans. The presence of at least some degree of phimosis is not

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uncommon. In more advances cases, the extensive sclerosis produces a marked narrowing of the preputial ring. Concurrent areas of squamous hyperplasia, differentiated PeIN, or even invasive SCC can be found ♦♦ Lichen sclerosus is frequently multicentric, may affect multiple anatomical compartments and even extend into the mucosa of the distal urethra

Microscopic ♦♦ Lichen sclerosus is characterized by epithelial atrophy, vacuolar degeneration of the basal layer and dense hyalinization of the subepithelial tissues (Fig. 40.5A, B). A band-like lymphocytic infiltrate is commonly seen. Edema of the lamina propria is observed in some cases. Preputial dartos and glans corpus spongiosum remain unaffected by the inflammatory process

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The atrophic areas can be intermingled with foci of squamous hyperplasia or differentiated PeIN. In the last case, the term “atypical lichen sclerosus” is appropriate (Fig.  40.5C, D). The presence of atypical changes is more prevalent when lichen sclerosus is found in the adjacent areas of an invasive SCC

Differential Diagnosis ♦♦ Sometimes the areas of hyalinization are scant or the edematous changes are prominent, making difficult the recognition of the lesion. A band-like infiltrate can also be observed in some unrelated penile dermatoses. Finally, care should be taken in order to recognize subtle forms of differentiated PeIN, since the malignant potential of typical and atypical lichen sclerosus is different

Fig. 40.5. Lichen sclerosus. (A, B) Lichen sclerosus: a dense hyalinization is noted underneath the squamous epithelium. A band of chronic inflammatory cells is seen at the bottom of the lesion. (C, D) Atypical lichen sclerosus: the presence of epithelial atypical cells with morphological features of differentiated PeIN in areas of lichen sclerosus is a common finding in keratinized variants of penile cancer. (C) Foreskin outer surface in the right field.

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SQUAMOUS CELL CARCINOMA General Features Epidemiology ♦♦ Penile cancer is very rare in certain geographical regions, such as the USA, Europe, Israel, and Japan but highly prevalent in others, especially South America, Africa and some regions of Asia. Highest age-standardized rates (ASR) are from Paraguay, Brazil, Uganda, and Thailand ♦♦ Mean age of affected patients is 58 years. Most of the patients are in their fifties to seventies. The disease is occasionally seen in young adults but is exceedingly rare in children

Risk Factors ♦♦ Phimosis, defined as a difficulty or impossibility of retracting the foreskin beyond the glans corona, is frequently present in patients with invasive penile cancer and several epidemiological studies have established its presence as a risk factor. Phimosis may be the consequence of unspecific chronic balanitis, lichen sclerosus (with which it frequently coexists) or other systemic conditions. The protective effect of circumcision at birth may be related to the prevention in the development of this condition ♦♦ Cigarette smoking has been convincingly linked to the development of penile cancer and several epidemiological studies have established a dose–response relation, with heavy smokers at higher risk ♦♦ The presence of lichen sclerosus is significantly associated with some special subtypes of HPV-unrelated penile carcinomas such as usual, pseudohyperplastic, verrucous, and papillary SCCs, especially when located exclusively in the foreskin. Almost 10% of patients with long-standing lichen sclerosus will develop a penile carcinoma ♦♦ Antecedents of penile tears, abrasions, or injuries are also associated with a higher risk of penile cancer, as well as the presence of chronic balanitis or genital warts. Other risk factors include immunosupression, human immunodeficiency virus (HIV) infection, treatment with psoralen and ultraviolet A (PUVA), radiation therapy and some other conditions such as lichen planus

Strategies for Cancer Prevention ♦♦ Circumcised patients are at much lower risk for presenting invasive penile cancer, especially when circumcision is practiced at birth ♦♦ A better penile hygiene can reduce the risk for penile cancer by reducing the incidence of chronic balanitis and the subsequent development of phimosis. Smegma is no more currently considered as a carcinogenic agent per se although its presence is a clear indicator of poor penile hygiene ♦♦ Since HPV infection, especially by high risk serotypes such as 16 or 18, is present in about one-half of penile carcinomas, vaccination in males could in fact prevent some of these cases. HPV vaccination should be done before the first sex-

ual contact. Seroconversion is observed in almost 100% of vaccinated boys

Pathological Features ♦♦ Most of the penile carcinomas are histologically squamous cell carcinomas originated in the epithelial lining covering the glans, coronal sulcus, or foreskin. The glans is the preferred site of origin (80%) followed by the foreskin (15%) and coronal sulcus (5%). Carcinomas originating in the skin of the shaft or the preputial outer skin are exceedingly rare ♦♦ Most of the penile cancers correspond to squamous cell carcinomas of the usual type, morphologically similar to those of other sites, especially vulva. The remainders are classified as special variants. Each one of these subtypes presents particular clinicopathological features and is associated with a specific biological behavior ♦♦ In geographical areas of high incidence up to half of the tumors are bulky and affect more than one anatomical compartment. Site of origin in these cases are difficult to establish ♦♦ Tumors located exclusively at the glans are usually of higher histological grade, more clinically aggressive, associated with PeIN showing warty and/or basaloid features and HPVrelated in a significant proportion of cases. Tumors exclusive of the foreskin are usually well-differentiated keratinizing carcinomas, frequently associated with differentiated PeIN and lichen sclerosus, mostly HPV-unrelated and of better prognosis

Patterns of Growth ♦♦ Four distinctive macroscopic patterns of growth are recognized in penile carcinomas: superficial spreading, vertical growth, verruciform, and multicentric. Each one of these patterns is associated with particular subtypes of penile SCC. The pattern of growth can also be used to predict the likeliness of regional nodal metastasis ♦♦ Superficial spreading: Low grade flat tumor with extension up to lamina propria or superficial corpus spongiosum, usually affecting more than one anatomical compartment with a horizontal pattern of growth. It is observed in about onethird of the cases. The presence of a more or less extensive PeIN component is a constant feature. Most of the SCC of the usual type presents this pattern of growth ♦♦ Vertical growth: High grade deeply infiltrative tumor with an ulcerated surface, usually affecting only one anatomical compartment, with a high rate of nodal metastases. Foci of necrosis and hemorrhage are common. Basaloid, sarcomatoid and high grade usual SCC usually present this pattern of growth ♦♦ Verruciform: Exophytic and usually bulky low grade tumors with a low rate of regional metastases despite their large size. The preferred anatomical site is the glans, but the foreskin and, infrequently, the coronal sulcus can also be involved. They include verrucous, warty (condylomatous), papillary,

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and cuniculatum carcinomas. Giant condylomata can also present a similar pattern of growth ♦♦ Multicentric: Two or more anatomically unconnected foci of carcinoma, with a tendency to affect multiple compartments. Tumors can be synchronous or metachronous. The epithelia between the malignant areas can be normal or hyperplasic. Any of the aforementioned patterns can be part of a multicentric carcinoma but is common in the presence of a superficial spreading component. Multicentricity is common in some special SCC variants such as pseudohyperplastic carcinoma ♦♦ In some cases a mixed pattern of growth is observed, usually a superficial spreading low grade SCC with a high grade component showing a vertical growth pattern. In a minority of the primary cases and in recurrent carcinomas the pattern of growth can be unclassifiable

Essentials of Anatomic Pathology, 3rd Ed.

♦♦

♦♦

♦♦

Criteria for Histological Grading ♦♦ Grade 1 (well differentiated): Tumors composed of welldifferentiated neoplastic cells almost undistinguishable from their normal counterparts, except for the presence of minimal basal/parabasal atypia ♦♦ Grade 2 (moderately differentiated): This is an exclusion category, encompassing all the tumors not fitting the established criteria for grade 1 or 3 ♦♦ Grade 3 (poorly differentiated): Tumors composed of any proportion of anaplastic cells showing nuclear pleomorphism, high nuclear-cytoplasm ratio, prominent nucleoli, coarse chromatin and irregular, and thickened nuclear membrane ♦♦ Up to one-half of the tumors are heterogeneous, harboring more than one histological grade. In these cases grading should be done using the higher grade component, regardless of its proportion. Most of penile SCCs are moderately well differentiated. Homogeneous grade 1 or grade 3 tumors are infrequent and usually correspond to special SCC variants

Prognostic Factors ♦♦ Histological grade: Is an important prognostic factor and should always be reported and using the aforementioned criteria. Any proportion of anaplastic cells carries implicit a risk for nodal metastasis ♦♦ Perineural invasion: Defined as the presence of tumoral cells in the perineural space. Presence of perineural invasion is an important indicator of tumoral aggressiveness and it is associated with a higher metastatic rate and higher mortality ♦♦ Vascular invasion: Either lymphatic (most frequent) or venous, is associated with an increased risk for nodal metastasis and should always be reported ♦♦ Tumoral thickness: Tumors invading up to 5 mm are associated with a low risk for metastasis while those invading more than 10 mm are prone to present nodal involvement. Invasion from 5 to 10  mm is more problematic to handle and other pathological features, especially perineural invasion and histological grade, should be used for predicting the likelihood of nodal involvement ♦♦ Anatomical level of infiltration: Tumors invading only lamina propria or superficial corpus spongiosum are at lower

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♦♦

risk for nodal metastasis than those invading deep corpus spongiosum or corpora cavernosa Site of the primary tumor: Tumors exclusively located at the foreskin have a better prognosis than those arising in the glans, especially because they tend to be of low grade and invade superficial anatomical layers Pattern of growth: Verruciform tumors are associated with good prognosis while tumors with vertical pattern of growth are more likely to present nodal metastasis, systemic dissemination, and cancer-related death. Superficial spreading SCCs are in the intermediate category Histological subtype: penile SCC subtypes can be stratified in three risk groups for nodal metastasis: low risk (verrucous, papillary, low grade warty, pseudohyperplastic, and low grade mixed carcinomas, as well as carcinoma cuniculatum), intermediate risk (low grade usual, high grade warty and high grade mixed carcinomas) and high risk (high grade usual, sarcomatoid, pseudoglandular, adenosquamous, and basaloid carcinomas) Resection margins: Local recurrence is most likely related to positive margins due to insufficient surgical resection of the primary tumor. Multicentricity, not clinically apparent during primary treatment, can explain some other cases. Local recurrence rate is also higher when penile preserving procedures, such as radiotherapy or laser ablation, are performed as primary therapeutic strategies. Patients with local recurrence are at higher risk for regional nodal metastasis

The Prognostic Index ♦♦ The Prognostic Index is a risk group stratification system for predicting the likelihood of nodal metastasis based on the pathological examination of the surgical specimen. It can be used for therapeutic planning in order to define which patients will benefit from a groin dissection ♦♦ It combines three of the most useful and powerful prognostic factors, the histological grade, the anatomical level of infiltration and presence of perineural invasion, to produce a score which is used to classify a patient into a risk group category. This score is constructed adding up three numerical values assigned to each one of the variables involved ♦♦ Histological grade: One point to well differentiated (grade 1), two point to moderately well differentiated (grade 2), and three points to poorly differentiated (grade 3) tumors. Grading should be done using the aforementioned criteria ♦♦ Anatomical level: For tumors located at the glans, one point for invasion up to lamina propria, two points for invasion of corpus spongiosum, and three points for invasion of corpora cavernosa, including its tunica albuginea. For tumors located at the foreskin, one point for invasion up to lamina propria, two point for invasion of preputial dartos, and three point for invasion of preputial skin, either dermis or epidermis ♦♦ Perineural invasion: Zero points if perineural invasion is absent and one point if perineural invasion is present. Caution should be exercised for not to confuse entrapped nerves with perineural invasion. Perineural invasion requires the presence of tumoral cells within the perineural space

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♦♦ Prognostic Index score: Is formed adding up the numerical values assigned to the histological grade, the anatomical level and the perineural invasion. A value from 2 to 7 is obtained. Risk group stratification is done as it follows:low risk (scores 2 and 3), intermediate risk (score 4), and high risk (scores 5–7) ♦♦ Risk group management: For patients in the low risk category the probability of nodal metastasis is very low, near to zero, and if there is no clinical evidence of nodal involvement (e.g., palpable inguinal nodes, imaging studies), a surveillance program should suffice. Groin dissection is likely to be unnecessary. For patients in the high risk group the probability of nodal metastasis is high and they should receive prophylactic inguinal lymphadenectomy, regardless of the clinical status of the inguinal nodes. Patients in the intermediate category are problematic to handle and other clinicopathological features (clinical status of inguinal nodes, imaging studies, histological subtype, vascular invasion) should be evaluated ♦♦ The Prognostic Index also predicts outcome. Patients with scores 2–4 have a good prognosis, with 5-year survival rate above 90%. In patients with score 5 and 6 the survival rate drops to about 60% and only 45% of patients with score 7 survives 5 years or more

Routes of Local Spread ♦♦ Horizontal spread: Tumors originated in one anatomical compartment spreads horizontally to others, for example, tumors originated at the foreskin extends to coronal sulcus and then to glans, or tumors originated at the glans extends through the meatus urethralis and invades distal urethra ♦♦ Vertical spread: Tumors originated in the mucosal surface of the penis invade vertically to deep anatomical tissues, for example, tumors of the glans that consecutively invades lamina propria, corpus spongiosum, tunica albuginea and corpus cavernosum, or tumors originated in the coronal sulcus that vertically invades lamina propria, dartos, and penile fascia

Patterns of Regional and Systemic Dissemination ♦♦ Lymphatic spreading occurs in a stepwise fashion, affecting first the superficial and deep inguinal nodes and then the pelvic nodes (regional spread). From the pelvic nodes it extends to the retroperitoneal nodes and then to other distantly located lymph nodes (systemic spread) ♦♦ Visceral involvement occurs late in the course of the disease. Most frequently affected sites are the liver, lungs, and heart. Other sites that can be affected include the spleen, bone, adrenals, kidneys, thyroid gland, and the brain. High grade tumors, such as basaloid, sarcomatoid, and high grade usual SCC, with deep invasion of anatomical levels are more likely to be found disseminated

Squamous Cell Carcinoma, Usual Type General Features ♦♦ Most common subtype of penile SCC, representing 60–65% of all cases. The tumor is composed of malignant epithelial cells with variable degrees of keratinization and maturation. For other pathological and outcome features see Table 40.2 ♦♦ Local and regional recurrences are observed in about onethird of the cases, usually due to insufficient surgery. Inguinal nodal metastases are present in 28–39% of the cases. The mortality rate ranges from 20 to 38%. The 10-year survival rate is 78%

Clinical ♦♦ Most of the patients are in their sixties to seventies, with an average age of 58 years. Is uncommon in young adults and extremely rare in children ♦♦ A self-appreciated painless tumoral mass is the most frequent complaint, although in some cases areas of erythema or ulceration are more evident. Pain, bleeding, and dysuria

Table 40.2. Pathological and Outcome Features of Penile SCC Histological Subtypes Usual Incidence (%)

AdenoMixed Verrucous Warty Papillary Basaloid Sarcomatoid squamous

60–65

10–33

3–7

6–10

5–15

10–14

1–4

1

Deep infiltration (%)

52

56

25

52

35

79

100

75

Thickness (mm)

7.3

8.6

5.5

6.5

6.6

10.9

10.3

13

High grade (%)

47

22

100

26

71

0

0

25

Vascular invasion (%)

28

23

0

9

12

69

33

75

Perineural invasion (%)

35

23

4

4

12

50

67

50

Urethral invasion (%)

40

42

29

39

12

60

100

50

Nodal metastasis (%)

28–39

9

0

17–18

21

50–100

75–89

43–50

28

19

0

10

12

36

67

25

20–38

3

0

0–9

0–6

21–67

75

0–14

Overall recurrence (%) Mortality rate (%)

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are uncommon. Up to one-half of the cases present at least some degree of phimosis

Macroscopic ♦♦ The gross picture is variegated and indistinctive. The predominant pattern of growth is superficial spreading. A more or less evident vertical growth phase can also be seen. Mulcentric and unclassifiable patterns are less common. Average tumor size is 2.0–4.8 cm ♦♦ When affecting only one compartment glans is the preferred anatomical site affected. Tumors exclusive of the foreskin are infrequent. In patients from high incidence geographical areas tumors tend to affect more than one anatomical compartment, extending through glans, coronal sulcus, and foreskin

Essentials of Anatomic Pathology, 3rd Ed.

Microscopic ♦♦ Most of the tumors are moderately differentiated with easily recognized keratinizing cells (Fig. 40.6A–C). Tumors composed exclusively of well or poorly differentiated cells are uncommon. Usually, when a higher grade is present it is in the form of more or less extensive foci of anaplastic cells, forming solid nests, trabeculae, or cords (Fig. 40.6D) ♦♦ Tumors limited to lamina propria are uncommon and most of them invade penile erectile tissues, either corpus spongiosum, or cavernosum. Vascular and perineural invasion are present in about one-third of the cases. Extension to distal urethra and presence of lichen sclerosus are seen in almost half of the cases

Fig. 40.6. SCC, usual type. (A) Well-differentiated, grade 1 SCC: tumoral nests composed of neoplastic cells with minimal atypia, epithelial maturation and prominent keratinization. (B) Moderately differentiated, grade 2 SCC: the neoplastic cells are more atypical, with moderate nuclear pleomorphism, coarse chromatin and prominent nucleoli; however, keratinization is maintained, as noted by the ample eosinophilic cytoplasm of the neoplastic cells. (C) Moderately to poorly differentiated, grades 2–3 SCC: a mixture of keratinizing neoplastic cells (lower left field) with more basophilic atypical cells is observed. This tumor should be classified as high grade. (D) Poorly differentiated, grade 3 SCC: solid nests and trabeculae composed of anaplastic cells with almost no tendency to keratinize. There is nuclear pleomorphism, prominent nucleoli, apoptosis and high mitotic rate.

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♦♦ Presence of areas of differentiated PeIN and squamous hyperplasia are frequent, either adjacent or isolated from the invasive component

Differential Diagnosis ♦♦ Pseudoepitheliomatous squamous hyperplasia can be confused with usual SCC, especially in small biopsies. The presence of even minimal cytological atypia, irregular borders, lack of peripheral palisading, and a stroma reaction are indicative of a neoplastic process ♦♦ High grade usual SCC can be difficult to distinguish from basaloid SCC, especially when there is a predominant nesting pattern of infiltration. Abrupt and central keratinization, basophilic cytoplasm and the presence of a clear space peripheral artifact, as well as evidence of HPV infection, are more suggestive of a basaloid SCC ♦♦ Urothelial carcinomas of the distal urethra with squamous differentiation also should be distinguished from usual SCC. Features suggestive of urothelial carcinoma include the absence of penile intraepithelial changes, presence of urothelial carcinoma in situ and previous or concurrent history of urothelial bladder carcinoma. Squamous metaplasia, microglandular hyperplasia, lichen sclerosus, and PeIN suggest a usual SCC

Basaloid Carcinoma General Features ♦♦ Basaloid SCC is a highly invasive and clinically aggressive HPV-related penile tumor. It accounts for 10–14% of all penile SCC. Evidence of HPV infection is found in up to 80% of all cases. HPV-16 is the most commonly found serotype. For other pathological and outcome features see Table 40.2 ♦♦ Inguinal nodal metastases are frequently present with a metastatic rate of 50–100%. Local recurrence is observed in more than one-third of the patients. The mortality rate ranges from 21 to 67%

Clinical ♦♦ Most of the patients are in their fifties, with an average age of 52–54 years. The typical aspect is that of a large ulcerated tumoral mass. The preferred anatomical location is the glans but secondary extension to other anatomical sites is not uncommon. Basaloid SCC exclusive of the foreskin is rare

Macroscopic ♦♦ Most of the cases exhibit a vertical pattern of growth. Basaloid SCCs are usually ulcerated, solid, unicentric, and deeply infiltrative tumors with more or less prominent foci of necrosis

Microscopic ♦♦ Basaloid SCC is recognized by its deeply infiltrative nesting pattern of invasion. Tumoral nests are composed of smallto medium-size cells with scant and basophilic cytoplasm, and slight to moderate pleomorphism, with indistinctive cellular borders, apoptotic bodies, and abundant mitoses (Fig. 40.7A–D)

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♦♦ A peripheral clear space artifact around the tumoral nests is a constant feature, as well as the presence of central and abrupt keratinization, sometimes with foci of comedonecrosis (see Fig. 40.7B, C) ♦♦ Invasion of deep erectile tissues is the rule. Most of the cases invade corpus cavernosum. Tumors limited to lamina propria are exceedingly rare. Vascular and perineural invasion and extension to distal urethra are frequent findings, present in more than one-half of the cases. PeIN, mostly basaloid, is frequently found in adjacent areas ♦♦ Focal areas of typical SCC can be found but should not exceed 20% of the tumoral mass; otherwise, the tumor should be classified as a usual-basaloid SCC. An exophytic papillary pattern of growth resembling an urothelial papillary carcinoma is sometimes seen

Differential Diagnosis ♦♦ High grade usual SCC with a predominant nesting pattern can be confused with basaloid SCC. The presence of neoplastic cells with ample, eosinophilic cytoplasm, distinctive cellular borders, and gradual keratinization are indicative of a usual SCC ♦♦ Neoplastic cells in urothelial carcinomas are more pleomorphic than those of basaloid SCC. The presence of urothelial carcinoma in situ or a previous or concurrent history of urothelial carcinoma of the urinary tract is helpful. Immunohistochemical urothelial markers, such as uroplakin-III and thrombomodulin, can be used in difficult cases ♦♦ Basal cell carcinomas are usually located at the skin of the shaft and the neoplastic nests are composed of less pleomorphic cells with an evident peripheral palisading. Stromal myxoid changes, not present in basaloid carcinomas, are also a constant feature of basal cell carcinomas

Verrucous Carcinoma General Features ♦♦ Verrucous carcinoma is a verruciform low grade penile tumor characterized by an indolent course and excellent prognosis. It accounts for 3–7% of all penile SCC and for 12–38% of all verruciform SCC. Verrucous carcinoma is consistently negative for HPV. For other pathological and outcome features see Table 40.2 ♦♦ The prognosis of properly diagnosed verrucous carcinomas is excellent. No inguinal nodal metastases are reported with this SCC variant. Local recurrences are observed in a minority of the cases. Five and ten-year survival is 100%

Clinical ♦♦ Verrucous carcinoma usually presents as a slow growing painless exophytic tumor. Glans is the preferred anatomical location, although other penile compartments can be secondarily affected. Tumor average size is about 3.0 cm, but larger and locally destructive lesions do occur. Verrucous SCC can be part of a mulcentric carcinoma, especially when located at the foreskin

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 40.7. Basaloid carcinoma: (A–C) Highly infiltrative solid tumoral nests composed of a small- to medium-size population of basophilic cells with scant cytoplasm, indistinct cellular borders, coarse chromatin, apoptotic bodies, and abundant mitoses. Keratinization, when present, is abrupt and focal. Foci of central necrotic debris (comedonecrosis) are commonly found. (D) Tumors composed of more anaplastic cells and irregular infiltrative nests are also classified as basaloid carcinomas for their cytological features and the absence of epithelial maturation.

Macroscopic ♦♦ Verrucous carcinoma is a verruciform tumor characterized by an exophytic cauliflower-like pattern of growth. At cut section the tumoral base is broad and well defined

Microscopic ♦♦ Verrucous carcinomas show prominent papillomatosis, acanthosis, and hyperkeratosis. The papillae are composed of well-differentiated neoplastic cells and usually lack a central fibrovascular core. Keratin plugs are frequently found within the tips of the papillae (Fig. 40.8A, B) ♦♦ The tumoral base is broad and pushing in all cases, with bulbous expansions and a well-defined tumor-stroma interface (Fig. 40.8C, D). A more or less prominent chronic inflammatory response is usually observed at the tumoral base ♦♦ Verrucous carcinomas usually invade up to lamina propria or superficial corpus spongiosum. Invasion of tunica albuginea or corpus cavernosum is less frequent

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♦♦ Vascular and perineural invasion are rare. Extension to distal urethra is observed in almost one-half of the patients. Is not infrequent in the coexistence of verrucoid squamous hyperplasia, differentiated PeIN, and lichen sclerosus with verrucous carcinomas

Differential Diagnosis ♦♦ In some cases distinguishing between a squamous hyperplasia and a verrucous carcinoma can be extremely difficult, especially in small biopsies. Clinically, verrucous carcinomas tend to be larger and more prominent than squamous hyperplasia. The bulging of the pushing border into the lamina propria and the moderate to intense stromal reaction are clues suggesting a verrucous carcinoma ♦♦ Verrucous carcinoma should be distinguished from other penile verruciform tumors (see Table 40.1). Giant condyloma and warty carcinoma can be confused with verrucous carcinomas if strict criteria are not maintained. Koilocytosis is a

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Fig.  40.8. Verrucous carcinoma. (A, B) Verrucous carcinoma is characterized by prominent acanthosis, papillomatosis, and hyperkeratosis. Fibrovascular cores are not a conspicuous feature and are lacking in most of the papillae. Interpapillary keratin plugs are frequently found. (C, D) Cytological atypia is minimal and there are no koilocytes. The tumoral base is broad and pushing. A chronic inflammatory reaction is seen.

constant feature in warty carcinomas and giant condylomata and in both the papillae present a prominent fibrovascular core. In addition, the neoplastic cells in warty carcinoma are more atypical and the tumoral base is jagged and irregular ♦♦ Papillary, not otherwise specified (NOS) carcinoma is another verruciform tumor that should be distinguished from verrucous carcinoma. In papillary, NOS carcinoma the papillae are composed of more atypical cells, fibrovascular cores are more or less prominent and architecturally are more complex than those of verrucous carcinoma. The tumoral base is jagged and irregular ♦♦ Neoplastic cells in carcinoma cuniculatum are undistinguishable from those of verrucous carcinomas. However, carcinoma cuniculatum exhibits a typical exoendophytic growth, with the presence of conspicuous sinus and cyst-like structures, in a characteristic burrowing pattern ♦♦ Pure verrucous carcinomas should be distinguished from mixed usual-verrucous carcinomas in which an other-

wise typical verrucous carcinoma is intermingled with foci of usual SCC. The distinction has clinical relevance, since mixed usual-verrucous carcinomas possess a metastatic potential not observed with verrucous carcinomas

Warty (Condylomatous) Carcinoma General Features ♦♦ Warty carcinoma is a verruciform HPV-related penile tumor similar to those occurring in the vulva, cervix, and anus. It accounts for 6–10% of all penile SCC and 35–36% of all verruciform carcinomas. HPV detection is variable, ranging from 22–100%. Most commonly found serotype is HPV-16. For other pathological and outcome features see Table 40.2 ♦♦ Local recurrence is observed in up to 10% of the cases. The metastatic rate of inguinal nodal involvement is 17–18%. Systemic dissemination is rare and cancer-specific mortality is very low, from 0–9%

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Clinical ♦♦ Most of the patients are in their fifties, with an average age of 48–55 years. The typical presentation is that of a slow growing painless tumoral mass, preferentially located at the glans but extending to other anatomical compartments. Is not unusual a previous history of genital warts

Macroscopic ♦♦ A cauliflower or cobblestone-like appearance is characteristic of warty carcinoma. The average tumoral size is 3.6– 6.3  cm. Cut surface reveals an exophytic neoplasm with a more or less prominent endophytic component

Microscopic ♦♦ Papillae are long and undulating, usually spiky, with prominent fibrovascular cores. Hyperkeratosis and parakeratosis are common (Fig.  40.9A, B). Koilocytosis (epithelial cells with hyperchromatic and wrinkled nuclei, clear perinuclear halos and frequent binucleation) is easily identified (Fig. 40.9C)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Koilocytic atypia is found not only at the surface of the papillae but also in deep infiltrative nests. Most of the tumors are moderately differentiated while well or poorly differentiated cases are less common ♦♦ The interface between tumor and stroma is jagged and irregular (Fig. 40.9D). A mixture of endo and exophytic component is seen in most of the cases, with a predominance of the latter ♦♦ Invasion into penile erectile tissues is the rule, either corpus spongiosum or cavernosum. Tumors limited to lamina propria are infrequent. Vascular and perineural invasion are observed in a minority of the cases. More than one-third of the cases show extension to distal urethra

Differential Diagnosis ♦♦ Warty carcinoma should be distinguished from other penile verruciform tumors (see Table 40.1). Giant condylomata can be clinically very similar to warty carcinomas. Histologically

Fig. 40.9. Warty carcinoma. (A) Papillomatosis with prominent fibrovascular cores and evident hyperkeratosis are typical features of warty carcinomas. (B, C) Koilocytosis is easily found. Atypia in neoplastic cells usually ranges from mild to moderate. Note the prominent parakeratotic layer covering the papillae and the fibrovascular cores. (D) The tumoral base is jagged and irregular. Koilocytes are identified as well in the deep infiltrative nests. A prominent stromal reaction is seen.

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they are also characterized by condylomatous papillae with prominent fibrovascular cores. However, koilocytic atypia is more conspicuous and restricted to the surface of the papillae, there is no nuclear pleomorphism and the tumoral base is broad and pushing. HPV serotypification can help in problematic cases ♦♦ In verrucous carcinoma the acanthosis and parakeratosis are usually more prominent, fibrovascular cores are either absent or very inconspicuous, there is no koilocytosis, the neoplastic cells are homogeneously well differentiated and the tumoral base is broad and pushing ♦♦ Papillary, NOS carcinomas can be confused with warty carcinomas. In both of them the papillae are architecturally similar and the tumoral base is jagged and irregular, but in papillary carcinoma there is no koilocytosis and the neoplastic cells are of lower grade. HPV detection can help in difficult cases ♦♦ When warty carcinomas present a predominant endophytic pattern of growth they can be very similar to carcinoma cuniculatum. However, carcinoma cuniculatum is cytologically similar to verrucous carcinoma, there is no true koilocytosis and the tumoral front of invasion is broad despite the deep penetration of the tumor

Papillary, Not Otherwise Specified Carcinoma General Features ♦♦ Papillary, not otherwise specified (NOS) carcinoma is a low grade verruciform penile tumor that is considered HPVunrelated. Diagnosis of papillary carcinoma is made only after exclusion of other verruciform and mixed tumors. They account for 5–15% of all penile carcinomas and 25–53% of all verruciform SCC. For other pathological and outcome features see Table 40.2 ♦♦ The prognosis is good with papillary carcinomas. Local recurrence and nodal metastasis are reported in up to 12% of the patients. The mortality rate is low, ranging from 0 to 6%

Clinical ♦♦ The average age of presentation is 63 years (range from 43 to 85 years). The preferred anatomical location is the glans, followed by the foreskin

Macroscopic ♦♦ The typical aspect is that of a cauliflower-like exophytic tumor with an average size of 4.5–5.8 cm. The cut surface reveals a jagged and poorly defined front of invasion

Microscopic ♦♦ Papillae are acanthotic and hyperkeratotic, with irregular shapes and more or less prominent fibrovascular cores (Fig.  40.10A). Neoplastic cells are well differentiated and there are no koilocytic changes (Fig. 40.10B). Front of invasion is jagged and irregular. Stromal reaction is usually evident (Fig. 40.10C) ♦♦ Papillary carcinomas usually invade up to corpus spongiosum. Tumors limited to lamina propria or invading corpora

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cavernosa are less frequent. Vascular and perineural invasion are rarely observed. Extension to distal urethra is uncommon

Differential Diagnosis ♦♦ Papillary carcinomas should be distinguished from other penile verruciform tumors (see Table 40.1). The papillae and the tumoral base in warty carcinomas are similar to papillary SCC, but in the former koilocytic changes are readily identified in the surface of the papillae and in deep tumoral nests. In addition, the neoplastic cells are more pleomorphic, the fibrovascular cores more prominent and the endophytic component more extensive in warty carcinomas ♦♦ Fibrovascular cores are inconspicuous in verrucous carcinomas and the papillae lack the characteristic complexity observed in papillary SCC. Also, the tumoral front is regular and pushing in verrucous carcinoma. Carcinoma cuniculatum is very similar to verrucous SCC but a deeply infiltrative burrowing pattern is observed while papillary carcinomas usually do not invade beyond corpus spongiosum ♦♦ A mixed usual-verrucous (hybrid) carcinoma can be sometimes confused with papillary SCC. The localized presence of irregular and infiltrative nests of pleomorphic squamous malignant cells at the tumoral front suggests a hybrid carcinoma

Sarcomatoid Carcinoma General Features ♦♦ Sarcomatoid carcinoma is a clinically aggressive SCC variant characterized by the presence of neoplastic cells with sarcomatous features and at least focal squamous differentiation. They represent 1–4% of all penile carcinomas. Evidence of HPV infection is found in a minority of the cases. For other pathological and outcome features see Table 40.2 ♦♦ Sarcomatoid SCC is the most ominous variant of penile cancer. Local and systemic recurrences are common and most of the patients die within 1 year from diagnosis. Inguinal nodal involvement is seen in 75–89% of the cases. The cancerspecific mortality rate ranges up to 75%

Clinical ♦♦ Most of the patients are in their sixties. The average age is 59 years (range from 28 to 81 years). It is not uncommon the antecedent of a rapidly enlarging tumoral mass. Sarcomatoid SCC has a predilection for the glans and frequently extents to other anatomical compartments. Tumors exclusive of the foreskin are rare

Macroscopic ♦♦ Sarcomatoid SCCs usually are polypoid, large, and irregular, with frequent areas of ulceration, hemorrhage, and necrosis. Average tumoral size is 3.0–5.0 cm. Most of the tumors present a vertical pattern of growth, with invasion of deep erectile tissues. The presence of multiple unconnected tumoral foci in the skin of the shaft or in deep corpora cavernosa (“satellitosis”) is a characteristic finding

Microscopic ♦♦ Most of the tumor is composed of a spindle-cell population, with a leiomiosarcoma or fibrosarcoma-like pattern

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Essentials of Anatomic Pathology, 3rd Ed.

Fig. 40.10. Papillary, NOS carcinoma. (A) Papillary carcinoma is characterized by papillomatosis, acanthosis, and hyperkeratosis. Papillae are architecturally complex and the fibrovascular cores are irregular. The tumoral base is jagged and there is a prominent stromal reaction. (B) The papillae show mild acanthosis, parakeratosis and slight-to-moderate cytological atypia. Koilocytes are not identified. Fibrovascular cores are irregular. (C) The tumoral base of papillary carcinomas is jagged and irregular and there is an intense chronic inflammatory reaction. of growth (Fig.  40.11A–C). Foci of highly anaplastic cells are not uncommon. Areas of myxosarcomatoid, rhabdomyosarcomatoid, osteosarcomatoid, and chondrosarcomatoid differentiation are observed in some cases. Occasionally a pseudoangiosarcomatous or hemangiopericytoma-like pattern predominates, with tumoral cells surrounding perivascular spaces ♦♦ Vascular and perineural invasion are common findings. Foci of necrosis are invariably present and tend to be prominent. Mitotic figures are abundant. More or less extensive areas of squamous differentiation are usually found (see Fig.  40.11B). Associated PeIN, either differentiated or showing warty and/or basaloid features, are frequently found in adjacent areas

melanocytic proliferation or a nevus component in a malignant spindle cell proliferation is indicative of melanoma. In addition, melanomas are usually positive for S-100, HMB45, and Melan-A ♦♦ The morphological distinction between a sarcomatoid carcinoma and a true penile sarcoma can be difficult in some cases, especially when no areas of squamous differentiation are identified. Immunohistochemistry is helpful in these cases (Fig.  40.11D). Sarcomatoid carcinomas are positive for p63 and 34bE12 and negative for muscle-specific actin, smoothmuscle actin, desmin, and S-100. Staining for EMA, AE1/ AE3, and CAM 5.2 are of less value

Differential Diagnosis

Pseudoglandular Carcinoma General Features

♦♦ Primary penile melanomas can be composed predominantly of spindle cells. The presence of melanin, intraepithelial

♦♦ Pseudoglandular carcinoma is an unusual SCC variant characterized by the presence of prominent acantholysis with

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Fig. 40.11. Sarcomatoid carcinoma. (A) Low power view of sarcomatoid carcinoma showing a prominent spindle-cell pattern, resembling leiomyosarcoma or fibrosarcoma. (B) Foci of typical squamous differentiation are identifiable in most of the cases. (C) Myxomatous stromal changes are seen in some cases. Note also the neoplastic giant cells with a malignant fibrous histiocytoma-like morphology. (D) Immunohistochemical nuclear staining for p63, as shown here, can be helpful in difficult cases for distinguishing sarcomatoid carcinoma from true penile sarcomas and malignant melanomas with spindle-cell features.

formation of pseudoglandular spaces. It is more aggressive than usual SCC, invading deeper anatomical levels and with a higher metastatic and mortality rate

Clinical ♦♦ Mean age of affected patients is 54 years. Tumors tend to be large and usually affect more than one anatomical compartment

Macroscopic ♦♦ Pseudoglandular carcinomas are exophytic, ulcerated, and deeply infiltrative tumors with an average size of 4.6 cm

Microscopic ♦♦ The distinguishing feature of this SCC variant is the pseudogland, a solid high grade tumoral nest with a central open space lined by flat, cubical, or cylindrical atypical cells

(Fig.  40.12A). This central space usually contains keratin, acantholytic cells, and necrotic debris (Fig. 40.12B) ♦♦ The presence of intracytoplasmic empty vacuoles is a constant feature in the neoplastic cells. The vacuoles can be observed in single or grouped cells, either in a collaret disposition or in confluent areas of acantholysis ♦♦ Invasion of deep erectile tissues is seen in most cases. Vascular and perineural invasion are common findings. Areas of associated PeIN are recognized in more than one-half of the cases

Differential Diagnosis ♦♦ Pseudoglandular carcinomas should be distinguished from tumors with true glandular differentiation such as adenosquamous SCC, mucoepidermoid carcinoma, and urethral adenocarcinoma. A broad spectrum of morphological changes

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Fig. 40.12. Pseudoglandular (acantholitic) carcinoma. (A, B) This SCC variant is characterized by the presence of highly infiltrative pseudoglandular structures composed of cubical malignant cells with frequent intracytoplasmic vacuolization. Filling up the pseudolumina there is necrotic and keratin debris. is more typical of pseudoglandular SCC while true glandforming tumors tend to be more homogeneous. CEA and mucin stains can be helpful ♦♦ Sarcomatoid SCC with predominant pseudoangiosarcomatous features can be confused with pseudoglandular SCC. However, in pseudoangiosarcomatous SCC the open spaces are lined by endothelial cells and the solid component is more spindle-shaped. More or less extensive areas of typical sarcomatoid carcinoma are found in most of the cases

Pseudohyperplastic Carcinoma General Features ♦♦ Pseudohyperplastic carcinoma is an extremely well-differentiated nonverruciform penile tumor, which preferentially affects the foreskin of older man. It is consistently negative for HPV infection ♦♦ The prognosis is excellent. Neither inguinal metastasis nor systemic dissemination has been reported

Clinical ♦♦ Most of the patients are in their seventies. Mean age is 69 years. Tumors preferentially affect the foreskin and they tend to be multicentric. Other anatomical compartments are affected less frequently

Macroscopic ♦♦ Grossly these tumors show a flat or slightly raised white and granular surface. Average size is 2 cm, ranging from 0.4 to 3.5 cm

Microscopic ♦♦ There is a striking resemblance with pseudoepitheliomatous hyperplasia. The lesion is usually flat with an orderly downward proliferation of tumoral nests composed of extremely well-differentiated neoplastic cells with minimal atypias (Fig. 40.13A–D). A more or less prominent chronic stromal reaction is frequently seen

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♦♦ Most of the tumors invade only superficial layers, usually lamina propria, or preputial dartos. Differentiated PeIN and squamous hyperplasia are frequently found in continuity with the invasive component, as well as lichen sclerosus, either distant, adjacent, or beneath the tumoral nests. Presence of vascular or perineural invasion is exceedingly rare

Differential Diagnosis ♦♦ The epithelial nests of pseudoepitheliomatous hyperplasia are more regular and peripheral palisading is usually evident. Although the epithelial nests appear detached from the superficial epithelium there is no true stromal invasion and serial sections demonstrate anatomical connection of all nests with the surface. In pseudohyperplastic carcinoma there is at least minimal epithelial atypia, nests are more irregular, there is no peripheral palisading, and a stromal reaction is usually seen ♦♦ Another important distinguishing feature is the extension of the epithelial nests. In pseudohyperplastic carcinoma invasion of at least lamina propria is the rule. Preputial dartos and superficial corpus spongiosum are not infrequently affected. Epithelial nests in pseudoepitheliomatous hyperplasia do not extend beyond lamina propria. Notwithstanding these morphological clues, differential diagnosis can be very difficult in small samples ♦♦ Usual SCC can be sometimes confused with pseudohyperplastic carcinoma. However, extremely well-differentiated usual SCC is rare and a pseudoepitheliomatous pattern is usually not a conspicuous feature. Also, usual SCC tends to be unicentric and located at the glans and affects patients slightly younger than those with pseudohyperplastic carcinoma

Carcinoma Cuniculatum General Features ♦♦ Carcinoma cuniculatum is a low grade verruciform tumor characterized by a burrowing pattern of growth and invasion

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Fig. 40.13. Pseudohyperplastic carcinoma. (A–C) Low power view of pseudohyperplastic carcinoma showing the characteristic pseudoepitheliomatous-like pattern of growth with highly differentiated neoplastic nests invading through the lamina propria. Note the hyperkeratotic flat surface and the intense stromal reaction. (D) Tumoral nests in pseudohyperplastic carcinoma are irregular and they are composed of neoplastic cells with minimal atypia. No peripheral palisading is observed.

of deep erectile tissues. It is consistently negative for HPV infection ♦♦ Despite the deep infiltration into penile erectile tissues, carcinoma cuniculatum has an excellent prognosis. No nodal metastasis or systemic dissemination has been reported

the presence of multiple sinuses and cyst-like tracts in a burrowing pattern of growth ♦♦ Invasion of deep erectile tissues is the rule. Skin fistulization, either to the shaft or the foreskin, is also common. The limits between tumor and stroma are sharply defined

Clinical

Microscopic

♦♦ Patients tend to be older than those with usual SCC. Mean age is 77 years. Tumors are large and exophytic and usually affect multiple anatomical compartments with predilection for the glans and coronal sulcus. Surface ulceration is a common finding

Macroscopic ♦♦ Carcinoma cuniculatum is an exophytic tumor with a verruciform pattern of growth. Average tumor size is 6.3 cm, ranging from 5.0 to 8.9  cm. The distinguishing feature of this variant is noted on cut surface: deep tumoral infiltration with

♦♦ Histologically carcinoma cuniculatum is undistinguishable from verrucous carcinoma, with papillomatosis, acanthosis, and hyperkeratosis (Fig.  40.14A, B). Neoplastic cells are extremely well differentiated. No koilocytes are identified ♦♦ The front of invasion is broad and pushing, even when penetrating deep into erectile tissues (Fig. 40.14C, D). In most of the cases the stromal reaction is intense. No vascular or perineural invasion are usually found ♦♦ Focal areas of irregular invasion undistinguishable from low grade usual squamous cell carcinoma may be seen

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Fig. 40.14. Carcinoma cuniculatum. (A) Papillomatosis, marked acanthosis and hyperkeratosis are features of carcinoma cuniculatum. (B) The neoplastic cells are extremely well differentiated and are morphologically similar to verrucous carcinoma. (C) The front of invasion is formed by tumoral nests of highly differentiated neoplastic cells. A broad and pushing pattern predominates but foci of irregular infiltration can also be seen. The stromal reaction is intense. (D) Cyst-like structures are commonly found in deep tissues and can fistulize to the penile surface.

Differential Diagnosis ♦♦ Carcinoma cuniculatum should be distinguished from other penile verruciform tumors (see Table 40.1). Verrucous carcinoma is similar from carcinoma cuniculatum regarding the cytological architecture and differentiation. However, verrucous carcinoma rarely invades beyond lamina propria and lack the burrowing pattern typical of carcinoma cuniculatum ♦♦ Warty carcinomas with a predominant endophytic pattern of growth can be sometimes confused with carcinoma cuniculatum. However, in warty carcinoma koilocytosis is a conspicuous feature and neoplastic cells are of higher grade. HPV detection and over expression of p16INK4a can help in difficult cases ♦♦ Carcinoma cuniculatum should be distinguished from mixed verrucous-usual (hybrid) carcinoma. This mixed variant is characterized by the presence of an otherwise typical verru-

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cous carcinoma intermingled with foci of usual SCC, commonly of high grade, which invades deeper into penile tissues. There is no burrowing pattern of growth. The distinction is important, since hybrid verrucous carcinoma presents a metastatic potential, which carcinoma cuniculatum does not have

Adenosquamous Carcinoma General Features ♦♦ Adenosquamous carcinoma is characterized by the presence of a dual population of neoplastic cells, one exhibiting squamous and the other glandular differentiation. For other pathological and outcome features see Table 40.2 ♦♦ The glandular component derives from embryologically misplaced mucous cells, preputial goblet cells or squamous cells with aberrant glandular differentiation

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♦♦ Local recurrence is observed in up to one-quarter of the patients and metastatic rate is high, ranging from 43–50%. However, cancer-specific mortality is low, ranging from 0–14%

Clinical ♦♦ The tumor preferentially affects the glans, although extension to coronal sulcus and foreskin is not rare. Mean age of patients is 55 years, ranging from 30 to 74 years

Macroscopic ♦♦ Tumors usually invade deep anatomical levels, replacing most of the glans and extending to coronal sulcus or foreskin. Average tumoral size is 7.5 cm

Microscopic ♦♦ In most of the cases the squamous and the glandular component are discrete. The squamous component corresponds to a usual SCC while the glandular component is composed of neoplastic glands lined by cubical or cylindrical epithelium with intracellular and intraluminal mucin (Fig. 40.15A, B). CEA is usually positive in the glandular component ♦♦ Solid squamous areas with isolated glandular cells can also be seen, simulating mucoepidermoid carcinoma. PeIN is frequently found in adjacent areas

Differential Diagnosis ♦♦ Pseudoglandular carcinoma can resemble adenosquamous carcinoma sometimes; however, no true glandular differentiation is observed in the former. The pseudoglands of pseudoglandular carcinoma are lined by acantholytic cells and the lumina contain keratotic material and necrotic debris ♦♦ Urothelial carcinoma of distal urethra with glandular differentiation can be confused with pseudoglandular carcinoma. However, the common presence of areas with typical urothelial carcinoma in situ helps in difficult cases

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♦♦ Infiltration of Littre glands by a usual SCC can simulate adenoquamous carcinoma. However, in these cases the glandular component looks benign. Conversely, adenocarcinoma of Littre glands does not exhibit a squamous component and the glandular component is clearly malignant ♦♦ Adenocarcinoma metastatic to the penis can also enter in the differential diagnosis. However, metastatic carcinomas tend to affect deep erectile tissues and only secondarily lamina propria, glans, or foreskin. The absence of PeIN in these cases is crucial for establishing the diagnosis

Mixed Carcinomas General Features ♦♦ The denomination of mixed carcinomas is restricted to penile SCC exhibiting two or more different histological variants in the same tumor. One of the components should represent at least 20% of the tumoral mass. Mixed carcinomas account for one-quarter to one-third of all penile carcinomas. Tumors with warty and/or basaloid features are usually HPV positive. For other pathological and outcome features see Table 40.2 ♦♦ Mixed carcinomas should not be considered as a single entity regarding clinical management and therapeutic planning. Although the reported rates of metastasis and cancer-specific mortality are low (9% and 3%, respectively) each case should be individually evaluated

Clinical ♦♦ Most of the tumors are located at the glans. Extension to other anatomical compartments is not infrequent. Mean age of patients is 56 years, ranging from 47 to 79 years. Mixed tumors exclusive of the foreskin are rare

Macroscopic ♦♦ The gross picture is variegated and is common the presence of mixed patterns of growth. Usually the low grade component

Fig. 40.15. Adenosquamous carcinoma. (A) Low power view of adenosquamous carcinoma showing the neoplastic glans infiltrating penile erectile tissues. (B) Tumoral nest showing easily recognizable glandular differentiation within a solid squamous component.

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presents a verruciform or a superficial spreading pattern while the high grade component shows a vertical growth pattern. Multicentricity is not uncommon

Microscopic ♦♦ Mixtures of tumors with basaloid and warty features are seen in up to one-half of all mixed tumors. These tumors present both the typical condylomatous exophytic appearance of warty carcinomas and the solid nesting pattern of basaloid carcinomas. Mixtures of koilocytes and basaloid cells are frequently observed in the papillae and in the invasive tumoral nests ♦♦ Mixed usual-verrucous carcinomas (hybrid verrucous carcinomas) are seen in one-quarter or more of the cases. They consist of an admixture of typical verrucous carcinomas with invasive foci of usual SCC. The usual component can be of low or high grade. However, even if the usual component is inconspicuous and the verrucous component predominates, hybrid verrucous carcinoma has a metastatic potential which the verrucous carcinoma does not, so the distinction is of clinical transcendence ♦♦ Mixtures of usual with other subtypes, such as warty, basaloid, and papillary are less common. Uncommon patterns

include the adenobasaloid, mucoepidermoid, and polymorphic variants ♦♦ Most of these mixed variants invade deep erectile tissues, either corpus spongiosum or corpus cavernosum. Histological grades are heterogeneously distributed among these variants, reflecting their mixed nature. Vascular and perineural invasion are seen in about one-quarter of the patients. Extension to distal urethra is observed in about one-half of the cases

Differential Diagnosis ♦♦ Mixed carcinomas should be distinguished from the pure forms. Strict morphological criteria for tumor subtyping should always be maintained. If two clearly distinctive histological subtypes are observed then the diagnosis of mixed carcinoma is warranted ♦♦ Special attention should be taken in identifying high grade areas in an otherwise low grade tumor (e.g., a verrucous carcinoma with a high grade usual component or a usual carcinoma with basaloid foci). These high grade foci will indicate the clinical course and biological behavior of these tumors

OTHER MALIGNANT EPITHELIAL TUMORS Clear Cell Carcinoma General Features ♦♦ Clear cell carcinomas are aggressive penile tumors with a predilection for the foreskin inner mucosa. They are usually HPV positive. A sweat gland origin has been proposed for them ♦♦ Nodal metastasis is present in a high proportion of the cases. Widespread dissemination is observed in about one-half of the patients

Macroscopic ♦♦ Clear cell carcinomas are large, exophytic, and ulcerated, ranging in size from 2.5 to 5.5 cm. They are located at the preputial inner mucosa

Microscopic ♦♦ Clear cell carcinomas are characterized by a solid proliferation of polygonal cells with ample clear cytoplasm. PAS and d-PAS stains are positive in most of these cells. Extensive areas of geographical necrosis are common. Vascular invasion is usually prominent. Warty PeIN and intraductal eccrine extension can be found in adjacent areas

Differential Diagnosis ♦♦ Clear cell changes can sometimes be observed either focally or extensively in warty and usual carcinomas. However, neoplastic cells in clear cell carcinoma are consistently positive for Muc-1 while this marker is usually negative in penile SCC

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♦♦ Other clear cell tumors, such as sebaceous carcinoma, clear cell metastatic renal cell carcinoma, or urothelial clear cell carcinoma can enter the differential diagnosis. Other clinicopathological features should be taken into account

Paget Disease General Features ♦♦ Primary Paget disease is a form of mucin-secreting intraepithelial adenocarcinoma located primary at the epidermis. It originates more commonly from an underlying sweat gland carcinoma or from apocrine ducts ♦♦ Secondary Paget disease refers to the presence of a pagetoid intraepithelial spread from carcinomas other than those of sweat gland origin, such as penile SCC and bladder/urethral urothelial carcinomas. It is more frequent than primary Paget disease

Clinical ♦♦ Primary Paget disease exclusive of the penis is rare. Most commonly, the penile shaft is affected as part of a more extensive disease involving the scrotum (where it is more prevalent) and the perineal, inguinal and perianal areas ♦♦ Secondary Paget disease tends to affect the perimeatal region of the glans

Macroscopic ♦♦ The presence of reddish, scaly maculae and papules with an eczematous aspect is typical

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Microscopic ♦♦ Paget disease is characterized by the intraepithelial presence of large atypical mucin-producing cells with ample cytoplasm. Nuclei are vesicular and nucleoli are prominent. Extension to adnexal glands and ducts can be observed

Differential Diagnosis ♦♦ Primary Paget disease should be distinguished from secondary Paget disease, especially from an urothelial carcinoma with pagetoid spread. PeIN, invasive penile SCC and melanomas should also be included in the differential diagnosis ♦♦ Immunohistochemistry is very helpful in difficult cases. Primary Paget disease usually expresses CEA, EMA, Muc-1, GCDFP-15, and low molecular weight cytokeratins, especially CK7. Paget disease is also consistently negative for CK20 ♦♦ Urothelial carcinoma with pagetoid spread usually express CK20 and is CEA negative. Urothelial markers, such as uroplakin-III and thrombomodulin, can also be helpful. Absence of melanocytic markers (HMB-45, Melan-A, S-100) aids in the distinction from malignant melanoma

Malignant Melanoma General Features ♦♦ It corresponds to a malignant proliferation of melanocytes primarily affecting the penis. Penile malignant melanoma accounts for 1.4% of all penile cancers and 0.2% of all nonocular melanomas. Prognosis is worst than for penile SCC ♦♦ The etiology is unknown but the previous existence of melanocytic nevi or history of malignant melanoma else-

where, as well as ultraviolet radiation, are reported risk factors ♦♦ Significant adverse prognostic factors include the presence of ulceration, tumor depth of 3.5 mm or more and tumor diameter greater than 15 mm. Pathological status of the inguinal lymph nodes is the single most important factor affecting outcome

Clinical ♦♦ Most of penile malignant melanomas are located in the glans, although any anatomical compartment can be affected. Patients are usually in their fifties to seventies

Macroscopic ♦♦ The gross picture varies from flat dark bluish maculae to ulcerated nodules with irregular and ill-defined borders

Microscopic ♦♦ Primary penile malignant melanoma is morphologically identical to melanomas elsewhere. All types of melanoma have been described in the penis

Differential Diagnosis ♦♦ Primary or secondary Paget disease can mimic malignant melanoma. Melanocytic markers, such as HMB-45, Melan-A, and S-100, are helpful in the differential diagnosis. Primary Paget disease usually expresses CEA, EMA, Muc-1, GCDFP-15, and CK7 ♦♦ Malignant melanoma with an extensive spindle cell component should be distinguished from sarcomatoid SCC and sarcomas. Immunohistochemical expression of 35bE12 and p63 is typical of sarcomatoid SCC. Negativity for melanocytic markers is characteristic of penile sarcomas

NONEPITHELIAL TUMORS Benign Mesenchymal Tumors General Features ♦♦ Despite their rarity a variegated spectrum of benign soft tissue tumors has been reported in the penis, including leiomyomas, hemangiomas, schwannomas, neurofibromas, lymphangiomas, glomus tumors, and fibrous histiocytomas ♦♦ Their morphological features are identical to those seen elsewhere. They tend to be localized in the glans

Granular Cell Tumor ♦♦ Granular cell tumors are very rare. Mean age of affected patients is 40 years. Almost one-half of the cases are located in the penile shaft. The remainders affect the foreskin and the glans corona. Tumor size range from 0.6 to 2.5 cm ♦♦ Microscopically a typical granular cell histology is seen. S-100 expression is present in all cases. No nodal metastases or recurrences have been reported

Angiokeratoma ♦♦ Penile angiokeratomas are morphologically similar to their more frequent scrotal or oral counterparts ♦♦ Microscopically, angiokeratomas are characterized by the presence of abundant capillary-type thin-walled vessels forming telangiectatic vascular channels located in the superficial dermis. The vascular component bulges into an overlying hyperplasic squamous epithelium with hyper and parakeratosis. The pathological diagnosis is straightforward

Epithelioid Hemangioma ♦♦ Penile epithelioid hemangioma is a very rare special subtype of hemangioma. Mean age of the patients is 45 years. Most of the tumors are monocentric and they preferentially affect the dorsal aspect of the penile shaft. Glans can be involved in some cases ♦♦ Microscopically there is a proliferation of epithelioid endothelial cells in a nodular or lobular pattern of growth

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with a surrounding inflammatory response composed of lymphocytes and eosinophiles. Endothelial cells express CD31 and muscle-specific actin stains the myopericytes surrounding the vascular spaces ♦♦ Epithelioid hemangioma has a low rate of local recurrence and no nodal metastasis has been reported

Myointimoma ♦♦ Myointimoma is a vascular and myointimal benign tumor which typically affects the corpus spongiosum of the glans. Mean age of the patients is 29 years, although it can be seen in children and older men ♦♦ Microscopically there is a myointimal proliferation of preexisting vascular spaces of the corpus spongiosum with a multinodular/plexiform pattern of growth. Tumoral cells express a-smooth-muscle actin, muscle-specific actin (HHF-35), and calponin ♦♦ Myointimoma should be distinguished from myofibroma, nodular fasciitis, vascular leiomyoma, and plexiform fibrohistiocytic tumor

Malignant Mesenchymal Tumors Vascular Tumors ♦♦ The majority of penile sarcomas are of vascular origin, including Kaposi sarcoma, angiosarcoma, epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Most of the patients are over 40 years old. Priapism is a frequent clinical finding, especially in sarcomas other than Kaposi, and appears in about one-quarter of the cases ♦♦ Kaposi sarcoma used to be a rare penile tumor 30 years ago, but with the increasing incidence of AIDS patients this tumor has become the most frequent penile soft-tissue malignancy. It is estimated that 20% of AIDS male patients will present a Kaposi sarcoma in a genital location. Preferred affected sites are the glans and the coronal sulcus. The gross and microscopic features are identical to those seen elsewhere

Leiomyosarcoma ♦♦ Penile leiomyosarcomas originate from the smooth-muscle cells which surrounds the vascular spaces of the erectile tissues.

Corpus spongiosum and cavernosum are both affected. Mean age of patients is 51 years, with range from 43 to 62 years ♦♦ Tumor size is highly variable, ranging from 0.5 to 10.0 cm. Most of the cases are located in the penile shaft and in the penile root. Tumors superficially located in the glans or shaft dermis are less aggressive than deep-seated tumors located in the corpora cavernosa ♦♦ Microscopically the histological features are identical to those seen elsewhere. Criteria for distinguishing leiomyomas from leiomyosarcoma are similar to those applied for uterine leiomyosarcomas ♦♦ Penile leiomyosarcoma should be distinguished from sarcomatoid carcinoma and from malignant melanoma. The former is usually positive for 34bE12 and p63 and the latter for HMB-45, Melan-A, and S-100. Neoplastic cells of leiomyosarcoma consistently express desmin

Other Primary Sarcomas ♦♦ Penile sarcomas are usually seen in adults, although some special and rare types, such as rhadomyosarcoma, are more frequent in children. They commonly are deepseated and tend to involve the erectile tissues of the corpora cavernosa. The tumors usually are large and with well-defined borders ♦♦ Cases of fibrosarcoma, epithelioid sarcoma, malignant fibrous histocytoma, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, and clear cell sarcoma have been reported

Malignant Lymphoma ♦♦ Penile malignant lymphomas are very rare and can originate in the penis (primary lymphoma) or be secondary to systemic dissemination (secondary lymphoma). All penile compartments can be affected. Priapism and Peyronie disease has been reported in association. Clinically a flesh white or ulcerated lesion is the commonest presentation ♦♦ Most of the cases correspond to diffuse large cell lymphomas, although other types, such as MALT, T-cell, anaplastic large cell, and CD30+ lymphomas, have been reported. Morphological and immunohistochemical criteria for differential diagnosis are similar to those applied elsewhere

SECONDARY TUMORS

General Features ♦♦ Despite its rich vascularity penile metastases from other primary sites are rare. Most of these primary tumors are located in the genitourinary tract, especially the bladder and the prostate, which account for more than two-thirds of the cases. However, less than 1% of genitourinary tract tumors metastasize to the penis ♦♦ Colorectal cancer is next in frequency to metastatize to penis followed by lung cancer. Malignant melanomas rarely metastasize to the penis. Other rare sites include pancreas, stom-

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ach, thyroid gland, and seminal vesicles. Secondary sarcomas are exceedingly rare ♦♦ Most of the tumors reach the penis through retrograde venous or lymphatic spread. Other less common routes of spread include arterial dissemination, direct extension from regional anatomical sites and secondary embolization ♦♦ Since penile metastases usually indicate systemic dissemination the prognosis is poor and most of the patients died within 1 year from the diagnosis

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Clinical

with their more aggressive behavior high grade tumors are more frequently found ♦♦ A pagetoid spread affecting the urothelium of the penile urethra is observed in some bladder urothelial carcinomas

♦♦ Most of the patients are in their sixties to seventies and they have a previous or concurrent history of malignancy. Almost half of the cases present priapism due to involvement of the erectile tissue of corpora cavernosa. Other symptoms include difficulty in urination, dysuria, and urinary retention

Macroscopic ♦♦ Corpora cavernosa are the most frequently affected sites. Corpus spongiosum of the shaft or glans is a less frequent location. Cutaneous metastases to the shaft or foreskin are rare

Microscopic ♦♦ The most conspicuous feature of penile metastases is the presence of tumoral cells within the vascular spaces of the erectile tissues, mainly corpora cavernosa. Tumoral involvement proceeds from proximal to distal corpora. Perineural invasion is also a frequent finding ♦♦ The histological picture of the metastatic tumor is consistent with the morphology of the primary site. In concordance

Differential Diagnosis ♦♦ In most of the cases a previous or concurrent history of cancer is present. However, a malignant priapism is also observed in penile sarcomas, thus in absence of clinical evidence of another primary site they should be rule out. The histological picture is characteristic for penile sarcomas and the pathological diagnosis should be straightforward. Immunohistochemistry can be useful in problematic cases ♦♦ Primary penile carcinomas are rarely confused with metastatic tumors. However, in some rare cases tumoral extension up to distal penis can simulate a penile SCC. Clinical and imaging data are very useful in this context. Pathological diagnosis is straightforward, but immunohistochemistry could be required in some cases

TNM STAGING SYSTEM (2010 REVISION) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ −− Ta: Noninvasive verrucous carcinoma −− T1a: Tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated (i.e., grade 3–4) −− T1b: Tumor invades subepithelial connective tissue with lymphovascular invasion or is poorly diffe­rentiated −− T2: Tumor invades corpus spongiosum or cavernosum −− T3: Tumor invades urethra −− T4: Tumor invades other adjacent structures ♦♦ Regional Lymph Nodes (N) −− Clinical Stage Definition (Based Upon Palpation and/or Imaging) −− −− −− −−

cNX: Regional lymph nodes cannot be assessed cN0: No palpable or visibly enlarged inguinal lymph nodes cN1: Palpable mobile unilateral inguinal lymph node cN2: Palpable mobile multiple or bilateral inguinal lymph nodes −− cN3: Palpable fixed inguinal nodal mass or pelvic lymphadenopathy unilateral or bilateral ♦♦ Pathologic Stage Definition (Based Upon Biopsy or Surgical Excision)

−− −− −− −−

pNX: Regional lymph nodes cannot be assessed pN0: No regional lymph node metastasis pN1: Metastasis in a single inguinal lymph node pN2: Metastasis in multiple or bilateral inguinal lymph nodes −− pN3: Extranodal extension of lymph node metastasis or pelvic lymph node(s) unilateral or bilateral ♦♦ Distant Metastasis (M) −− M0: No distant metastasis −− M1: Distant metastasis (lymph node metastases outside of the true pelvis in addition to visceral or bone sites) ♦♦ Pathological Stages/Prognostic Groups of Penile Carcinomas Group T N M −− Stage 0 −− Stage I −− Stage II −− Stage IIIa −− Stage IIIb −− Stage IV

Tis Ta T1a T1b T2 T3 T1–3 T1–3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N1 N2 Any N N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

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noma: A Study of 202 Cases From Paraguay. Am J Surg Pathol 2010;34:104–114.

Backes DM, Kurman RJ, Pimenta JM, et al. Systematic review of human papillomavirus prevalence in invasive penile cancer. Canc Causes Contr 2009;20:449–457.

Cubilla AL, Meijer CJ, Young RH. Morphological features of epithelial abnormalities and precancerous lesions of the penis. Scand J Urol Nephrol 2000;34:215–219.

Barbagli G, Palminteri E, Mirri F, et al. Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey. J Urol 2006;175: 1359–1363.

Cubilla AL, Piris A, Pfannl R, et al. Anatomic levels: important landmarks in penectomy specimens: a detailed anatomic and histologic study based on examination of 44 cases. Am J Surg Pathol 2001;25: 1091–1094.

Barreto J, Velazquez E, Ayala E, et al. Carcinoma cuniculatum: a distinctive variant of penile squamous cell carcinoma: report of 7 cases. Am J Surg Pathol 2007;31:71–75.

Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol 1998;22:755–761.

Bezerra A, Lopes A, Landman G, et al. Clinicopathologic features and human papillomavirus DNA prevalence of warty and squamous cell carcinoma of the penis. Am J Surg Pathol 2001;25:673–678.

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Chaux A, Caballero C, Soares F, et  al. The Prognostic Index: A useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol 2009;33: 1049–1057. Chaux A, Pfannl R, Lloveras B, et al. Distinctive association of p16INK4a overexpression with penile intraepithelial neoplasia depicting warty and/or basaloid features: a study of 141 cases evaluating a new nomenclature. Am J Surg Pathol 2010;34:385–392. Chaux A, Reuter VE, Lezcano C, et al. Comparison of morphological features and outcome of resected recurrent and non-recurrent squamous cell carcinoma of the penis: a study of 81 cases. Am J Surg Pathol 2009;33:1299–1306. Chaux A, Reuter V, Lezcano C, et al. Autopsy findings in 14 patients with penile squamous cell carcinoma. Int J Surg Pathol Published online on May 1, 2009 [Epub ahead of print]. DOI: 2010.1177/1066896909333781. Chaux A, Soares F, Rodriguez I, et al. Papillary squamous cell carcinoma, not otherwise specified (NOS) of the penis: clinicopathologic features, differential diagnosis, and outcome of 35 cases. Am J Surg Pathol 2010;34:223–230.

Cubilla AL, Velazques EF, Reuter VE, et  al. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of ‘verruciform’ penile tumors. Am J Surg Pathol 2000;24:505–512. Cubilla AL, Velazquez EF, Young RH. Epithelial lesions associated with invasive penile squamous cell carcinoma: a pathologic study of 288 cases. Int J Surg Pathol 2004;12:351–364. Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. An extremely well-differentiated, nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases of a distinctive clinicopathologic entity. Am J Surg Pathol 2004;28:895–900. Cunha IW, Guimaraes GC, Soares F, et  al. Pseudoglandular (adenoid, acantholytic) penile squamous cell carcinoma: a clinicopathologic and outcome study of 7 patients. Am J Surg Pathol 2009;33:551–555.

Chaux A, Tamboli P, Ayala A, et al. Warty-basaloid carcinoma: clinicopathological features of a distinctive penile neoplasm. Report of 45 cases. Mod Pathol 2010;23:896-904.

Dai B, Ye D, Kong Y, et al. Predicting regional lymph node metastasis in Chinese patients with penile squamous cell carcinoma: the role of histopathological classification, tumor stage and depth of invasion. J Urol 2006;176:1431–1435.

Chaux A, Tamboli P, Lezcano C, et al. Comparison of subtypes of penile squamous cell carcinoma from high and low incidence geographical regions Int J Surg Pathol Published online on Jul 3, 2009 [Epub ahead of print]. DOI: 2010.1177/1066896909339184.

Fetsch JF, Brinsko RW, Davis CJ, Jr., et al. A distinctive myointimal proliferation (‘myointimoma’) involving the corpus spongiosum of the glans penis: a clinicopathologic and immunohistochemical analysis of 10 cases. Am J Surg Pathol 2000;24:1524–1530.

Chaux A, Torres J, Pfannl R, et al. Histologic grade in penile squamous cell carcinoma: visual estimation versus digital measurement of proportions of grades, adverse prognosis with any proportion of grade 3 and correlation of a gleason-like system with nodal metastasis. Am J Surg Pathol 2009;33:1042–1048.

Fetsch JF, Davis Jr CJ, Miettinen M, et al. Leiomyosarcoma of the penis: a clinicopathologic study of 14 cases with review of the literature and discussion of the differential diagnosis. Am J Surg Pathol 2004;28: 115–125.

Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol 2009;27:169–177. Cubilla AL, Ayala MT, Barreto JE, et  al. Surface adenosquamous carcinoma of the penis. A report of three cases. Am J Surg Pathol 1996;20:156–160. Cubilla AL, Barreto JE, Caballero C, et al. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993;17:753–763. Cubilla AL, Lloveras B, Alejo M, et al. The basaloid cell is the best tissue marker for human papillomavirus in invasive penile squamous cell carci-

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Fetsch JF, Sesterhenn IA, Miettinen M, et al. Epithelioid hemangioma of the penis: a clinicopathologic and immunohistochemical analysis of 19 cases, with special reference to exuberant examples often confused with epithelioid hemangioendothelioma and epithelioid angiosarcoma. Am J Surg Pathol 2004;28:523–533. Giuliano A, Tortolero-Luna G, Ferrer E, et al. Epidemiology of human papillomavirus infection in men, cancers other than cervical and benign conditions. Vaccine 2008;26 (Suppl 10):K17–28. Gregoire L, Cubilla AL, Reuter VE, et  al. Preferential association of human papillomavirus with high-grade histologic variants of penileinvasive squamous cell carcinoma. J Natl Cancer Inst 1995;87: 1705–1709.

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Guimaraes GC, Cunha IW, Soares FA, et  al. Penile squamous cell ­carcinoma clinicopathological features, nodal metastasis and outcome in 333 cases. J Urol 2009.

Sanchez-Ortiz R, Huang SF, Tamboli P, et  al. Melanoma of the penis, scrotum and male urethra: a 40-year single institution experience. J Urol 2005;173:1958–1965.

Innocenzi D, Nasca M, Skroza N, et al. Penile lichen sclerosus: correlation between histopathologic features and risk of cancer. Acta Dermatovenerol Croat 2006;14:225–229.

Slaton J, Morgenstern N, Levy D, et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol 2001;165:1138–1142.

Katona T, Lopez-Beltran A, MacLennan G, et al. Soft tissue tumors of the penis: a review. Anal Quant Cytol Histol 2006;28:193–206. Liegl B, Regauer S. Penile clear cell carcinoma: a report of 5 cases of a distinct entity. Am J Surg Pathol 2004;28:1513–1517. Lont A, Gallee M, Snijders P, et al. Sarcomatoid squamous cell carcinoma of the penis: a clinical and pathological study of 5 cases. J Urol 2004;172:932–935. Masih AS, Stoler MH, Farrow GM, et al. Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis. Mod Pathol 1992;5:48–55. Micali G, Nasca M, Innocenzi D. Lichen sclerosus of the glans is significantly associated with penile carcinoma. Sex Transm Infect 2001; 77:226. Nordenvall C, Chang ET, Adami HO, et al. Cancer risk among patients with condylomata acuminata. Int J Cancer 2006;119:888–893. Novara G, Galfano A, De Marco V, et al. Prognostic factors in squamous cell carcinoma of the penis. Nat Clin Pract Urol 2007;4:140–146.

Velazquez EF, Cubilla AL. Lichen sclerosus in 68 patients with squamous cell carcinoma of the penis: frequent atypias and correlation with special carcinoma variants suggests a precancerous role. Am J Surg Pathol 2003;27:1448–1453. Velazquez EF, Cubilla AL. Penile squamous cell carcinoma: anatomic, pathologic and viral studies in Paraguay (1993–2007). Anal Quant Cytol Histol 2007;29:185–198. Velazquez EF, Bock A, Soskin A, et al. Preputial variability and preferential association of long phimotic foreskins with penile cancer: an anatomic comparative study of types of foreskin in a general population and cancer patients. Am J Surg Pathol 2003;27:994–998. Velazquez EF, Melamed J, Barreto JE, et al. Sarcomatoid carcinoma of the penis: a clinicopathologic study of 15 cases. Am J Surg Pathol 2005;29:1152–1158.

Pandey D, Mahajan V, Kannan R. Prognostic factors in node-positive carcinoma of the penis. J Surg Oncol 2006;93:133–138.

Velazquez EF, Soskin A, Bock A, et  al. Positive resection margins in partial penectomies: sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol 2004;28: 384–389.

Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 2001;159: 1211–1218.

Velazquez EF, Soskin A, Bock A, et  al. Epithelial abnormalities and ­precancerous lesions of anterior urethra in patients with penile carcinoma: a report of 89 cases. Mod Pathol 2005;18:917–923.

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41 Esophagus and Stomach Thomas P. Plesec, md and John R. Goldblum, md

CONTENTS

I. Esophagus..........................................41-3

Nonneoplastic Anomalies.................................41-3 Webs and Rings.......................................41-3 Atresia......................................................41-3 Achalasia.................................................41-3 Glycogen Acanthosis..............................41-3 Cysts.........................................................41-4 Diverticula...............................................41-4 Heterotopic Gastric Mucosa (Inlet Patch)........................................41-4 Esophagitis........................................................41-4 Caustic (Corrosive).................................41-4 Pill-Induced.............................................41-5 Radiation.................................................41-5 Eosinophilic.............................................41-5 Infectious.................................................41-6 Gastroesophageal Reflux Disease....................41-7 Varices...............................................................41-8 Metaplasia.........................................................41-8 Barrett Esophagus..................................41-8 Sebaceous Gland Metaplasia...............41-10 Neoplastic: Epithelial.....................................41-10 Squamous Papilloma............................41-10 Squamous Cell Carcinoma..................41-10 Adenocarcinoma...................................41-12 Adenosquamous Carcinoma................41-13 Small Cell Carcinoma..........................41-13 Neoplastic: Mesenchymal..............................41-13 Leiomyoma............................................41-13 Granular Cell Tumor...........................41-14 Fibrovascular Polyp..............................41-14 Neoplastic: Miscellaneous Tumors...............41-14 Lymphoma.............................................41-14

Melanoma..............................................41-14 Metastatic..............................................41-15 Staging Esophageal Malignancies.................41-15

II. Stomach...........................................41-16 Nonneoplastic Anomalies...............................41-16 Hypertrophic Pyloric Stenosis.............41-16 Diverticula.............................................41-16 Heterotopic Pancreas...........................41-16 Pancreatic Acinar Metaplasia.............41-16 Xanthelasma..........................................41-16 Nonneoplastic: Hyperplasias, Polyps, and Reactive Lesions.................................41-17 Hyperplastic Polyp...............................41-17 Fundic Gland Polyp..............................41-17 Polyposis Syndromes............................41-17 Reactive Gastropathy...........................41-17 Inflammatory Fibroid Polyp................41-17 Ménétrier Disease.................................41-18 Zollinger–Ellison Syndrome................41-19 Gastric Antral Vascular Ectasia...............................................41-19 Gastritis...........................................................41-20 Helicobacter pylori-Associated............41-20 Autoimmune..........................................41-21 Acute Hemorrhagic..............................41-21 Phlegmonous.........................................41-21 Eosinophilic...........................................41-22 Lymphocytic..........................................41-22 Granulomatous.....................................41-22 Gastric Ulcer...................................................41-23 Neoplastic: Epithelial.....................................41-23 Adenoma................................................41-23

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_41, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Adenocarcinoma...................................41-24 Neoplastic: Mesenchymal..............................41-26 Gastrointestinal Stromal Tumor.........41-26 Leiomyoma............................................41-27 Schwannoma.........................................41-27 Lymphoid Neoplasms (See Lymph Node Chapter)..................................41-27 Neoplastic: Miscellaneous Tumors...............41-29

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Neuroendocrine Tumor (Carcinoid)........................................41-29 Glomus Tumor......................................41-30 Staging Gastric Neoplasms............................41-30

III. TNM Classification of Gastric Tumors.............................................41-31 IV. Suggested Reading...........................41-32

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ESOPHAGUS Nonneoplastic Anomalies Webs and Rings Clinical ♦♦ Webs and rings appear as thin mucosal membrane ­projections into the esophageal lumen and are composed of hyperplastic squamous mucosa overlying fibrous tissue ♦♦ Rings occur in the lower esophagus, while webs are found in the upper and middle esophagus. The most common is Schatzki ring of the lower esophagus. Patients usually complain of dysphagia ♦♦ They may be associated with Plummer–Vinson syndrome, characterized by the triad of glossitis, esophageal webs, and iron-deficiency anemia. Eosinophilic esophagitis is emerging as an important underlying etiology of esophageal rings

Atresia Clinical

There is an increased risk of squamous cell carcinoma (SCC), if untreated ♦♦ Classically, barium studies show distal “beak-like” deformity and proximal dilatation. End stage achalasia is often characterized by a sigmoid appearance to the esophagus, usually requiring esophagectomy

Macroscopic ♦♦ The esophagus shows proximal dilatation with distal fibrosis, stenosis, and ulceration. Mucosa may have a cerebriform appearance from marked squamous hyperplasia

Microscopic (Fig. 41.1) ♦♦ The histologic hallmark is loss of myenteric ganglion cells with a myenteric lymphocytic infiltrate. Secondary changes include hypertrophy of all muscle layers, squamous hyperplasia, and fibrosis in end-stage disease

Differential Diagnosis

♦♦ See Table 41.1 ♦♦ Newborns present in the first few days of life with regurgitation, choking, aspiration, and cyanosis ♦♦ Complete atresia is rare (1:30,000 live births), but atresia associated with tracheoesophageal fistula is more common (1:3,000– 4,000 live births). Atresia is usually associated with other abnormalities, including cardiac, genitourinary, and skeletal

Achalasia Clinical ♦♦ Achalasia is an esophageal motility disorder secondary to failure of relaxation of the lower esophageal sphincter. Although usually idiopathic, achalasia may be secondary to Chagas disease, sarcoidosis, intrathoracic malignancies, or numerous inflammatory conditions. Adults typically are affected, but achalasia does occur occasionally in children.

♦♦ Scleroderma (systemic sclerosis) is an important diagnostic consideration. The hallmark of esophageal scleroderma is fibrosis of the inner circular layer of the muscularis propria. The wall can be paper thin rather than hypertrophied as in achalasia

Glycogen Acanthosis Clinical ♦♦ Glycogen acanthosis is very common and is found in 15–30% of individuals, usually in the distal esophagus. Patients are typically asymptomatic, but the endoscopic differential includes candidiasis and ulcer exudate ♦♦ It is occasionally associated with the PTEN hamartoma syndrome (10q23.3 mutations), including Cowden syndrome (facial trichilemmomas, acral keratosis, gastrointestinal (GI) hamartomatous polyposis)

Table 41.1. Types of Tracheoesophageal Fistula/Esophageal Atresia Type

Macroscopic description

I

Esophageal atresia; No tracheoesophageal fistula (8%).

II

Esophageal atresia with upper-pouch fistula (upper pouch connected to the trachea; 1%).

III

Esophageal atresia with lower-pouch fistula (lower pouch connect to the trachea or main-stem bronchus; 88%).

IV

Esophageal atresia with upper and lower pouch fistula (1%).

V

Tracheoesophageal fistula; no atresia (4%).

Fig. 41.1. Achalasia.

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Macroscopic ♦♦ The gross appearance typically consists of uniform, round to oval, white, longitudinally oriented plaques. The plaques may be single or multiple and are usually small (<3 mm)

Microscopic ♦♦ The squamous mucosa is hyperplastic with glycogenization of the superficial cells, but may be indistinguishable from normal

Cysts Clinical

♦♦ Endoscopically, inlet patches are identified as an island of columnar mucosa surrounded by squamous mucosa ♦♦ These are congenital anomalies, not true metaplasias; therefore, there is no increased risk of malignancy, although case reports of adenocarcinoma arising within an inlet patch do exist

Macroscopic ♦♦ Inlet patches appear as an orange-reddish patch with sharply demarcated borders

Microscopic (Fig. 41.2)

♦♦ See Table 41.2 ♦♦ The majority of cysts are asymptomatic, but patients (both children and adults) may present with dysphagia and cough

Macroscopic

♦♦ Gastric-type mucosa with fundic glands or foveolar-type epithelium is the typical histologic finding, but goblet cells may be present. These patients probably do not require Barretttype surveillance; however, some do advocate endoscopic surveillance of inlet patches with intestinal metaplasia

Differential Diagnosis

♦♦ Generally, the esophagus is dilated

Diverticula ♦♦ See Table 41.3

Heterotopic Gastric Mucosa (Inlet Patch) Clinical ♦♦ One to ten percent of patients undergoing upper endoscopy have an inlet patch, usually in the cervical esophagus

♦♦ Adenocarcinoma −− Inlet patches lack an infiltrative pattern or cytologically malignant glands ♦♦ Barrett esophagus −− This is caused by gastroesophageal reflux; thus, the metaplasia begins at the gastroesophageal junction and extends ­proximally. Unlike Barrett, inlet patches generally are not considered to be preneoplastic

Esophagitis Table 41.2. Types of Cysts Type

Location

Etiology

Zenker

Upper third

Weakness in the muscle wall

Traction

Lower third

Caused by attachment of inflamed lymph nodes

Epiphrenic

Immediately superior to the diaphragm

Unknown

Caustic (Corrosive) Clinical ♦♦ Common agents include alkali (drain openers) and acids (cleaners, battery fluids). Children typically present as an accidental ingestion; adults are more often an intended ­suicide attempt ♦♦ Signs and symptoms vary, but include nausea, vomiting, dysphagia, refusal to drink, abdominal pain, increased salivation, and oropharyngeal burns ♦♦ Upper endoscopy is the most reliable method to document the extent of injury to esophagus and stomach and thus ­predict

Table 41.3. Types of Diverticula Type

Microscopic description

Bronchogenic

Ciliated columnar (respiratory epithelium lining; wall with smooth muscle, mucous glands, cartilage)

Esophageal

Stratified squamous lining; wall with muscularis mucosa, submucosal glands

Duplication

Squamous, gastric (fundic), ciliated columnar or small intestinal epithelial wall with muscularis mucosa, submucosa, and muscularis propria

Pseudodiverticula

Squamous metaplasia of esophageal gland and ducts

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Fig. 41.2. Inlet patch.

Esophagus and Stomach

prognosis. Injury occurs most commonly at sites of esophageal narrowing (aortic arch). Endoscopy may not be necessary if the patient is asymptomatic without swallowing difficulties ♦♦ Radiography may show mediastinitis, pneumonitis, pleural effusion, or perforation. Stricture formation is the most common chronic complication, usually when a circumferential burn occurred

Macroscopic ♦♦ Depending on the severity of exposure and underlying agent, the endoscopic appearance varies from erythema and ulceration to extensive tissue necrosis, and even perforation

Microscopic ♦♦ Biopsies are rarely taken in the acute phase, but these may show mucosal congestion, ulceration, or necrosis. Biopsies are more frequently taken to assess the chronic complications that may develop such as fibrosis and strictures

Differential Diagnosis ♦♦ Infectious esophagitis −− Fungal organisms may be identifiable (e.g., Candida), and ­special stains such as Gomori methenamine silver (GMS) may  be helpful. Characteristic viral cytopathic effect (e.g., herpes simplex virus [HSV], cytomegalovirus [CMV]) may be seen

Pill-Induced Clinical ♦♦ This form of espophagitis is due to prolonged contact of medication with esophageal mucosa and is often associated with drinking inadequate fluid or lying down after ingesting medications ♦♦ Multiple different medications have been implicated, including doxycycline, ferrous sulfate, NSAIDs, alendronate, chemotherapeutic drugs, and many others

Macroscopic ♦♦ Pill esophagitis tends to occur in the mid-esophagus (narrowed by aortic arch) and is marked by erythema/ulceration surrounded by normal mucosa

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s­ tricture. Fistula formation may also occur as a chronic complication

Macroscopic ♦♦ Endoscopic features include erythema, ulceration, necrosis, and telangiectasia

Microscopic ♦♦ Endoscopic biopsies usually only show nonspecific active esophagitis with ulcer and granulation tissue ♦♦ More characteristic changes of radiation-induced injury include bizarre epithelial and stromal cells with low N/C ratio and “smudgy” chromatin, vascular sclerosis, hyalinized collagen, and submucosal fibrosis

Eosinophilic Clinical ♦♦ Eosinophilic esophagitis is a clinicopathologic entity that requires exclusion of pathologic gastroesophageal reflux via refractoriness to standard antireflux medical therapy or normal pH on manometry ♦♦ Children are affected more commonly than adults and males more than females. Patients may present with gastroesophageal reflux disease (GERD)-like symptoms of heartburn and regurgitation. Other symptoms include dysphagia, food impaction, and abdominal pain. Children may present with failure to thrive, food refusal, and feeding intolerance

Macroscopic ♦♦ Although not pathognomic, the following endoscopic appearances have been associated with eosinophilic eosphagitis: linear furrowing, vertical lines of the esophageal mucosa, white exudates, white specks, nodules, granularity, transient or fixed circular rings, linear shearing/crepe paper mucosa, and strictures. Endoscopic-pathologic correlation is critical to the diagnosis

Microscopic (Figs. 41.3 and 41.4) ♦♦ Histologically, there is a marked intraepithelial eosinophilic infiltrate with at least one HPF demonstrating ³15

Microscopic ♦♦ Active inflammation with eosinophilic infiltration and occasional ulceration is typical; these features may be indistinguishable from reflux esophagitis or eosinophilic esophagitis ♦♦ Rarely, polarizable or iron-stainable material is found

Radiation Clinical ♦♦ The esophagus is the second most tolerant GI organ to radiation (rectum is first), but radiation esophagitis may still develop as a consequence of radiotherapy directed at pulmonary, mediastinal, or esophageal neoplasms ♦♦ Patients may complain of dysphagia, odynophagia, or ­retrosternal burning with acute injury. Acute toxicity only rarely causes bleeding or perforation. Dysphagia is the most ­common chronic complaint, usually because of

Fig. 41.3. Eosinophilic esophagitis.

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Fig. 41.5. Candida esophagitis. Fig. 41.4. Eosinophilic esophagitis. i­ntraepithelial eosinophils. Superficial eosinophil layering and eosinophilic microabscesses (tight clusters of >4 eosinophils) are also helpful clues to the diagnosis ♦♦ Less specific changes include basal cell hyperplasia, elongated papillae, lamina propria fibrosis, and other accompanying intraepithelial inflammatory cells ♦♦ Histopathologic changes seen in idiopathic eosinophilic esophagitis are not specific and may be found in eosinophilic gastroenteritis, GERD, allergy, parasite infection, or pillinduced esophagitis. Biopsy of mid/proximal esophagus is recommended and may be helpful in ­excluding GERD

be identified. True hyphae also may be seen. PAS and GMS can confirm the diagnosis. Bacterial colonization of ulcers is a frequent associated finding

Differential Diagnosis ♦♦ Hyalohyphomycoses: ♦♦ These fungi are characterized by true septated hyphae with acute angle branching and may be confused with Candida. Important hyaline septate molds include Aspergillus spp, Fusarium spp, and Pseudallescheria boydii, and these organisms may be refractory to Candida therapy. The specific organism must be identified by a validated method (e.g., culture, PCR, etc.), because histology is not a reliable means of differentiation

Infectious Candida Species Clinical

Herpes Simplex Virus Clinical

♦♦ Symptoms in most patients are from C. albicans, even when C. glabrata or C. tropicalis are coisolates. However, highly immunosuppressed patients may suffer from non-C. albicans disease. Affected patients often have some predisposing risk factor, such as extremes of ages, diabetes mellitus, transplantation, leukemia, lymphoma, AIDS, head and neck radiation, broad-spectrum antibiotics, or corticosteroids. Some patients have no apparent risk factors ♦♦ The hallmark symptom is odynophagia, often localized retrosternally, and most cases are accurately diagnosed with endoscopic brushing and biopsy. Complications are rare, but include deep invasion, systemic dissemination, strictures, and intramural pseudodiverticulosis

♦♦ The esophagus is the organ most commonly involved by HSV in immunodeficient patients, such as those affected malignancy, radiotherapy, or immunosuppressive therapy, but healthy adults and children can be affected. All affected adults show serologic evidence of a previous infection ♦♦ Symptoms include odynophagia, nausea, vomiting, hematemesis, and fever, which are frequently preceded by 3–7 days of upper respiratory infection. HSV is transmitted through direct contact, and shedding of viable virus seen in 2% of adults ♦♦ The diagnosis is based on identifying HSV by histology, cytology, and culture. Culture may only represent colonization, so histologic correlation is important

Macroscopic

Macroscopic

♦♦ Classic endoscopic appearance consists of multiple yellowwhite discrete or confluent plaques with erythematous, edematous, and friable mucosa of the mid or distal esophagus. Many patients also show oral thrush

♦♦ The mucosa shows sharply demarcated vesicles that evolve into shallow ulcerations. Severe cases demonstrate extensive mucosal denudation

Microscopic (Fig. 41.5) ♦♦ Given the ubiquity of Candida, invasion into tissue or fibrinopurulent exudate by budding yeasts and pseudohyphae must

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Microscopic (Fig. 41.6) ♦♦ Nonspecific ulceration with neutrophil-rich inflammatory ulcer in an at-risk patient is the first clue and warrants close examination for diagnostic HSV changes

Esophagus and Stomach

Fig. 41.6. Herpes esophagitis.

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Fig. 41.7. Cytomegalovirus inclusion.

♦♦ HSV cytopathic effect is best identified within the squamous cells at the edge of the ulcer; therefore, sampling is always an issue ♦♦ The classic changes include “ground glass” nuclei and Cowdry type A (dense eosinophilic) nuclear inclusions along with the “3 Ms” – nuclear molding, chromatin margination, and multinucleation. HSV immunostain is available for confirmation or if diagnostic cytopathic changes are not seen

Cytomegalovirus Clinical ♦♦ Infection with CMV is most frequently seen in posttransplant (60–70%) and AIDS patients and is rare among immunocompetent patients ♦♦ Patients may be asymptomatic or experience a mild mononucleosis-like syndrome. Other possible symptoms include odynophagia, nausea, vomiting, GI bleeding, and fever ♦♦ Similar to HSV, diagnosis is based on histology, cytology, and culture. Culture may only represent colonization, hence histologic correlation is important

Macroscopic ♦♦ The endoscopic appearance is similar to HSV, usually characterized by discrete erosions or ulcers

Microscopic (Fig. 41.7) ♦♦ In contrast to HSV targeting squamous cells, CMV cytopathic effect is best identified in the ulcer bed mesenchymal cells. CMV infection causes conspicuous intranuclear inclusions (“owl eye”) surrounded by halo as well as intracytoplasmic granular inclusions. Treated or early infections may not be as characteristic, and immunostaining can prove invaluable

Gastroesophageal Reflux Disease Clinical ♦♦ GERD is the most frequent cause of esophagitis, affecting 3–4% of the population. Patients present with regurgitation, heartburn,

Fig. 41.8. Gastroesophageal reflux changes.

pain, and dysphagia. The pathogenesis is poorly understood, since some degree of reflux is a normal physiologic process. Actual disease probably results from an imbalance between reflux and acid resistance of the esophageal epithelium ♦♦ GERD is associated with hiatal hernia, acid hypersecretion (e.g., Zollinger–Ellison syndrome [ZES]), nasogastric intubation, pregnancy, diabetes, and scleroderma

Macroscopic ♦♦ Changes predominantly affect the distal esophagus, consisting of hyperemia, erosion/ulceration, and strictures. Up to 50% of patients show either no or only minimal abnormalities

Microscopic (Fig. 41.8) ♦♦ No single specific diagnostic criterion exists, and the features may be similar to those seen in pill-induced, corrosive, radiation, eosinophilic esophagitis, and even physiologic reflux. Therefore, clinical correlation is imperative

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♦♦ Epithelial hyperplasia, evidenced by basal cell proliferation >15% of the total epithelial thickness and lengthened lamina propria papillae >67% of the epithelial thickness is helpful, but requires well-oriented sections. Dilatation and congestion of capillaries in the superficial lamina propria papillae is a soft sign ♦♦ Intraepithelial eosinophils may be particularly useful in maloriented biopsies; Greater than six eosinophils per biopsy have been cited as a minimum cut-off in adults ♦♦ Increased intraepithelial lymphocytes >10  hpf are often seen; neutrophils indicate more severe epithelial injury with erosion, ulceration, and granulation tissue ­representing the most severe GERD manifestation. Atypical, “bizarre” mesenchymal cells and multinucleated cells may be ­present in the granulation tissue

Essentials of Anatomic Pathology, 3rd Ed.

Caucasian adult males are the most commonly affected group ♦♦ The diagnosis requires both endoscopic and histopathologic confirmation. BE is considered as a preneoplastic lesion and is the only known risk factor for glandular dysplasia and adenocarcinoma. The risk of adenocarcinoma in BE patients is about 0.5%/year

Macroscopic (Fig. 41.10) ♦♦ Columnar-type epithelium of any length must be identified in the distal tubular esophagus. Flat, salmon-pink mucosa involving a portion of the lower tubular esophagus is the typical gross appearance

Table 41.4. Etiology of Varices

Varices (Fig. 41.9) Clinical

Cirrhotic

♦♦ Varies occur when portal vein pressures exceed 12 mmHg ♦♦ Etiology, see Table 41.4

Alcohol Hepatitis

Macroscopic ♦♦ The endoscopic appearance is characterized by prominently congested blood vessels in the mucosa with short, bright red, curved streaks on the surface of the varices

Metaplasia Barrett Esophagus Clinical

Noncirrhotic AV fistula Splenomegaly Splenic/portal vein thrombosis Idiopathic portal hypertension Toxins Schistosomiasis Malignancy Sarcoidosis Nodular regenerative hyperplasia Focal nodular hyperplasia Hepatic vein thrombosis Veno-occlusive disease Right-sided heart disease

♦♦ Chronic reflux is the only established predisposing factor for Barrett esophagus (BE), causing re-epithelialization of the squamous lined esophagus by a more acid-resistant columnar mucosa. In general, BE is considered irreversible ♦ ♦ About 3–12% of patients with symptomatic GERD ­harbor BE. The incidence increases with age, and older

Fig. 41.9. Varices.

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Fig. 41.10. Barrett esophagus.

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Microscopic (Figs. 41.11 and 41.12)

Differential Diagnosis

♦♦ Intestinal metaplasia (IM) of the tubular esophagus characterized by columnar epithelium with goblet cells is required for the diagnosis. Goblet cells can be confirmed by their characteristic blue staining on alcian blue at pH 2.5 ♦♦ Grading of dysplasia suffers from observer variability, and “expert” confirmation is recommended (Table  41.5 and Figs. 41.13 and 41.14). A diagnosis of high grade dysplasia (HGD) often leads to therapeutic intervention, including esophagectomy, various ablation therapies, or endoscopic mucosal resection ♦♦ Less commonly, Barrett's dysplasia is characterized by a "gastric-type" or "foveolar-type" of dysplasia. These cases should remain associated with intestinal metaplasia. This type of dysplasia is more difficult to recognize and grade since the characteristic nuclear stratification, elongation, and polarity alterations are typically absent. Criteria for dysplasia grading in gastric-type dysplasia are evolving, but remain rooted in epithelial architecture and cytology (nuclear size and nucleoli)

♦♦ Intestinal metaplasia of the cardia −− The esophagogastric junction (EGJ) is most reliably identified by the most proximal extent of the gastric folds; however, this may also be challenging endoscopically. EGJ IM in patients without apparent BE is relatively common, and therefore almost certainly does not have the same neoplastic risk as BE −− Morphologic features of BE rather than cardia intestinal metaplasia include crypt disarray, incomplete and diffuse intestinal metaplasia, multilayered epithelium, squamous epithelium overlying intestinal metaplasia, hybrid glands, and IM in the vicinity of esophageal glands/ducts −− A number of immunohistochemical markers have been evaluated, including CK7/CK20, hep par-1, CDX-2, and CD10, but none have been found to be particularly clinically useful ♦♦ Pancreatic acinar metaplasia −− This is composed of benign pancreatic acinar cells without goblet cells and is of little diagnostic significance

Fig. 41.11. Barrett esophagus, negative for dysplasia.

Fig. 41.12. Barrett esophagus, alcian blue/PAS.

Table 41.5. Dysplasia in Barrett Esophagus Negative Regular glands Mild nuclear crowding and hyperchromasia restricted to the basal portion Maturation onto the surface

Indefinite for dysplasia Mild cytoarchitectural changes with surface involvement; falls short of low grade dysplasia Marked changes, but evaluation of surface involvement is not possible

Low grade dysplasia

High grade dysplasia

Mild architectural distortion with discrete glands Nuclear enlargement, crowding, and hyperchromasia extending to surface epithelium Preservation of nuclear polarity (long nuclear axis perpendicular to the basement membrane)

Distortion of crypt architecture (marked crowding, villiform, cribiform or back-to-back glandular patterns) Marked nuclear enlargement, crowding, hypercromasia, and pleomorphism Loss of nuclear polarity Dilated glands containing necrotic debris

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Fig. 41.15. Squamous papilloma. Fig. 41.13. Barrett esophagus with low grade dysplasia.

Neoplastic: Epithelial Squamous Papilloma Clinical ♦♦ Squamous papillomas are the most common benign epithelial neoplasm, but are actually quite rare (0.01–0.04%) and are typically incidentally found. Generally, these are not considered to be premalignant ♦♦ Human papilloma virus (HPV) has been implicated in the pathogenesis, but evidence of HPV DNA in these lesions is conflicting in the literature

Macroscopic

Fig. 41.14. Barrett esophagus with high grade dysplasia. ♦♦ Inlet patch −− Inlet patches are composed of gastric-type mucosa that may harbor goblet cells, but is surrounded by squamous mucosa and is not in continuity with the GEJ

Sebaceous Gland Metaplasia Clinical ♦♦ Sebaceous gland metaplasia is very rarely detected at upper endoscopy as small yellow papules. It is, however, found microscopically in 2% of autopsy series. Sebaceous glands have been found at all levels of the esophagus, usually with multifocal involvement ♦♦ These lesions have not been described in children, indicating that they are likely a metaplastic phenomenon

Microscopic ♦♦ One sees sebaceous glands in the lamina propria or epithelium, often with accompanying lymphocytic infiltrate or associated reflux-type changes, if located in the distal esophagus

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♦♦ Most papillomas are small (<5 mm) and arise in the distal esophagus. Endoscopically, they may appear cauliflowerlike and polypoid, sessile (verrucoid), or as smooth nodules (endophytic)

Microscopic (Fig. 41.15) ♦♦ Squamous papillomas demonstrate exophytic growth with fibrovascular cores. Orderly maturation is preserved, and cytologic atypia is lacking. HPV changes, including koilocytosis, binucleation, hypergranulosis, and enlarged nuclei are inconsistently present

Squamous Cell Carcinoma Clinical ♦♦ SCC is the most common neoplasm of the esophagus worldwide, but the incidence differs significantly in different countries. North America and western Europe are considered “low-risk,” with African-Americans and men over 50  years disproportionately affected in these regions. In US, the incidence roughly equals that of the esophageal adenocarcinoma ♦♦ Risk factors include smoking, alcohol, consumption of food rich in nitrates and nitrosamines, hot beverages, achalasia, chronic stricture, tylosis, and Plummer–Vinson syndrome. HPV as etiologic agent is controversial ♦♦ SCC often presents at a late stage with patients complaining of dysphagia and weight loss. In about 60%, there are lymph node metastases at diagnosis. The overall prognosis is ­dismal,

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with a median survival of 1 year after diagnosis. The prognosis is most closely linked to tumor stage and lymph node metastases

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the dysplasia is of high grade. Carcinoma in situ corresponds to full-thickness dysplasia and may be considered as the end of the spectrum of HGD

Macroscopic

Variants

♦♦ The most common sites are the middle and lower thirds of the esophagus. Esophageal squamous carcinomas may be multifocal in up to 20% of patients. The masses are gray-white and circumferential with sharply demarcated margins and fungating, ulcerative, or infiltrative configuration. “Superficial” carcinomas are limited to the mucosa and submucosa

♦♦ Spindle cell carcinoma (Fig. 41.18) −− These are also known as carcinosarcoma or polypoid carcinoma and often exhibit intraluminal, exophytic growth with a short, thick stalk and a smooth or knobby surface. Because of the growth pattern, mural invasion is often limited, portending a better prognosis for these lesions −− Histologically, the tumors are often biphasic with both squamous carcinoma and sarcoma-like spindle cell elements. About 10% will show malignant stromal differentiation toward bone, cartilage, or skeletal muscle. These tumors are pankeratin positive (often only focal) ♦♦ Basaloid squamous carcinoma (Fig. 41.19) −− The clinical features and prognosis are similar to those of ­typical SCC. The tumor cells grow in solid nests and are

Microscopic (Fig. 41.16) ♦♦ The histology is similar to SCC of other sites with enlarged, often vesicular nuclei, densely eosinophilic cytoplasm, and intercellular bridges. Desmoplasia, mitotic rate, pleomorphism, and degree of keratinization vary from case to case, and gland formation is not uncommon. Invasion is expansile or infiltrative, but submucosal spread can occur up to 5 cm beyond grossly visible margins. Vascular invasion occurs in up to 75% of cases

Immunohistochemistry ♦♦ p63 (nuclear) and cytokeratin 5/6 are sensitive and specific markers of squamous differentiaton

Precursor/Related Lesions ♦♦ Squamous dysplasia (Fig. 41.17) −− Squamous dysplasia is found at the periphery of 60–90% of invasive cancers −− Similar to glandular esophageal neoplasia, squamous ­dysplasia may be graded as low grade or high grade. Dysplastic features include nuclear overlapping, pleomorphism, increased N/C ratios, architectural disarray, and lack of maturation −− In general, if the dysplastic epithelia are confined to basal half of the epithelium, then the lesion is considered low grade; if the dysplasia occupies more than one-half of the epithelium with more severe cytologic alterations, then

Fig. 41.16. Invasive squamous cell carcinoma.

Fig. 41.17. High grade squamous dysplasia.

Fig. 41.18. Spindle cell carcinoma.

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Fig. 41.19. Basaloid squamous carcinoma. large with hyperchromatic, pleomorphic nuclei, and scant cytoplasm. Occasional gland-like spaces are seen. Palisading at the periphery of the nests with central ­necrosis is characteristic. The mitotic rate is high ♦♦ Verrucous carcinoma −− The tumor resembles its counterparts at other sites, characterized by a large, exophytic papillary mass. Histologically, the tumor is composed of spires of well-differentiated squamous epithelium with minimal cytologic atypia. Keratohyaline granules are characteristically inconspicuous. The invasive border is blunt and pushing, and there is typically a striking chronic inflammatory reaction −− The natural history is not well-defined, but esophageal verrucous carcinomas tend to grow slowly with very low metastatic potential

Adenocarcinoma Clinical ♦♦ The incidence of esophageal adenocarcinoma is dramatically increasing, disproportionately affecting Caucasian males in their sixth to seventh decades. Adenocarcinoma represents approximately half of all esophageal carcinomas in US and is the second most common esophageal malignancy worldwide ♦♦ Ninety-five percent arise in Barrett metaplasia, which engenders a 30- to 125-fold risk of adenocarcinoma. However, most patients with Barrett will not develop adenocarcinoma. Case reports exist of adenocarcinoma developing in nonBarrett mucosa such as esophageal glands and heterotopic gastric mucosa ♦♦ The prognosis is poor (»20% 5-year survival) because most patients present at an advanced stage

Macroscopic ♦♦ Most adenocarcinomas are situated in the lower third of the esophagus. The gross appearance is variable and ranges from small, slight mucosal irregularities or plaques to large masses. The tumors are typically flat and ulcerated (70%), but may

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Fig.  41.20. Intramucosal adenocarcinoma arising in Barrett esophagus. be polypoid and fungating (30%). Neoadjuvant therapy may eliminate all visible tumors

Microscopic (Figs. 41.20 and 41.21) ♦♦ Accompanying adjacent Barrett metaplasia can usually be identified. Most are well to moderately differentiated ­intestinal-type adenocarcinomas, but mucinous, papillary, signet-ring, or squamous differentiation can occur ♦♦ Typical malignant features of nuclear hyperchromasia, cellular pleomorphism, and increased mitotic rate are usually present. The glands are often abortive and have a jagged, infiltrative growth pattern. Occasionally, tumors are so well differentiated that submucosal invasion, rather than the aforementioned cytoarchitectural features, is required to establish the diagnosis. Submucosal infiltration is often characterized by a desmoplastic stromal response

Differential Diagnosis ♦♦ High grade dysplasia −− The distinction of HGD from intramucosal adenocarcinoma (IMC) is often difficult, particularly on biopsy. By definition, HGD is an intraepithelial neoplastic process, without disruption of the basement membrane. Therefore, HGD is not composed of small, distorted glands, densely packed glands, fenestrations, or single cells within the lamina propria or muscularis mucosae that characterize IMC

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Fig. 41.21. Invasive esophageal adenocarcinoma.

Fig. 41.22. Leiomyoma.

Adenosquamous Carcinoma Clinical

Immunohistochemistry

♦♦ This is a rare aggressive malignancy with a prognosis comparable to squamous carcinoma. Squamous differentiation in adenocarcinoma or glandular differentiation in squamous carcinoma may be seen, but these are usually minor components. When malignant glandular and squamous components coexist in relatively equal proportions, the neoplasm can be considered an adenosquamous carcinoma

Differential Diagnosis ♦♦ Mucoepidermoid carcinoma −− One must recognize the classic triphasic differentiation, characterized by an intimate admixture of islands of squamous elements, intermediate cells, and mucus-secreting cells rather than distinct malignant squamous and glandular elements

Small Cell Carcinoma Clinical ♦♦ The esophagus serves as the most common extrapulmonary site for small cell carcinoma and is the most common in men aged 50–60 years. Risk factors include smoking and achalasia. Patients typically present at an advanced stage, and the prognosis is very poor with an average survival of <6 months

Macroscopic ♦♦ Tumors may be polypoid, fungating masses, or stenotic lesions with ulceration. These malignancies most commonly arise in the distal half of the esophagus

Microscopic ♦♦ Similar to pulmonary small cell carcinoma, small cell carcinoma of the esophagus is composed of solid sheets, nests, or ribbons of small blue cells with diffuse infiltration and nuclear molding. Cells are round-oval with scant cytoplasm and hyperchromatic nuclei with speckled chromatin and ­frequent mitotic figures. Nucleoli are indistinct

♦♦ Keratin AE1/AE3, CAM 5.2, Synaptophysin, and chromogranin are positive in most cases, but these may be weak and patchy

Neoplastic: Mesenchymal Leiomyoma Clinical ♦♦ More common in males (M:F = 2:1) with average age at diagnosis of 45–50 years. Patients may complain of chest pain or ­dysphagia if the tumor is large ♦♦ Leiomyomas are the most common mesenchymal tumor in the esophagus, usually arising from the inner circular layer of the muscularis propria. Leiomyomas are often difficult to see endoscopically, but radiography reveals a well-defined intra­mural mass

Macroscopic ♦♦ Ninety percent occur in the lower and middle third of the esophagus, and most are only a few millimeters in size. They are ­usually sessile, single, well-circumscribed nodules, but may be polypoid or multiple. Leiomyomas are firm, rubbery masses with pale pink-white, lobulated, and whorled cut surface

Microscopic (Fig. 41.22) ♦♦ Leiomyomas are composed of fascicles of mature, hypertrophic smooth muscle cells. The nuclei are bland and monomorphic, and mitotic figures are absent to rare. So-called symplastic leiomyomas with striking nuclear atypia have been described; mitotic activity should be very low without tumor necrosis. Hyalinization is common in esophageal leiomyomas

Immunohistochemistry ♦♦ Smooth muscle actin and desmin are usually diffusely and strongly positive, while CD117 and CD34 are negative, excluding esophageal gastrointestinal stromal tumor (GIST)

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♦♦ Radiographic findings include a long, smooth, mobile, intraluminal mass with a spectrum of appearances depending on the predominant underlying histologic component. Local excision is curative and justified to relieve symptoms and prevent the risk of regurgitation with subsequent asphyxiation

Macroscopic ♦♦ More than 80% are located in the upper third of the esophagus with a mean length of 15 cm. They have a characteristic long, slender shape and pedunculated configuration. Rarely, the tip of the polyp may ulcerate and serve as a source of upper gastrointestinal bleeding

Microscopic

Fig. 41.23. Granular cell tumor.

♦♦ Histology is variable, consisting of a mixture of collagenous to myxoid stroma, numerous dilated blood vessels, fat, and a chronic inflammatory infiltrate with overlying normal to hyperplastic squamous mucosa

Neoplastic: Miscellaneous Tumors Granular Cell Tumor Clinical ♦♦ Granular cell tumor is the second most common stromal tumor in the esophagus and usually is found in patients in their fifth to sixth decade of life as an incidental finding. Males are affected more commonly than females and African-Americans more so than Caucasians ♦♦ Characteristic endoscopic features of a sessile, yellow-white, firm lesion with intact epithelium can be strongly suggestive of granular cell tumor. The prognosis is generally excellent

Macroscopic ♦♦ These are small tumors, usually located in the distal esophagus and may be multiple in a minority of patients

Microscopic (Fig. 41.23)

Lymphoma Clinical ♦♦ The esophagus is the least common primary site of lymphoma in the GI tract; usually, the esophagus is involved secondarily. Symptoms mimic those seen in carcinoma

Macroscopic ♦♦ Esophageal lymphoma may present as a polypoid mass or thickened folds with proximal esophageal dilatation

Microscopic ♦♦ Almost all esophageal lymphoma have a B-cell phenotype, either large B-cell or MALT-type, but rare case reports of Hodgkin lymphoma and T-cell lymphoma exist

♦♦ The tumor is superficial and composed of plump epithelioid cells with small nuclei and abundant eosinophilic granular ­cytoplasm. The cells are arranged in nests or clusters and are separated by collagenous septae ♦♦ Pseudoepitheliomatous hyperplasia of the overlying epithelium is common, and misdiagnosis of SCC is a potential pitfall

Melanoma Clinical

Immunohistochemistry

Macroscopic

♦♦ Granular cell tumors are typically diffusely S-100 protein and CD68 immunoreactive. The tumor is thought to be derived from peripheral nerves, and the CD68 immunoreactivity results from the abundant cytoplasmic lysosomes, which also impart the cytoplasmic granularity

Fibrovascular Polyp Clinical ♦♦ Although fibrovascular polyps are rare, they are the most common benign intraluminal neoplasm in the esophagus, affecting males three times more frequently than females. Patients are usually in their sixth to seventh decade and asymptomatic; however, patients may also complain of dysphagia or respiratory symptoms, including acute respiratory distress

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♦♦ This is an extremely rare (<0.5% of all primary esophageal tumors) esophageal malignancy, usually arising in men over 50  years. Prognosis is extremely poor with average 5-year survival of 2% ♦♦ These are usually found in the lower esophagus as a pigmented, polypoid mass

Microscopic ♦♦ Histologically, these share similar features with cutaneous melanoma, being characterized by nests of large, atypical melanocytes with hyperchromatic and bizarre nuclei and prominent eosinophilic nucleoli. The growth pattern varies from epithelioid to spindled ♦♦ Although cytoplasmic melanin granules are usually found, amelanotic variants do occur; immunohistochemical confirmation can be quite helpful. An adjacent junctional melanocytic component can help to substantiate the esophagus as the primary site of origin

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Immunohistochemistry ♦♦ Almost all melanomas are at least focally S-100 protein +. Melan A, HMB 45, tyrosinase, and MITF are important melanocyte markers to help confirm the diagnosis

Differential Diagnosis ♦♦ Melanoma may have a variety of histologic appearances, ­making the list of possible differential diagnoses broad. Immunohisto­chemistry is often necessary in narrowing this differential diagnosis ♦♦ Carcinomas often have an epithelioid appearance and possibly signet-ring cells; they are pankeratin +, while S-100 protein, LCA, Melan A, and HMB 45-. Lymphoma demonstrates discohesive cells with scant cytoplasm; they are LCA + and usually CD20+,

but pankeratin, S-100 protein, Melan A, and HMB 45–. Sarcomas are usually spindled and pankeratin, LCA, and HMB 45–

Metastatic Clinical ♦♦ The most common primary sites of metastases to the esophagus are lung, breast, and skin (melanoma); clinical information is crucial to rule out a primary lesion. Metastases most commonly involve the submucosa of the middle third of the esophagus without mucosal involvement

Staging Esophageal Malignancies ♦♦ See Table 41.6

Table 41.6. Anatomic Stage/Prognostic Groups - Esophageal and Esophagogastric Junction Carcinoma Squamous Cell Carcinoma

Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIIA

Stage IIIB Stage IIIC

Stage IV

Tis T1 T1 T2 or T3 T2 or T3 T2 or T3 T2 or T3 T1 or T2 T1 or T2 T3 T4a T3 T4a T4b Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1 or N2 Any N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Grade

Location

1 1 2 or 3 1 1 2 or 3 2 or 3 Any Any Any Any Any Any Any Any Any

Any Any Any Lower Upper, middle Lower Upper, middle Any Any Any Any Any Any Any Any Any

Adenocarcinoma Grade Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIIA

Stage IIIB Stage IIIC

Stage IV

Tis T1 T1 T2 T2 T3 T1 or T2 T1 or T2 T3 T4a T3 T4a T4b Any T Any T

N0 N0 N0 N0 N0 N0 N1 N2 N1 N0 N2 N1 or N2 Any N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

1 1 or 2 3 1 to 2 3 Any Any Any Any Any Any Any Any Any Any

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STOMACH Nonneoplastic Anomalies Hypertrophic Pyloric Stenosis Clinical ♦♦ Hypertrophic pyloric stenosis represents one of the most ­common congenital anomalies (6–8 per 1,000 live births). First born male Caucasian infants are disproportionately affected. The average age of onset is 3–12 weeks, and this is very rare in adults. The etiology is unknown, but is thought to be a primary muscle disorder with secondary neuronal changes ♦♦ Patients classically present with projectile vomiting and a ­palpable pyloric mass. X-rays show dilated stomach and absent gas distal to the pylorus. Ultrasound can be confirmatory via measuring thickness and length of the pyloric muscle

Macroscopic ♦♦ The pyloric muscle, mainly the circular portion, is markedly thickened with abrupt termination distally

Diverticula Clinical ♦♦ Diverticula are most common in the cardia; they are presumably caused by anatomic weakness

Heterotopic Pancreas Clinical ♦♦ May be discovered incidentally or as a gastric mass. Approximately 85% occur in the antrum and prepyloric region, but pancreatic heterotopia may occur in more proximal regions of the stomach

Macroscopic ♦♦ Most (75–85%) heterotopic pancreata are in the submucosa, but they may be within the muscularis propria or subserosa as well. Generally, heterotopic pancreas appears as a raised lesion with central dimple, corresponding to the pancreatic duct, and the cut surface resembles normal pancreas. Occasionally, cysts are seen

Fig. 41.24. Heterotopic pancreas.

Xanthelasma Clinical ♦♦ These lesions are common and occur in up to 58% of autopsy series and 1% of endoscopic biopsies. They are asymptomatic, and incidence increases with age. Xanthelasma occur less commonly in other GI sites ♦♦ The pathogenesis is unknown, but xanthelasma has been associated with mucosal injury, especially H. pylori and atrophic gastritis. Xanthelasma has not been linked to any type of hypercholesterolemia

Macroscopic ♦♦ The endoscopic appearance is characterized by pale yellow well-demarcated nodules or plaques, measuring up to 10 mm

Microscopic (Fig. 41.24)

Microscopic

♦♦ Typical pancreatic acini and ducts intermixed with smooth ­muscle bundles. Only one-third of cases contain islets

♦♦ The lamina propria is expanded by loosely organized foamy histiocytes

Pancreatic Acinar Metaplasia Clinical

Differential Diagnosis

♦♦ Pancreatic acinar metaplasia is relatively common, occurring in about 1% of gastric biopsies, predominantly in the antrum and cardia. The etiology is unknown

Microscopic ♦♦ Pancreatic acinar cells in the gastric mucosa with a lobular arrangement are encountered histologically. Islets and ducts are absent

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♦♦ Infection – the cytoplasm of the foamy histiocytes is PASnegative, distinguishing these histiocytes from Whipple ­disease and MAI infection ♦♦ Signet-ring cell carcinoma (SRC) - SRC should have a infiltrative pattern with disruption of the glandular architecture. The cells usually manifest some degree of nuclear atypia. Always maintaining a high index of suspicion for SRC and a low threshold for pankeratin immunostains or mucin stains will help to prevent most diagnostic errors

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Nonneoplastic: Hyperplasias, Polyps, and Reactive Lesions Hyperplastic Polyp Clinical

♦♦ FGP are usually small (<10 mm), nondescript polyps in the body and fundus of the stomach

♦♦ Hyperplastic polyps are reported to account for 75% of gastric polyps and are generally considered as a reactive process to various insults, including chronic gastritis, bile reflux, alcohol, and drugs, ­particularly NSAIDs. Biopsies of nonpolypoid gastric mucosa may be helpful to recognize possible associated gastritis. The polyps may shrink after H. pylori eradication ♦♦ One to twenty percent of gastric hyperplastic polyps harbor ­dysplasia, but these very rarely progress to adenocarcinoma

Polyposis Syndromes

Macroscopic ♦♦ They are usually small and may be single or randomly distributed with smooth to slightly lobulated contours. They are most commonly found in the antrum, but may be encountered anywhere in stomach

Microscopic (Fig. 41.25) ♦♦ Hyperplastic polyps are characterized by elongated, tortuous, dilated foveolar epithelium embedded in an inflamed, edematous stroma with patchy fibrosis. Erosion and granulation tissue are common

Fundic Gland Polyp Clinical ♦♦ These are the second most common gastric polyp and have a female predominance. Fundic gland polyp (FGP) are usually sporadic, but they are also a characteristic finding in familial adenomatous polyposis (FAP) patients. If FAP-related, they have been associated with somatic mutations of the APC gene with high-risk of dysplasia (up to 42%). If sporadic, they are associated with mutations in the b-catenin gene with a low risk of dysplasia. There is a controversial association with the use of proton pump inhibitors

Fig. 41.25. Hyperplastic polyp.

Macroscopic Microscopic (Fig. 41.26) ♦♦ FGP arise within fundic/body mucosa; polyps are composed of dilated oxyntic glands lined by attenuated gastric parietal, chief, and mucous neck cells. If dysplasia is present (“foveolar dysplasia”), this strongly suggests FAP ♦♦ See Table 41.7

Reactive Gastropathy Clinical ♦♦ Reactive gastropathy, a.k.a. chemical or bile-reflux gastritis, is most commonly related to duodenogastric reflux (usually postgastrectomy), NSAIDs, or alcohol. Less commonly, reactive gastropathy is secondary to burns, trauma, or severe illness

Macroscopic ♦♦ Endoscopic appearance varies from normal to mucosal erosions or ulcers. The mucosa may be polypoid or demonstrate petechiae

Microscopic (Figs. 41.27 and 41.28) ♦♦ Reactive gastropathy is characterized by foveolar hyperplasia, imparting a “corkscrew” appearance to the gastric pits, reactive epithelial changes of mucin depletion and hyperchromatic nuclei as well as lack of inflammation. The nuclei lack the pleomorphism or stratification of epithelial dysplasia

Inflammatory Fibroid Polyp Clinical ♦♦ Inflammatory fibroid polyp (IFP) are most commonly found in the stomach of adults, but may occur in other locations in the GI tract. In the stomach, they are typically located in the

Fig. 41.26. Fundic gland polyp.

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Table 41.7. Hereditary Polyposis Syndromes and Gastric Manifestations Syndrome

Gene(s) altered

Microscopic

Associated gastric tumor

Familial adenomatous polyposisa

APC (5q21-22)

Adenomas, fundic gland polyps (± dysplasia)

Adenocarcinoma (rare)

Peutz-Jeghers

STK11 (19p13.3)

Hamartomatous polyps (± dysplasia)

Adenoma + Adenocarcinoma

Juvenile polyposis

SMAD4 (18q21.1) or BMPR1A (10q22.3)

Hyperplastic-like polyps (rare foveolar dysplasia)

Adenocarcinoma (rare)

PTEN hamartoma tumor syndromeb

PTEN (10q23.3)

Hamartomatous polyps

Not documented

Hereditary nonpolyposis colorectal cancer (HNPCC)c

Multiple, including MLH1, MSH2, MSH6, and PMS2 (3p21.3, 2p22-p21, 2p16, 7p22)

Nonspecific changes

Adenocarcinoma, intestinal type

Cronkhite–Canadad

–

Widespread hyperplastic polyp-like change

Adenocarcinoma

Includes classical FAP, attenuated FAP, Gardner syndrome, and some cases of Turcot syndrome Includes Cowden and Bannayan–Riley–Ruvalcaba syndromes c Includes some cases of Turcot syndrome d Nonhereditary a

b

Fig. 41.27. Reactive gastropathy. antrum and may be asymptomatic or cause bleeding, abdominal pain, or obstruction ♦♦ Although most consider IFPs to represent a benign, reactive process to mucosal trauma, IFPs may in fact be neoplastic, as one series found that 70% of IFPs are associated with activating PDGFR-alpha mutations, similar to those found in some GISTs

Macroscopic ♦♦ These polyps arise within the submucosa and are usually <5 cm and sessile

Microscopic (Figs. 41.29 and 41.30) ♦♦ IFPs consist of a proliferation of granulation-type vascular and fibroblastic elements with an intermixed inflammatory

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Fig. 41.28. Cytologic atypia in reactive gastropathy. infiltrate, which is often eosinophil-rich. The background stroma is typically loose and myxoid. Mucosal involvement is common and not a feature of malignancy

Immunohistochemistry ♦♦ IFPs are typically CD34 positive, but CD117 negative

Ménétrier Disease Clinical ♦♦ Patients present with abdominal pain, nausea and vomiting, and anemia (due to gastric bleeding). Hypochlorhydria results from loss of parietal cells, whereas hypoproteinemia and edema result from gastric protein loss ♦♦ In adults, the disease is progressive; however, in children, it tends to resolve spontaneously and may be CMV-related.

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Fig. 41.29. Inflammatory fibroid polyp. Fig. 41.31. Ménétrier disease.

vari­ably reduced, usually markedly. The stroma is ­moderately edematous and inflamed, often with a prominent eosinophil component

Zollinger–Ellison Syndrome Clinical ♦♦ ZES results from excess gastrin production, usually by a ­pancreatic or duodenal tumor. About 20% of cases are related to multiple endocrine neoplasia (MEN) type 1

Macroscopic ♦♦ The rugae of the corpus and fundus are diffusely enlarged, ­similar to Ménétrier disease

Microscopic Fig. 41.30. Inflammatory fibroid polyp. Men are more commonly affected than women, and the ­average age at diagnosis is 55 years. Ménétrier disease carries an increased risk of gastric cancer of uncertain magnitude ♦♦ Although the etiology is uncertain, Ménétrier disease ­probably results from local TGF-a overproduction and increased ­signaling through the EGFR pathway. Preliminary evidence suggests that pharmacologic blockage of EGFR signaling is beneficial and may obviate the need for gastrectomy for i­ntractable disease

♦♦ The gastric parietal cell compartment is thickened to twice the size of normal, crowding out chief and mucous neck cells. Endocrine cell hyperplasia or carcinoid tumors may be encountered in the corpus and fundus

Gastric Antral Vascular Ectasia Clinical ♦♦ The cause of Gastric antral vascular ectasia (GAVE) is unknown, but it is associated with cirrhosis and portal hypertension, bone marrow transplantation, renal insufficiency, and scleroderma. Females, usually elderly, are affected five times more than males and tend to present with iron deficiency anemia due to occult bleeding

Macroscopic

Macroscopic

♦♦ Diffusely hypertrophic rugae are encountered in the corpus and fundus with relative sparing of the antrum. Abundant luminal mucus is usually found at endoscopy

♦♦ Red patches or longitudinal, nearly parallel linear streaks radiating proximally from the pylorus are identified endoscopically, imparting a watermelon-like appearance

Microscopic (Fig. 41.31)

Microscopic (Fig. 41.32)

♦♦ Extreme foveolar hyperplasia with elongation and corkscrew appearance is uniformly present. The gastric pits may be ­cystically dilated. Gastric parietal and chief cells are

♦♦ Biopsy of the red areas shows dilated superficial mucosal blood vessels containing fibrin thrombi. The blood vessels also may be surrounded by homogeneous pink material

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Fig. 41.32. Gastric antral vascular ectasia.

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Fig. 41.33. Helicobacter pylori gastritis.

(fibrohyalinosis). The lamina propria sometimes reveals fibromuscular hyperplasia, and mucosal prolapse has been suggested as an etiology

Differential Diagnosis ♦♦ Portal hypertensive gastropathy −− Portal hypertensive gastropathy (PHG) typically affects the ­corpus and fundus and does not reveal fibrin thrombi, fibrohyalinosis, or lamina propria fibromuscular hyperplasia ♦♦ Dieulafoy lesion −− This is a large caliber artery in the gastric submucosa attached to the muscularis mucosae

Gastritis Helicobacter pylori-Associated ♦♦ There is a general lack of consensus for the classification of “chronic” gastritis, but H. pylori is considered the most common etiologic agent. The Sydney system requires at least five targeted biopsies and is not widely in everyday use ♦♦ H. pylori affects up to 100% population in several underdeveloped tropical countries and up to 50% of US population (Figs. 41.33 and 41.34). There are two main forms of gastritis associated with H. pylori: multifocal atrophic gastritis (MAG) and diffuse antral gastritis (DAG)

Macroscopic ♦♦ The mucosa shows congestion, erosions, ulcerations, and ­atrophy, but these features are not particularly distinctive

Diffuse Antral-Predominant Gastritis Clinical ♦♦ As the name implies, inflammation is most prominent in the antrum. It is H. pylori-associated in 90–100% of cases and is the typical pattern of injury in US and western Europe Caucasians. DAG may result in duodenal and pyloric ulcers. There is no increased risk of gastric adenocarcinoma, but the risk of gastric MALT lymphoma is increased

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Fig. 41.34. Helicobacter pylori.

Microscopic ♦♦ Histologically, the gastritis is characterized by lymphoid ­follicles and lamina propria expansion by mononuclear cells. Active, neutrophil-mediated epithelial injury is common, but intestinal metaplasia is relatively uncommon

Multifocal Intestinalized Pangastritis Clinical ♦♦ Gastritis may affect any region of the stomach in a patchy distribution. Although MAG is H. pylori associated 75–100% of the time, genetic and environmental factors play a role, as African-Americans, Asians, Hispanics, Scandinavians, and immigrants to the US are typically affected. Patients are at increased risk of gastric ulcers, gastric MALT lymphoma, and gastric adenocarcinoma

Microscopic ♦♦ The histology is similar to DAG except that intestinal metaplasia is characteristic and the gastritis may involve any

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Fig. 41.35. Helicobacter heilmannii. region of the stomach. Pyloric metaplasia of the corpus and fundus is also common

Histochemistry ♦♦ Giemsa, Diff-Quik, Warthin–Starry, Steiner, or Genta stains are often employed to highlight H. pylori (4 µm, gram negative curved/spiral shaped rod). H. heilmannii (spiral shaped, Fig. 41.35) measures 5–9 µm and usually produces less epithelial damage than H. pylori. Immunohistochemical stains for H. pylori are more sensitive than histochemical methods

Autoimmune Clinical ♦♦ Accounts for <5% of chronic gastritis and is usually asymptomatic unless pernicious anemia is present. It typically affects those of Northern European descent, and, in some families, it is inherited in an autosomal dominant manner. Females are affected three times more often than males ♦♦ H. pylori may serve as a trigger, but patients with autoimmune gastritis actually are less likely than matched controls to harbor H. pylori infection. Anti-parietal cell and anti-intrinsic factor antibodies are common. Patients demonstrate hypochlorhydria with resultant hypergastrinemia from parietal cell loss

Macroscopic

Fig.  41.36. Autoimmune gastritis with intestinal metaplasia (atrophy) and neuroendocrine hyperplasia. ♦♦ Enterochromaffin-like (ECL) cell hyperplasia is common, being stimulated by hypergastrinemia ♦♦ Carcinoid tumors, if present, are not aggressive

Acute Hemorrhagic Clinical ♦♦ Patients may be asymptomatic or present with epigastric pain and hematemesis, and up to one-fourth of hospital admissions for acute upper GI bleeding may be caused by acute hemorrhagic gastritis. Several causes have been implicated, including NSAIDs, alcohol, or severe stress. Curling ulcer, secondary to severe burns, is included in this category

♦♦ Gastritis is restricted to the corpus and fundus – the location of the parietal cells – and spares the antrum. Therefore, biopsy of the antrum and body/fundus is required to separate autoimmune atrophic gastritis (antral-sparing) from H. pylori-associated/environmental atrophic gastritis (antral-inclusive)

Macroscopic

Microscopic (Fig. 41.36)

Microscopic

♦♦ Changes are restricted to the oxyntic mucosa of the corpus and fundus and are characterized by loss of parietal cells and atrophy along with pyloric metaplasia and intestinal metaplasia. The histopathologic alterations undergo a characteristic progression: deep lamina propia expansion by lymphoplasmacytic infiltrate and parietal cell pseudohypertrophy → loss of oxyntic glands → marked intestinal and pyloric metaplasia

♦♦ The mucosa shows hyperemia and edema along with multiple erosions and hemorrhage ♦♦ Biopsies are rarely taken, but histology shows mucosal erosions with edema and hemorrhage

Phlegmonous Clinical ♦♦ Classically, patients are severely ill with abdominal pain, vomiting, high fevers, and underlying predisposing factors

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such as alcoholism, chronic renal failure, debilitation, ­achlorhydria, or immunodeficiency. Phlegmonous gastritis is a suppurative bacterial gastritis, either from local or hematogenous spread, and is most commonly due to Streptococcus pyogenes. The mortality rate is high, about 40%

Macroscopic ♦♦ The stomach is distended and demonstrates mural thickening due to submucosal edema. There can be focal or diffuse involvement

Microscopic ♦♦ The submucosa is the primary site of involvement with diffuse neutrophilic infiltration, edema, and vessel thrombosis. The process can progress to transmural involvement. Bacterial organisms are often identified

Eosinophilic Clinical ♦♦ Symptoms will vary according to the layer of stomach involved. Nausea, vomiting, and abdominal pain result from mucosal involvement. Involvement of the muscularis propria engenders thickening and pyloric stenosis. Serosal involvement causes peritonitis with ascites ♦♦ Exclusion of the multitude of other causes of eosinophilic infiltration of the stomach, including parasite infection, collagen vascular disease, H. pylori, Crohn disease, drug effect, food allergy, among others, is necessary. Peripheral blood eosinophilia is a useful clinical correlate

Microscopic (Fig. 41.37) ♦♦ Good normative data does not exist for gastric lamina propria eosinophils in adults, and eosinophil numbers are known to vary widely based on geography, individual variation, and time of the year. However, eosinophilic cryptitis and crypt abscesses along with abundant ­muscularis mucosae infiltration by eosinophils are useful findings on biopsy

Fig. 41.37. Eosinophilic gastritis.

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Lymphocytic Clinical ♦♦ Lymphocytic gastritis is relatively uncommon, occurring in <1% of gastric biopsies. Patients may be either asymptomatic or present with weight loss and hypoalbuminemia. Lymphocytic gastritis is most commonly associated with celiac disease or H. pylori infection

Macroscopic ♦♦ The endoscopic appearance varies according to the severity of inflammation. Endoscopy may be normal to “varioliform” with multiple bulging erosions. Similarities to Ménétrier disease, severe lymphocytic gastritis may show prominent gastric rugae, protein loss, and bleeding

Microscopic (Fig. 41.38) ♦♦ There is both increased lymphocytes in the lamina propria and foveolar and surface epithelium (often >25 lymphocytes per 100 epithelial cells). The lymphocytes are small, round, and mature without nuclear atypia; however, lymphoepithelial lesions containing ³3 lymphocytes may be rarely encountered

Immunohistochemistry ♦♦ Immunohistochemical analysis of the lymphoid infiltrate is useful if MALT lymphoma is in the differential diagnosis. The epithelial infiltrate is composed of T-cells (CD3+, CD8+) in lymphocytic gastritis rather than B-cells of MALT lymphoma

Granulomatous Clinical ♦♦ Another uncommon gastritis cause, granulomatous gastritis is most frequently seen in the setting of either H. pylori infection of Crohn disease. Other causes include sarcoidosis, postgastrectomy foreign body reaction, histoplasmosis, tuberculosis, Wegener disease, and malignancy-associated. Idiopathic granulomatous gastritis is a diagnosis of exclusion and extremely rare

Fig. 41.38. Lymphocytic gastritis.

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Microscopic (Fig. 41.39)

Differential Diagnosis

♦♦ Granulomas may involve any layer. Often the histology is nonspecific. Necrotizing granulomas are suggestive of infection. “Focally enhanced” gastritis is composed of lymphocytes, histiocytes, and sometimes neutrophils involving or surrounding gastric glands may indicate Crohn disease ♦♦ Sarcoidal and primary idiopathic granulomas are often pauciinflamed

♦♦ Ulcerated carcinoma −− Endoscopy reveals a mass protruding into the lumen or irregular, thickened, overhanging ulcer margins. Microscopically, malignant-appearing cells with a desmoplastic response may be seen. Cytokeratin immunostain may be helpful to highlight the malignant epithelial cells

Histochemistry

Neoplastic: Epithelial Adenoma Clinical

♦♦ Stains for acid-fast bacilli and fungi are helpful in the differential diagnosis

Gastric Ulcer Clinical ♦♦ Males are more commonly affected than females, and the average age at diagnosis is 50  years. Patients present with abdominal pain soon after eating. Gastric ulcers are most often associated with NSAIDs or H. pylori infection, and 95% occur along the lesser curvature. Endoscopy is the gold standard for diagnosis with >90% accuracy, whereas radiology is only 70% accurate

Macroscopic ♦♦ Gastric ulcers are sharply delineated from the surrounding mucosa. They may be oval, round, or linear and about 5% of ulcers are multiple. The edges are regular and rounded, and the ulcer base is smooth and often filled with exudate. The muscle wall and subserosa may be fibrotic with adjacent reactive lymph node hyperplasia

Microscopic ♦♦ Ulcers are composed of four layers (from superficial to deep) – purulent exudate, fibrinoid necrosis, granulation tissue, and fibrosis. Other histologic changes include thickened blood vessels, hypertrophied nerve bundles, and intestinal ­metaplasia with evidence of epithelial r­egeneration. H. pylori may be seen

Fig. 41.39. Granulomatous gastritis.

♦♦ Adenomas account for approximately 10% of all gastric polyps, increasing in prevalence with increasing patient age. The ­majority of adenomas are associated with chronic gastritis and intestinal metaplasia or FAP. Adenomas are considered precursor lesions of gastric adenocarcinoma, and, thus, adenoma incidence parallels the incidence of gastric adenocarcinoma. Adenocarcinoma arises in up to 30% of adenomas, particularly those >2 cm

Macroscopic ♦♦ Adenomas are discrete, raised sessile or pedunculated lesions that may occur anywhere, but are most common in the antrum. Most are solitary with an average size of 1 cm

Microscopic (Fig. 41.40, Left) ♦♦ Most adenomas are intestinal-type, composed of columnar epithelium, brush border, goblet cells, Paneth cells, and endocrine cells. Less commonly, gastric adenomas are composed of gastric-type mucinous epithelium, so-called foveolar adenomas, and these are less likely to harbor HGD. An emerging third entity, the pyloric gland adenoma, is a proliferation of pyloric-type mucinous glands lacking the apical mucin cap and nuclear stratification of foveolar adenomas ♦♦ Pyloric gland adenomas do not necessarily demonstrate telltale cytologic features of dysplasia, including nuclear pleomorphism, enlargement, hyperchromasia, and stratification. Dysplasia is typically classified as low or high grade in all adenomas

Fig. 41.40. Gastric adenoma (left) and high grade dysplasia arising in intestinalized gastritis (right).

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Adenocarcinoma Clinical ♦♦ Adenocarcinoma usually arises in individuals over 50 years of age. There are strong associations among adenocarcinoma and H. pylori infection, prior partial gastrectomy, and hypochlorhydria. Adenocarcinoma is considered to arise from the basal cells of the foveolae, usually in a background of chronic gastritis with intestinal metaplasia ♦♦ Carcinoma of the gastric cardia is increasing in frequency in US, and these tumors have similar clinicopathologic features to Barrett adenocarcinoma. Distal-type gastric carcinoma is more common in Eastern Asia, South America, and eastern Europe than the US ♦♦ There are two main histologic classification schemes. The Laurén classification identifies intestinal type (53%; arises from metaplastic epithelium), diffuse (33%; linitis plastica, signet-ring carcinoma; results in a thick, rigid organ with pyloric obstruction), and mixed (14%). The WHO classification not only recognizes the Laurén classification, but also identifies several other subtypes, including tubular, papillary, mucinous (>50% extracellular mucin pools), signet-ring cell (>50% composed by signet-ring cells), and other more rare entities ♦♦ Gastric cancer is also subdivided in to early and advanced gastric cancer. Early gastric carcinomas are defined as carcinomas with invasion limited to the submucosa. Most are welldifferentiated adenocarcinomas and found incidentally on endoscopy. Lymph node metastases may be present; however, the prognosis is generally excellent, especially with intramucosal carcinoma. Advanced gastric cancers invade beyond the submucosa and carry a worse prognosis. Symptoms include anemia, weight loss, abdominal pain, and dyspepsia ♦♦ The overall 5-year survival is about 10%, primarily because of late stage at presentation. Local extension to duodenum, esophagus, omentum, colon, pancreas, or spleen may occur, and metastases to lymph nodes, liver, peritoneum, lung, adrenal gland, ovary, uterus, and cervix have been described

Fig. 41.41. Adenocarcinoma, intestinal type.

Macroscopic ♦♦ Carcinomas are usually solitary, but may be multiple in 5% of cases. The gross appearance varies from fungating and ­exophytic to flat, ulcerated, and deeply invasive, and the cut surface of the intestinal type may be fleshy, fibrous, or gelatinous, depending on the amount of mucin present and extent of desmoplastic response. Diffuse-type carcinomas usually demonstrate submucosal fibrosis, mucosal ulceration, muscular hypertrophy, and subserosal thickening

Microscopic (Figs. 41.41 and 41.42) ♦♦ Gastric carcinomas are typically heterogeneous. The intestinal-type resembles colonic adenocarcinoma (Fig.  41.41), composed of glandular to solid growth of columnar, mucussecreting cells, whereas the diffuse-type (Fig. 41.42) is characterized by growth of individual signet-ring cells, marked desmoplasia, and inflammation ♦♦ The intestinal type may have prominent tubular or papillary growth or abundant extracellular mucin, resulting in mucous lakes with fragments of glands floating in mucin

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Fig. 41.42. Adenocarcinoma, diffuse type.

Histochemistry ♦♦ Mucin is PAS + and diastase resistant

Immunohistochemistry ♦♦ Gastric adenocarcinomas are at least focally pankeratin +

Esophagus and Stomach

♦♦ HER2 status −− After encouraging results from the phase III ToGA trial, determination of HER2 status in gastroesophageal (GE) and gastric cancer has become quite relevant. About 20% of these cancers are HER2+, similar to breast cancer. HER2+ cancers are more commonly intestinal-type than diffuse-type and GE than gastric −− Two important differences between HER2 IHC in GE and gastric carcinoma and breast cancer exist. First, GE and gastric cancer more often show incomplete membranous immunoreactivity sparing the luminal aspect, and this should not be interpreted as negative. Second, GE and gastric cancers seem to show more HER2 heterogeneity such that % cut-offs should not apply to 3+ biopsy samples −− See Hofmann (2008) for a proposed HER2 grading system

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♦♦

♦♦

Precursor/Related Lesions ♦♦ Dysplasia (Fig. 41.40) −− As in any other site, gastric epithelial dysplasia must be distinguished from regenerative hyperplasia. Gastric dysplasia can be classified as intestinal or the more rare foveolar. Indefinite for dysplasia is a valid diagnostic category and is used when differentiation from reactive/regenerative changes is not possible. Dysplasia is classified as low or high grade, based on the severity of alterations, and may be flat if no lesion is recognized or polypoid (adenoma) −− Dysplasia is intraepithelial neoplasia and is recognized based on architectural and cytologic alterations, including increased nuclear to cytoplasmic ratio, nuclear stratification (less so in foveolar dysplasia), reduced or absent mucus secretion, nuclear pleomorphism and hyperchromasia, frequent mitotic figures, cellular crowding, and glandular complexity and irregularity ♦♦ Intramucosal carcinoma −− Intramucosal carcinoma represents the earliest invasion beyond the basement membrane. Distinction between HGD and intramucosal carcinoma may be quite difficult on biopsy material, but intramucosal carcinoma is characterized by isolated malignant cells in the lamina propria or muscularis mucosae, very complex glandular architecture, and small, abortive glands. Desmoplasia signifies submucosal invasion. There is a small, but real risk of lymph node metastases (5%) in intramucosal carcinoma ♦♦ Hereditary diffuse gastric carcinoma −− This is an autosomal dominant inherited gastric cancer syndrome caused by germline E-cadherin mutations. Patients are also at increased risk of lobular breast cancer. Patients tend to be younger than those with sporadic gastric cancer. Tumors are diffuse-type with signet-ring cell differentiation

Differential Diagnosis ♦♦ Reactive/regenerative changes −− Ulcer with granulation tissue in the GI tract is notorious for demonstrating bizarre stromal cells (cytokeratin −) that may be misconstrued as malignant. The intact epithe-

♦♦

♦♦

lium may show reactive changes, but the epithelium should demonstrate maturation toward the surface, regular arrangement of glands, and uniform vesicular nuclei, often with prominent nucleoli Lymphoma −− Gastric lymphoma is usually B-cell type and can be distinguished from carcinoma by lack of mucin production, discohesive arrangement, LCA and CD20+, and cytokeratin − Metastasis −− Metastasis, especially from breast, lung, or skin (melanoma) shows multifocal involvement, lack of intestinal metaplasia or intraepithelial neoplasia, serosal location, and marked desmoplastic response. Immunohistochemistry is occasionally helpful, including TTF-1, GCDFP-15, estrogen receptor, S-100 protein, and cytokeratin 7/20 pattern. Clinical history is often the most helpful at distinguishing primary from metastasis Neuroendocrine neoplasm −− Gastric neuroendocrine tumor may show a prominent pseudoacinar growth pattern, mimicking adenocarcinoma. The characteristic “salt-and-pepper” chromatin, round nuclei, abundant granular pink cytoplasm, stromal hyalinization, and nested or trabecular growth pattern are helpful clues for neuroendocrine differentiation. Immuno­histochemistry for chromogranin and synaptophysin is also helpful in confirming neuroendocrine differentiation Granular cell tumor −− Gastric granular cell tumors are centered in the submucosa. They are histologically characterized by small, monomorphic nuclei, lack of mitotic figures, and granular eosinophilic cytoplasm. Granular cell tumors are S-100 protein and CD68+. They are very rarely malignant

Variants of Gastric Carcinoma ♦♦ Medullary carcinoma −− Similar to lymphoepithelial carcinoma of the upper respiratory tract, this tumor is poorly differentiated with prominent lymphoid stroma and pushing borders. The tumor cells are syncytially arranged with vesicular nuclei and prominent nucleoli. Most cases are EBV + by in situ hybridization, and the prognosis may be better than conventional gastric carcinoma ♦♦ Hepatoid adenocarcinoma −− This is characterized by large polygonal cells resembling hepatocytes. Bile production may be present. The tumor cells may also show PAS +, diastase-resistant hyaline globules and abundant cytoplasmic glycogen. The tumor cells are alpha-fetoprotein, alpha-1-antitrypsin, and albumin + ♦♦ Adenosquamous carcinoma and squamous cell carcinoma −− Adenosquamous carcinomas are characterized by a mixture of malignant glandular and squamous components, without either predominating. If the squamous component is histologically benign, then the carcinoma is best

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considered as adenocarcinoma with squamous differentiation. If the tumor is exclusively squamous, then it is best considered as squamous carcinoma

Neoplastic: Mesenchymal Gastrointestinal Stromal Tumor Clinical ♦♦ These tumors typically arise in adults in their sixth to eighth decade. The stomach serves as the most common site for GIST (50%). GISTs are derived from interstitial cells of Cajal (pacemaker cells). There is no sex predilection, except when associated with the female-predominant Carney triad. Presenting symptoms include abdominal pain and GI bleeding, but many small tumors are incidentally found ♦♦ Although there are no known risk factors for GIST, there are reports of familial GIST and syndrome-associated GIST, including neurofibromatosis type 1 (von Recklinghausen ­disease) and Carney triad (malignant epithelioid gastric GIST, pulmonary chondroma, and extra-adrenal paraganglioma) ♦♦ The clinical behavior is variable (see Table 41.8). Metastases, when they occur, are to the liver, peritoneum, and lungs. GISTs are associated with c-kit (75–80%) and PDGFR-alpha (5–10%) activating mutations; these mutations are mutually exclusive. c-kit mutations most commonly involve the juxtamembrane domain (exon 11) and less commonly exons 8, 9, 13, and 17. Treatment has been revolutionized by targeted therapy with tyrosine kinase inhibitors (e.g., Imatinib mesylate [Gleevec])

Fig. 41.43. Spindle cell GIST.

Macroscopic ♦♦ Most GISTs arise from the bowel wall as a well-circumscribed nodule in the serosa, submucosa, or muscularis propria. The cut surface is granular, often showing hemorrhage, necrosis, or cystic change. Mucosal ulceration is frequent. Tumor size is a critical parameter for predicting prognosis after complete resection

Microscopic (Figs. 41.43–41.46) ♦♦ GISTs are composed of monomorphic spindle or epithelioid cell types, or both, and show diverse histologic appearances, engendering a broad differential diagnosis ♦♦ Spindle cell gastric GISTs are composed of spindle cells with pale to eosinophilic fibrillar cytoplasm arranged in whorls or short fascicles. Nuclear palisading may be abundant, and perinuclear vacuoles (fixation artifact) are a characteristic finding. The stroma may be hyalinized or calcified ♦♦ Epithelioid GISTs or mixed epithelioid and spindle cell GISTs are the most common type of GIST in the stomach. Epithelioid GISTs are composed of epithelioid cells with eosinophilic cytoplasm arranged in nests and sheets. Scattered multinucleated, “floret-type” cells may be present. The stroma may show hyalinization, myxoid change, or calcification ♦♦ Prediction of clinical behavior is ideally based on a multiparametric analytic approach; for instance, mucosal invasion is an insensitive, but highly specific feature of aggressive behavior in GIST. However, a NIH sponsored consensus

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Fig. 41.44. Spindle cell GIST, CD117.

Fig.  41.45. Aggressive spindle cell GIST displaying mucosal invasion and several mitotic figures.

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Table 41.8. Risk of Progressive Disease in Gastric GIST

Fig. 41.46. Epithelioid GIST.

workshop proposed size and mitotic count to define risk for aggressive behavior in GIST (Table 41.8), and most ascribe to this classification scheme

Immunohistochemistry

Mitoses (per 50 hpf)*

Size (cm)

£5

£2

None (0%)

£5

>2 £ 5

Very low (1.9%)

£5

>5 £ 10

Low (3.6%)

£5

>10

Moderate (10%)

>5

£2

None (few cases)

>5

>2 £ 5

Moderate (16%)

>5

>5 £ 10

High (55%)

>5

>10

High (86%)

Risk

* In the original studies, 50 hpf were defined over an area of 5 mm2. For modern microscopes, 5 mm2 equates to about 25 hpf. Calibration with one's own microscope is recommended. Although the pathologist should count mitotic figures/5 mm2, the mitotic count should continue to be reported per 50 hpf to avoid confusion.

♦♦ CD117 (c-kit) marks 95% of GIST, and 60–70% GISTs are CD34+. Even CD117 negative GIST may respond to tyrosine kinase inhibitor therapy; expert confirmation is suggested in these unusual cases. Importantly, actin, desmin, and S-100 protein may be positive, but this immunoreactivity is usually focal. S-100 protein immunoreactivity is particularly rare (<1%) in gastric GIST

Macroscopic

Leiomyoma Clinical

Microscopic (Figs. 41.47 and 41.48)

♦♦ True smooth muscle tumors are exceedingly rare in the stomach and are much less common than GIST

Macroscopic

♦♦ Schwannomas are well-circumscribed, unencapsulated ­mural-based nodules, measuring up to 10 cm. These tumors are not associated with neurofibromatosis

♦♦ Schwannomas are variably cellular spindle cell neoplasms ­composed of wavy nuclei. Peripheral lymphoid aggregates are commonly encountered. Hyalinized vessels and Verocay bodies are less often seen than in other locations. Scattered cytologic atypia may be present, but mitotic activity is low

♦♦ Similar to their uterine counterparts, leiomyomas are well-­ circumscribed, nonencapsulated, and firm nodules with a Immunohistochemistry whorled, bulging cut surface ♦♦ Schwannomas stain diffusely and strongly for S-100 protein (Fig. 41.48), but are negative for SMA, desmin, and CD117. Microscopic CD34 may show focal positivity ♦♦ Leiomyomas are histologically characterized by bland spindle cells of low to moderate cellularity arranged in fascicles. Lymphoid Neoplasms (See Lymph Node The cytoplasm is densely eosinophilic Chapter)

Immunohistochemistry ♦♦ Leiomyomas stain strongly for a variety of muscle markers, including smooth muscle actin and desmin and are uniformly negative for CD117

Schwannoma Clinical ♦♦ These are rare, benign neoplasms of middle-aged adults

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) Clinical ♦♦ MALT lymphoma is composed of 50% of gastric lymphomas, and most patients are >50  years in age at diagnosis. Patients may present with nonspecific complaints of dyspepsia and abdominal pain. There is a strong association with chronic H. pylori infection, and remissions have been induced via H. pylori eradication

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Fig. 41.47. Gastric schwannoma.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 41.49. Low grade B-cell lymphoma of MALT type.

Fig. 41.48. Gastric schwannoma, S-100 protein.

Fig. 41.50. Low grade B-cell lymphoma of MALT type.

♦♦ MALT lymphomas have an indolent clinical course, but cases with t(11;18)(q21;q21) involving API2 and MALT1 appear to be resistant to H. pylori eradication therapy. Transformation to diffuse large B-cell lymphoma (DLBCL) may occur; these should not be termed “high grade MALT lymphoma”

architecture. The marginal zone B-cells are small to medium and centrocyte-like. They have relatively abundant pale cytoplasm, which may impart a monocytoid appearance. A minority of cells are large, transformed cells ♦♦ Lymphoepithelial lesions are defined as intraepithelial aggregates of three or more marginal zone cells causing ­epithelial distortion or destruction. Plasmacytic differentiation is relatively common, occurring in one-third of gastric MALT lymphoma. Plasma cells may show intranuclear Dutcher bodies

Macroscopic ♦♦ Endoscopically, mucosal nodularity, ulceration, and enlarged rugal folds may be seen. The cut surface shows the typical ­fish-flesh appearance of highly cellular neoplasms

Microscopic (Figs. 41.49 and 41.50) ♦♦ The lymphoma cells surround lymphoid follicles, external to the preserved mantle zone. Eventually, the infiltrate will overrun the follicles and destroy the underlying follicular

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Immunohistochemistry ♦♦ There is no specific marker for MALT lymphoma. MALT ­lymphoma demonstrates a B-cell phenotype (CD20, CD79a+)

Esophagus and Stomach

and light chain restriction. Demonstrating monotypic plasma cells by Kappa/Lambda immunostains can be quite helpful in a minority of cases, especially if flow cytometry was not ­performed. CD5 and CD10 are typically negative

Differential Diagnosis ♦♦ Florid gastritis −− Distinction of MALT lymphoma from reactive processes is based on the presence of destructive infiltrates of marginal zone B-cells in lymphoma. Gastritis-related inflammation is polyclonal with a predominance of T-cells and polytypic plasma cells ♦♦ Follicular lymphoma −− Follicular lymphoma shows a dense follicular architecture with “naked” mantle zones and absent germinal center polarization or tingible body macrophages. Follicular lymphoma shows a distinctive B-cell immunophenotype with coexpression of CD10 and bcl-6 and lack of CD5. bcl-2 immunoreactivity is not helpful in distinguishing MALT lymphoma from follicular lymphoma. Follicular lymphoma is characterized by the translocation t(14;18) (q32;q21)

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with hypergastrinemia. They are usually malignant and develop lymph node metastasis in 60%

Macroscopic ♦♦ Neuroendocrine tumors may be mass lesions or polypoid. Type I tumors are commonly multifocal. If ECL-type, they are found in the body and fundus, whereas G-cell carcinoids (<1%) are found in the antrum. Type III tumors are usually >2 cm and transmurally invasive

Microscopic (Figs. 41.51 and 41.52) ♦♦ The growth pattern is usually mixed, composed of acinar, trabecular, and insular growth. Cytologic features are bland with regular, normochromatic nuclei, few mitotic figures, and no necrosis

Diffuse Large B-cell Lymphoma Clinical ♦♦ The stomach is the most common extranodal site of involvement by DLBCL and typically presents in symptomatic adults >60 years. DLBCL are aggressive, but potentially curable; the prognosis has improved significantly in the Rituximab era

Microscopic ♦♦ There are several morphologic variants of DLBCL, but all are characterized by a diffuse proliferation of medium to large lymphoid cells. The nuclei are vesicular and contain single to multiple nucleoli

Fig. 41.51. Carcinoid, arising in a background of atrophic (intestinalized) gastritis.

Immunohistochemistry ♦♦ Most DLBCL will manifest a B-cell phenotype (CD20+)

Neoplastic: Miscellaneous Tumors Neuroendocrine Tumor (Carcinoid) Clinical ♦♦ Enterochromaffin-like (ECL) carcinoid is by far the most ­common; G (gastrin)-cell-type is less frequent. Blood gastrin measurement is critical to the classification of gastric neuroendocrine tumors ♦♦ Gastric neuroendocrine tumors may be subdivided into three types. Type I tumors are the most common and are associated with autoimmune chronic gastritis. These arise in the setting of hypergastrinemia and are almost invariably indolent. Type II tumors are syndrome-associated (MEN-1 and ZES) and also arise in the hypergastrinemic state. They are usually indolent, but a small proportion is aggressive. Type III tumors are ­considered sporadic and are not associated

Fig. 41.52. Carcinoid, chromogranin.

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Immunohistochemistry ♦♦ Synaptophysin, chromogranin, and cytokeratin are at least focally positive

Glomus Tumor Clinical ♦♦ These are rare gastric tumors with an excellent prognosis. Patients present with nonspecific signs and symptoms, such as GI bleeding and epigastric pain. Glomus tumors may be found incidentally

Macroscopic ♦♦ Glomus tumors are well-circumscribed, intramural tumors with a rubbery texture and frequent hemorrhage. They usually occur in the antrum. Mucosal ulceration is often present

Microscopic (Fig. 41.53) ♦♦ Glomus tumors are composed of nodules of tumor cells separated by smooth muscle bundles. The cells are uniform with well-defined cell membranes and round, centrally located nuclei and inconspicuous nucleoli. Oncocytic or clear cell change may be present. The stroma may be hyaline or myxoid. Size >5 cm and nuclear atypia are worrisome findings. Many glomus tumors with benign behavior show intravascular invasion

Essentials of Anatomic Pathology, 3rd Ed.

Table 41.9. Anatomic Stage/Prognostic Groups – Gastric Carcinoma Stage 0 Stage IA Stage 1B Stage IIA

Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC Stage IV

Tis T1 T2 T1 T3 T2 T1 T4a T3 T2 T1 T4a T3 T2 T4b T4a T3 T4b T4a Any T

N0 N0 N0 N1 N0 N1 N2 N0 N1 N2 N3 N1 N2 N3 N0 or N1 N2 N3 N2 or N3 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Immunohistochemistry ♦♦ Glomus tumors are strongly smooth muscle actin positive CD117-negativity and focal to negative ♦♦ CD34 immunoreactivity helps to differentiate glomus tumors from epithelioid GIST. Synaptophysin is occasionally positive in glomus tumors

Staging Gastric Neoplasms ♦♦ See Tables 41.9 through 41.11

Table 41.10. Anatomic Stage/Prognostic Groups – Gastric GISTs Mitotic Rate Stage IA Stage IB Stage II

Stage IIIA Stage IIIB Stage IV

T1 or T2 T3 T1 T2 T4 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

Low Low High High Low High High Any rate Any rate

Table 41.11. Anatomic Stage/Prognostic Groups – Gastric Neuroendocrine Tumors Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IV

Fig. 41.53. Glomus tumor.

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Tis T1 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M1

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TNM Classification of Gastric Tumors Definitions of Pathologic TNM – Esophageal and Esophagogastric Junction Carcinoma ♦♦ Primary Tumor (pT) −− pT0: No evidence of primary tumor −− pTis: High grade dysplasia −− pT1: Tumor invades lamina propria, muscularis mucosae, or submucosa −− pT1a: Tumor invades lamina propria or muscularis mucosae −− pT1b: Tumor invades submucosa −− pT2: Tumor invades muscularis propria −− pT3: Tumor invades adventitia −− pT4: Tumor invades adjacent structures −− pT4a: Resectable tumor invading pleura, pericardium, or diaphragm −− pT4b: Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc. ♦♦ Regional Lymph Nodes (pN) −− pN0: No regional lymph node metastasis −− pN1: Regional lymph node metastasis involving 1 to 2 nodes −− pN2: 3 to 6 regional nodes involved −− pN3: 7 or more regional nodes involved ♦♦ Distant Metastasis (pM) −− pM1: Distant metastasis

Definitions of Pathologic TNM – Gastric Carcinoma ♦♦ Primary Tumor (pT) −− pT0: No evidence of primary tumor −− pTis: High grade dysplasia −− pT1: Tumor invades lamina propria, muscularis mucosae, or submucosa −− pT1a: Tumor invades lamina propria or muscularis mucosae −− pT1b: Tumor invades submucosa −− pT2: Tumor invades muscularis propria −− pT3: Tumor invades subserosal connective tissue, without involvement of visceral peritoneum or adjacent structures −− pT4: Tumor involves serosa (visceral peritoneum) or adjacent structures −− pT4a: Tumor invades serosa (visceral peritoneum) −− pT4b: Tumor invades adjacent structures

♦♦ Regional Lymph Nodes (pN) −− pN0: No regional lymph node metastasis −− pN1: Metastasis in 1 to 2 perigastric lymph nodes −− pN2: Metastasis in 3 to 6 perigastric lymph nodes −− pN3: Metastasis in 7 or more perigastric lymph nodes −− pN3a: Metastasis in 7 to 15 perigastric lymph nodes −− pN3b: Metastasis in 16 or more perigastric lymph nodes ♦♦ Distant Metastasis (pM) −− pM1: Distant metastasis

Definitions of Pathologic TNM – Gastric GISTs ♦♦ Primary Tumor (pT) −− pT0: No evidence of primary tumor −− pT1: Tumor 2 cm or less −− pT2: Tumor more than 2 cm but not more than 5 cm −− pT3: Tumor more than 5 cm but not more than 10 cm −− pT4: Tumor more than 10 cm in greatest dimension ♦♦ Regional Lymph Nodes (pN) −− pN0: No regional lymph node metastasis −− pN1: Regional lymph node metastasis ♦♦ Distant Metastasis (pM) −− pM1: Distant metastasis

Definitions of Pathologic TNM – Gastric Neuroendocrine Tumors ♦♦ Primary Tumor (pT) −− pT0: No evidence of primary tumor −− pTis: Carcinoma in situ/dysplasia (tumor size less than 0.5 mm), confined to mucosa −− pT1: Tumor invades lamina propria or submucosa and 1 cm or less in size −− pT2: Tumor invades muscularis propria or more than 1 cm in size −− pT3: Tumor penetrates subserosa −− pT4: Tumor invades visceral peritoneum (serosal) or other organs or adjacent structures ♦♦ Regional Lymph Nodes (pN) −− pN0: No regional lymph node metastasis −− pN1: Metastasis in regional lymph nodes ♦♦ Distant Metastasis (pM) −− pM1: Distant metastasis

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42 Small Intestine, Appendix, Colorectum, and Anus Stephen C. Lawhorn, md and Shuan C. Li, md

Contents

I. Inflammatory and Malabsorptive III. Appendix.........................................42-14 Inflammatory Lesions....................................42-14 Disorder............................................42-3 Specific Inflammatory Disease........................42-3 Infectious Enteritis specific....................42-3 Acute Infectious Enterocolitis...............42-3 Specific Bacterial Infection....................42-3 Whipple Disease...............................................42-4 Giardiasis..........................................................42-4 Spirochetosis.....................................................42-5 Celiac Disease...................................................42-5 Tropical Sprue Syndrome......................42-6 Ulcerative Jejunitis.................................42-6 Eosinophilic Gastroenteritis..................42-6 Xanthoma (Xanthomatous Polyp).........42-7 Idiopathic Inflammatory Bowel Disease........42-7 Ulcerative Colitis....................................42-7 Crohn Disease.........................................42-8 Microscopic Colitis...........................................42-9 Lymphocytic Colitis................................42-9 Collagenous Colitis...............................42-10 Diversion Colitis....................................42-10 Solitary Rectal Ulcer Syndrome..........42-10 Radiation Proctitis/Colitis....................42-11 Diverticular Disease..............................42-11

II. Vascular Lesions...............................42-12 Acute Intestinal Ischemia..............................42-12 Chronic Ischemic Injury................................42-12 Angiodysplasia................................................42-13 Vasculitis.........................................................42-13 Scleroderma....................................................42-14

Acute Appendicitis................................42-14 Tumors.............................................................42-15 Noncarcinoid Tumors...........................42-15

IV. Intestinal Polyps...............................42-16 Developmental Polyps....................................42-16 Hamartomatous Polyp, Peutz–Jeghers Type........................42-16 Hamartomatous Polyp, Juvenile Type....................................42-16 Inflammatory Polyp..............................42-17 Hyperplastic Polyp...............................42-17 Inflammatory Fibrous Polyp...............42-18 Neoplastic Polyps: Adenomas.........................................42-18 Ganglioneuroma...................................42-21

V. Malignant Tumors............................42-21 Adenocarcinoma.............................................42-21 Carcinoid Tumors...........................................42-22 Gastrointestinsal Stromal Tumor.................42-24 Gastrointestinal Lymphoma..........................42-25 B-Cell Lymphoma of MALT.........................42-25 Mantel Cell Lymphoma (Lymphomatous Polyposis).............42-25 Burkitt and Burkitt-Like Lymphomas......................................42-26 Sprue-Associated T-Cell Lymphoma........................................42-26

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_42, © Springer Science+Business Media, LLC 2002, 2006, 2011

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42-2

Essentials of Anatomic Pathology, 3rd Ed.

VI. Anus.................................................42-26

Adenocarcinoma of Anal Duct/Gland.......................................42-28 Small Cell Carcinoma..........................42-28 Melanoma..............................................42-28

Benign Lesions................................................42-26 Hemorrhoids.........................................42-26 Fissure....................................................42-26 Fistula....................................................42-27 Tumors of Anal region...................................42-27 Condyloma Acuminatum.....................42-27 Anal Intraepithelial Neoplasia.............42-27 Giant Condyloma Acuminatum..........42-28 Squamous Cell Carcinoma..................42-28

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VII. TNM Classification of Colorectal Adenocarcinoma (2010 Revision)................................42-29 VIII. Suggested Reading...........................42-29

Small Intestine, Appendix, Colorectum, and Anus

42-3

INFLAMMATORY AND MALABSORPTIVE DISORDER Specific Inflammatory Disease Infectious Enteritis specific Clinical ♦♦ Viral > bacterial > parasitic ♦♦ Acute onset of diarrhea, usually resolves within days ♦♦ May develop a chronic malabsorption to one or various test substances ♦♦ Transient intolerance to cow’s milk or gluten; disaccharidase deficiency may occur in children

♦♦ Neutrophils within superficial lamina propria (LP) and crypts −− No chronic mucosal architectural damage −− No basal lymphoplasmacytosis

Specific Bacterial Infection Vibrios ♦♦ Unremarkable histology ♦♦ Increased mononuclear cell in LP of small intestine ♦♦ Widened intercellular spaces and junctional complexes on electron microscopy

Macroscopic

Shigellosis

♦♦ Normal to mildly erythematous mucosa

♦♦ Almost always involves rectosigmoid with variable proximal extension ♦♦ May involve cecum and the terminal ileum ♦♦ Indistinguishable from other enteric infections −− Purulent LP in severe disease, with cryptitis, crypt abscess, and pseudomembrane −− Usually associated with lymphoid follicles ♦♦ May resolve to an atrophic mucosa, mimicking inactive ulcerative colitis

Microscopic ♦♦ Intraepithelial lymphocytic infiltrate ♦♦ Mild villous blunting ♦♦ Focal active inflammation may occur

Acute Infectious Enterocolitis (Fig. 42.1) Clinical Acute onset of abdominal pain, diarrhea, and bloody diarrhea ♦♦ Symptoms are short-lived or self-limited ♦♦ Stool cultures are negative in half of the cases ♦♦ Common pathogens: Campylobacter, Salmonella, Shigella, Yersinia, and Escherichia coli

Salmonellosis

♦♦ Patchy, extremely variable mucosal erythema, inflammation, and erosion

♦♦ The most common bloodborne pathogens causing outbreaks ♦♦ Many serotypes ♦♦ Erythematous, friable mucosa, preferentially in proximal colon ♦♦ Rectum also frequently involved ♦♦ Indistinguishable from other enteric infections

Microscopic

Campylobacter Enterocolitis

♦♦ Extremely variable ♦♦ Mild mucosal edema, congestion, and nonspecific chronic inflammation

♦♦ Numerous species ♦♦ Fecal-oral transmission in contaminated water, or sexually transmitted ♦♦ Rectal involvement with variable proximal extension, mimicking ulcerative colitis endoscopically ♦♦ May have focal and segmental diseases mimicking Crohn disease ♦♦ Frequent aphthoid ulcer or inflammation ♦♦ Indistinguishable from other enteric infections

Macroscopic

Yersiniosis

Fig. 42.1. Acute infectious enterocolitis.

♦♦ Two species −− Yersinia pseudotuberculosis −− Yersinia enterocolitica ♦♦ Cause acute terminal ileitis ♦♦ Markedly thickened terminal ileum with enlarged mesenteric lymph nodes ♦♦ Necrotizing granulomas with central necrosis, neutrophilic infiltrate, and peripheral palisading histiocytes in the background of dense lymphocytic infiltration

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Pseudomembranous Colitis (Figs. 42.2 and 42.3) ♦♦ Most common in hospitals and nursing homes ♦♦ Clostridium difficile in 15–20%, occasionally others ­(verotoxin-producing E. coli); unknown cause in most of the remaining cases ♦♦ Cramping, abdominal pain, profuse diarrhea, and fever a few days or up to 8 weeks after use of antibiotics ♦♦ Affects entire colon, but most severe in the distal colorectum ♦♦ Pinpoint or plaque-like smooth, shiny lesions in milder cases ♦♦ Diffuse pseudomembrane in severe cases ♦♦ Mushroom or volcano-like exudate of neutrophils, mucin, and necrotic epithelium from superficial crypt lumen with relatively intact basal crypt ♦♦ Diffuse lamina propria neutrophilic infiltration and edema

Enterohemorrhagic E. coli (O157:H7) (Fig. 42.4) ♦♦ 3% of all acute diarrhea, but 15–36% of all acute bloody diarrhea ♦♦ Food (hamburger) outbreaks

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Diffuse friable mucosa with patchy hemorrhagic erosion ♦♦ Similar to other infectious colitis plus features of acute ischemia

Whipple Disease (Figs. 42.5 and 42.6) Clinical ♦♦ Rare, a systemic infectious disease often diagnosed through duodenal biopsies ♦♦ Caused by Tropheryma whippelii ♦♦ M > F ♦♦ Fever, weight loss, polyarthralgias, diarrhea, and central ­nervous system (CNS) symptoms

Macroscopic ♦♦ Primarily involves the jejunum ♦♦ Edematous and thickened intestinal wall with enlarged ­mesenteric lymph nodes ♦♦ Club-shaped villi show white-yellow appearance

Microscopic ♦♦ Marked villous blunting ♦♦ Foamy macrophages in LP −− Rod-like intracellular organisms strongly + on periodic acid-Schiff (PAS) with diastase stain −− Polymerase chain reaction (PCR) specifically identifies the bacterial genome

Giardiasis (Fig. 42.7) ♦♦ Most commonly reported parasitic disease in the USA and Canada

Fig. 42.2. Pseudomembranous colitis (Gross).

Fig. 42.3. Pseudomembranous colitis (Micro).

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Fig. 42.4. Enterohemorrhagic E. coli (O157:H7).

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♦♦ Cysts are ingested, then trophozoites colonize the proximal 25% of the intestines

Microscopic ♦♦ Three patterns ♦♦ Characteristic pear shaped, binucleate, gray or faintly basophilic organisms seen adherent to surface epithelium, and between villi, in otherwise normal mucosa ♦♦ Organisms seen with preserved villous architecture, but with increased intraepithelial lymphocytes ♦♦ Organisms seen with intraepithelial lymphocytes, and varying degrees of villous atrophy from partial to complete

Fig. 42.5. Whipple disease (H&E).

Spirochetosis Clinical ♦♦ Majority represents a commensal relationship with host with no associated symptoms or disease. ♦♦ Small minority may develop pathogenicity and become invasive leading to enterocolitis, hepatitis, and bacteremia −− Due to augmented virulence of the organisms −− Due to reduced host defense ♦♦ Two main organisms −− Brachyspira aalborgi −− Brachyspira pilosicoli ♦♦ Metronidazole effective therapy

Macroscopic ♦♦ Almost always normal Fig. 42.6. Whipple disease (PAS with diastase).

Microscopic ♦♦ Normal colonic architecture with minimal inflammation ♦♦ A continuous blue-gray band on the surface, and infundibular area of crypts on H&E

Celiac Disease (Fig. 42.8) Clinical

Fig. 42.7. Giardiasis. ♦♦ Clinical presentation varies from asymptomatic to chronic diarrhea, usually 5–7 days of watery diarrhea ♦♦ Usually waterborne, where cysts are ingested, can also be fecal oral, and from food contamination

♦♦ Incidence of 0.5% of general population, but may be severely underestimated ♦♦ Strong family clustering: 10% prevalence among first-degree relatives, 30% in human leukocyte antigens (HLA) identical siblings, and 70% in identical twins ♦♦ Intestinal epithelial injury caused by dietary wheat gluten (and particularly, its alcohol-soluble fraction, gliadin) ♦♦ Variable presentation from minor nutritional deficiencies to more severe steatorrhea, malnutrition, and weight loss ♦♦ Bimodal peaks: first 3 years of life and 3rd to 5th decades ♦♦ Symptoms appear during the first 3 years of life and persist throughout childhood if left untreated ♦♦ Often diminish during adolescence, only to reappear in early adult life ♦ ♦ Circulating antigliadin, antiendomysial, and tissue transglutaminase antibodies + in > 90% of the untreated patients

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Fig. 42.9. Tropical sprue syndrome. Fig. 42.8. Celiac disease. ♦♦ Increased incidence of malignancy (small intestinal T-cell lymphoma and adenocarcinoma)

Macroscopic ♦♦ Most severe in the proximal jejunum and duodenum ♦♦ Ileum is usually spared or minimally affected ♦♦ Loss of valvulae resulting in a smooth, tubular appearance of the small intestine ♦♦ Scalloped, ridged appearance of mucosa on a close-up view

Microscopic ♦♦ Increased intraepithelial T lymphocytes −− May be the only finding −− Immunostain for CD3 highlights the increase −− Should report increase in CD3 positive intraepithelial lymphocytes even in the absence of villous blunting ♦♦ Villous blunting from mild to totally flat mucosa ♦♦ Cuboidal or flattened surface epithelium with loss of goblet cells ♦♦ Increased crypt epithelial mitosis ♦♦ Dense lymphoplasmacytic infiltrate in LP ♦♦ In subclinical sprue, partial villous blunting and mild, patchy changes as mentioned above ♦♦ Mucosal architecture restores quickly following a glutenfree diet  along with a dramatic improvement of clinical symptoms

Differential Diagnosis ♦♦ Latent Celiac Sprue −− Asymptomatic or with skin manifestations (dermatitis herpetiformis) −− Become symptomatic following an intestinal viral infection or high-gluten diet −− Mild villous blunting of the duodenal mucosa with increased intraepithelial lymphocytes ♦♦ Refractory Celiac Sprue

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−− Uncommon, may be de novo or initially responsive to a gluten-free diet −− Relapse while on gluten-free diet; only responsive to corticosteroids −− Persistent flat mucosal lesion −− Poor prognosis with relentless and progressive malabsorption ♦♦ Collagenous Sprue −− Rare complication with ominous prognosis −− Typical mucosal changes of celiac sprue with a striking broadband of subepithelial collagen layer

Tropical Sprue Syndrome (Fig. 42.9) ♦♦ A malabsorptive syndrome associated with small bowel abnormalities ♦♦ Occurs in tropical regions in the world ♦♦ Unclear pathogenesis, environmental factors (especially intestinal microbial flora and enterotoxin production) ♦♦ Flat mucosal lesion throughout the small intestine ♦♦ Responsive to antibiotics, not to a gluten-free diet

Ulcerative Jejunitis ♦♦ A rare condition in the 6th or 7th decades of life with a poor prognosis ♦♦ Unknown pathogenesis; may have a history of celiac sprue ♦♦ May be associated with intestinal T-cell lymphoma, which typically forms the base of the ulceration ♦♦ Multiple mucosal ulcers in the jejunoileum ♦♦ Flattened intervening mucosa seen with celiac sprue ♦♦ Normal villous height in nonceliac associated lesions ♦♦ Nonresponsive to a gluten-free diet

Eosinophilic Gastroenteritis Clinical ♦♦ Wide range of clinical presentation including nausea, vomiting, diarrhea, abdominal pain, etc., (the usual suspects)

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♦♦ May involve any part of the GI tract but most commonly involves the esophagus, stomach, and small intestine ♦♦ Must exclude parasitic infection, specific food sensitivity, etc., so it is important to report increased eosinophils, to initiate further evaluation if indicated ♦♦ Most patients have allergic histories, allergic rhinitis, hay fever, asthma, etc. ♦♦ Over 70% of patients have peripheral eosinophilia

Macroscopic ♦♦ Variable from mild patchy erythema to diffuse bowel wall thickening, with edema, and adhesions

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Eosinophilic infiltrate, up to 50 per high power field Eosinophilic infiltrate of the submucosa with edema Eosinophils infiltrating the crypt and surface epithelium Eosinophilic infiltrate of the muscularis propria

Fig. 42.10. Ulcerative colitis.

Xanthoma (Xanthomatous Polyp) ♦♦ Collections of CD68 positive foamy histiocytes ♦♦ Usually small incidental finding ♦♦ Contain PAS with diastase positive, mucicarmine negative lipid like material ♦♦ Probably a response to past injury ♦♦ Sometimes seen in hypertriglyceridemia, and hypercho­ lesterolemia ♦♦ Differential diagnosis includes −− Infection (mycobacteria, fungi, Whipple), which can be ruled out or in with the appropriate stains −− Lipid storage disease (clinical history) −− High grade mucinous adenocarcinoma (cytokeratin positive)

Fig. 42.11. Ulcerative colitis.

−− When severe, the ulcers have “tram-line” like appearance −− Nonulcerated mucosa often appears polypoid ♦♦ Fulminant phase −− Toxic megacolon may occur, where the bowel is markedly dilated and thin-walled with diffuse congested and Idiopathic Inflammatory Bowel Disease grossly ulcerated mucosa Ulcerative Colitis (Figs. 42.10 and 42.11) −− Perforation may also occur ♦♦ Quiescent phase Clinical −− Featureless atrophic mucosa ♦♦ Incidence of 3.8–13/100,000; F slightly > M; Jews >  Caucasians > African Americans −− Shortened colon with decreased caliber and thickening of the muscularis propria ♦♦ Most common in 20–50  years of life, with second peak at age 70 Microscopic ♦♦ Causes unknown ♦♦ Inflammation exclusively confined to the mucosa in the non♦♦ 10–20% affected first-degree relatives ulcerated area

Macroscopic ♦♦ Involves the rectum with variable proximal spread in a continuous fashion ♦♦ No intervening areas of uninvolved mucosa ♦♦ The terminal ileum can be involved in 10–20% of the ulcerative pancolitis cases ♦♦ Active phase −− Mucosa appears hyperemic and granular, with inconspicuous or multiple punctate ulcers

♦♦ Active phase −− Diffuse cryptitis, crypt abscess −− Dense basal lymphoplasmacytosis −− Marked crypt distortion −− Paneth cell metaplasia ♦♦ Fulminant phase −− Indistinguishable from other causes of fulminant colitis such as ischemic colitis, severe infectious colitis, or Crohn disease

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♦♦ Quiescent phase −− Lack of cryptitis and crypt abscess −− Mucosal architectural abnormalities with crypt distortion −− Basal lymphoplasmacytosis −− Paneth cell metaplasia −− Mucosal atrophy ♦♦ Multinucleated giant cells can be seen due to histiocytic response to the ruptured crypts; true noncaseating epithelioid granulomas are not seen

Differential Diagnosis ♦♦ Crohn disease −− Involvement of terminal ileum −− Skip lesions −− Focally intense cryptitis −− Aphthoid lesions −− Epithelioid granulomas ♦♦ Infectious (bacterial) colitis −− Superficial neutrophilic infiltrate −− Preservation of mucosal architecture −− No basal lymphoplasmacytosis ♦♦ Collagenous colitis −− Intraepithelial lymphocytosis −− Subepithelial collagen table thickening −− Cuboidal or flat surface epithelium −− Lack of mucosal architectural distortion ♦♦ Lymphocytic colitis −− Intraepithelial lymphocytosis −− Cuboidal or flat surface epithelium −− Lack of mucosal architectural distortion ♦♦ Ischemic colitis −− Mucosal collapse −− LP neutrophilic infiltrate −− Microcrypts −− Intramucosal hyalinization (fibrosis) ♦♦ Drug-induced colitis and proctitis −− Lack of active inflammation −− No mucosal architectural distortion −− May have increased epithelial apoptosis −− May also mimic ischemic injury −− Seen with nonsteroidal anti-inflammatory drugs (NSAID), penicillamine, sulfasalazine, and methyldopa −− Drug history required for the evaluation

Essentials of Anatomic Pathology, 3rd Ed.

−− May be focal and often inconspicuous −− Systemic, multiple mucosal biopsies increase the chance of detection −− Histologically similar to those of colonic adenomas −− Three grades: indefinite, low-, and high grade dysplasia based on both architectural and cytological abnormalities −− Low grade dysplasia may regress or progress to higher grade −− High grade dysplasia may coexist with or progress to adenocarcinoma ♦♦ Adenocarcinoma −− Annual increment of 0.8–1% in risk after 15–20 years of disease −− Preceded by epithelial dysplasia

Crohn Disease (Fig. 42.12) Clinical ♦♦ Incidence of 3–8/100,000, and is increasing ♦♦ M:F = 1:1, one-third presents before age of 20, one-fifth presents after age of 50 ♦♦ Etiology unknown, but strong genetic predisposition; 17–35 times of risk in siblings of patients ♦♦ Chronic or nocturnal diarrhea ♦♦ Intermittent right lower-quadrant intraabdominal pain ♦♦ Anorexia, weight loss, and fever ♦♦ Recurrent oral aphthous ulcerations, perianal fissures, fistulae, or abscesses ♦♦ Extraintestinal manifestations affecting the skin, eyes, and joints ♦♦ Complications include small bowel obstruction, malabsorption, salpingitis, fistulae, and perianal abscess formation

Macroscopic ♦♦ Inflammation anywhere from mouth to anus ♦♦ Most with lesions of small and large intestines −− Small intestine only (30–40%) −− Both small and large intestines (40–50%) −− Colorectum alone (15–25%) −− Terminal ileum (90%)

Associated Conditions ♦♦ Ulcerative colitis-associated epithelial dysplasia −− Incident increases over the duration of the disease −− Risk is highest with ulcerative pancolitis −− Occur anywhere in the colon as patchy flat or slightly raised mucosal lesions

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Fig. 42.12. Crohn disease.

Small Intestine, Appendix, Colorectum, and Anus

♦♦ Colonoscopy −− Mucosal cobblestoning, aphthoid or longitudinal ulcers, and strictures −− Normal intervening mucosa (skip lesions) ♦♦ Resected specimen −− Markedly thickened bowel wall with luminal narrowing −− Mucosal cobblestoning, pseudopolyps −− Fat rapping of the serosal surface −− Fissures, fistulae, and mesenteric abscesses may also be seen

Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Transmural inflammation with multiple lymphoid aggregates Noncaseating epithelioid granulomas (in 25–50%) Aphthoid and fissuring ulcers Focally intense cryptitis, crypt abscess Skipped, normal intervening mucosa Focal, mild crypt distortion and basal lymphoplasmacytic infiltrates ♦♦ Paneth cell metaplasia ± ♦♦ Neural hyperplasia, submucosal fibrosis, and hypertrophy of the muscularis mucosae

Differential Diagnosis ♦♦ Gastrointestinal tuberculosis (TB) −− Very rare −− Granuloma with central caseous necrosis −− Travel to or residential history in areas where abdominal TB is common ♦♦ Yersinia enterocolitica −− Necrotizing granulomas within the lymphoid follicle of the bowel wall and mesenteric lymph nodes −− Positive Yersinia serology with rising antibody titer ♦♦ Ulcerative colitis −− See above ♦♦ Ischemic enterocolitis −− No epithelioid granulomas −− Lack transmural lymphoid aggregates, neural hyperplasia, or fissuring ulcer −− May be difficult to distinguish a low grade ischemic colitis in elderly patients from Crohn; subsequent clinical course may provide better differentiation ♦♦ Infectious colitis −− Most common cause of aphthous ulcers of the small and large intestine −− Diffuse superficial neutrophilic infiltrates −− Lack significant chronic inflammation −− Absence of crypt distortion or basal lymphoplasmacytosis −− No epithelioid granulomas ♦♦ Diverticular disease-associated segmental colitis −− Commonly seen in sigmoid colon

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−− Diverticula per colonoscopy −− Histologic changes may be very similar to those of Crohn −− Foreign body type granulomas ♦♦ Solitary rectal ulcer syndrome (SRUS)/mucosal prolapse change −− Usually seen in the rectum and distal sigmoid −− Polypoid, nodular, or mass-like lesion −− Intramucosal smooth muscle proliferation on histology −− Normal adjacent flat mucosa and proximal colon

Associated Conditions ♦♦ Crohn colitis-associated epithelial dysplasia −− Similar to ulcerative colitis-associated epithelial dysplasia at slightly lower incidence ♦♦ Malignancy in Crohn disease −− 0.5% of prevalence in both small and large intestines −− Most tumors occur in the colon −− Adenocarcinoma is the most common type −− Metachronous or synchronous tumors may occur −− May be preceded by detectable epithelial dysplasia

Microscopic Colitis Lymphocytic Colitis (Fig. 42.13) Clinical ♦♦ ♦♦ ♦♦ ♦♦

Affects all ages, M = F Unknown etiology Prolonged watery diarrhea Associated with autoimmune diseases (celiac sprue, arthritis, and thyroiditis)

Macroscopic ♦♦ Normal colonoscopic and radiographic examinations

Microscopic ♦♦ A marked increase of lymphocytes in the surface and crypt epithelium

Fig. 42.13. Lymphocytic colitis.

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♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Absence of a thickened subepithelial collagen layer Cuboidal and flattened surface epithelium Chronic inflammation in the LP No crypt distortion Acute cryptitis may be seen

Collagenous Colitis (Fig. 42.14 and 42.15) Clinical ♦♦ Affects middle-aged and older women, F:M = 10:1 ♦♦ Unknown causes ♦♦ Protracted watery diarrhea without systemic symptoms

Macroscopic ♦♦ Normal colonoscopic and radiographic examinations

Microscopic ♦♦ Proximal colon is more affected ♦♦ Thickened subepithelial collagen layer (usually >10  µm, ­normal: 2–3 µm); best viewed by Masson trichrome stain

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ ♦♦ ♦♦ ♦♦

Increased intraepithelial lymphocytes Chronic inflammation of the LP Surface epithelial damage May have active inflammation

Diversion Colitis (Fig. 42.16) Clinical ♦♦ In 90–100% of patients with a history of colostomy or ileostomy for various reasons, including inflammatory bowel disease (IBD) ♦♦ Related to the depletion of fecal short-chain free fatty acids and/or luminal bacterial stasis ♦♦ Persistent symptom unless re-anastomosis takes place

Macroscopic ♦♦ Mucosa erythema, friability, edema, and granularity, ­mimicking ulcerative colitis ♦♦ More severe in rectum than in the proximal colon

Microscopic ♦♦ Mild-to-moderate chronic inflammation with mild architectural change ♦♦ Cryptitis, crypt abscess, and erosion may be seen ♦♦ Prominent mucosal lymphoid hyperplasia ♦♦ Mucosal atrophy may be seen

Solitary Rectal Ulcer Syndrome (Fig. 42.17) Clinical ♦♦ Affects all age groups, but more common in the young ♦♦ Constipation, excessive straining, rectal pain, and mucus discharge

Macroscopic ♦♦ Affect anterior and anterolateral rectal wall

Fig. 42.14. Collagenous colitis.

Fig. 42.15. Collagenous colitis.

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Fig. 42.16. Diversion colitis.

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♦♦ Acute phase −− Diarrhea, tenesmus, mucoid rectal discharge, and rectal bleeding ♦♦ Chronic phase/complications −− 10% of the cases −− Tenesmus, mucoid rectal discharge, which may be bloody −− Persistent decrease in stool caliber and constipation

Macroscopic ♦♦ Focal, limited to the immediate field of irradiation ♦♦ Variably dusky and edematous mucosa with a blurred vascular pattern ♦♦ Friability and ulceration with a high dose of radiation ♦♦ Multiple mucosal telangiectasias and luminal narrowing with fibrosis Fig. 42.17. Solitary rectal ulcer syndrome (SRUS).

♦♦ Indurated, polypoid lesion, solitary or multiple ♦♦ Surface ulceration

Microscopic ♦♦ Thickened muscularis mucosae with intramucosal smooth muscle proliferation between the crypts ♦♦ Variable acute and chronic inflammation of the LP ♦♦ Surface erosion and inflammatory exudate ♦♦ Submucosa entrapment of crypts filled with mucin (colitis cystica profunda)

Differential Diagnosis ♦♦ Crohn disease −− See above −− Clinical history −− Abnormal proximal colonic biopsies ♦♦ Malignancy-induced SRUS/mucosal prolapse −− SRUS-like changes in the mucosa overlying a malignant infiltrate located in the submucosa or muscularis propria due to primary tumor or metastasis −− Tumor cells may be seen in the biopsy −− Immunohistochemistry may be required to identify these rare tumor cells −− Perirectal mass or rectal wall thickening on computed tomography ♦♦ Radiation proctitis/colitis −− See below

Radiation Proctitis/Colitis Clinical ♦♦ History of radiation to pelvic or intraabdominal malignancies ♦♦ Most common in rectosigmoid ♦♦ Symptoms appear during or shortly after therapy; may even appear months or years later

Microscopic ♦♦ Acute changes −− Last for 1–2 months −− Edematous LP with fibrinoid vascular necrosis −− Reactive endothelial and epithelial cells −− Excess of apoptosis in the basal crypts −− Mucosal neutrophilic infiltration ♦♦ Late changes −− Mucosal atrophy with reduction of crypt epithelium −− Crypt distortion, Paneth cell metaplasia, fibrosis, and smooth muscle proliferation −− Dilated, telangiectatic blood vessels approaching the luminal surface

Diverticular Disease Clinical ♦♦ Uncommon before age 40; approaching 50% by the 9th decade of life ♦♦ Most common in sigmoid in USA; right-sided lesion more common in Asia ♦♦ Multifactorial pathogenesis including increased intraluminal pressure, colonic wall aging and motor dysfunction, and lack of dietary fiber ♦♦ Majority are asymptomatic ♦♦ Presents with bloating, excessive flatulence, and intermittent abdominal pain ♦♦ Fever is associated with inflamed diverticula (diverticulitis)

Macroscopic ♦♦ Two rows on either side of the colon between mesenteric and antimesenteric teniae ♦♦ <1 cm, lie within the pericolic fat, and especially the appendices epiploicae ♦♦ Markedly thickened colon wall ♦♦ Prominent mucosal ridges and intervening saccular dilatations ♦♦ Pericolic abscess formation is common

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Microscopic ♦♦ Diverticula are lined by mucosa and submucosa and covered by pericolic connective tissue and serosa ♦♦ Hypertrophied muscularis propria (MP) at the neck of diverticulum

♦♦ In diverticulitis −− Neutrophilic infiltration of the crypts, LP, and surrounding pericolic fat −− Prominent chronic inflammation and fibrosis −− Foreign body giant cells

VASCULAR LESIONS Acute Intestinal Ischemia (Table 42.1) Clinical ♦♦ Occlusive causes −− Arterial thrombosis and embolism (a) Most common cause of acute small intestinal ischemia (b) Frequently superimposed on severe superior mesenteric artery (SMA) atherosclerosis (c) Sources of emboli include ischemic heart disease, spontaneous or procedure-related cholesterol emboli, and iatrogenic embolization by “Gelfoam” −− Atherosclerosis (a) Most common mesenteric vascular disease but rarely the cause of acute ischemia by itself (b) Usual cause of chronic ischemia −− Arteritis (a) Usually as part of a systemic disorder (b) Examples include polyarteritis nodosa (PAN), rheumatoid arthritis, systemic lupus erythematosus (SLE), and Takayasu disease −− Small vessel disease (a) Henoch–Schönlein purpura, leukocytoclastic vasculitis, and disseminated intravascular coagulation (DIC) −− Mesenteric venous thrombosis

(a) Rare, <10% of the causes (b) Associated with portal hypertension, hypercoagulable state, abdominal surgery or trauma, and intraabdominal sepsis −− Mechanical obstruction (a) Volvulus, strangulation, and intussusception ♦♦ Others −− Dissecting aneurysm involving SMA −− Arteriopathies with intimal hypertrophy in systemic hypertension −− Radiation injury or fibroelastosis adjacent to carcinoid tumors ♦♦ Nonocclusive causes −− Account for 25–50% of all cases −− A consequence of vasoconstriction in response to decreased cardiac output, hypotension, hypovolemia, dehydration, or drugs (digitalis, cocaine), frequently with underlying arterial atherosclerosis

Macroscopic and Microscopic (See Table 42.1) Chronic Ischemic Injury Clinical ♦♦ A consequence of acute mural infarct or chronic mesenteric insufficiency

Table 42.1. Acute Ischemic Injury of the GI Tract Stage of injury Mucosal necrosis:

Gross

Histology

Mucosal congestion and erythema

Disintegration of surface and crypt epithelium Interstitial hemorrhage, edema, and neutrophilic infiltrate Mucosal outline usually preserved Mucosal and submucosal necrosis and hemorrhage Eosinophilic necrosis of inner smooth muscle layer Smooth muscle necrosis with marked edema and neutrophilic infiltrate Marked congestion involving subserosa

Shallow ulcers

Mural necrosis:

Marked mucosal congestion, hemorrhage, and ulcers Serosal congestion

Transmural necrosis:

Gangrenous, flaccid, dilated, and serosal fibrinous exudate May have perforation

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Prognosis Usually reversible

Progress to transmural necrosis Perforation Perforation Surgery is always indicated; if massive, may not survive

Small Intestine, Appendix, Colorectum, and Anus

♦♦ SMA atherosclerotic narrowing is the most common cause ♦♦ Other causes include aortic aneurysm and congenital anomalies of SMA ♦♦ Usually manifests as abdominal pain ♦♦ Poor correlation with angiographic studies

Macroscopic ♦♦ Segmental chronic ulcers with excessive fibrosis and stricture

Microscopic ♦♦ Ulcer bed with inflamed granulation tissue, excessive fibrosis, hemosiderin-laden macrophages, and fibrous replacement of the muscle layers ♦♦ Regenerative epithelial hyperplasia at the margins ♦♦ Chronic inflammation at the periphery of the ulcer ♦♦ Mucosa away from the ulcers is usually normal

Differential Diagnosis ♦♦ Crohn Disease −− Mucosal inflammation away from the ulcer −− Dense, aggregated inflammation extends to the serosa −− Presence of granulomas ♦♦ Drug-Induced Ulcers −− Morphologically very similar −− History of medication −− Lack of hypotensive and vascular diseases

Special Forms ♦♦ Ischemic Colitis (Fig. 42.18) −− More common in 6th and 7th decades −− Torsion or hernia strangulation are uncommon causes due to the location of the large intestine being primarily retroperitoneal −− More prone to primary vascular causes of ischemia

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−− Inferior mesenteric artery (IMA) is less prone to embolization than the SMA −− Splenic flexure (watershed area) is the most common site of ischemia −− Acute fulminant disease with progression to transmural necrosis is rare −− Complete resolution of symptoms within 4 weeks in 50% of patients; 5–12% recurrence rate −− Chronic ischemia may lead to progressive stenosis and obstruction ♦♦ Ischemic Enteritis −− SMA embolism is the most common cause (40–50%), followed by nonocclusive mesenteric ischemia and SMA thrombosis (5–10%), torsion or hernia strangulation −− Most common in elderly with underlying cardiovascular disease −− Frequently presents with an acute onset of abdominal pain

Angiodysplasia Clinical ♦♦ Vast majority occurs in the right colon, occasionally in the small intestine ♦♦ Presents with chronic intestinal bleed, anemia, and weight loss ♦♦ Three types −− Type I: most common, >55  years of age, usually in the right colon −− Type II: mean age of 29, usually in the stomach and proximal small bowel −− Type III: with family history and punctate telangiectatic lesions in GI tract, oral mucosa, and skin

Macroscopic ♦♦ One or more sharply delineated red flat or slightly raised mucosa with scalloped edges and a prominent draining vein

Microscopic ♦♦ Dilated, tortuous submucosal veins with distended branches piercing through the muscularis mucosae, connecting with dilated capillaries between the crypts in the LP ♦♦ Ectatic small vessels may fill the entire mucosa ♦♦ Surface mucosa erosion and acute and chronic inflammation

Vasculitis (Table 42.2) Clinical

Fig. 42.18. Ischemic colitis.

♦♦ Part of systemic vasculitis with GI tract involvement; or an isolated vasculitis affecting only the GI tract (serum autoantibodies frequently negative) ♦♦ The frequency of GI tract involvement by a systemic vasculitis −− 25% in polyarteritis nodosa

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Table 42.2. Types of Vasculitis Affecting the GI Tract Type of vasculitis

Fibrinoid necrosis

Type of vessel affected

Thrombi

Histological pattern Mixed acute and chronic necrotizing inflammation; may be focal and segmental Lymphocytic infiltrate of veins with sparing of artery Extravascular granuloma with eosinophilic microabscess

Polyarteritis nodosa

Medium arteries, arterioles, large arteries

Very common, often segmental

Uncommon

Phlebitis

Medium veins, venules, large veins

Uncommon

Uncommon

Churg–Strauss angiitis

Medium veins and arteries, arterioles and venules, large veins and arteries (less common) Arterioles, venules

Common

Uncommon

Common

Uncommon

Small-vessel vasculitis

−− 25% in rheumatoid arthritis −− 2% in SLE −− Very high frequency in Henoch–Schönlein purpura ♦♦ Organ involvement varies among the types of vasculitis −− Polyarteritis often affects the small intestine −− Phlebitis usually affects the colon

Macroscopic ♦♦ Solitary or multiple ulcers, mucosal or transmural necrosis ♦♦ Short or long segment of involvement ♦♦ Stricture may follow recovery of transmural ischemic necrosis ♦♦ Unremarkable mesenteric vessels grossly ♦♦ Histological examination is required to diagnose vasculitis

Microscopic ♦♦ All vasculitides, regardless of systemic or localized forms, demonstrate similar histological changes ♦♦ Specific types of vasculitis can only be distinguished by microscopic examinations (Table 42.2)

Lymphocytic cuffing Numerous nuclear dust

Scleroderma Clinical ♦♦ A progressive systemic sclerosis involving multiple organs that include skin, cardiovascular system, and GI tract ♦♦ Affect medium and small arteries causing tissue damage ♦♦ Visceral involvement may precede or occur in the absence of skin changes ♦♦ Esophagus is most frequently affected in the GI tract

Macroscopic ♦♦ Rigid, fibrotic, and often dilated intestinal tract ♦♦ Mucosal inflammation is often seen due to bacterial stasis ♦♦ Large diverticula have also been reported

Microscopic ♦♦ Atrophy of MP with disappearance and fibrous replacement of inner circular muscle coat ♦♦ Concentric intimal thickening, medial fibrosis, and fibrin deposition in medium- and small-sized arteries ♦♦ Nonspecific mucosal chronic or active inflammation

APPENDIX Inflammatory Lesions Acute Appendicitis Clinical ♦♦ Definitive causes unknown, but most likely secondary to luminal obstruction by fecalith, or less commonly, a gallstone, tumor, or worms, which results in ischemic injury

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♦♦ Usually presents with acute onset of right lower quadrant pain with chills and fever

Macroscopic ♦♦ Enlarged and congested appendix with often purulent serosal surface ♦♦ Reddened mucosa on cut surface ♦♦ Often with luminal pus

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♦♦ Gangrenous necrosis of the muscular wall in advanced cases ♦♦ With or without perforation

Microscopic ♦♦ Neutrophilic infiltrate of the mucosa and the muscularis ­propria; the latter is generally required the diagnosis ♦♦ Luminal inflammatory exudate ♦♦ Acute inflammation may be focal

Differential Diagnosis ♦♦ Y. enterocolitis −− Prominent lymphoid aggregate with central zone necrotizing granuloma ♦♦ Parasitic Infection −− Luminal parasites of enterobius vermicularis, amebiasis, and schistosomiasis ♦♦ Crohn Disease −− Lymphoplasmacytic transmural inflammation with lymphoid aggregates −− Mural thickening −− Occasional granulomas ♦♦ Ischemia −− May be involved in ischemic injury of the right colon

Fig. 42.19. Appendiceal villous adenoma.

Tumors Noncarcinoid Tumors Clinical ♦♦ Uncommon, with overall incidence of 1–2% of the resected appendiceal specimens ♦♦ Often an incidental finding after appendectomy for acute appendicitis ♦♦ Adenocarcinoma accounts for 0.3% of all GI tract tumors ♦♦ Rarely diagnosed pre- or intraoperatively ♦♦ May preceded by metastatic ovarian tumors (Krukenberg tumors) ♦♦ The terminology of mucocele and pseudomyxoma peritonei does not truly reflect the underlying pathology

Fig. 42.20. Appendiceal hyperplastic polyp.

Macroscopic ♦♦ Normal, inflamed, or enlarged appendix filled with mucus (mucocele) ♦♦ Mucus may be seen on appendiceal or peritoneal surface due to rupture ♦♦ May have identifiable tumor

Microscopic ♦♦ Adenoma (Fig. 42.19) −− Identical to the colonic counterpart −− More often tubulovillous adenoma ♦♦ Hyperplastic polyps (HPPs) (Fig. 42.20)

−− Identical to the colonic counterpart ♦♦ Mixed adenoma and HPP −− Identical to the colonic counterpart ♦♦ Adenocarcinoma −− Identical to the colonic counterpart −− Often mucinous type −− May be positive for both CK7 and CK20 −− Malignant pseudomyxoma peritonei frequently occur ♦♦ Soft tissue tumors −− Leiomyoma and neuroma (fibrous obliteration)

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♦♦ Lymphoma −− Very rare ♦♦ Carcinoid tumors (Fig. 42.21) −− Occur near the appendiceal tip −− Gross nodule or expansion of the appendiceal wall by neuroendocrine cells −− Neuroendocrine cells in insular or tubular pattern into or through the appendiceal wall −− Three variants (a) Insular carcinoid: 5-year survival of 95% (b) Tubular carcinoid: 5-year survival of 95% (c) Goblet cell carcinoid: 5-year survival of 80% −− Also see intestinal neoplasms

Fig. 42.21. Appendiceal goblet cell carcinoid tumor.

INTESTINAL POLYPS Developmental Polyps Hamartomatous Polyp, Peutz–Jeghers Type (Fig. 42.22) Clinical ♦♦ An autosomal dominant trait with variable penetrance ♦♦ Most common manifestation of Peutz–Jeghers syndrome ♦♦ Polyp itself has no or very low malignant potential, but epithelial dysplasia can occur ♦♦ Increased GI tract malignancy, 2–3% in Western countries and up to 17% in Japanese series ♦♦ Increased extraintestinal benign and malignant tumors, especially ovarian sex cord tumors and adenoma malignum of the endocervix

Macroscopic ♦♦ GI tract polyps, usually <100 ♦♦ Most common in small bowel but can occur in the stomach and colon ♦♦ Large, lobulated mass, sessile, or pedunculated and may cause obstruction and intussusception

Microscopic ♦♦ Mucosal components in fairly normal proportion, typical of their site of origin, arranged on a complex branching of MM ♦♦ May have surface erosion and active chronic inflammation ♦♦ Epithelial dysplasia may occur

Differential Diagnosis ♦♦ Juvenile polyp (see below)

Hamartomatous Polyp, Juvenile Type (Fig. 42.23) Clinical

Fig. 42.22. Hamartomatous polyp, Peutz-Jeghers type.

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♦♦ Appear in 1st and 2nd decades of life with the peak incidence at 4–5 years of age ♦♦ As isolated cases or as juvenile polyposis (JP) syndrome ♦♦ JP is defined as −− More than five juvenile polyps of the colorectum −− Juvenile polyps throughout the GI tract −− Any number of juvenile polyps with a family history of JP ♦♦ An autosomal dominant trait with high penetrance in onethird of JP patients; new mutations may occur in nonfamilial cases

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Fig. 42.23. Hamartomatous polyp, juvenile type.

Fig. 42.24. Inflammatory polyp.

♦♦ Presents with small amount of bright red blood during defecation, or less frequently, severe bleed, anemia, intussusception, failure to thrive, and rectal prolapse ♦♦ Most lesions, if undetected, regress before adolescence ♦♦ High incidence of allergic symptoms such as asthma and hay fever ♦♦ Polyp itself has no increased malignant potential ♦♦ JP patients have shown an increased incidence of GI cancer (>10%)

♦♦ Commonly seen in ulcerative colitis and Crohn disease ♦♦ Rare in infectious colitis ♦♦ Polyp itself has no intrinsic malignant potential

Macroscopic ♦♦ Commonly occur in colorectum ♦♦ A few solitary (in nonpolyposis cases) or multiple (usually 50–200 in JP) pedunculated polyps ♦♦ 0.1–5 cm in size ♦♦ Smooth rounded surface, may be diffusely ulcerated, and numerous mucus-filled cysts on cut surface

Microscopic ♦♦ Expanded edematous LP permeated with inflammatory cells frequently including eosinophils ♦♦ Rare thin strips of smooth muscle of vascular origin in the LP, may become collagenous in older lesions ♦♦ Distorted or dilated crypts filled with mucin and inflammatory exudate, and lined by normal colonic-type goblet and absorptive cells with regenerative and hyperplastic features ♦♦ May contain adenomatous (dysplastic) foci or true adenomas of all grades of dysplasia

Differential Diagnosis ♦♦ Peutz–Jeghers polyp (see above) ♦♦ Inflammatory polyp (see below)

Inflammatory Polyp (Fig. 42.24) Clinical ♦♦ As a result of colonic inflammatory condition

Macroscopic ♦♦ May be multiple ♦♦ Polypoid mucosal projections with varying length of stalk ♦♦ Abnormal surrounding mucosa that may be diffusely ulcerated

Microscopic ♦♦ Polypoid mucosal lesions composed of distorted, dilated, and branched crypts surrounded by inflammatory granulation ­tissue that usually contains bundles of smooth muscle ♦♦ Cryptitis or crypt abscess is commonly seen −− Some crypts may show regenerative changes −− Some may be composed entirely of granulation tissue ♦♦ Adjacent or distant colonic mucosa shows underlying disease if associated with IBD

Differential Diagnosis ♦♦ Juvenile polyp (see above) ♦♦ Pseudopolyp (composed of inflamed to relatively normal looking residual mucosa among an ulcer bed)

Hyperplastic Polyp (Fig. 42.25) (Table 42.3) Clinical ♦♦ The most common colonic polyps (ten times that of colonic adenomas) ♦♦ Caused by delayed surface epithelial loss and normal basal crypt production ♦♦ Asymptomatic; increasing incidence with age ♦♦ No clear association with IBD or neoplasms ♦♦ Generally not considered as a neoplastic polyp ♦♦ Possible link to cancer through serrated pathway in giant HPP or hyperplastic polyposis

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Table 42.3. Serrated Polyps of the Colon Hyperplastic polyp Serrated deep crypts: Crypts:

Usually minimal Usually straight

Pseudostratified nuclei: Nuclei:

Minimal Small, dark, usually at basal location in cell

Proliferative zone:

Lower one-third of crypt even proliferation

Sessile serrated polyp Often prominent Branched, cystic dilation, horizontal orientation to muscularis mucosa Prominent Larger, open chromatin, occasional nucleoli, often central location in cells

Serrated polyp Variable Variable

Characteristic Obvious dysplasia with hyperchromasia, irregular nuclear membranes, clumped chromatin pattern; High N/C ratio Lower two-thirds of crypt with occasional Everywhere mitosis in upper one-third of crypt; uneven proliferation causes much if not all of the crypt distortion mentioned above

Inflammatory Fibrous Polyp (Fig. 42.26) ♦♦ ♦♦ ♦♦ ♦♦

Mostly seen in ileum (following stomach), rare in the colon Episodic pain, intussusception, and bleed Pedunculated polyp with surface erosion Hypocellular fibrous and myxoid stroma with CD34+ stromal cells ♦♦ Numerous small vessels with hyalinized wall ♦♦ Increased inflammatory cells, especially eosinophils

Neoplastic Polyps: Adenomas Clinical

Fig. 42.25. Hyperplastic polyp (HPP).

Macroscopic ♦♦ Occur only in the colorectum and appendix ♦♦ Frequently multiple rounded to oval mucosal elevations or plaques ♦♦ 1–3 mm but may rarely reach 1 cm

♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Microscopic ♦♦ Localized mucosal expansion (both crypts and LP) ♦♦ Mature columnar and goblet cells piling up along the crypt creating a serrated surface ♦♦ Thickened subepithelial basement membrane ♦♦ Occasional crypt epithelial neutrophilic infiltration ♦♦ May occasionally superimpose on an adenoma (mixed adenoma and hyperplastic polyp)

Differential Diagnosis ♦♦ Sessile serrated adenoma/polyp (see below)

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♦♦ ♦♦

Second most common GI tract polyps A precancerous lesion Affecting 30% or more individuals after 40 years of age Peak incidence in the 6th and 7th decade of life Mostly sporadic and are not associated with familiar adenomatous polyposis (FAP) syndrome Asymptomatic, discovered by colonoscopy examination Tumor of rectosigmoid location may be traumatized and bleed Multiple factors in adenoma to cancer progression −− Tumor size, number, and duration −− Family history of colorectal cancer −− Additional molecular alterations Overall 21–41% recurrent rate after polypectomy Incomplete removal is common in villous and sessile adenomas

Macroscopic ♦♦ Pedunculated, sessile, or carpet-like mucosal lesions with multilobulated, friable outer surface and homogeneous cut surface ♦♦ Tubular adenomas predominate and usually measure >1 cm

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Fig. 42.27. Tubular adenoma: tube-like crypts. Fig. 42.26. Inflammatory fibrous polyp. ♦♦ Villous adenomas or tubulovillous adenomas are usually larger and sessile, and they are more likely to be located in the cecum and rectosigmoid

Microscopic ♦♦ Four types based on architecture −− Tubular adenoma: tube-like crypts (Fig. 42.27) −− Villous adenoma: finger-like crypts (Fig. 42.28) −− Tubulovillous adenoma: both tubule and finger-like features −− Serrated adenoma (SA) (Fig. 42.29) (a) Rare, <1% (b) Nuclear features of adenoma but architectural ­features of hyperplastic polyp ♦♦ Tall columnar cells with enlarged, elongated, and hyperchromatic nuclei arranged in a pseudostratified pattern, usually along the basement membrane ♦♦ Intraepithelial mucus content may be decreased, increased, or of no change ♦♦ Dystrophic goblet cells, endocrine cells, Paneth cells, or even squamous cells ♦♦ Nonspecific chronic inflammation and immature fibroblasts in the LP ♦♦ Sharp transition between adenomas and adjacent normal crypts ♦♦ Pedunculated stalk usually contains submucosa

Fig. 42.28. Villous adenoma: finger-like crypts.

Special Considerations ♦♦ Serrated adenoma −− See above ♦♦ Mixed hyperplastic and adenomatous polyp −− Polyp with both adenomatous and hyperplastic components of variable proportion ♦♦ Sessile serrated polyp (SSP) (sessile serrated adenoma) (Fig. 42.30) −− Tendency to be right sided

Fig. 42.29. Serrated adenoma. −− Endoscopically poorly circumscribed, mimicking enlarged folds −− Basal crypt dilatation with horizontal orientation, marked serration, and branching −− Prominent surface serration with inverted crypts

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Fig.  42.30. Sessile serrated polyp (SSP) (sessile serrated adenoma).

♦♦

♦♦

♦♦

♦♦

−− Nuclear atypia with mitosis in mid/upper crypts −− Focal loss of hMHL-1 positivity Dysplasia-associated lesion or mass (DALM) in IBD −− Two morphologic subtypes (a) Adenoma-like: may be indistinguishable from sporadic adenoma (b) Nonadenoma-like: large, sessile irregular masses/ nodules/strictures −− Flat dysplasia at the base of polyp stalk or surrounding mucosa −− Histological evidence of IBD in adjacent mucosa −− Younger age favors IBD-dysplasia Adenoma with high grade dysplasia (Fig. 42.31) −− Confined entirely within the LP −− Complex and cribriform glands lined by enlarged, rounded nuclei containing vesicular nuclear chromatin and prominent nucleolus −− Loss of nuclei polarity −− Focal or multifocal in a large adenoma −− May overlay invasive adenocarcinoma if a mass lesion is present −− No metastatic potential −− Not to be confused with polypoid adenocarcinoma (see below) Adenoma with pseudoinvasion (Fig. 42.32) −− Misplaced adenomatous glands in the submucosa, therefore mimicking submucosal invasion by carcinoma −− Caused by ulceration and healing fibrosis due to trauma to the polyp; therefore, more common in the rectosigmoid −− Lack of cancer-like cytology and desmoplasia of the surrounding stroma −− Frequent submucosal hemosiderin pigment Polypoid adenocarcinoma −− Carcinoma entirely fills the polyp −− Often with intramucosal or submucosal invasion

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Fig. 42.31. Adenoma with high grade dysplasia.

Fig. 42.32. Adenoma with pseudoinvasion. −− Has metastatic potential, and therefore cannot be cured by polypectomy ♦♦ Familial adenomatous polyposis (Fig. 42.33) −− One of the two best understood inherited predispositions to colorectal cancer −− Caused by germ-line mutations of the APC (adenomatous polyposis coli) gene, located on 5q21

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Fig. 42.33. Familial adenomatous polyposis (FAP). −− Overall incidence of 1 in every 10,000 births −− Two-thirds inherit the disease as an autosomal dominant trait, and one-third have no family history (represent new mutation) −− Average of onset of polyposis is 25 years of age −− Colonoscopy and molecular test detect patients at a much younger age −− Hundreds to thousands polyps (usually <1  cm) evenly distributed throughout colorectum with occasional rectal sparing −− Adenocarcinoma inevitably develops in all patients if left unattended, usually during the 3rd decade of life −− Colonic carcinomas rarely exceeds three in numbers −− Early carcinomas are usually found in polyps >1 cm −− Histologically similar to those of sporadic tubular adenomas −− Microadenomas, the flat mucosa, are more characteristic of FAP

Fig. 42.34. Ganglioneuroma.

−− Extracolonic manifestations (a) Periampullary, jejunal, ileal, and rarely gastric adenomas with an overall incidence of upper GI tract carcinoma of 4.5% (b) Desmoid tumor (Gardener syndrome) (c) Medulloblastoma (Turcot syndrome)

Ganglioneuroma (Fig. 42.34) ♦♦ Affect colon ♦♦ Mixture of S-100 (+) neurogenic fibers and ganglion cells ♦♦ Ganglioneuromatous polyposis is associated with multiple skin lipomas ♦♦ Diffuse intestinal ganglioneuromatosis is associated with MEN2b, von Recklinghausen disease

MALIGNANT TUMORS Adenocarcinoma Clinical ♦♦ The most common malignant tumors of the large intestine; account for 98% of all large intestinal cancers ♦♦ Approximately 150,000 new cases and 55,000 deaths each year; account for 15% of all cancer-related death ♦♦ Peak incidence in 60–70 years of age; 20% occur under the age of 50 ♦♦ If seen in younger patients, predispositions such as ulcerative colitis, FAP, or hereditary nonpolyposis colorectal carcinoma (HNPCC) should be suspected ♦♦ 90–93% are sporadic; HNPCC- and FAP-associated carcinomas account for 5 and 1%, respectively ♦♦ Rare in the small intestine, accounts for <1% of all GI tract malignancies

♦♦ Within the small bowel, the tumor favors the duodenum, including ampulla vater ♦♦ Most of the cancers are located in the rectosigmoid region. The incidence of right-sided tumor is rising ♦♦ Prognosis correlates best with tumor staging (see TMN classification of colorectal adenocarcinoma) ♦♦ K-RAS proto-oncogene mutation, is associated with resistance to epidermal growth factor receptor inhibitor therapy

Macroscopic ♦♦ Polypoid type −− Exophytic intraluminal mass −− More common in the cecum and the right colon −− Likely to arise in an adenoma

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♦♦ Fungating type −− Polypoid type with prominent ulceration ♦♦ Ulcerative type −− Invades deeply into the colonic wall with ulcerative surface ♦♦ Infiltrative type −− Invades intestinal wall diffusely and often circumferentially, without forming a nodular mass

Microscopic ♦♦ Most are well to moderately differentiated gland-forming adenocarcinoma ♦♦ Well-differentiated type −− >75% of the tumor contains glands ♦♦ Moderately differentiated type −− >25% of the tumor contains solid sheets of tumor cells ♦♦ Poorly differentiated type −− >75% of the tumor is solid sheets

Specific Variants ♦♦ Medullary type −− Uniform polygonal tumor cells −− Solid growth in nested, organoid, or trabecular pattern −− Lymphocytic infiltrate −− Associated with microsatellite instability, DNA repair gene dysfunction, and hereditary nonpolyposis colon cancer syndrome −− Favorable prognostic type independent of stage ♦♦ Mucinous type −− >50% of the tumor appears mucinous ♦♦ Colloid type −− Large extracellular mucinous pools with floating tumor cells −− Tumor cells may not be abundant and often show signetring features ♦♦ Signet-ring cell type −− Solid sheets of tumor cells with prominent intracellular mucin −− Rare and are often seen in IBD-associated cancers −− Unfavorable prognostic type independent of stage ♦♦ Mixed carcinoid-adenocarcinoma type −− Typically affects the appendix but arises in the colon as well −− Mucinous tumor cells arranged in nests or trabeculae with admixed endocrine or Paneth cells −− Highly aggressive −− Often presents with intraabdominal metastasis such as bilateral ovaries ♦♦ Small cell carcinoma −− Rare, highly aggressive, favors right colon and rectum −− Mean age of 63

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−− Grossly indistinguishable from ordinary types −− Histologically similar to those of oat cell carcinoma of the lung −− Unfavorable prognostic type independent of stage ♦♦ Adenosquamous type −− Rare (0.05% of colorectal cancers) −− Poor prognosis −− Often occur in the rectosigmoid as fungating masses −− Histologically both adeno- and squamous carcinoma of varying proportion −− Differs from adenocarcinoma, containing occasional metaplastic squamous cells, seen in approximately 5% of the cases

Carcinoid Tumors (Fig. 42.35) Clinical ♦♦ Malignant, slow growing, locally infiltrative with the potential for metastasis ♦♦ 2% of all malignant GI tract tumors ♦♦ 50% in the small intestine, 34% in the appendix, and the remaining in the colorectum and stomach ♦♦ Carcinoid syndrome rare, mostly ileal location, with liver metastasis ♦♦ Neuroendocrine cell carcinoma applies for tumor with distant metastasis ♦♦ Metastatic potential is related to the site and the size of the tumor (Table 42.4)

Macroscopic ♦♦ Duodenal carcinoids −− Usually small polypoid lesions up to a few millimeters in size −− Covered by intact mucosa ♦♦ Small intestinal carcinoids (other than duodenum)

Fig. 42.35. Carcinoid tumor.

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Table 42.4. Metastatic Potential of Carcinoid Tumor of the GI Tract Site and size Stomach <1.8 cm >5 cm Appendix <2 cm >2 cm Small bowel and colorectum <1 cm >1 cm

Metastasis 15% 80% Almost never 31% 22% 58%

−− Usually <2 cm −− Indurated, yellowish nodules lie predominantly in the submucosa −− Attenuated, rarely ulcerated overlying mucosa −− Multiple tumors in up to 40% of the cases −− When invading the MP and serosa, it often produces dense fibrosis, which causes kinking of the bowel wall and peritoneal adhesions ♦♦ Appendiceal carcinoids −− Usually small, <1 cm −− Round nodule located in the tip, forming solid, bulbous swelling and causing luminal obliteration −− Often discovered incidentally −− Rarely, patients present with acute appendicitis or mucocele ♦♦ Colorectal carcinoids −− Vast majority occur in the rectum −− Solitary, occasionally multiple, small, rubbery, polypoid nodules −− Attenuated, sometimes friable overlying mucosa −− Cecal and proximal colonic tumors tend to be large and bulky

Microscopic ♦♦ Duodenal carcinoids −− Trabecular or ribbon patterns with occasional rosette formation −− May contain gastrin, somatostatin, substance P, serotonin, or glucagon, or may be multihormonal ♦♦ Carcinoids of the small intestine (excluding duodenum) −− Monotonous appearing tumor cells −− Centrally located nuclei, stippled nuclear chromatin, and small nucleoli −− Indistinct cytoplasmic borders −− Insular and/or trabecular anastomosing ribbon-like cords in a vascularized stroma −− Many produce serotonin and other hormones

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♦♦ Appendiceal carcinoids −− Similar to that of small intestinal carcinoids −− Contain serotonin −− Often show intimate association with nerve fibers −− Often show diffuse muscularis invasion −− Lymphatic permeation is also common −− Malignancy is exceedingly rare, even with muscular and lymphatic invasion −− Malignancy best correlates with tumor size ♦♦ Tubular carcinoids −− Almost entirely composed of tubular structures and trabeculae containing primarily endocrine cells with a few goblet cells −− Diffusely infiltrative among the smooth muscles of the muscularis −− Lack cytological atypia −− Mitotically inactive (0–2 mitosis/10 hpf) −− Share the same biological behavior with typical appendiceal carcinoids ♦♦ Goblet cell carcinoids −− Tubular structures containing variable number of goblet lining cells + on mucin stains −− Diffusely infiltrative among the smooth muscles of the muscularis −− Usually without cytological atypia −− Mitosis in average one-tenth high power fields (HPF) ♦♦ Colorectal carcinoids −− Most tumors show trabecular with mixed alveolar patterns −− Many are multihormonal by immunohistochemistry, but rarely they are functional −− Therefore, carcinoid syndrome is rare

Immunohistochemistry ♦♦ Positive for chromogranin, synaptophysin, neuron-specific enolase (NSE), and cytokeratin ♦♦ Goblet carcinoids may also express carcinoembryonic antigen (CEA)

Differential Diagnosis ♦♦ Mixed carcinoid-adenocarcinoma −− Usually affects the appendix and occasionally the colon and stomach −− Mucous tumor cells arranged in nests, glands, trabeculae, or single signet-ring cells with admixed endocrine or Paneth cells −− Prominent cytological atypia with high mitotic count (average 10/10 HPF) −− Scattered chromogranin reactivity −− Highly aggressive −− Often presents with intraabdominal metastasis such as bilateral ovaries

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Gastrointestinsal Stromal Tumor (Fig. 42.36) Clinical ♦♦ Rare before the 4th decade, gradually increasing with peak incidence in the 8th decade of life ♦♦ Affect males slightly more than females ♦♦ 50% occur in the stomach, 30% in the small intestine, and small numbers in the rectosigmoid −− Very rarely seen in the proximal colon ♦♦ Typical presentation includes obstruction, intraabdominal mass, bleeding, and weight loss ♦♦ Cells of origin are the interstitial cells of Cajal

Macroscopic ♦♦ Usually single intramural mass ♦♦ Expands the wall, or in large tumors, outside the wall, with a narrow attachment to the muscularis propria ♦♦ Cut sections show circumscribed, expansile masses with flat, granular surface ♦♦ May contain hemorrhage, cystic changes, or necrosis

Microscopic ♦♦ Spindle cell with elongated nuclei, often arranged in bundles with palisading reassembling those of either leiomyoma or schwannoma

Fig. 42.36. Gastrointestinal stromal tumor (GIST).

♦♦ Some may also contain epithelioid cells that are usually rounded with abundant cytoplasm, admixed with spindle cells ♦♦ Stroma may be hyalinized, fibrotic, myxoid, or necrotic ♦♦ Evaluation for malignancy is difficult, often requires extensive sampling

Immunohistochemistry ♦♦ C-kit: ++++; CD34: +++ to ++++; S-100: ±; smooth muscle actin (SMA): ±, cytokeratin ±

Benign or Malignant ♦♦ Malignant potential of gastrointestinsal stromal tumor (GIST) is largely determined by the tumor location, the size, the presence or absence of tumor necrosis and invasion, and finally, mitotic activity (Table 42.5)

Differential Diagnosis ♦♦ Leiomyoma −− Usually located in the esophagus −− If occurs in the small and large intestine, often as a small submucosal polypoid mass −− Positive for SMA, but negative for c-kit, CD34, or S-100 ♦♦ Schwannoma −− Almost always occurs in the stomach −− Can be cystic, and usually associated with lymphoplasmacytic infiltrate −− Positive for S-100, but negative for SMA, c-kit, or CD34 ♦♦ Gastrointestinal autonomic nerve tumors (GANT) −− Rare, have only been described in the stomach and small intestine −− Ovoid tumor cells with cytoplasmic clearing, resembling epithelioid GIST −− Usually positive for synaptophysin and NSE, negative for S-100, CD34, or c-kit −− Criteria for malignancy are similar to those of GIST ♦♦ Mesenteric fibromatosis −− The bulk of the tumor is usually in the serosa or the mesentery −− Often invades the muscularis −− Spindle tumor cells, but less cellular than GIST −− Lack nuclear pleomorphism −− Stroma tends to be myxoid

Table 42.5. Gastrointestinal Stromal Tumor Characteristics of tumor Location Size Invasion of mucosa or adjacent organ Parenchymal necrosis (excluding surface erosion) Mitotic figures

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Likely benign

Likely malignant

Esophagus, two-thirds of stomach <2 cm (<5 cm in stomach) No No <5/50 HPF

Small and large intestines >2 cm (>5 cm in stomach) Yes Yes >10/50 HPF

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Gastrointestinal Lymphoma (Table 42.6) General Features

B-Cell Lymphoma of MALT Clinical

♦♦ Almost exclusively of non-Hodgkin type ♦♦ Constitute 4–18% of all non-Hodgkin lymphoma (NHL) and 1–4% of all GI tract malignancies −− May be secondarily involved by systemic non-Hodgkin lymphoma −− GI tract most common site for extranodal lymphomas −− Up to 40% arise as primary GI tract lymphoma defined as (a) The main bulk of tumor is limited in the GI tract (b) With or without the involvement of contiguous lymph nodes (c) No involvement of the liver, spleen, or palpable lymph nodes ♦♦ Usually arise as sporadic neoplasms (B-cell MALTomas) ♦♦ Also occur in certain patient populations −− Sprue-associated lymphoma (T-cell in origin) −− Mediterranean lymphoma (alpha heavy chain disease) −− HIV or organ transplantation associated lymphoma (B large-cell lymphoma) ♦♦ Usually affects adults, with equal sex distribution ♦♦ May arise anywhere in the GI tract −− Stomach: 50–60% −− Small intestine: 25–30% −− Proximal colon: 10–15% −− Distal colorectum: Up to 10% ♦♦ Any lymphoma may occur as a primary tumor of the GI tract ♦♦ Most, however, are distinct entities that do not arise in peripheral lymph nodes, and do not form a part of any current lymphoma classification ♦♦ Unlike nodal low grade B-cell lymphoma, low grade mucosaassociated lymphoid tissue (MALT) lymphoma of the GI tract is usually confined to the site of origin at presentation; the prognosis is more favorable than the equivalent nodal disease ♦♦ Specific types (also see Chap. 15)

♦♦ The majority arise in the stomach as a single lesion −− Strong association with Helicobacter pylori infection −− 75% complete remission after Helicobacter eradication ♦♦ Colorectal involvement are distinctly rare ♦♦ More common in the elderly ♦♦ Presents with melena or obstruction ♦♦ Mesenteric lymph node involvement is common ♦♦ Extraabdominal spread is unusual at presentation ♦♦ Prognosis is not as favorable for tumors arising in the lower GI tract

Table 42.6. Lymphomas of GI Tract B-cell   Lymphoma of mucosa-associated lymphoid tissue (MALT)   Low grade B-cell lymphoma of MALT  High grade B-cell lymphoma of MALT with/without a low grade component   Mantle cell lymphoma (lymphomatous polyposis)   Burkitt or Burkitt-like lymphoma   Other types (corresponding to peripheral lymph node equivalents) T-cell   Sprue-associated T-cell lymphoma

Macroscopic ♦♦ Most are grossly single lesions, although can be multifocal microscopically ♦♦ Poorly defined, fleshy, thickened bowel wall with extensive mucosal ulceration ♦♦ Mesenteric lymph nodes may be enlarged

Microscopic ♦♦ Heavy intramucosal lymphoid infiltrate that usually forms the base of a mucosal ulceration ♦♦ Lymphoepithelial lesions ♦♦ Small-to-medium size lymphocytes with irregular nuclei and moderate amount of cytoplasm (centrocyte-like [CCL] cells) infiltrates around reactive, nonneoplastic follicles (Peyer patch marginal zone), spreading diffusely into the surrounding mucosa ♦♦ Small number of transformed blasts and plasma cell differentiation are characteristic ♦♦ Tumor cells invade nonneoplastic follicles in several different ways −− Total replacement −− Partial replacement −− Striking and uniform blastic transformation −− Plasma cell differentiation ♦♦ High grade MALT lymphoma in the intestines is more common, compared to gastric counterpart ♦♦ It is characterized by confluent clusters of transformed cells outside of the colonized follicles ♦♦ Small foci of tumor are often present at remote distances from the main tumor mass

Immunohistochemistry ♦♦ CD20+, CD5–, CD10–, CD43 usually –, bcl-2+/– ♦♦ Monoclonal plasma cells

Mantel Cell Lymphoma (Lymphomatous Polyposis) Clinical ♦♦ Affects patients >50 years of age

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♦♦ Abdominal pain and melena ♦♦ Involves any part of the GI tract, but the most predominant mass is usually seen in the ileocecal region ♦♦ Tend to disseminate early to lymph nodes, liver, spleen, and bone marrow

Macroscopic

Microscopic ♦♦ Effacement of mucosa by sheets of monomorphic blasts interspersed with macrophages gives a characteristic “starry sky” appearance ♦♦ The blasts are small, noncleaved cells with granular nuclear chromatin, 3–4 nucleoli, and a well-defined ring of deeply basophilic cytoplasm ♦♦ Lymphoepithelial lesions are rare

♦♦ Multiple fleshy mucosal polyps ranging from 0.5–2 cm, or even larger ♦♦ Mesenteric lymph nodes often involved

Immunohistochemistry

Microscopic

♦♦ CD10+

♦♦ Intramucosal lymphoid aggregates, single or multiple ♦♦ Entrapped, reactive follicular centers in the lymphomatous infiltrate ♦♦ Follicular centers may be entirely replaced ♦♦ Lymphomatous infiltrate selectively replaces the mantle zones

Sprue-Associated T-Cell Lymphoma Clinical

Immunohistochemistry ♦♦ CD5+, CD20+, CD10– CD43+, bcl-2+, bcl-1+, cyclin D-1+

Burkitt and Burkitt-Like Lymphomas Clinical

♦♦ Median age of 60, rare under the age of 30, with slight male predominance ♦♦ Most patients have a history of abdominal pain and weight loss for a few months or a few years ♦♦ Some patients have a remote history of malabsorption ♦♦ Not infrequently, patients present with an acute emergency with GI tract perforation, obstruction, and hemorrhage

Macroscopic

♦♦ Two forms −− Endemic Burkitt lymphoma −− Sporadic Burkitt lymphoma ♦♦ Patients are usually young; present with abdominal pain and obstructive symptoms ♦♦ Epstein–Barr virus (EBV) genomes are found in all cases of endemic form, but in only one-third of the sporadic form ♦♦ t(8,14) in 80% of the cases

Macroscopic ♦♦ Favor ileocecal region ♦♦ Localized obstructing masses or huge masses involving long segments of intestine ♦♦ Mesenteric lymph node and retroperitoneal involvement are common

♦♦ Most common in the jejunum ♦♦ Frequently multiple, circumferential ulcers without forming large tumor masses ♦♦ Mesenteric lymph nodes are usually enlarged, due to both tumor involvement and reactive changes

Microscopic ♦♦ Mucosal ulceration is common, with dense lymphocytic infiltration forming the base of the ulcer ♦♦ Adjacent, nonulcerated mucosa shows extensive villous atrophy with prominent intraepithelial T lymphocytes ♦♦ Highly pleomorphic T lymphocytes with bizarre, multinucleated forms

Immunohistochemistry ♦♦ CD3+, CD20–

ANUS Benign Lesions Hemorrhoids (Fig. 42.37) ♦♦ Cushion blood vessels, smooth muscle, and connective tissue normally present in the anal submucosa above dentate line on left lateral, right anterior, and right posterior ♦♦ Become engorged during defecation to protect anal canal ♦♦ Gradual loss of support with aging causing luminal bulging, prone to trauma and bleed ♦♦ Internal hemorrhoid is covered by rectal mucosa

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♦♦ External hemorrhoid is covered by anal mucosa or perianal skin ♦♦ Large, dilated vessels with prominent mussel wall show congestion and thrombosis

Fissure ♦♦ Mostly seen in the posterior midline of the canal below dentate line ♦♦ An elongated, triangular ulcer of anal canal due to traumatic tearing

Small Intestine, Appendix, Colorectum, and Anus

Fig. 42.37. Hemorrhoids.

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Fig. 42.38. Condyloma acuminatum.

♦♦ Histologically nonspecific inflammation, granulation tissue, and fibrosis

Fistula ♦♦ Result of chronic phase of acute suppurative inflammation of anal duct ♦♦ Four types −− Intersphincteric −− Transsphincteric −− Suprasphincteric −− Extrasphincteric ♦♦ Lined by granulation tissue and nonspecific acute and chronic inflammation ♦♦ Giant cells of foreign body type are common ♦♦ Differential diagnoses includes Crohn disease and carcinoma Fig. 42.39. Anal intraepithelial neoplasia (AIN), low grade.

Tumors of Anal region Condyloma Acuminatum (Fig. 42.38) Clinical ♦♦ Risk factor −− HPV infection (HPV 6, 11, 16, 18) −− Immunosuppression, HIV, homosexuality −− Genital cancers, irradiation

Macroscopic ♦♦ Small warty lesion, often multiple

Microscopic ♦♦ Acanthotic squamous papillary hyperplasia ♦♦ Elongation of rete ridges ♦♦ Maintain cellular polarity

♦♦ 1–3 layers of basal cells ♦♦ Surface koilocytic changes

Anal Intraepithelial Neoplasia (Fig. 42.39) ♦♦ Complication of condyloma following recurrence ♦♦ Rare as de novo lesion ♦♦ Two grades −− Low grade anal intraepithelial neoplasia (AIN) (a) Dysplastic cells in lower one-third (b) Maintain cellular maturation −− High grade AIN (a) Dysplastic cells extend to the surface (b) Loss of polarity and maturation

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Fig. 42.41. Melanoma. Fig.  42.40. Verrucous squamous cell carcinoma (giant condyloma acuminatum).

Giant Condyloma Acuminatum (Fig. 42.40) ♦♦ ♦♦ ♦♦ ♦♦

Synonymous to verrucous squamous cell carcinoma >2 cm, often single lesion Minimal cytologic dysplasia Downward growth with broad pushing and infiltrating islands ♦♦ Locally recurrent but do not metastasize

Squamous Cell Carcinoma Clinical ♦♦ Accounts for 90–95% of anal region tumors ♦♦ Risk factors: Crohn disease, fistula, and HPV infection ♦♦ F:M = 2:1 in tumors above dentate line (anal transitional zone or pectinate) ♦♦ F:M = 1:4 in tumors beneath dentate line (pecten and perianal skin)

Macroscopic ♦♦ Ulcer with raised and everted edge ♦♦ Rarely polypoid

Microscopic ♦♦ Usual type −− Three-fourths are moderately to poorly differentiated, typical squamous cell carcinoma −− Koilocytic (HPV) changes are common ♦♦ Basaloid (cloacogenic) type −− Accounts for one-third of tumors of anal transitional zone (anal canal) −− Arise from cloaca −− Islands of basaloid cells with peripheral palisading and desmoplasia

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−− High mitosis with atypical forms −− May mimic small cell carcinoma (see below) ♦♦ Spindle cell type −− Rare −− May be confused with melanoma −− Cytokeratin positive

Adenocarcinoma of Anal Duct/Gland ♦♦ Rare, direct invasion from rectal carcinoma is more common ♦♦ Two types −− Intramural type: haphazard small tumor ducts grow deeply in the muscular wall (a) No surface lesion until late stage −− Low grade mucinous carcinoma (a) Present as anal mass with pain and bleed (b) Large, colloid-filled cysts with low grade mucinous lining cells (c) Frequently seen in Crohn disease, grow around fistular tract

Small Cell Carcinoma ♦♦ Arise from the endocrine cells in the anal transitional zone ♦♦ Very aggressive, disseminate widely, with poor prognosis ♦♦ May mimic basaloid carcinoma ♦♦ Synaptophysin and chromogranin positive

Melanoma (Fig. 42.41) Clinical ♦♦ Present in 3rd to 8th decades of life with pain, bleeding, and a mass ♦♦ May be an incidental finding of hemorrhoid ♦♦ Sun exposure not a risk factor ♦♦ Arise from transitional zone above dentate line

Small Intestine, Appendix, Colorectum, and Anus

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Macroscopic ♦♦ Two-thirds of lesions are polypoid, with visible pigment ♦♦ Average size: 4 cm

Microscopic ♦♦ Mostly epithelioid and spindle cell types ♦♦ Junctional activity may be difficult to find ♦♦ Positive for S-100, HMB-45, and Melan-A

Differential Diagnosis ♦♦ Granular cell tumor (Fig. 42.42) −− Lacks prominent nucleoli, S-100 protein positive, HMB-45 negative

Fig. 42.42. Granular cell tumor of perianal region.

TNM CLASSIFICATION OF COLORECTAL ADENOCARCINOMA (2010 REVISION) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary Tumor −− Tis: Carcinoma in situ: intraepithelial or invasion of lamina propria −− T1: Tumor invades submucosa −− T2: Tumor invades muscularis propria −− T3: Tumor invades through the muscularis propria into pericolorectal tissues −− T4a: Tumor penetrates to the surface of the visceral peritoneum −− T4b: Tumor directly invades or is adherent to other organs or structures ♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Metastasis in 1-3 regional lymph nodes −− N1a: Metastasis in one regional lymph node −− N1b: Metastasis in 2-3 regional lymph nodes −− N1c: Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis

−− N2: Metastasis in four or more regional lymph nodes −− N2a: Metastasis in 4-6 regional lymph nodes −− N2b: Metastasis in seven or more regional lymph nodes ♦♦ Distant Metastasis (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis −− M1a: Metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node) −− M1b: Metastasis in more than one organ/site or the peritoneum ♦♦ Residual Tumor (R) −− R0: Complete resection, margins histologically negative, no residual tumor left after resection (primary tumor, regional nodes) −− R1: Incomplete resection, margins histologically involved, microscopic tumor remains after resection of gross disease (primary tumor, regional nodes) −− R2: Incomplete resection, margins macroscopically involved or gross disease remains after resection (e.g., primary tumor, regional nodes, or liver metastasis)

SUGGESTED READING Abreu MT, Harpaz N. Diagnosis of colitis: making the initial diagnosis. Clin Gastroenterol Hepatol 2007;5:295–301.

Banks PM. Gastrointestinal lymphoproliferative disorders. Histopathology 2007;50:42–54.

Azimuddin K, Stasik JJ, Khubchandani IT, et al. Hyperplastic polyps: “more than meets the eye”? Report of sixteen cases. Dis Colon Rectum 2000;43:1309–1313.

Bariol C, Hawkins NJ, Turner JJ, et  al. Histopathological and clinical evaluation of serrated adenomas of the colon and rectum. Mod Pathol 2003;16:417–423.

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Batts KP, Burgart LJ, Goldblum JR, et al. Sessile serrated polyp: a multiinstitutional incidence study (abstract). Mod Pathol 2002;15:113A. Bond JH. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 2000;95:3053–3063. Burke AP, Sobin LH, Virmani R. Localized vasculitis of the gastrointestinal tract. Am J Surg Pathol 1995;19:338–349. Chang F, Deere H, Vu C. Atypical forms of microscopic colitis: morphological features and review of the literature. Adv Anat Pathol 2005;12:203–211. Chang F, Mahadeva U, Deere H. Pathological and clinical significance of increased intraepithelial lymphocytes (IELs) in small bowel mucosa. APMIS 2005;113:385–399. Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003;16:376–388. Goldstein NS, Cinenza AN. The histopathology of nonsteroidal antiinflammatory drug-associated colitis. Am J Clin Pathol 1998;110: 622–628. Goldstein NS, Bhanot P, Odish E, et al. Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas. Am J Clin Pathol 2003;119:778–796. Gurbuxani S, Anastasi J. What to do when you suspect gastrointestinal lymphoma: a pathologist's perspective. Clin Gastroenterol Hepatol 2007;5:417–421.

Essentials of Anatomic Pathology, 3rd Ed.

McCusker ME, Cote TR, Clegg LX, et  al. Primary malignant neoplasms of the appendix: a population-based study from the surveillance, epidemiology and end-results program, 1973-1998. Cancer 2002 15;94:3307–3312. Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 2006;130:1466–1478. Mueller S. Classification of eosinophilic gastrointestinal diseases. Best Pract Res Clin Gastroenterol 2008;22:425–440. Nielsen OH, Vainer B, Rask-Madsen J. Non-IBD and noninfectious colitis. Nat Clin Pract Gastroenterol Hepatol 2008;5:28–39. Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007;133:1670–1689. Odze RD. Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical, pathological, and molecular review. Am J Gastroenterol 1999;94:1746–1750. Riddell RH. Premalignant and early malignant lesions in the gastrointestinal tract: definitions, terminology, and problems. Am J Gastroenterol 1996;91:864–872. Rubin PH. Adenomas in ulcerative colitis: endoscopic polypectomy or colectomy? Inflamm Bowel Dis 1999;5:304–305. Siddiqui AA, Miner PB, Jr. The role of mast cells in common gastrointestinal diseases. Curr Allergy Asthma Rep 2004;4:47–54.

Isaacson PG, Du MQ. Gastrointestinal lymphoma: where morphology meets molecular biology. J Pathol 2005;205:255–274.

Snover DC, Jass JR, Fenoglio-Preiser C, et  al. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 2005;124:380–391.

Jass JR. Serrated route to colorectal cancer: back street or super highway? J Pathol 2001;193:283–285.

Sreenarasimhaiah J. Diagnosis and management of ischemic colitis. Curr Gastroenterol Rep 2005;7:421–426.

Jass JR. Hyperplastic-like polyps as precursors of microsatellite-unstable colorectal cancer. Am J Clin Pathol 2003;119:773–775.

Steigen SE, Eide TJ. Gastrointestinal stromal tumors (GISTs): a review. APMIS 2009;117:73–86.

Jass JR. Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract 2008;204:431–447.

van Mook WN, Koek GH, van der Ven AJ, et al. Human intestinal spirochaetosis: any clinical significance? Eur J Gastroenterol Hepatol 2004;16:83–87.

Klump B, Nehls O, Okech T, et al. Molecular lesions in colorectal cancer: impact on prognosis? Original data and review of the literature. Int J Colorectal Dis 2004;19:23–42. Li SC, Hamilton SR. Malignant tumors in the rectum simulating solitary rectal ulcer syndrome in endoscopic biopsy specimens. Am J Surg Pathol 1998;22:106–112. Longacre TA, Kong CS, Welton ML. Diagnostic problems in anal pathology. Adv Anat Pathol 2008;15:263–278.

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Washington MK. Colorectal carcinoma: selected issues in pathologic examination and staging and determination of prognostic factors. Arch Pathol Lab Med 2008;132:1600–1607. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;20;26: 3063–3072.

43 Pancreas Olca Basturk, md and N. Volkan Adsay, md

CONTENTS

I. Congenital Anomalies........................43-2

Annular Pancreas.............................................43-2 Heterotopic Pancreas.......................................43-2 Pancreas Divisum.............................................43-2 Congenital Cysts...............................................43-2

II. Pancreas in Metabolic and Other Medical Disorders.............................43-2 Nesidioblastosis.................................................43-2 Diabetes Mellitus..............................................43-2 Cystic Fibrosis..................................................43-3

III. Inflammatory Conditions...................43-3 Acute Pancreatitis............................................43-3 Chronic Pancreatitis.........................................43-3 Alcohol or Obstruction-Related............43-3 Autoimmune Pancreatitis Lymphoplasmacytic Sclerosing Type..................................43-4 Autoimmune Pancreatitis with Granulocytic Epithelial Lesions (“Idiopathic Duct-Centric Type”).....43-4 Paraduodenal Pancreatitis....................43-5 Pseudocysts.......................................................43-5 Infections...........................................................43-6

IV. Neoplasia...........................................43-6 Ductal Neoplasia...............................................43-6 Invasive Ductal Carcinoma...................43-6 Rare Carcinomas of Presumed Ductal Origin.....................................43-8 Preinvasive Ductal Neoplasia..............43-10 Serous Cystic Neoplasms.....................43-15

Acinar Cell Neoplasia....................................43-16 Acinar Cell Carcinoma........................43-16 Acinar Cell Cystadenoma....................43-17 Endocrine Neoplasia......................................43-17 Pancreatic Endocrine Neoplasia (PENs, Islet Cell Tumors)...............43-17 Poorly Differentiated Endocrine (Small Cell) Carcinoma..................43-18 Solid Pseudopapillary Neoplasm..................43-18 Pancreatoblastoma.........................................43-19 Mixed Carcinomas (Mixed AcinarEndocrine and Mixed Acinar-Ductal).....43-20 Miscellaneous Cystic Lesions........................43-20 Lymphoepithelial Cyst.........................43-20 Squamoid Cyst of Pancreatic Ducts.................................................43-20 Epidermoid Cyst within Intrapancreatic Accessory Spleen...............................................43-20 Lymphangioma.....................................43-20 Miscellaneous Tumors....................................43-20 Secondary Tumors...............................43-20 Mesenchymal Tumors..........................43-20 Hematopoietic Tumors.........................43-21

V. Reporting of Pancreatic Neoplasia.........................................43-21 VI. Tnm Classification of Pancreatic Tumors (2010 Revision)...................43-21 VII. Suggested Reading...........................43-22

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_43, © Springer Science+Business Media, LLC 2002, 2006, 2011

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CONGENITAL ANOMALIES Annular Pancreas Clinical

Microscopic

♦♦ Very rare embryologic abnormality ♦♦ Pancreatic parenchyma encircles the duodenum ♦♦ Main pancreatic duct follows a course different than usual ♦♦ Some associated with Down syndrome or other congenital conditions

Differential Diagnosis

Microscopic

♦♦ Failed fusion of the dorsal (Santorini) and ventral (Wirsung) ducts in embryologic life ♦♦ “Division” of drainage between the anterosuperior and posteroinferior head ♦♦ Usually clinically inconsequential ♦♦ Some patients develop pancreatitis, usually dorsally ♦♦ Diagnosis is radiologic; pathologic documentation is difficult, if not impossible

♦♦ Irregularly shaped islets composed of pancreatic polypeptide (PP) cells (consistent with ventral bud origin) ♦♦ May be associated with pancreatitis

Heterotopic Pancreas Clinical ♦♦ Occurs in a variety of organs; most common in gastrointestinal and biliary tracts ♦♦ Most are incidental ♦♦ May form macroscopic nodules ♦♦ May rarely show pancreatic pathology (pancreatitis, pancreatic neoplasia), or local complications such as ulceration and hemorrhage

♦♦ All or some components of the pancreas (acini, ducts, or islets) ♦♦ Metaplasia −− Microscopic −− Usually, acini only

Pancreas Divisum

Congenital Cysts ♦♦ Intestinal duplication may present as a cystic lesion ♦♦ Foregut cysts (some with ciliated/respiratory type epithelia) ♦♦ “Fibrocystic” type changes may occur in a variety of congenital syndromes

PANCREAS IN METABOLIC AND OTHER MEDICAL DISORDERS Nesidioblastosis ♦♦ Functional disorder of the b-cells ♦♦ Associated with persistent hyperinsulinemic hypoglycemia (PHH) in newborns and very rarely in adults ♦♦ Etiopathogenesis not fully understood; a genetic susceptibility to develop abnormal reaction to abrupt metabolic changes (such as substantial weight loss or gastric bypass) has been implicated ♦♦ Potential susceptibility genes include ABCC8 and KCNJ11

Microscopic ♦♦ Newborn type −− Can be focal (in about 40% of the patients) −− Characterized by the presence of hypertrophic insulin cells. Many islets are large, typically measuring up to several millimeters (much more pronounced in the newborns than in the adults) −− b-cells are disproportionally higher in number −− Clinicopathologic correlation is necessary; no good criteria for “hyperplastic” vs. normal islet

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♦♦ Adult type −− Focal nesidioblastosis is not seen in adults −− Pathologic findings vary greatly; in one-third of the cases, the pancreatic changes are minimal (not recognizable without clinical correlation) −− The most consistent finding is the presence of cytologically conspicuous islet cells −− All other criteria, such as a lobulated arrangement of the cells within the islets, hyperplasia, and hypertrophy of islets or an increased b-cell number, are only found in a fraction of the patients −− The final diagnosis relies on the pathologic analysis of the pancreatic tissue specimen, which must first exclude a small insulinoma and then use the criteria given above

Diabetes Mellitus ♦♦ No identifiable changes in most cases ♦♦ Subtle alterations in the islets of some patients including −− Altered number or size (no established criteria) −− Mild fibrosis

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Fig. 43.1. Amyloid deposition in the islets of Langerhans.

−− Amyloid deposition (of “amyloid islet” – amylin type; Fig. 43.1) −− Mild leukocytic infiltrates

Fig. 43.2. Acute pancreatitis with fat necrosis. There is a rim of neutrophils around the necrotic focus.

♦♦ Hyperviscous mucus precipitates in the ducts resulting in ductectasia ♦♦ Obstruction-related changes including acinar atrophy and replacement of atrophic lobules by interstitial fibrosis

Cystic Fibrosis ♦♦ Pancreatic involvement with “fibrocystic” appearance in 80–90%

INFLAMMATORY CONDITIONS Acute Pancreatitis Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Most are due to alcohol abuse; some are related to gallstones Pain and elevated serum enzyme levels (especially amylase) In some, pain is associated with nausea and vomiting Variety of other metabolic complications Local anatomic complications such as pseudocysts (see below), abscesses, hemorrhage, or thrombi

Microscopic ♦♦ Findings range from “mild edematous pancreatitis” to “severe necrotizing pancreatitis” ♦♦ Mild edematous pancreatitis: interstitial edema and usually microscopic fat necrosis, mainly on the surface ♦♦ Severe necrotizing pancreatitis: extensive and sometimes hemorrhagic tissue necrosis involving both pancreatic parenchyma and extrapancreatic fat tissue, development of complications ♦♦ Fat necrosis (Fig. 43.2) −− Grossly chalky white-yellow areas −− Fragmented adipocytes with saponification and/or calcification, and a rim of neutrophils

Chronic Pancreatitis Alcohol or Obstruction-Related Clinical ♦♦ Most are related to alcohol abuse, obstruction (lithiasis or tumors), or other chemical/metabolic factors (hypercalcemia) ♦♦ Recurrent abdominal pain that is later accompanied by exocrine insufficiency and diabetes ♦♦ Increased risk of developing a pancreatic carcinoma ♦♦ Complications such as pseudocyst, persistent stenosis of the bile duct, duodenal stenosis, fistulas

Macroscopic ♦♦ Fibrosis and effacement of pancreatic lobular architecture ♦♦ In some cases, calcifications and intraluminal stones

Microscopic ♦♦ Ductal dilatation with eosinophilic mucoprotein plugs (with/ without calcifications; Fig. 43.3) ♦♦ Remaining small ductules may appear pseudoinfiltrative ♦♦ Acinar dilatation and atrophy ♦♦ Interstitial fibrosis with variable cellularity

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Fig.  43.3. Alcohol or obstruction-related chronic pancreatitis (acinar atrophy and interstitial fibrosis) associated with lithiasis represented in this section as calcified intraluminal material.

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  43.5. Lymphoplasmacytic sclerosing pancreatitis. Characteristic periductal lymphoplasmacytic inflammation, with a dense rim of inflammatory cells, and concentric bands of periductal fibrous tissue surrounding the narrowed pancreatic duct. ♦♦ Slight increase in jaundice compared to autoimmune pancreatitis with granulocytic epithelial lesions ♦♦ About one-fourth associated with established autoimmune conditions (primary sclerosing cholangitis, Sjogren, etc.) ♦♦ Some with “multifocal inflammatory fibrosclerosis” (Riedel thyroiditis, orbital pseudotumor, mediastinal and retroperitoneal fibrosis, etc.) ♦♦ Radiographically, simulates pancreatic carcinoma; sausage-like appearance of the pancreas and halo formation are characteristic ♦♦ Elevated serum IgG4 levels (usually >135 mg/dL) ♦♦ Often responds well to steroid administration

Fig.  43.4. “Hyperplastic islets.” Islets of Langerhans become prominent or appear proliferative in some pathologic conditions of the pancreas, in particular chronic pancreatitis. ♦♦ Remaining islets become prominent; may appear pseudoinfiltrative or form micronodules (Fig. 43.4)

Differential Diagnosis ♦♦ Ductal carcinoma −− Irregularities in the number, distribution and contours of the ducts −− In some cases: pale, foamy, microvesicular cytoplasm, and a dense chromophilic, apical condensation −− Cytologic atypia with nuclear enlargement and contour irregularities −− Ducts in places that they do not belong: perineurial, intravascular, and in adipose tissue (naked ducts without associated islets or acini)

Macroscopic ♦♦ Localized region of fibrosis and effacement of pancreatic lobular architecture producing mass-like enlargement ♦♦ Scarring; adhesions to adjacent organs

Microscopic ♦♦ Dense “duct-centric” inflammation of predominantly lymphoplasmacytic cells and expansion of periductal fibrous tissue (Fig. 43.5) ♦♦ Periphlebitis and obliterative venulitis common (Fig.  43.6); frank vasculitis may be seen (not common) ♦♦ Interstitial fibroblastic proliferation with storiform architecture (“inflammatory pseudotumor”-like) ♦♦ Immunohistologically, IgG4-positive plasma cells, a minimum of >10/HPF is of diagnostic help; proposed cut-off ranges from 10 to 30 depending on the study

Autoimmune Pancreatitis Lymphoplasmacytic Sclerosing Type Clinical

Autoimmune Pancreatitis with Granulocytic Epithelial Lesions (“Idiopathic Duct-Centric Type”) Clinical

♦♦ Typically seen in 6th to 7th decade, male predominance

♦♦ Seen in 5th to 6th decade, almost equal male/female ratio

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Pancreas

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Fig. 43.7. Paraduodenal pancreatitis. In most cases, there is some degree of thickening and scarring of duodenal wall with trabeculations and associated cysts. Sometimes one or more cysts achieve large sizes and form paraduodenal wall cyst. Fig. 43.6. Lymphoplasmacytic sclerosing pancreatitis. Characteristic venulitis, with aggregates of lymphoid cells in the wall and undermining the epithelium. Sometimes veins are completely obliterated and replaced by the inflammation and are recognized by their proximity to uninvolved arteries.

♦♦ Have been linked to the concurrent presence or future development of ulcerative colitis ♦♦ Serum IgG4 levels may be normal

Microscopic ♦♦ Intraepithelial neutrophils and occasionally eosinophils (“granulocytic epithelial lesions-GELs”), especially in intralobular ducts, is the hallmark ♦♦ In the cases with the most severe GELs, the acute inflammatory infiltrate extends into the ductules, acini, and interstitial spaces ♦♦ Phlebitis is not a common pattern ♦♦ IgG4-positive plasma cell infiltration may be mild

Paraduodenal Pancreatitis Synonyms ♦♦ Cystic dystrophy of heterotopic pancreas; groove pancreatitis

Clinical ♦♦ Predominantly in 40- to 50-year-old males ♦♦ History of alcohol abuse is common ♦♦ Waxing and waning severe upper abdominal pain and postparandial vomiting is common ♦♦ Predominantly solid ones often mimic pancreas cancer or ampullary/periampullary tumors, radiographically

Macroscopic ♦♦ Often centered in the region of minor papilla (and the adjacent pancreas) ♦♦ Scarring of duodenal wall and/or distal common bile duct and/ or the “groove” between the duodenum, common bile duct, and pancreas

Fig.  43.8. Paraduodenal pancreatitis. Myoadenomatosis type changes, which are often associated with accessory duct abnormalities, may form a pseudotumor that can be mistaken clinically as cancer. ♦♦ Trabeculation of duodenal musculature with occasional cysts (Fig. 43.7) ♦♦ Paraduodenal wall cyst (up to 10 cm) mimicking intestinal duplication may occur

Microscopic ♦♦ Dense myoid stromal proliferation with intervening rounded lobules of pancreatic tissue (“myoadenomatosis”; Fig. 43.8) ♦♦ Brunner gland hyperplasia ♦♦ Small cystic spaces lined by cellular stroma ♦♦ Extravasated (stromal) mucoprotein plugs surrounded by eosinophiles or multinucleated giant cells ♦♦ Prominence of nerve bundles mimicking traumatic neuroma

Pseudocysts Clinical ♦♦ Complication of pancreatitis

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Most frequently seen in alcoholic males ♦♦ Most common cystic lesion of the pancreatic region (60–70%), but rarely sampled for pathologic examination ♦♦ Occurs due to postnecrotic resorption of peripancreatic fat necrosis

Macroscopic ♦♦ 1–15 cm unilocular cyst, filled with necrotic material fluid ♦♦ Peripancreatic

Microscopic ♦♦ Depends on the stage of the process ♦♦ No epithelial lining by definition ♦♦ The lumen contains necrotic adipose tissue, precipitated acinar secretions, mucoprotein plugs

♦♦ The wall consists of dense fibrous tissue with various degrees of granulation type changes

Differential Diagnosis ♦♦ Mucinous cystic neoplasm −− Epithelial lining −− Ovarian-like stroma with more wavy and layered appearance (compared to haphazard cellularity of fibroblastic reaction in pseudocysts) ♦♦ Other cystic lesions −− Epithelial lining or specific characteristic features

Infections ♦♦ Bacterial, fungal, or parasitic infections may involve the pancreas but none has any particular affinity for this organ

NEOPLASIA Ductal Neoplasia Invasive Ductal Carcinoma Synonyms ♦♦ Pancreatobiliary; scirrhous; tubular; ductal adenocarcinoma

Clinical ♦♦ >85% of all pancreatic tumors ♦♦ More common in developed countries; fourth leading cause of cancer deaths in the USA ♦♦ M/F = 1.5/1; African-American/Caucasian = 2/1; mean age 63; very seldom under the age of 40 ♦♦ Proposed risk factors include longstanding diabetes mellitus, smoking and chronic pancreatitis (especially hereditary pancreatitis); a few are familial; some associated with familial atypical multiple mole/melanoma (FAMM) syndrome (p16 related) ♦♦ Common symptoms: abdominal or back pain, weight loss, and jaundice ♦♦ Some patients develop diabetes mellitus ♦♦ 80% are deemed “unresectable” due to early spread (to mesenteric vessels/retroperitoneum, liver, or peritoneum) ♦♦ Median survival: 8  months if unresectable but treated with chemo/radiotherapy and 12 months if resected; 5-year survival <5%; very few patients are alive at 7 years ♦♦ Almost all develop metastasis (mostly to liver or peritoneum)

♦♦ Obstruction of the ducts (in particular, the common bile duct) is typical ♦♦ May ulcerate into the duodenum

Microscopic ♦♦ Infiltrating tubular units (often widely scattered with open luminae), cords, or individual cells (Fig. 43.10) ♦♦ Abundant desmoplastic stroma of variable cellularity ♦♦ Cuboidal to columnar cells, with variable mucin and nuclear atypia ♦♦ Perineurial invasion in >75% of the cases (Fig. 43.11)

Macroscopic ♦♦ 70% occur in the head ♦♦ Typical size = 3 cm; the tumor is widely disseminated or fatal by the time it reaches 6–7 cm ♦♦ “Scirrhous” pattern: firm, white-gray or yellow mass with ill-defined borders (Fig. 43.9)

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Fig.  43.9. Ductal adenocarcinoma is grossly a scirrhous carcinoma, characterized by firm white mass with ill-defined irregular borders.

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Fig. 43.10. Invasive ductal carcinomas of the pancreas are characterized by infiltrating small tubular units with open lumina, surrounded by desmpoplastic stroma of variable cellularity.

Fig.  43.12. Invasive ductal adenocarcinoma with foamy-gland pattern can be deceptively benign appearing, as reflected in this focus of lymph node metastasis.

Fig.  43.11. Perineural invasion is common in invasive ductal carcinoma.

Fig. 43.13. Cribriform/vacuolated pattern is not uncommon in ductal adenocarcinoma and may help recognize this tumor type in metastatic sites.

♦♦ Gland formation and bland cytology may be retained even in perineurial or vascular invasion ♦♦ Extension to retroperitoneal tissue, especially through the posterior uncinate region is very common

Variants ♦♦ Foamy gland pattern (Fig. 43.12) −− Abundant pale, foamy, microvesicular cytoplasm stuffed with small, evenly shaped vesicles −− Thin, distinct band of chromophilic condensation in the apical cytoplasm forming a brushborder-like zone ♦♦ Vacuolated cribriform pattern (Fig. 43.13) −− Multi-cell-sized vacuoles resembling lipocytes (or signetring cells) and forming a cribriform architecture −− Vacuoles contain necrotic debris and neutrophils −− Nuclear atypia is prominent

♦♦ Other rare patterns: Large duct pattern (mimicking intraductal neoplasia), cord-like formation (Fig.  43.14), clear-cell pattern (mimicking renal cell carcinoma), signet-ring, hepatoid, oncocytic, and rhabdoid patterns ♦♦ May mimic the primary tumors at metastatic sites −− Bronchioloalveolar pattern (“lepidic” growth) in lung −− Mucinous cystic pattern mimicking primary borderline tumors in ovary

Immunohistochemistry ♦♦ CK7+, CK20+/− ♦♦ Mucin positive, especially acidic sialomucin ♦♦ Mucin-related glycoproteins and oncoproteins [CA19-9, CEA, B72.3, MUC1 (Fig. 43.15), MUC5AC, DUPAN2]+ ♦♦ May contain scattered endocrine cells

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Fig. 43.14. Invasive ductal carcinoma, cord-like pattern. Often glandular areas are admixed with less differentiated patterns such as this one mimicking mammary lobular carcinoma.

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Pseudotumoral pancreatitis −− Approximately 5% of pancreatectomies performed with the clinical diagnosis of “pancreas cancer” prove to be chronic pancreatitis (see pancreatitis section) ♦♦ Ampullary/common bile duct carcinomas −− May be morphologically identical −− Location is determined by gross examination −− Preinvasive neoplasia in the corresponding sites ♦♦ Nonductal tumors (acinar, endocrine, solid pseudopapillary neoplasia and pancreatoblastoma) −− Stroma-poor (no desmoplasia) −− Cellular, nonglandular neoplasia with sheet-like or nested growth patterns −− Relatively uniform cytology ♦♦ Intestinal-type adenocarcinoma (gastrointestinal or ampullary origin) −− Basophilic appearance; columnar cells; nuclear strati­ fication −− Large, tubular units with relatively compressed luminae −− CK7−, CK20+, MUC1−/+, MUC2+, MUC5AC− ♦♦ Ovarian adenocarcinoma −− Cellular; tubular areas composed of long, branching units with slit-like spaces −− Many psammoma bodies −− Tufts and micropapillae −− WT1+/MUC5AC−

Other Related Carcinomas

Fig.  43.15. MUC1 in ductal adenocarcinoma. The labeling is typically apical membraneous in the glandular areas and becomes more intracytoplasmic in the less differentiated (nonglandular) component of the tumor. ♦♦ Acinar enzymes typically lacking ♦♦ Loss of DPC4 (SMAD4) is also a finding strongly in favor of adenocarcinoma, provided that in-built controls are working properly ♦♦ Alterations in codon12 of K-ras oncogene (90%), p16 (95%), p53 (50%), DPC4 (>50%), BRCA-2 (7%), and Peutz–Jeghers genes (5%)

Differential Diagnosis ♦♦ Noninvasive ducts (benign reactive ducts or intraductal neoplasia) −− Smooth contours −− Lobular, organized distribution; spatially related to acini and/or islets −− Smaller ducts tend to be in clusters; larger ones have elongated lumina

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♦♦ Anaplastic and sarcomatoid (Fig.  43.16): often, ordinary tubular pattern in the background ♦♦ Adenosquamous and squamous −− Also have dismal prognosis like ordinary ductal adenocarcinomas −− Immunohistochemical stains for p63 and CK903 confirm the squamous differentiation

Rare Carcinomas of Presumed Ductal Origin Colloid Carcinoma Synonyms ♦♦ Mucinous noncystic carcinoma

Definition ♦♦ Invasive carcinoma composed almost exclusively of extracellular mucin pools that contain scanty, detached carcinoma cells ♦♦ Often associated with intraductal papillary mucinous neoplasia

Clinical ♦♦ Mean age mid-60s ♦♦ Thromboembolism in some cases ♦♦ Pure examples may have a protracted clinical course

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♦♦ In situ neoplasia (mucinous cystic tumors, intraductal neoplasia) −− Epithelium continuous and well attached to the stroma −− Mucin not abundant in histologic sections (washed off during processing)

Osteoclastic Giant Cell Carcinoma Synonym ♦♦ “Undifferentiated carcinoma with osteoclast-like giant cells” is a more accurate name and description of this tumor

Clinical Fig. 43.16. Anaplastic/sarcomatoid carcinoma. This undifferentiated carcinoma is composed of large, pleomorphic cells with sarcomatoid transformation.

♦♦ Very rare ♦♦ Aggressive behavior

Macroscopic ♦♦ ♦♦ ♦♦ ♦♦

Average size = 10 cm May appear well-demarcated Most are soft, white-yellow to tan Some are almost completely cystic or have intraductal growth

Microscopic (Fig. 43.18) ♦♦ Sarcomatoid background, often with invasive ductal carcinoma ♦♦ Abundant benign osteoclast-like giant cells

Immunohistochemistry ♦♦ Sarcomatoid and tubular elements show ductal differentiation (Table 43.1) ♦♦ Giant cells are of macrophagic nature; CD45+, CD68+

Medullary Carcinoma

Fig. 43.17. Colloid carcinoma. Pools of mucin some of which contain scanty, detached malignant cells.

Macroscopic ♦♦ Mean size = 4.5 cm ♦♦ Relatively well-demarcated ♦♦ Gelatinous

Microscopic (Fig. 43.17) ♦♦ Well-defined pools of extracellular mucin that contain scanty, detached carcinoma cells ♦♦ Cells floating in mucin may form strips, signet-ring cells, glands, or stellate clusters

Differential Diagnosis ♦♦ Other invasive carcinomas (ductal, signet-ring, or others) −− Invasive carcinoma cells outside the mucin or at least attached to the stroma −− More cells than mucin −− Loss of DPC4

♦♦ ♦♦ ♦♦ ♦♦

Very rare Similar to the medullary carcinomas of the breast and colon Has protracted clinical course Some have synchronous and metachronous colon carcinomas, and some of these have hereditary nonpolyposis colorectal (HNPCC) syndrome

Microscopic ♦♦ Pushing-border type infiltration ♦♦ Syncytial growth pattern ♦♦ Lymphoplasmacytic infiltrates

Immunohistochemistry ♦♦ Associated with microsatellite instability (loss of either MLH1 or MSH2 expression)

Differential Diagnosis ♦♦ Metastatic carcinomas ♦♦ Acinar cell carcinoma −− Trypsin+, MLH1, and MLSH2+ (not lost) ♦♦ Poorly differentiated ductal carcinoma −− Scirrhous (scar-like) pattern −− Small unit infiltration (tubules or cords) ♦♦ Desmoplasia

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Preinvasive Ductal Neoplasia Mucinous Cystic Neoplasms (Table 43.2) Clinical ♦♦ Almost exclusively in perimenopausal females (mean age 48; >95% females) ♦♦ Graded as low grade dysplasia (adenoma), moderate dysplasia (borderline), and high grade dysplasia (carcinoma in situ or CIS) based on the cytoarchitectural atypia ♦♦ Recent studies confirm that grade accurately predicts the outcome, but (only) if the tumor is sampled/examined thoroughly

Macroscopic ♦♦ Large (average size = 7–10  cm), multilocular, thick-walled cyst (Fig. 43.19) ♦♦ Typically in the body or tail ♦♦ Do not communicate with the ducts ♦♦ Thick mucinous content ♦♦ May become purulent ♦♦ Areas of carcinoma often not evident macroscopically

Microscopic

Fig.  43.18. “Osteoclastic giant cell carcinoma.” Sarcomatoid carcinomas with abundant osteoclastic giant cells are also referred to as osteoclastic giant cell carcinoma.

♦♦ Ovarian-type stroma is diagnostic, specific, and almost a prerequisite (Fig. 43.20) −− Identical to ovarian stroma morphologically and immunophenotypically −− May contain sclerotic foci, hypervascularity and rarely even luteal cells ♦♦ Mucinous lining with varying degrees of atypia (see below) ♦♦ Abrupt transition from areas with no atypia to frank CIS is common (Fig. 43.21) ♦♦ Scattered goblet and endocrine cells ♦♦ Papillae may be seen, forming large nodules in some cases

Table 43.1. Markers of Differentiation/Lineage in Pancreatic Neoplasia Lineage

Light microscopy

Histochemical

Immunohistochemical

Ultrastructural

Ductal

Gland, papilla, lumen, mucin

Mucin markers+

Mucin-related glycoproteins and oncoproteins [MUCs, CA19-9, CEA, B72.3 (TAG-72), DUPAN-2]

Mucigen granules, lumina

Acinar

Sheets of cells, prominent nucleoli, chromophilic (basophilic) cytoplasm, sometimes with granules. Some show acinar pattern

PAS and dPAS+ granules

Enzyme markers (trypsina, chymotrypsin, lipase, amylase, and elastase)

Zymogen granules

Endocrine

Nested, trabecular, gyriform, sheet-like patterns, cytologic uniformity with round nuclei, neuroendocrine-type chromatin

Silver (Grimelius) positive granules

Neuroendocrine markers [chromogranin, synaptophysin, NSE, CD56, and leu7 (CD57)]

Membrane-bound neurosecretory type granules

a

The most specific and sensitive markers

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Table 43.2. Differential Diagnosis of Preinvasive Ductal Neoplasia (Intraductal and Cystic Neoplasia With/Without Papilla Formation)

Mean age Gender Specific endoscopic finding Specific radiologic finding Preferential location Ductal communication Degree of papilla Pattern of papilla Specific histologic findings

Mucinous cystic neoplasms

Intraductal papillary mucinous neoplasms

Intraductal oncocytic papillary neoplasms

48 Females (>90%) None Multilocular cyst in the tail of the pancreas Body or tail (>90%) No Variable Variable

68 Males>females Mucin extrusion from ampulla Cystically dilated pancreatic ducts

67 Males~Females None Cystically dilated pancreatic ducts

Head (>80%) Yes Prominent Intestinal Pancreatobiliary Gastric Cystically dilated native ducts with villous nodules

None Yes (some cases) Prominent Complex-arborizing

Ovarian stroma (diagnostic/ pathognomonic)

Arborizing papilla with intraepithelial lumina and oncocytic cells

Fig. 43.19. Mucinous cystic neoplasm typically forms a thickwalled, multilocular cyst in the tail of the pancreas.

Classification/Grading ♦♦ The neoplasm is graded based on the highest degree of atypia identified, not the average ♦♦ Grading is valid only if the tumor is thoroughly examined ♦♦ Low grade dysplasia (adenoma): tall columnar mucinous cells with abundant apical mucin, and well-polarized, uniform small nuclei without atypia ♦♦ Moderate dysplasia (borderline) ♦♦ High grade dysplasia (CIS): severe cytologic or architectural atypia (florid papillary nodules) with cuboidal nuclei, prominent nucleoli, mitotic figures, tufts and necrosis ♦♦ Invasive carcinoma arising in association with MCN is almost exclusively of tubular type with all the morphologic features of invasive ductal adenocarcinoma (see section on ductal adenocarcinoma) ♦♦ Some cases are associated with a sarcoma

Fig. 43.20. Ovarian-like stroma is pathognomonic for mucinous cystic neoplasms.

Immunohistochemistry ♦♦ Ductal lineage markers positive (Table 43.1) ♦♦ Progesterone receptors positive in ovarian stroma

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Fig. 43.21. Mucinous cystadenocarcinoma in situ. The epithelium shows abrupt transition from areas of adenoma to those with frank carcinoma in situ.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 43.22. Intraductal papillary mucinous neoplasm. In many examples of IPMNs, the papillae are morphologically similar to colonic villous adenomas.

Differential Diagnosis ♦♦ Intraductal papillary mucinous neoplasms −− Intraductal (communication with the native ducts demonstrable radiologically or on gross examination) −− Intestinal type papillae may be seen −− More common in the head −− More common in elderly males ♦♦ Intraductal oncocytic papillary neoplasms −− Complex papillae; intraepithelial lumina; oncocytic cells ♦♦ Pseudocyst −− No epithelial lining −− Granulation type tissue (but not ovarian type stroma) −− Fat necrosis

Intraductal Papillary Mucinous Neoplasms (Table 43.2) Definition ♦♦ Intraductal proliferation of mucinous cells of variable papillae formation and cystic change in the ducts −− Some look like villous adenoma −− Some give rise to multilocular cystic transformation of the ducts (with minimal or no papillae)

Clinical ♦♦ Increasing frequency due to detection of small cystic “incidentalomas” ♦♦ Elderly (mean age 68); slightly more common in men; some with history of pancreatitis ♦♦ 30% have coexisting tumors of other organs ♦♦ Endoscopic: Mucin extrusion from ampulla of Vater ♦♦ Radiologic: Dilatation of the ductal system ♦♦ Graded as IPMN with low grade dysplasia (previously, “adenoma”), IPMN with moderate dysplasia (previously,

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♦♦

♦♦

♦♦

♦♦ ♦♦

“borderline”), and IPMN with high grade dysplasia/CIS (previously “carcinoma”) based on the cytoarchitectural atypia Grade seems to correlate with clinical outcome but unexpected clinical course has been noted in some, attributed to missed foci of invasive cancer that are either unresected because of unrecognized multifocality or undiagnosed during pathologic examination Presence of associated invasive carcinoma and the size of the invasive component are the most important prognostic factors “Branch-duct” type tends to be smaller, more cystic and often prove to have only low grade dysplasia, thus amenable for “watchful waiting” “Main duct” type is often more complex, more diffuse, and prone to harbor carcinoma Overall 5-year survival >70%; noncarcinomatous ones have a much better prognosis than carcinomatous; noninvasive much more benign than invasive

Macroscopic ♦♦ Dilatation of the main duct or one of its branches; sometimes multilocular cysts ♦♦ Tan, friable papillary nodules filling the ducts in some cases

Microscopic ♦♦ ♦♦ ♦♦ ♦♦

Intraductal proliferation of mucinous cells In cystic areas, tall columnar cells with abundant apical mucin Papillary areas have more atypia Papillae may have intestinal (villous adenoma like; Fig. 43.22), pancreatobiliary (similar to biliary papillomatosis), or gastric (foveolar; Fig.  43.23) appearance; their significance not yet determined

Classification/Grading ♦♦ Pathologic classification and grading are valid only if the tumor is thoroughly examined

Pancreas

Fig.  43.23. Intraductal papillary mucinous neoplasm. In this example, the lining epithelium resembles gastric foveolar epithelium. There is no atypia (i.e., IPM adenoma).

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Fig. 43.24. Intraductal papillary mucinous neoplasms and intraductal oncocytic papillary neoplasms are characterized by cystically dilated ducts many of which are filled with papillary nodules.

♦♦ IPMN with low grade dysplasia: Tall columnar mucinous cells with abundant apical mucin, and well-polarized, uniform small nuclei without atypia ♦♦ IPMN with moderate dysplasia ♦♦ IPMN with high grade dysplasia/carcinoma in situ): Severe cytologic or architectural atypia (florid papillary nodules) with cuboidal nuclei, prominent nucleoli, mitotic figures, tufts, and necrosis

Immunohistochemistry ♦♦ Ductal differentiation markers (Table 43.1) ♦♦ MUC2 and CDX2 commonly expressed (especially in those that have villous adenoma pattern)

Differential Diagnosis ♦♦ Mucinous cystic neoplasms −− Perimenopausal females −− Tail of the pancreas −− Thick-walled cyst −− No communication with the ducts −− Ovarian-type stroma (most helpful) ♦♦ Intraductal oncocytic papillary neoplasms −− Complex papillae; intraepithelial lumina; oncocytic cells ♦♦ Invasive ductal carcinoma −− Irregular clustering and haphazard distribution −− Contour irregularities −− Small units with round, open luminae −− Perineurial invasion ♦♦ Pancreatic intraepithelial neoplasia −− Microscopic/incidental (not mass-forming) −− Simple mucosal folds or at most, short papillae −− Lack MUC2

Fig.  43.25. Intraductal oncocytic papillary neoplasms. These tumors are characterized by complex-branching papillae, oncocytic cells, and intraepithelial lumina formation.

Intraductal Oncocytic Papillary Neoplasms (Table 43.2) Immunohistochemistry ♦♦ Very similar to intraductal papillary mucinous neoplasms; may be a variant

Microscopic ♦♦ Complex (arborizing) papillae (Fig. 43.24) ♦♦ Intraepithelial lumina (multi-cell size punched-out spaces) with mucin ♦♦ Oncocytic cells (abundant, granular, acidophilic cytoplasm – due to an abundance of mitochondria; round nuclei; prominent, eccentric nucleoli; Fig. 43.25)

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Differential Diagnosis ♦♦ Same as intraductal papillary mucinous neoplasms

Intraductal Tubular Neoplasms Definition and Classification ♦♦ Cystic epithelial neoplasm that grows within the pancreatic ducts and is composed of back-to-back tubular units ♦♦ Common expression of MUC6, in the absence of MUC5AC, raises the possibility of pyloric differentiation ♦♦ Many show marked atypia, high mitotic count, and necrosis and classified as intraductal tubular neoplasm with high grade dysplasia (intraductal tubular carcinoma) ♦♦ Data on the prognosis are limited in the literature: despite the histologic indicators of a high grade malignancy (atypia, mitosis, and necrosis), overall outcome appears relatively favorable if lacking an invasive component ♦♦ Approximately, one-third have foci of invasion ranging from microscopic to larger foci

Fig. 43.26. PanIN-1. In the background of PanIN-1A, the mucosal folds at the center show mild stratification of cells (PanIN-1B).

Pancreatic Intraepithelial Neoplasia Definition and Classification ♦♦ Microscopic/incidental, clinically nonmanifest forms of preinvasive neoplasia in the ducts ♦♦ Previously also referred to as hyperplasia, atypical hyperplasia, dysplasia, etc ♦♦ Encompasses a spectrum of changes from those previously called mucinous hypertrophy/metaplasia to frank CIS ♦♦ Spectrum graded as PanIN-1A (mucinous duct lesion), 1B, 2 and 3 (CIS) ♦♦ Presumed precursors of ductal adenocarcinoma ♦♦ PanIN-1 is a common, incidental finding even in normal pancreata ♦♦ PanIN-3 (CIS) is very common in pancreata with invasive ductal carcinoma and is exceedingly uncommon otherwise

Fig.  43.27. PanIN-2. This duct shows papillary folds with stratification of mildly irregular cells. Some of the nuclei are dyspolarized.

Microscopic ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

♦♦

♦♦

Not grossly detectable Atypical proliferative changes in the native ducts Ducts involved are typically <0.5 cm PanIN-1A: simple, columnar, mucin-filled, perfectly polarized cells with small nuclei PanIN- 1B: 1A + mild folding of the epithelium and early (basal) stratification (Fig. 43.26) PanIN-2: pseudostratification of nuclei; nuclear enlargement, more prominent folding (papillae); some cytologic atypia (Fig. 43.27) PanIN-3: loss of polarity; irregular stratification; tufting; necrosis; mitosis; cytologic atypia (nuclear enlargement, pleomorphism, nuclear irregularities; Fig. 43.28) Clinical significance and rate of progression to invasive carcinoma undetermined

Immunohistochemistry ♦♦ Mucin of usually acidic sialomucin type

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Fig. 43.28. PanIN-3 (carcinoma in situ). There is loss of polarity, and tuft formation is evident. There are necrotic cells detached into the lumen of the duct. The nuclei are hyperchromatic and irregular.

Pancreas

♦♦ Molecular alterations of ductal carcinogenesis increasing from 1A to 3 (see ductal adenocarcinoma section)

Differential Diagnosis

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♦♦ Central stellate scar common ♦♦ Characteristic microcystic pattern with innumerable small cysts, each measuring a few millimeters

♦♦ Intraductal papillary mucinous neoplasms −− Mass-forming neoplasia (clinically/grossly detectable papillary or cystic changes) −− Size typically >1 cm −− Many clinically symptomatic −− Tall papillae, some with intestinal phenotype −− MUC2 and CDX2 expression common ♦♦ Invasive ductal carcinoma −− Contour irregularities −− Irregular clustering and haphazard distribution

Microscopic (Fig. 43.30)

Serous Cystic Neoplasms Synonyms

♦♦ Oligocystic variant −− Smaller number of larger cysts −− Slightly more common in men −− No apparent biologic differences form the microcystic type ♦♦ Solid variant −− Packed with small gland-like units without cystic transformation −− Very uncommon

♦♦ Glycogen-rich adenoma, microcystic serous cystadenoma

Clinical ♦♦ Elderly females (mean age 61; M/F = 1/3) ♦♦ Present with nonspecific symptoms, or detected incidentally ♦♦ Have well-established association with von Hippel–Lindau (vHL) syndrome ♦♦ Cyst fluid analysis does not show oncoproteins seen in mucinous tumors (CEA, CA19-9 and others) ♦♦ Almost exclusively benign; very rare (questionable) examples of a malignant counterpart

Macroscopic (Fig. 43.29) ♦♦ Mean size = 9 cm (may become very large, up to 30 cm) ♦♦ Well-demarcated; sponge-like appearance is diagnostic

Fig. 43.29. Serous cystadenoma. Microcystic pattern (innumerable small cysts most of which are smaller than a few millimeters) creating a sponge-like appearance is diagnostic. A stellate scar is commonly present. These tumors may become very large.

♦♦ Conglomerate of innumerable tubules and cysts ♦♦ Simple cuboidal epithelium ♦♦ Clear (glycogen-rich) cells with distinct cytoplasmic borders ♦♦ Small, round nuclei with dense, homogenous chromatin ♦♦ The tumor cells are intimately admixed with prominent capillary network akin to other clear cell tumors also associated with vHL syndrome

Variants

Immunohistochemistry ♦♦ Epithelial differentiation markers + ♦♦ Virtually the only ductal tumor that does not show the “pancreatic ductal” differentiation markers (mucins, mucin-related oncoproteins, K-ras mutation) ♦♦ Chromosome 10q and vHL gene alterations in a subset (40%)

Fig.  43.30. Microcystic adenoma (serous cystadenoma) is characterized by innumerable, tightly packed tubular elements that are lined by glycogen-rich cells that show distinct cytoplasmic borders and small, round, uniform nuclei with dense, homogenous chromatin.

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Differential Diagnosis ♦♦ Polycystic disease and vHL −− Individual cysts indistinguishable from serous tumors −− More widely spread in the pancreas −− Often multifocal −− Association with cysts in other organs ♦♦ Megacystic tumors (for the rare oligocystic variant) −− Corresponding patterns in the epithelial lining (see corresponding sections in ductal neoplasia and miscellaneous cysts sections)

Acinar Cell Neoplasia Acinar Cell Carcinoma Clinical

♦♦ May contain cytoplasmic granules (sometimes acidophilic) ♦♦ Rosette-like acinar formations may be seen ♦♦ If trabecular pattern, the cells palisade on the adjacent fibrovascular stroma ♦♦ Variable amounts of endocrine elements are quite common. If the endocrine component is larger than 25% of the tumor; by convention, the case is classified as “mixed” ♦♦ Ultrastructurally, electron dense large granules typical of zymogenic granules

Immunohistochemistry (Tables 43.1 and 43.3) ♦♦ PAS positive and diastase resistant granules ♦♦ Immunoreactivity with epithelial and enzymatic markers (trypsin most reliable, but also chymotrypsin and lipases) ♦♦ Lack of ductal markers (mucin and mucin-related oncoproteins)

♦♦ ♦♦ ♦♦ ♦♦

Uncommon; <1% of pancreatic neoplasia Mean age 60 Rarely in children Lipase hypersecretion syndrome (subcutaneous fat necrosis, polyathralgia, and polyarthritis) in 10% ♦♦ 50% with metastasis (usually to liver) at diagnosis ♦♦ 5-year survival 30%; recent studies suggesting better overall prognosis

Macroscopic ♦♦ Typically large (>10 cm) ♦♦ Well-delineated, nodular, fleshy (soft yellow-tan) mass with fibrous bands and frequent necrosis ♦♦ Focal degenerative cystic changes may occur

Microscopic (Fig. 43.31) ♦♦ Sheet-like, stroma-poor growth pattern ♦♦ Overall basophilia ♦♦ Round nuclei with prominent nucleoli

Fig. 43.31. Acinar cell carcinomas form sheets of round cells with prominent nucleoli. In some cases such as this one, abortive acinar formations resembling rosettes may be seen.

Table 43.3. Nonductal Pancreatic Tumors Antibody Keratins Trypsin Chromogranin Synaptophysin CD56 CD10 PR b-catenin E-cadherin

ACC Positive Positive Focally positive Focally positive Usually negative Positive Negative

PEN Positive Scattered cells Positive Positive Positive N/C positivity may be seen Loss of membrane staining and/or abnormal nuclear staining may be seen

N/C positivity: Nuclear and cytoplasmic positivity

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SPT Negative or very focal/weak Negative Negative Positive Positive Positive Positive N/C positivity Loss of membrane staining and/or abnormal nuclear staining

Pancreatoblastoma Positive Positive Positive Positive

N/C positivity

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♦♦ Endocrine neoplasia −− Nested or trabecular pattern −− Lack of overall basophilia −− Endocrine chromatin; nucleoli not too prominent −− Diffuse and strong reactivity for the endocrine markers (chromogranin and synaptophysin) ♦♦ Solid pseudopapillary neoplasm −− Almost exclusively in young females (mean age, 30) −− Solid and pseudopapillary patterns; may have myxoid stroma −− Round to ovoid bland appearing nuclei with small (if at all visible) nucleoli; nuclear grooves −− Degenerative changes including zones of macrophages and hyaline globules −− Lack of specific acinar markers (trypsin, chymotrypsin, and lipases) ♦♦ Pancreatoblastoma −− Ductal and endocrine components (in addition to acinar, which is most common) −− Squamoid corpuscles ♦♦ Ductal adenocarcinoma −− Scirrhous pattern (firm, ill-defined, scar-like appearance) −− Often primary tumor is <5 cm at the time of diagnosis −− Tubular units within desmoplastic stroma

♦♦ According to WHO, PENs are to be classified as −− Microadenoma: Small (<0.5  cm), often incidental and nonfunctional −− Well-differentiated endocrine tumor: Confined to the pancreas at the time of diagnosis (a) “Benign behavior” category * Tumor size <2 cm * No vascular or perineural invasion * Mitotic activity <2/10 HPF * Low proliferation index (Ki-67 <2 %) ♦♦ “Uncertain behavior” category −− Tumor size ³2 cm −− Vascular or perineural invasion −− Mitotic activity 2–10/10 HPF −− Intermediate proliferation index (Ki-67 >2 %) ♦♦ Well-differentiated endocrine carcinoma: Extrapancreatic spread or metastasis at the time of diagnosis ♦♦ The other approach (favored by the authors) proposed by the group at Memorial Sloan–Kettering regards all PENs as potentially malignant and divides them into two groups −− Low grade (a) No necrosis (b) Mitotic activity <2/50 HPF −− Intermediate-grade (a) Necrosis or (b) Mitotic activity ³2/50 HPF ♦♦ Several studies from various institutions have also shown that CK19 immunostaining may serve as another reliable, independent predictor of aggressive behavior

Acinar Cell Cystadenoma

Macroscopic

♦♦ Rare cystic and papillocystic variants ♦♦ Mixed acinar-endocrine carcinomas

Differential Diagnosis

♦♦ Also called “acinar cystic transformation” ♦♦ Very uncommon ♦♦ Usually microscopic; rarely becomes several centimeters

Endocrine Neoplasia Pancreatic Endocrine Neoplasia (PENs, Islet Cell Tumors) Clinical ♦♦ May be functional (50%) or present as a mass without hormone activity (nonfunctioning) ♦♦ Some are associated with MEN-1 or other syndromes ♦♦ MEN-associated examples tend to be multiple and less aggressive ♦♦ Most insulinomas follow a benign course, possibly because they are typically functional from the beginning and are detected and removed when very small

Classification ♦♦ There are different approaches in classifying PENs based on the potential behavior of these tumors

♦♦ Generally well delineated with partial to complete encapsulation ♦♦ Fleshy (tan, soft, homogenous)

Microscopic (Fig. 43.32) ♦♦ Nested, gyriform (trabecular), acinar and even gland-like or solid appearing patterns ♦♦ Uniform cells with fair amount of acidophilic cytoplasm ♦♦ Round, centrally located nuclei with distinctive stippled (“salt and pepper”) chromatin ♦♦ Nucleoli may be present but not prominent ♦♦ Scattered atypical cells (“endocrine atypia”) may be seen ♦♦ Ultrastructurally, membrane-bound neurosecretory granules are typical; some hormones, especially insulin has distinctive appearance

Immunohistochemistry (Tables 43.1 and 43.3) ♦♦ Silver stains (Grimelius) + ♦♦ Epithelial markers +; neuroendocrine markers [chromogranin, synaptophysin, NSE, neural cell adhesion molecule (CD56), and leu-7 (CD57)] +

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−− Immunoreactivity with enzymes (trypsin); chromogranin− ♦♦ Solid pseudopapillary neoplasm −− More ovoid cells with overlapping of nuclei; nesting is vague −− Pseudopapillary pattern, nuclear grooves, hyaline globules, and zones of macrophages −− Chromogranin-, keratin may be focal or weak

Poorly Differentiated Endocrine (Small Cell) Carcinoma

Fig. 43.32. Pancreatic endocrine neoplasia is characterized by sheets of round, uniform cells forming nests that are separated by delicate fibrovascular stroma. ♦♦ Hormone markers (insulin, glucagon, somatostatin, gastrin, vasoactive intestinal polypeptide, and PP) may be positive ♦♦ However, hormone immunochemistry in the tumor does not correlate with the “functionality” status

Variants ♦♦ Cystic: 5% of PENs, results from a degenerative process ♦♦ Clear cell: may mimic renal cell carcinomas; often associated with von Hippel–Lindau ♦♦ Pleomorphic: degenerative endocrine atypia in which many of the nuclei are enlarged, have smudgy, dense chromatin and irregular contours is more pronounced than usual ♦♦ Lipid-rich: microvesicular, foamy cytoplasm creates a picture indistinguishable from adrenocortical cells ♦♦ Signet-ring-like or rhabdoid: homogenous cytoplasmic contents that push the nucleus to the periphery of the cell ♦♦ Paraganglioma-like: nested pattern in which cells form smaller clusters surrounded by stromal cells resembling sustentacular cells

Differential Diagnosis ♦♦ Carcinoid −− May be indistinguishable −− Cytologic uniformity more striking −− Serotonin activity is typical −− Cytoplasmic basophilia, granularity at the periphery of the nests, and lipofuscin pigment ♦♦ “Hyperplastic islets” (nonneoplastic islets in chronic pancreatitis) −− Cord-like pseudoinfiltrative pattern or micronodules −− In the background of other pathologic changes −− Hormone immunohistoprofile is similar to that of normal islets (the presence of multiple hormones and their spatial distribution) ♦♦ Acinar cell carcinoma −− Overall basophilia; prominence of nucleoli; nesting not prominent

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♦♦ Primary high grade neuroendocrine carcinomas are exceedingly uncommon ♦♦ Most small cell carcinomas in the pancreas are metastatic from lung ♦♦ Present with metastasis to liver ♦♦ Rapidly fatal ♦♦ Pathologically similar to their pulmonary counterparts ♦♦ Necrosis and abundant mitotic activity are characteristic

Solid Pseudopapillary Neoplasm Clinical ♦♦ Uncommon; 1–2% of pancreatic tumors ♦♦ Previously known as “papillary-cystic,” “solid and cystic,” and “solid and papillary” ♦♦ Origin undetermined ♦♦ Almost exclusively in young females (mean age 30); other tumors, in particular endocrine neoplasia, to be ruled out if in a male ♦♦ Indolent (low grade) neoplasm −− Complete removal = 85% cure rate −− Metastasis, if occurs, is usually to the liver or peritoneum and is often present at the time of diagnosis −− Even patients with metastases may have a protracted clinical course −− Almost never fatal ♦♦ No reliable criteria to distinguish metastatic cases

Macroscopic ♦♦ Round and deceptively well demarcated (satellites and projections are common under microscopy) ♦♦ Commonly cystic and hemorrhagic with scattered fleshy-tan foci of viable tumor ♦♦ Typical size = 8–10 cm

Microscopic (Fig. 43.33) ♦♦ Solid areas with sheets of neoplastic cells punctuated by fibrotic and/or myxoid stroma ♦♦ Calcifications and psammoma bodies may be seen ♦♦ Ependymoma-like pseudopapillary pattern, presumably related to the alterations in cell adhesion molecules such as E-cadherin, culminating in distinctive dyscohesiveness of the cells away from the microvasculature

Pancreas

Fig. 43.33. Solid pseudopapillary neoplasm. Ependymoma-like pseudopapillary pattern is characteristic. The nuclei are round to ovoid. ♦♦ Round to ovoid, cytologically bland nuclei with small (if at all visible) nucleoli; overlapping of nuclei; nuclear grooves ♦♦ Hyaline globules and zones of foamy macrophages in the more degenerated areas ♦♦ Satellites and projections to adjacent pancreas; entrapped pancreatic elements within the main lesion

Variants ♦♦ Some have spindle cell areas resembling hemangiopericytomas

Immunohistochemistry (Table  43.3) ♦♦ Diffuse and consistent immunoreactivity for vimentin, progesterone receptors, CD10, and b-catenin (see below) ♦♦ So-called neuroendocrine markers NSE, synaptophysin, and CD56 consistently positive; however, chromogranin is mostly negative or very focal/weak positive ♦♦ Inhibin and estrogen receptors less consistent; keratins may be focal or weak ♦♦ Wnt-signaling pathway alterations with abnormal nuclear accumulation of b-catenin, overexpression of cyclin D1, and loss of E-cadherin membraneous expression with/without relocalization to nucleus

Differential Diagnosis ♦♦ Pseudocyst −− No epithelial lining (may require extensive sampling to prove) ♦♦ Pancreatic endocrine neoplasia (islet cell tumors) −− Nested pattern prominent; neuroendocrine chromatin; more uniform, round cells; less overlapping; chromogranin+ ♦♦ Acinar cell carcinoma −− Overall basophilia; prominent nucleoli; PAS+ acidophilic granules −− Immunoreactivity for acinar enzymes ♦♦ Pancreatoblastoma −− Squamoid corpuscles

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Fig.  43.34. Pancreatoblastoma. Diffuse sheets of relatively uniform cells with distinct foci of ductal, acinar, and endocrine differentiation. Morule-like formations referred to as squamoid corpuscles are diagnostic.

−− Ductal, endocrine, and acinar differentiation (Table 43.1) −− Childhood tumor

Pancreatoblastoma Clinical ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Extremely rare Early childhood tumor (mean age 4); second peak in 30s Two-thirds described in Asians Elevated alpha-fetoprotein in some cases Occasionally seen in Beckwith–Wiedemann and FAP syndromes ♦♦ 5-year survival 25%

Macroscopic ♦♦ Well-demarcated, solitary, solid, multilobulated, encapsulated tumor; yellow-tan cut surface ♦♦ Typical size = 7–18 cm

Microscopic (Fig. 43.34) ♦♦ Cellular, stroma-poor neoplasm ♦♦ Multiphenotypic differentiation with a mixture of acinar (most consistent), ductal and endocrine elements ♦♦ Typically, round nondescript cells with moderate amount of cytoplasm predominate ♦♦ Squamoid corpuscles (small, distinct “morule” like formations with meningothelial appearance, including nuclear pseudoinclusions) ♦♦ Necrosis may be seen

Immunohistochemistry (Tables 43.1 and 43.3) ♦♦ Acinar, ductal, and endocrine components show corresponding staining patterns ♦♦ APC/b-catenin pathway and chromosome 11p alterations

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♦♦ Abnormal (nuclear/cytoplasmic) immunolabeling for b-catenin and overexpression of cyclin D1, more strikingly in squamoid corpuscles

Differential Diagnosis ♦♦ Acinar cell carcinoma −− Absence of squamoid corpuscles ♦♦ Endocrine neoplasia −− Adults −− Absence of squamoid corpuscles and other lineage elements ♦♦ Solid pseudopapillary neoplasm −− Pseudopapillary (ependymoma-like) pattern, zones of macrophages, hyaline globules −− Nuclear grooves −− Absence of squamoid corpuscles

Mixed Carcinomas (Mixed Acinar-Endocrine and Mixed Acinar-Ductal) ♦♦ Extremely uncommon ♦♦ Arbitrarily defined as carcinomas with a second component constituting >25% of the tumor ♦♦ Pitfall: Scattered endocrine cells are common in other neoplasia ♦♦ Behavior along the more aggressive component? (see the corresponding sections)

Miscellaneous Cystic Lesions Lymphoepithelial Cyst Clinical ♦♦ ♦♦ ♦♦ ♦♦

Peripancreatic Adult men (M/F = 3/1, mean age, 52) No association with any syndromes No association with malignancy

Microscopic (Fig. 43.35)

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Contain distinctive mucoproteinaceous acidophilic acinar secretions forming concretions ♦♦ The wall is composed of a thin band of fibrous tissue devoid of any lymphoid tissue ♦♦ Nuclear p63 expression confirms the squamous/transitional nature of the epithelial lining

Epidermoid Cyst within Intrapancreatic Accessory Spleen ♦♦ ♦♦ ♦♦ ♦♦

Very rare Young patients (mean age 37) Typically in the tail of the pancreas Attenuated keratinizing squamous epithelium, surrounded by unremarkable splenic tissue

Lymphangioma ♦♦ Young females (M/F = 1/3; mean age 29) ♦♦ Endothelial-lined cysts (CD31, CD34, factor VIII+) ♦♦ Lymphoid tissue

Miscellaneous Tumors Secondary Tumors ♦♦ Direct spread from ampullary, duodenal and biliary tumors −− May be morphologically identical −− Location is determined by gross examination −− Preinvasive neoplasia in the corresponding sites ♦♦ Metastasis to pancreas are rare −− Lung and GI tumors are the most common at autopsy −− Renal cell carcinomas and melanomas may be mistaken clinically as a primary −− Should be considered in the differential diagnosis if a pattern not described for the primary tumors is encountered

Mesenchymal Tumors ♦♦ Most are secondary from neighboring sites (GISTs or retroperitoneal tumors)

♦♦ ♦♦ ♦♦ ♦♦

Epidermal-lined cyst with variable keratinization Some with transitional or attenuated lining Rarely, goblet cells or scanty sebaceous elements A distinct band of lymphoid tissue composed of mature T lymphocytes surrounds the epithelium ♦♦ Lymphoid tissue may have lymph node architecture (germinal centers, sinusoids, capsule, and subcapsular sinus) ♦♦ Granulomas, cholesterol clefts, and solid epithelial cell nests may be seen

Squamoid Cyst of Pancreatic Ducts ♦♦ Small, unilocular cysts (median size = 1.5 cm) ♦♦ Some are large and might undergo resection with the clinical impression of being an IPMN ♦♦ Have variable lining ranging from attenuated, nonstratified squamous to transitional to stratified squamous epithelium

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Fig. 43.35. Lymphoepithelial cyst is characterized by epidermallined cyst surrounded by a distinct band of lymphoid tissue.

Pancreas

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♦♦ Primary ones are very rare ♦♦ Some, especially schwannomas, may be cystic ♦♦ Small blue cell tumors of childhood including primitive neuroectodermal tumors and desmoplastic small round cell tumors may also occur in the pancreas

Hematopoietic Tumors ♦♦ Very uncommon ♦♦ Virtually every hematopoietic tumor type may present as a primary mass in the pancreas including B-cell, T-cell, Hodgkin, and myeloma

REPORTING OF PANCREATIC NEOPLASIA ♦♦ Contents of the specimen ♦♦ Type of operation −− Pancreatoduodenectomy is the preferred term over Whipple (since most current operations are not the original Whipple operation) −− Distal pancreatectomy (with or without splenectomy) ♦♦ Origin/location of the tumor (mostly based on gross examination and clinical findings) −− Pancreatic vs. periampullary (nonspecific), ampullary, common bile duct, duodenal or peripancreatic ♦♦ Type of the tumor −− For example, pancreatobiliary vs. adenosquamous, colloid, medullary, intestinal, etc −− Invasive and preinvasive (noninvasive) components reported separately −− Generic diagnoses, such as “mucinous carcinoma,” should be further specified ♦♦ Size of the tumor −− Size of invasive and noninvasive components reported separately −− An estimated size, based on the correlation of gross and microscopic findings, is necessary in many cases ♦♦ Distribution of the tumor −− Specify involvement of organs (ampulla, CBD, duodenum, etc.) ♦♦ Preinvasive neoplasia −− Even if associated with invasive carcinoma, the features of intraductal neoplasia, mucinous cystic neoplasia, etc., should be duly noted

♦♦ Vascular and perineurial invasion −− Some authors use perineurial invasion as an additional “soft” criteria for inclusion into radiotherapy protocols ♦♦ Lymph nodes −− An average of 12 lymph nodes are identifiable in a typical pancreatoduodenectomy specimen; most are embedded on the surfaces of the pancreatic head and pancreatoduodenal groove ♦♦ Margins −− In a right-sided (pancreatoduodenectomy) specimen (a) Retroperitoneal (uncinate, posterior), pancreatic duct (neck), common bile duct, and gastrointestinal mucosal margins (b) Posterior and anterior free surfaces are reported separately as “surfaces” by some and as “margins” by others (c) Retroperitoneal margin is the most important. If sampled like the prostatic apex (removed as a 3–4  mm slice, serially sectioned and submitted entirely as perpendicular margin), this margin proves positive in 50–85% of the cases with ductal carcinoma. This area also contains lymph nodes −− In a left-sided (distal) pancreatectomy (a) Pancreatic ductal margin, anterior surface, posterior surface, and perisplenic soft tissue surface ♦♦ Uninvolved segments of organs −− Uninvolved pancreas (for PanINs, other precursor lesions, pancreatitis, etc.), as well as uninvolved CBD, gastrointestinal, gallbladder, spleen ♦♦ Surgical hardware, especially stents

TNM CLASSIFICATION OF PANCREATIC TUMORS (2010 REVISION) ♦♦ Primary Tumor (T) −− TX: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− Tis: Carcinoma in situ* −− T1: Tumor limited to the pancreas, £2  cm in greatest dimension

−− T2: Tumor limited to the pancreas, >2  cm in greatest dimension −− T3:  Tumor extends beyond pancreas but without involvement of the celiac axis or the superior mesenteric artery −− T4:  Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

*Carcinoma in situ also includes PanIN III classification

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♦♦ Regional Lymph Nodes (N) −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis ♦♦ Distant Metastasis (M) −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis

Table 43.4. Anatomic Stage/Prognostic Groups STAGE 0

Tis

N0

M0

STAGE IA

T1

N0

M0

STAGE IB

T2

N0

M0

STAGE IIA

T3

N0

M0

STAGE IIB

T1, T2, or T3

N1

M0

Anatomic Stage/Prognostic Groups

STAGE III

T4

Any N

M0

♦♦ See Table 43.4

STAGE IV

Any T

Any N

M1

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Basturk O, Coban I, Adsay NV. Cystic neoplasms of the pancreas. Arch Pathol Lab Med 2009;133:423–438. Basturk O, Zamboni G, Klimstra D, et  al. Intraductal and papillary variants of acinar cell carcinomas: A new addition to the challenging differential diagnosis of intraductal neoplasms. Am J Surg Pathol 2007;31: 363–370. Chetty R, Serra S. Membrane loss and aberrant nuclear localization of E-cadherin are consistent features of solid pseudopapillary tumour of the pancreas. An immunohistochemical study using two antibodies recognizing different domains of the E-cadherin molecule. Histopathology 2008; 52:325–330. Chetty R, Serra S, Asa SL. Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors. Am J Surg Pathol 2008;32:413–419. Compton CC. Serous cystic tumors of the pancreas. Semin Diagn Pathol 2000;17:43–56. Deshpande V, Fernandez-del Castillo C, Muzikansky A, et  al. Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors. Am J Surg Pathol 2004;28:1145–1153. Deshpande V, Mino-Kenudson M, Brugge W, et al. Autoimmune pancreatitis: more than just a pancreatic disease? A contemporary review of its pathology. Arch Pathol Lab Med 2005;129:1148–1154.

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Hruban RH, Adsay NV. Molecular classification of neoplasms of the pancreas. Hum Pathol 2009;40:612–623. Hruban RH, Pitman MB, Klimstra DS. 2007. Tumors of the Pancreas. In AFIP Atlas of Tumor Pathology Series. AFIP: Washington, DC. Hruban RH, Adsay NV, Albores-Saavedra J, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25:579–586.

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44 Nonneoplastic Hepatobiliary Disease Romil Saxena, mbbs, frcpath

Contents

I. Viral Hepatitis....................................44-3 Grading and Staging of Viral Hepatitis.........44-4 Hepatitis A........................................................44-6 Hepatitis B.........................................................44-6 Hepatitis C........................................................44-7 Hepatitis D........................................................44-8 Hepatitis E.........................................................44-9 Hepatitis F.........................................................44-9 Hepatitis G........................................................44-9 Human Immunodeficiency Virus Infection and AIDS......................................44-9 Epstein–Barr Virus Infection........................44-10 Cytomegalovirus Infection............................44-11 Herpes Simplex Virus Infection....................44-11

II. Nonviral Infections..........................44-12 Bacterial Infections........................................44-12 Pyogenic Bacterial Infection................44-12 Brucellosis.............................................44-12 Salmonellosis.........................................44-13 Recurrent Pyogenic Cholangitis...................44-13 Syphilis............................................................44-14 Mycobacterial Infections...............................44-14 Tuberculosis..........................................44-14 Mycobacterium Avium-Intracellulare Infection.......44-15 Leprosy..................................................44-15 Rickettsial Infection.......................................44-15 Fungal Infections............................................44-15 Histoplasmosis......................................44-15 Coccidioidomycoses..............................44-16 Parasite Infections..........................................44-17

Amebic Abscess....................................44-17 Malaria..................................................44-17 Hydatid Cyst.........................................44-18 Clonorchiasis (Infection by Liver Flukes).............................................44-18 Schistosomiasis.....................................44-19

III. Drug and Toxin-Induced Liver Injury......................................44-20 General Features............................................44-20 Pure Hepatocellular Necrosis........................44-20 Common Example: Acetaminophen................................44-20 Other Drugs Causing Hepatocellular Necrosis..................44-21 Acute Hepatitis...............................................44-21 Common Example: Isoniazid..............44-21 Common Example: Phenytoin............44-21 Common Example: Halothane............44-21 Other Drugs Causing Acute Hepatitis...........................................44-22 Chronic Hepatitis...........................................44-22 Common Example: Nitrofurantoin..................................44-22 Other Drugs Causing Chronic Hepatitis...........................................44-22 Cholestasis and Duct Injury..........................44-22 Common Example: Oral Contraceptives........................44-22 Other Drugs Causing Cholestasis and Drug Injury...............................44-22 Fibrosis............................................................44-22

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_44, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Common Example: Methotrexate.......44-22 Other Drugs Causing Liver Fibrosis.............................................44-22 Steatosis...........................................................44-22 Macrovesicular.....................................44-22 Microvesicular......................................44-23 Vascular Abnormalities.................................44-23 Peliosis-Like Lesions............................44-23 Sinusoidal Dilatation............................44-23 Veno-Occlusive Disease........................44-23 Vasculitis................................................44-23 Granulomas....................................................44-23 Neoplasms.......................................................44-23 Hepatocellular Adenoma.....................44-23 Hepatocellular Carcinoma...................44-23 Cholangiocarcinoma............................44-23 Angiosarcoma.......................................44-23

IV. Alcoholic and Nonalcoholic Fatty Liver Disease...........................44-23 Acute Alcoholic Liver Disease.......................44-23 Steatosis.................................................44-23 Steatohepatitis.......................................44-24 Chronic Alcoholic Liver Disease...................44-25 Progressive Perivenular Fibrosis.........44-25 Cirrhosis................................................44-25 Nonalcoholic Fatty Liver Disease..................44-25 Jejunoileal Bypass................................44-27 Total Parenteral Nutrition.............................44-28 Acute Fatty Liver of Pregnancy....................44-28

V. Vascular Disorders...........................44-28 Hepatic Venous Outflow Obstruction...........44-28 Congestive Heart Failure.....................44-28 Budd–Chiari Syndrome.......................44-29 Veno-Occlusive Disease........................44-29 Hypotensive Anoxia........................................44-30 Inflammatory Vascular Lesions....................44-30 Pylephlebitis..........................................44-30 Polyarteritis...........................................44-31 Miscellaneous Vascular Disorders................44-31 Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Disease).......44-31 Idiopathic Portal Hypertension (Noncirrhotic Portal Hypertension)...................................44-31

VI. Cholestasis and Biliary Tract Disorders.........................................44-31 Acute Mechanical Duct Obstruction............44-31 Chronic Mechanical Duct Obstruction........44-32 Primary Biliary Cirrhosis..............................44-32 Primary Sclerosing Cholangitis....................44-33 Intrahepatic Cholestasis................................44-34

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Postoperative Cholestasis.....................44-34 Intrahepatic Cholestasis of Pregnancy.....................................44-34 Paucity of Intrahepatic Bile Ducts......44-35

VII. Developmental, Hereditary, and Metabolic Liver Disease...................44-35 Cystic Liver Disease.......................................44-35 Solitary Unilocular Cyst......................44-35 Autosomal Recessive Polycystic Kidney Disease (ARPKD)...............44-35 Autosomal Dominant Polycystic Kidney Disease (ADPKD)...............44-36 Congenital Hepatic Fibrosis................44-37 Bile Duct Dilatation........................................44-37 Choledochal Cyst..................................44-37 Caroli Disease.......................................44-38 Extrahepatic Biliary Atresia.........................44-38 Alagille Syndrome................................44-39 Disorders of Bilirubin Metabolism...............44-40 Conjugated Hyperbilirubinemias.......44-40 Unconjugated Hyperbilirubinemias.......................44-41 Progressive Familial Intrahepatic Cholestasis........................................44-41 Cystic Fibrosis................................................44-42 Alpha-1 Antitrypsin Deficiency.....................44-43 Genetic Hemochromatosis.............................44-44 Copper Storage Disorders.............................44-45 Wilson Disease......................................44-45 Indian Childhood Cirrhosis.................44-46 Amyloidosis...........................................44-47 Porphyrias.......................................................44-48 Porphyria Cutanea Tarda....................44-48 Erythropoietic Protoporphyria...........44-48 Sickle Cell Anemia.........................................44-49 Storage Disorders...........................................44-49

VIII. Miscellaneous Conditions................44-51 Autoimmune Hepatitis...................................44-51 Granulomatous Liver Disease.......................44-52 Sarcoidosis......................................................44-53 Inflammatory Bowel Disease.........................44-53 Neonatal Giant Cell Hepatitis.......................44-54 Reye Syndrome...............................................44-54 Toxemia of Pregnancy....................................44-55

IX. Disorders of the Gallbladder...........44-55 Acute Cholecystitis.........................................44-55 Chronic Cholecystitis.....................................44-55 Cholelithiasis...................................................44-55 Choledocholithiasis........................................44-56 Postcholecystectomy Syndrome....................44-56

X. Suggested Reading...........................44-56

Nonneoplastic Hepatobiliary Disease

44-3

VIRAL HEPATITIS ♦♦ The liver may be involved by both hepatotropic and nonhepatotropic viruses (Table 44.1) −− Hepatotropic viruses preferentially and predominantly involve the liver while nonhepatotropic viruses involve the liver as part of a systemic or multiorgan infection −− The hepatotropic viruses include hepatitis A, B, C, E, and the delta agent −− Commonest nonhepatotropic viruses affecting the liver are cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpesvirus, and adenovirus ♦♦ The clinical syndromes caused by viral hepatitis include acute viral hepatitis, acute liver failure also known as fulminant hepatic failure, and chronic hepatitis ♦♦ Acute hepatitis may resolve spontaneously (self-limited hepatitis) or progress to chronic liver disease −− In a minority of cases, acute viral hepatitis may progress to acute liver failure

♦♦ Chronic liver disease is progressive but the rate of progression is variable −− The factors underlying this variability are not accurately defined but include both host and viral factors ♦♦ Acute hepatitis is characterized microscopically by lobular changes that overshadow the changes in the portal tracts, or are at least as severe as those in the portal tracts −− The lobular changes in acute hepatitis are characterized by lobular inflammation, necrosis, apoptotic bodies, hepatocyte degeneration, and Kupffer cell prominence giving an appearance of “lobular disarray” (Figs. 44.1–44.4) −− Portal inflammation may be present to a variable degree but is overshadowed by lobular changes −− All causes of acute hepatitis show similar features (a) Therefore, the differential diagnosis of acute viral hepatitis includes other causes of acute hepatitis such as drug-induced hepatitis and autoimmune hepatitis (b) Diagnosis is established by correlation with serological and clinical findings

Table 44.1. Comparison of Hepatotropic and Nonhepatotropic Viruses Hepatotropic viruses

Nonhepatotropic viruses

Viruses that preferentially and predominantly infect liver

Viruses that involve liver as part of systemic or multiorgan infection

Hepatitis viruses A, B, C, E, and delta agent

Cytomegalovirus, Epstein–Barr virus, herpes virus, adenovirus, human immunodeficiency virus

Can cause acute hepatitis, chronic hepatitis, or acute liver failure

Usually cause acute hepatitis or acute liver failure

Affect immunocompetent individuals

Usually affect immunocompromised individuals

Fig. 44.1. Acute hepatitis showing “lobular disarray” caused by lobular inflammation, Kupffer cell prominence, cell degeneration, and necrosis.

Fig.  44.2. Acute hepatitis showing cellular degeneration and apoptotic bodies.

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Fig.  44.3. Acute hepatitis with areas of parenchymal collapse containing pigment laden macrophages.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 44.5. Chronic hepatitis showing interface hepatitis (piecemeal necrosis) with a mononuclear inflammatory cell infiltrate destroying hepatocytes at the limiting plate. Several necrotic hepatocytes are seen surrounded by lymphocytes.

Fig. 44.4. Reticulin stain in acute hepatitis showing collapse of hepatic plates. ♦♦ Chronic hepatitis is characterized by portal inflammation and progressive destruction of hepatocytes present at the interface with portal tracts. This is also called interface hepatitis or piecemeal necrosis; the former term is preferred (Fig. 44.5) −− Lobular inflammation and damage are present but are not the predominant finding −− Determination of the cause of chronic hepatitis requires knowledge of clinical and serological data as all hepatotropic viruses show similar histological findings; the exceptions to this are as follows (a) The presence of ground glass cells in hepatitis B (Fig. 44.6) * Immunohistochemical positivity with specific antibodies against the Hepatitis B surface and core antigens, or the delta agent −− The presence of a triad of mild bile duct destruction, mild fatty change and portal lymphoid follicles/aggregates in chronic hepatitis C infection (Figs. 44.7 and 44.8)

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Fig. 44.6, Ground glass hepatocytes in chronic hepatitis B infection. The ground glass appearance results from accumulation of surface antigen in endoplasmic reticulum. (b) Portal lymphoid aggregates may also be present in a host of other chronic liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, and chronic hepatitis B infection * No specific immunohistochemical stains are available for diagnosis of hepatitis C infection

Grading and Staging of Viral Hepatitis (Table 44.2) ♦♦ The grade of hepatitis indicates the “aggressiveness” of the disease process which is reflected by the degree of inflammatory activity ♦♦ The grade of hepatitis is determined by −− The degree of lobular inflammation and damage

Nonneoplastic Hepatobiliary Disease

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Table 44.2. Grading and Staging of Chronic Viral Hepatitis Grading

Staging

Determines aggressiveness of hepatitis

Determines progress of hepatitis along the path of portal fibrosis towards cirrhosis

Assessed by

Assessed by degree of fibrosis

 Lobular inflammation and damage  Inflammation and damage at interface of portal tracts with hepatocytes (“limiting plate”)

Fig. 44.7. Chronic hepatitis C infection showing a portal lymphoid follicle.

Systems with numeric values

Systems with numeric values

  Semiquantitative

 Four stage systems (commonly used, see Table 44.3)   Six-stage system of Ishak

Systems with descriptive terms (none, minimal, mild, moderate, severe)

Fig. 44.8. Chronic hepatitis C infection showing epithelial damage of bile duct, which is surrounded by lymphoid aggregate. −− The degree of interface hepatitis which is inflammation and damage of hepatocytes at the interface with portal tracts (Fig. 44.9) (a) The synonymous term “piecemeal necrosis” is no longer favored ♦♦ Several semiquantitative, numeric grading systems exist but the most practical one is a grading system using descriptive terms such as “none, minimal, mild, moderate, and severe” −− The older system of chronic persistent hepatitis, chronic active hepatitis, and chronic lobular hepatitis is no longer in use ♦♦ A more detailed system called the Histological Activity Index was devised by Knodell et al −− A numerical and highly complex schema, the Knodell score is best suited for clinical trials, which require statistical analysis of complex data in large cohorts of patients

Fig. 44.9. Severe interface hepatitis in chronic hepatitis B infection; interface hepatitis was seen around the entire circumference of all portal tracts.

♦♦ Stage refers to the progression of disease as determined by the degree of fibrosis −− The stage of hepatitis indicates how far the disease has progressed along the path to cirrhosis −− There are several published staging systems, most of which comprise four stages −− A six-stage system devised by Ishak et al. provides greater discriminatory value

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Table 44.3. A Commonly Used Staging System

Hepatitis B Clinical

♦♦ The microscopic features are as those described for acute hepatitis ♦♦ Plasma cells predominate in the inflammatory infiltrate, which involves portal, periportal, and lobular areas ♦♦ Some cases show a predominantly cholestatic clinical picture with marked centrilobular cholestasis

♦♦ Hepatitis B virus is a 42 nm enveloped particle with an inner hexagonal core containing a circular double-stranded DNA genome ♦♦ Hepatitis B is the most common viral hepatitis worldwide −− It is endemic in parts of Asia, Africa, and Latin America ♦♦ The virus is transmitted by exposure to contaminated blood and body fluids −− The modes of transmission include transfusions, sexual contact, and use of contaminated needles and syringes −− In highly endemic areas, such as parts of Asia, the virus is transmitted through the placenta from mother to fetus. This is called vertical transmission: (a) Infection acquired vertically from mother to fetus usually leads to a chronic carrier state. ♦♦ Active immunization is successful in preventing the disease ♦♦ Most cases of hepatitis B infection are subclinical −− Approximately 10% progress to acute liver failure or chronic liver disease −− The risks for progression to chronic liver disease are not entirely known but host factors undoubtedly play a major role ♦♦ Following infection, the hepatitis B surface antigen (HBsAg) appears first in serum, followed by HBeAg −− These are followed by the appearance of anti-HBc IgM and anti-HBe −− The HBsAg is lost after approximately 2 months and antiHBsAg appears in blood after a 1- to 4-month window period −− Persistence of HBeAg indicates persistent infection and the likelihood of progression to chronic hepatitis ♦♦ The virus is not directly cytopathic but causes liver damage secondary to immune-mediated injury −− An exception is fibrosing cholestatic hepatitis, a rapidly progressive form of recurrent hepatitis B which occurs following transplantation (a) Fibrosing cholestatic hepatitis is a direct cytopathic effect of rapid intracellular proliferation of the virus in these immunosuppressed patients (b) Fibrosing cholestatic hepatitis has been virtually eliminated by the routine administration of HBIg and Lamivudine in patients transplanted for hepatitis B infection ♦♦ There is a high risk of hepatocellular carcinoma even in the absence of significant inflammation or fibrosis

Differential Diagnosis

Microscopic (Acute Hepatitis B)

♦♦ All causes of acute hepatitis including autoimmune and drug-induced hepatitis ♦♦ Hepatitis E infection has a clinical profile and endemicity similar to hepatitis A infection

♦♦ Acute hepatitis B is marked by lobular-predominant inflammation with varying degrees of hepatocellular degeneration, ballooning, necrosis, and regenerative changes ♦♦ A mononuclear portal inflammatory infiltrate is also present

Stage

Description

Stage 1

Fibrosis restricted to portal tracts

Stage 2

Periportal fibrosis and rare portal-portal septa

Stage 3

Numerous septa leading to architectural distortion, no nodules are present

Stage 4

Bridging fibrosis with regenerative nodules (cirrhosis)

−− The most widely used staging system in clinical practice is shown in Table 44.3 −− Accurate staging requires a connective tissue stain such as the Masson trichrome stain

Hepatitis A Clinical ♦♦ Hepatitis A virus is a 27  nm icosahedral, nonenveloped, single-stranded RNA picornavirus that is transmitted by the fecal-oral route ♦♦ Hepatitis A infection is endemic in hot, tropical countries with poor sanitation, and overcrowding ♦♦ The incubation period of the virus is approximately 4–6 weeks ♦♦ Most patients develop an acute, self-limited hepatitis −− The virus may rarely cause acute liver failure and is responsible for fatality in <0.1% of cases −− The virus does not cause a chronic carrier state or chronic liver disease ♦♦ Antibodies appear in serum following the incubation period −− The first to appear is anti-HAV IgM followed by antiHAV IgG −− Anti-HAV IgM may persist in serum for as long as 1 year and its presence indicates recent infection −− Anti-HAV IgG imparts lifelong immunity against reinfection and its presence indicates remote exposure

Microscopic

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Nonneoplastic Hepatobiliary Disease

♦♦ The number of ground glass hepatocytes are inversely proportional to degree of inflammation −− Ground glass cells represent an admixture of cytoplasmic aggregates of HBsAg and smooth endoplasmic reticulin, which distend the cytoplasm and displace the nucleus to the periphery (a) The ground glass change appears as a cytoplasmic inclusion and is usually surrounded by a clear halo

Microscopic (Chronic Hepatitis B) ♦♦ The microscopic appearance of chronic hepatitis B shows varying degrees of portal mononuclear inflammatory infiltrate accompanied by varying degrees of periportal inflammation with destruction of the limiting plate −− This is accompanied by variable lobular inflammation and damage, which is inversely proportional to the number of ground glass hepatocytes ♦♦ Carriers of the disease show numerous ground glass hepatocytes without any accompanying inflammation ♦♦ In contrast to hepatitis C, steatosis is not a feature of chronic hepatitis B infection −− When present, alcoholic or nonalcoholic fatty liver disease should be ruled out ♦♦ Varying degrees of portal-based fibrosis are present

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♦♦ Immunohistochemical staining for hepatitis B core antigen show nuclear positivity and is indicative of active viral replication (Fig. 44.11) −− The presence of additional cytoplasmic positivity for core antigen indicates replication so active that excess core antigen spills from the nucleus into the cytoplasm −− Membranous positivity for HBsAg and cytoplasmic positivity for HBcAg are characteristic features of fibrosing cholestatic hepatitis indicating brisk and unopposed viral replication in immunocompromised individuals

Differential Diagnosis ♦♦ Other viral hepatitis ♦♦ Drug-induced hepatitis ♦♦ Autoimmune hepatitis

Hepatitis C Clinical

♦♦ Immunohistochemical stains for hepatitis B surface and core antigens are not uncommonly negative in acute hepatitis B especially in patients with an active hepatitis −− These makers may be positive in chronic hepatitis B −− The extent of positivity is inversely proportional to the degree of inflammation ♦♦ Immunohistochemical staining for hepatitis B surface antigen shows cytoplasmic positivity with or without hepatitis B core antigen positivity (Fig. 44.10) −− The presence of membranous staining for hepatitis B surface is indirect evidence of active viral replication

♦♦ Hepatitis C virus is an enveloped single-stranded RNA flavivirus, which is related to hepatitis G, dengue virus, and yellow fever virus ♦♦ Hepatitis C viral infection is a global disease, albeit one with a wide range of prevalence rates −− The prevalence of anti-HCV antibodies is 1.8% in the USA and 22% in Egypt −− No effective vaccine exists against hepatitis C infection ♦♦ The mode of transmission is blood borne −− Hepatitis C virus was the major cause of posttransfusion non-A, non-B hepatitis before the initiation of routine screening of blood donors in 1991 −− New infections in developed countries are now acquired though contaminated needles in intravenous drug-abusers −− Other means of transmission include acupuncture, tattooing, sharing razors, and needlestick injuries in healthcare workers

Fig. 44.10. Immunohistochemical stain for hepatitis B surface antigen showing extensive cytoplasmic positivity.

Fig.  44.11. Immunohistochemical stain for hepatitis B core antigen shows nuclear positivity.

Special Studies

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♦♦

♦♦

♦♦

♦♦

♦♦

♦♦

−− Less stringent precautions in the healthcare setting may be responsible for infections in developed countries −− Sexual and transplacental infections are responsible for a minority of cases Six major genotypes with 40 subtypes are known to exist −− An individual patient may harbor several subtypes (quasispecies) −− Genotypes 1a, 1b, 2a, 2b, and 3a are common in Western Europe and the USA −− Genotype 4 is common in Africa and the Middle East The incubation period is 6–7 weeks; acute infection is subclinical and asymptomatic in 90% of cases −− The majority of infected individuals are, however, unable to clear the virus due to the rapid generation of quasispecies, which escape the body’s immune responses Most patients pursue a relatively indolent course over many years −− The major clinical manifestations include significant fatigue (50% at 10 years), cirrhosis (25% at 20 years), and hepatocellular carcinoma (5% at 30 years) Diagnosis of hepatitis C infection is established by detecting antibodies by an enzyme immunoassay with subsequent confirmation by recombinant immunoblot assay Treatment protocols are based on interferon and ribavirin −− Several different protocols exist, which vary for genotype and other host factors −− Liver transplantation is performed for end-stage liver disease Cirrhosis due to chronic HCV infection is the leading cause for liver transplantation in the USA −− Hepatitis C infection recurs in the allograft (a) The rate of progression is highly variable (b) The factors underlying this variability are poorly understood

Microscopic (Acute Hepatitis C) ♦♦ Acute hepatitis C is rarely biopsied −− The histology of acute hepatitis C is best seen when the liver allograft is biopsied for diagnosis of recurrent hepatitis C infection ♦♦ The features are those of acute hepatitis with lobular inflammation, hepatocyte damage, and disarray −− Confluent and bridging necrosis is rare ♦♦ Significant portal inflammation and lymphoid aggregates are common ♦♦ The overall picture is similar to chronic hepatitis C; however, fibrosis is absent

Microscopic (Chronic Hepatitis C) ♦♦ There is prominent portal and periportal inflammation consisting mainly of lymphocytes ♦♦ Lymphoid aggregates and follicles are typically present −− These are not specific for hepatitis C infection and also occur in hepatitis B infection, autoimmune hepatitis, and primary biliary cirrhosis

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Fig.  44.12. Chronic hepatitis C infection showing sinusoidal lymphocytosis; the so-called “string of beads” appearance. ♦♦ Mild and focal bile duct damage is seen in a significant number of cases −− Progressive bile duct damage and ductopenia do not occur ♦♦ Macrovesicular steatosis, usually occurs and is generally mild and nonzonal ♦♦ Lymphocytic interface hepatitis, lobular inflammation, and hepatocellular necrosis define disease activity (grade) −− These changes are common, but usually mild −− A distinctive pattern is the presence of sinusoidal lymphocytes and macrophages (“string of beads”) (Fig. 44.12) ♦♦ Grading continues to be important in assessing disease activity because other reliable surrogate markers are not available −− Grading also plays a role in assessment of prognosis and predicating response to therapy ♦♦ Staging predicts time to development of cirrhosis, response to medical therapy, rate of disease progression in untreated patients, and efficacy of therapy

Special Studies ♦♦ Reliable immunohistochemical and/or in situ hybridization methods are not available for diagnosis of HCV ♦♦ HCV RNA levels and HCV genotype help predict and assess response to therapy

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Other viral hepatitis Steatohepatitis of other causes Drug-induced hepatitis Autoimmune hepatitis

Hepatitis D ♦♦ Hepatitis D virus, also called the delta agent, is a small RNA virus that requires the presence of the hepatitis B virus for replication and infection

Nonneoplastic Hepatobiliary Disease

♦♦

♦♦

♦♦

♦♦

♦♦

♦♦ ♦♦ ♦♦

♦♦

−− Approximately 5% of patients with hepatitis B virus infection are also infected with the hepatitis delta agent (a) Hepatitis D infection increases the severity of acute and chronic HBV infection and decreases the likelihood of becoming an HBV carrier The virus has a worldwide distribution, albeit with significant geographic variation in prevalence −− The prevalence is highest in South America −− High prevalence is also present in southern Italy, North Africa, Middle East, and the American South Pacific islands The virus is transmitted parenterally through contaminated needles and blood transfusions −− Sexual and vertical transmissions also occur but are less common than for hepatitis B virus HDV infection may occur simultaneously with hepatitis B infection (coinfection) or sequentially in a patient who is already infected with the hepatitis B virus (superinfection) Coinfection results in clearance of both viruses in the majority of patients −− Fulminant hepatic failure occurs in 1% and chronic B and D hepatitis in 5% of coinfected individuals Superinfection of hepatitis B infection with hepatitis D virus results in fulminant liver failure in 5% of individuals −− 80–90% of individuals develop chronic hepatitis D infection (a) These patients progress faster to cirrhosis Microscopic features are similar to those of hepatitis B viral infection Diagnosis is made by serologic testing or RT-PCR which is the method of choice Treatment is based on interferon but is of uncertain benefit −− Antiviral drugs used for treatment of hepatitis B infection are not effective Liver transplantation is a valid treatment option; risk of allograft reinfection is much less than that for chronic hepatitis B infection

Hepatitis E Clinical ♦♦ Hepatitis E is a single-stranded RNA virus (calicivirus), which is transmitted by the fecal-oral route through contaminated water ♦♦ The infection is endemic and/or epidemic in developing countries with a tropical climate and conditions of poor sanitation and overcrowding ♦♦ The prevalence of anti-HEV antibodies in the USA is 2% and is probably related to travel to endemic areas ♦♦ The clinical manifestations are indistinguishable from hepatitis A −− The incubation period is 15–60 days −− A prodromal phase is followed by an icteric phase ♦♦ The infection is self-limited in the majority of patients −− Chronic disease or a carrier state do not occur

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♦♦

♦♦ ♦♦ ♦♦

−− The overall fatality rate is approximately 4% (a) The fatality rate in pregnant women is 20% and is associated with encephalopathy and disseminated intravascular coagulation Microscopically, the features resembles acute hepatitis from other causes −− Centrilobular cholestasis and gland-like transformation of hepatocytes (rosettes) may be seen Diagnosis is made by serologic testing or by PCR There is no specific treatment Prevention involves improving sanitation in endemic areas and precautionary measures by travelers to these areas

Hepatitis F ♦♦ The name Hepatitis F has been used for various undesignated viruses causing hepatitis ♦♦ A few cases were reported from France in which experimental transmission to primates was demonstrated ♦♦ Several cases reported from England showed a hemorrhagic hepatitis and a toga virus-like particle on electron microscopy ♦♦ The virology, epidemiology, hepatotropism, and clinical significance of the hepatitis F virus is uncertain −− This diagnosis is rarely made in current clinical practice

Hepatitis G ♦♦ Hepatitis G virus, also known as GBV-C, is a flavivirus and distant relative of HCV −− Two percent of healthy blood donors test positive for HGV RNA −− Coinfection may be found in patients with hepatitis B and C infections ♦♦ The role of HGV as a cause of hepatitis is uncertain −− It does not cause worsening of hepatitis B or C infection −− HGV has been described as a “virus looking for a disease,” which does not cause acute hepatitis, but may be a cofactor in chronic hepatitis in certain risk groups

Human Immunodeficiency Virus Infection and AIDS Clinical ♦♦ Liver function tests are abnormal in the majority of patients with human immunodeficiency virus (HIV) infection −− This does not always correspond to liver disease −− The liver may, however, be involved in patients infected with HIV through a variety of mechanisms, which include infection by HIV virus itself, secondary infections, neoplasms, and toxicity of drugs that are used to treat the HIV infection or associated infections and comorbidities ♦♦ As patients with HIV and AIDS live longer due to the efficacy of HAART (highly active antiretroviral therapy), coinfections with hepatitis B and C viruses have emerged as major long-term hepatic comorbidities

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Microscopic ♦♦ Infection of the liver by the HIV virus produces a pattern of reactivity characterized by minimal to mild portal inflammatory infiltrate, marked prominence of Kupffer cells, foci of lobular inflammation and minimal degree of steatosis −− The Kupffer cells show PAS-positive granules, which are resistant to enzyme digestion ♦♦ A ductular reaction, portal edema, and fibrosis may be seen in patients with end-stage AIDS who have infection of the biliary tree by cryptosporidium −− Imaging in these cases shows features of sclerosing cholangitis ♦♦ Steatosis is a common finding in livers of patients with HIV infection −− Steatosis may be due to a variety of underlying causes such as drug toxicity and comorbidities such as nonalcoholic steatohepatitis and chronic viral hepatitis ♦♦ Patients who are coinfected with hepatitis B or hepatitis C viruses show pathologic features characteristic of these hepatotropic viruses ♦♦ Patients with superimposed infections such as CMV, herpes, or toxoplasmosis show viral inclusions characteristic of these viruses −− Herpes infections and toxoplasmosis produces punched out lesions of necrosis ♦♦ Granulomas may be seen in patients who are infected by Mycobacterium tuberculosis, M. avium-intracellulare (MAI), histoplasmosis, or other fungal infections −− Patients who are severely immunosuppressed may not show well-formed granulomas and organisms may be seen in Kupffer cells and within loose aggregates of macrophages (Fig. 44.13) ♦♦ AIDS-complicating or AIDS-defining neoplasms such as Kaposi sarcoma or lymphoma may be present in the liver

Fig. 44.13. Pneumocystis infection in a patient with HIV showing the typical pink frothy material characteristic of this infection.

Special Stains ♦♦ The Ziehl–Neelsen stain is useful to demonstrate acid-fast alcohol resistant bacilli such as M. tuberculosis and M. avium-intracellulare ♦♦ The methenamine silver stain is useful to demonstrate fungal organisms (Fig. 44.14) ♦♦ Trichrome stain is useful for demonstrating the degree of fibrosis, especially in patients who are coinfected with hepatitis B and hepatitis C viruses

Fig. 44.14. Methanamine silver stain showing round and ­semilunar yeast forms of pneumocystis carinii in a patient with HIV infection.

Differential Diagnosis

Microscopic

♦♦ Other viral infections of the liver

♦♦ The microscopic features of infectious mononucleosis include a marked lymphocytic infiltration of the liver by large, atypical-appearing lymphocytes ♦♦ The inflammatory infiltrate is present in portal tracts as well as the lobules ♦♦ The latter show a typical sinusoidal pattern of infiltration (sinusoidal lymphocytosis) (Figs. 44.15 and 44.16) ♦♦ There is no hepatocellular damage, necrosis, or fibrosis (Fig. 44.15)

Epstein–Barr Virus Infection Clinical ♦♦ The Epstein–Barr virus causes an acute infection called infectious mononucleosis ♦♦ The incubation period is 5 weeks and 50% of patients are clinically asymptomatic

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♦♦ The liver is involved in 90% of patients who show elevated liver function tests −− However, jaundice is seen in only 5% of patients

Nonneoplastic Hepatobiliary Disease

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Cytomegalovirus Infection Clinical ♦♦ Cytomegalovirus infection is clinically mild and selflimiting in most cases −− However, significant liver disease including acute liver failure occurs due to reactivation of latent infection in patients who are immunosuppressed (a) This is usually associated with multiorgan damage ♦♦ Cytomegalovirus infection may be congenital or acquired by blood transfusions

Microscopic

Fig. 44.15. Involvement of the liver by Epstein–Barr virus showing sinusoidal lymphocytosis without hepatocyte damage, necrosis or fibrosis.

♦♦ The neonatal form of infection is typified by giant cell hepatitis with portal and lobular inflammation, giant cell transformation of hepatocytes and severe cholestasis ♦♦ CMV infection may mimic the histological features of infectious mononucleosis with sinusoidal lymphocytosis ♦♦ CMV infection may show randomly distributed punched out areas of necrosis, which usually contain typical CMV inclusions ♦♦ Infection occurring in the liver allograft following transplantation may present as small microabscesses scattered in the liver parenchyma −− These microabscesses usually surround infected cells and typical CMV inclusions may be seen in their center ♦♦ Typical CMV inclusions consist of large intranuclear amphophilic bodies with a surrounding halo, often referred to as “owl eye” inclusions −− CMV inclusions are usually present in endothelial cells, but may also be seen within hepatocytes and bile duct epithelium

Special Studies ♦♦ The diagnosis can be confirmed by CMV-specific serum antibodies ♦♦ A sensitive and specific immunohistochemical stain is available, which highlights the CMV antigen in nuclei Fig. 44.16. Involvement of the liver by Epstein–Barr virus showing large atypical lymphocytes in hepatic sinusoids.

Special Studies ♦♦ The Monospot test is sensitive and specific for diagnosis of infectious mononucleosis infection ♦♦ The virus can be demonstrated in liver biopsy specimens by in situ hybridization, which demonstrates a positive reaction in the lymphoid infiltrate

Differential Diagnosis ♦♦ CMV and hepatitis C may cause a similar pattern of sinusoidal lymphocytosis ♦♦ Drug-induced hepatitis ♦♦ Low grade lymphoproliferative diseases, such as lymphocytic leukemia and gamma delta T-cell lymphoma

Differential Diagnosis ♦♦ Other forms of acute viral hepatitis ♦♦ Drug-induced hepatitis ♦♦ EBV infection if there is a pattern of sinusoidal lymphocytosis

Herpes Simplex Virus Infection Clinical ♦♦ Liver infection by the herpes simplex virus affects patients who have been immunocompromised due to solid organ transplantation, various immunodeficiency states, or who have HIV infection ♦♦ Both type 1 and type 2 herpes simplex viruses may infect the liver ♦♦ Patients present with acute hepatitis or acute liver failure −− There is marked elevation of LFTs and disseminated intravascular coagulation is common

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Fig. 44.17. Herpes simplex hepatitis showing areas of hemorrhagic necrosis. −− Herpes liver infections are associated with a high rate of mortality

Microscopic ♦♦ Herpes simplex virus typically causes punched out areas of necrosis within the hepatic parenchyma −− These areas are random in distribution and may appear intensely hemorrhagic both on gross and microscopic examination (Fig. 44.17) (a) Viral inclusions are present at the edge of these areas at their interface with viable liver parenchyma (b) Typical inclusions are intranuclear and amphophilic with a ground glass appearance (Fig. 44.18)

Fig.  44.18. Herpes simplex hepatitis showing amphophilic ground glass intranuclear inclusions of herpes simplex virus.

(c) Cells containing these inclusions often show multinucleation

Special Studies ♦♦ Sensitive and specific immunohistochemical stains are available for diagnosis of herpes simplex 1 and herpes simplex 2 viruses ♦♦ PCR-amplification and genome sequencing helps to distinguish between type 1 and 2 herpes simplex virus infection

Differential Diagnosis ♦♦ CMV infection ♦♦ Toxoplasmosis

NONVIRAL INFECTIONS Bacterial Infections Pyogenic Bacterial Infection Clinical

♦♦ The lobules show varying degrees of canalicular cholestasis and sinusoidal infiltration by neutrophils ♦♦ Microabscesses may be present which may coalesce to give larger macroscopic abscesses

♦♦ A wide variety of bacterial organisms may gain access to the liver through the arterial or venous vascular supply, or from the biliary tree ♦♦ Clinical manifestations may be nonspecific such as malaise and fever, or specific to the liver such as hepatomegaly and right upper quadrant pain ♦♦ Prognosis is related to the underlying condition giving rise to the bacterial infection

Special Stains

Microscopic ♦♦ The findings may be nonspecific in patients who have liver disease due to underlying sepsis ♦♦ There may be portal edema, ductular reaction, and inflammatory infiltrate

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♦♦ Gram stain demonstrates bacteria and bacterial colonies ♦♦ PAS stain demonstrates Entamoeba histolytica, a diagnostic consideration for large abscesses

Differential Diagnosis ♦♦ Amebic abscess ♦♦ Extrahepatic biliary obstruction

Brucellosis Clinical ♦♦ Brucellosis is caused by the Gram-negative bacilli of Brucella species (Brucella melitensis, B. abortus, B. suis)

Nonneoplastic Hepatobiliary Disease

♦♦ The bacillus is transmitted to humans through ingestion of infected milk products, direct contact with an infected animal, or inhalation of aerosols −− Zookeepers or veterinarians occupationally exposed to placental tissues or vaginal secretions of infected animals are most at risk −− Human-to-human transmission is not known to occur except in very rare cases ♦♦ The liver is involved in about 10–15% of cases by hematogenous transmission of the bacilli ♦♦ The disease is characterized by intermittent fever, which explains its alternative name, “undulant fever” −− Brucellosis is also known as Malta fever and Mediterranean fever ♦♦ The fever is accompanied by headaches, chills, profound weakness, myalgia, and depression

Microscopic ♦♦ The liver may show a picture of nonspecific reactive hepatitis with prominence of Kupffer cells, a mild inflammatory infiltrate in portal tracts, and portal lobular inflammation ♦♦ Varying numbers of microgranulomas consisting of small, tight clusters of epithelioid cells are found scattered in the lobules −− Rarely, microabscesses may be present

Special Studies ♦♦ The diagnosis is made by culturing the organism from blood or bone marrow ♦♦ Specific antibodies against brucella can be detected in serum −− Demonstration of a rising titer over 2 weeks is necessary to establish the diagnosis

Differential Diagnosis ♦♦ Typhoid fever ♦♦ Tularemia ♦♦ Other granulomatous inflammations

Salmonellosis Clinical

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♦♦ Typhoid nodules, which are aggregates of macrophages with focal necrosis, may be randomly scattered in the parenchyma −− Mild portal inflammation may be present

Special Studies ♦♦ The diagnosis is established by culture the bacillus from stools, urine, or blood ♦♦ Gram-negative organisms may be demonstrated in Kupffer cells

Differential Diagnosis ♦♦ Brucellosis

Recurrent Pyogenic Cholangitis Clinical ♦♦ Recurrent pyogenic cholangitis, a disease seen in Far Eastern countries, is associated with Clonorchis sinensis infection in about 50% of cases −− The exact etiopathogenesis, however, has not been elucidated ♦♦ The main clinical manifestations consist of recurrent symptoms of acute cholangitis −− Complications include pancreatitis, liver abscesses, septicemia, cholangiocarcinoma, and portal vein thrombosis −− The prognosis is related to complications associated with the recurrent cholangitis

Microscopic ♦♦ Microscopically, the disease shows dilated intrahepatic ducts surrounded by an acute and chronic inflammatory infiltrate −− There may be biliary epithelial damage (Fig. 44.19) −− Scarring of the bile ducts might lead to features that resemble sclerosing cholangitis ♦♦ The dilated bile ducts contain bile sludge and stones −− Eggs of liver flukes and numerous bacterial colonies are frequently present (Fig. 44.20)

♦♦ Salmonellosis is caused by the Gram-negative bacilli, Salmonella typhi or Salmonella paratyphi, which are acquired by ingesting infected animal products and less commonly, infected vegetables ♦♦ Clinical manifestations of suspected salmonellosis include high fever and relative bradycardia −− The liver is almost always involved but clinical hepatitis is present in 25% of cases −− The bacillus can infect the biliary tract (a) The gallbladder serves as a reservoir for a chronic carrier state which occurs in about 3% of individuals ♦♦ Diagnosis is made by culturing the bacilli from stool or blood

Microscopic ♦♦ The main microscopic feature is marked hypertrophy and hyperplasia of the Kupffer cells

Fig. 44.19. Recurrent pyogenic cholangitis showing periductal inflammation, fibrosis, and epithelial damage.

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Fig.  44.20. Same case as shown in Fig.  44.19. Several ducts were dilated and contained bile sludge along with eggs of Ascaris lumbricoides.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 44.22. Tertiary syphilis showing gumma with central necrosis surrounded by fibrosis. ♦♦ Secondary syphilis shows scattered nonnecrotizing epithelioid granulomas, and small vessel vasculitis ♦♦ Tertiary syphilis shows gumma (necrotizing granulomas) formation and obliterative endarteritis with dense scar formation (Fig. 44.22) −− The extensive scarring gives rise to a nodular liver, which has been referred to as hepar lobatum ♦♦ Amyloid deposition may also be seen

Special Studies

Fig.  44.21. Congenital syphilis showing marked sinusoidal fibrosis in the absence of inflammation, necrosis, and fibrosis.

Differential Diagnosis ♦♦ Extrahepatic obstruction from other causes ♦♦ Primary sclerosing cholangitis ♦♦ Caroli disease

Syphilis Clinical ♦♦ Syphilis is caused by the spirochete Treponema pallidum ♦♦ The liver may be involved in all three stages of the disease ♦♦ Congenital syphilis is acquired by transmission from mother to fetus −− The liver disease may manifest years after birth

Microscopic ♦♦ Congenital syphilis is characterized by extensive perisinusoidal fibrosis without accompanying inflammation, necrosis, or regeneration (Fig. 44.21)

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♦♦ The spirochetes can be demonstrated by darkfield microscopy, usually in primary chancres ♦♦ The spirochetes can also be demonstrated in the liver by silver stains −− The organism is present in necrotizing lesions as well as in congenital syphilis

Differential Diagnosis ♦♦ Neonatal giant cell hepatitis ♦♦ Brucellosis/salmonellosis ♦♦ Drug-induced granulomatous hepatitis

Mycobacterial Infections Tuberculosis Clinical ♦♦ Tuberculosis is caused by an acid-fast alcohol-resistent bacillus, M. tuberculosis ♦♦ The liver is usually involved as part of a systemic infection, in approximately 25% of cases of chronic tuberculosis and 95% of cases of miliary tuberculosis ♦♦ The liver disease is usually clinically silent −− Severe hepatic dysfunction is rare, being overshadowed by the systemic involvement −− Liver disease is never the cause of mortality ♦♦ Elevated liver function tests may be seen

Nonneoplastic Hepatobiliary Disease

♦♦ A high degree of suspicion is necessary to diagnose tuberculosis on a liver biopsy because the granulomas are usually nonnecrotizing and the yield of organisms on an acid-fast stain or on culture is relatively low

Microscopic ♦♦ The microscopic features of tuberculosis include welldefined portal and parenchymal epithelioid granulomas ♦♦ The granulomas may be necrotizing or nonnecrotizing −− Necrotizing granulomas are relatively rare and seen only in very active disease

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Microscopic ♦♦ The microscopic picture resembles the entire spectrum of lesions seen in the skin disease ♦♦ The tuberculoid type of leprosy shows well-formed granulomas whereas the lepromatous type shows ill-formed granulomas and clusters of foamy histiocytes ♦♦ During a lepromatous reaction, necrosis is seen within the liver lesions

Special Studies

Special Studies

♦♦ The Fite stain demonstrates the acid-fast bacilli ♦♦ Silver stains may demonstrate nonviable organisms

♦♦ The bacilli can be demonstrated by a Ziehl–Neelsen stain but the yield is relatively low

Differential Diagnosis

Differential Diagnosis ♦♦ Sarcoidosis ♦♦ Other granulomatous liver diseases

Mycobacterium Avium-Intracellulare Infection Clinical ♦♦ Infection with M. avium-intracellulare usually occurs in immunocompromised patients such as those with AIDS −− Infection of the liver occurs as part of a disseminated infection ♦♦ The clinical manifestations are systemic and not usually related to the liver

Microscopic ♦♦ Nonnecrotizing ill-defined granulomas are present in portal tracts and lobules ♦♦ Severely immunocompromised patients may not be able to mount a granulomatous response and the bacilli may be present in Kupffer cells and clusters of foamy macrophages −− The lesions are nonzonal in distribution

Special Studies ♦♦ The PAS and Ziehl–Neelsen stains demonstrate abundant bacilli within macrophages and Kupffer cells

Differential Diagnosis ♦♦ Tuberculosis ♦♦ Fungal infections

Leprosy Clinical ♦♦ Leprosy is caused by M. leprae and affects an estimated 20 million people worldwide, especially in tropical climates ♦♦ Hepatic granulomas are present in more than 50% of patients who are infected −− Hepatic involvement does not lead to clinical mani-festations ♦♦ Systemic amyloidosis is a frequent complication ♦♦ The disease is difficult to eradicate and most of the morbidity occurs from consequences of nerve destruction

♦♦ Sarcoidosis ♦♦ Tuberculosis

Rickettsial Infection Clinical ♦♦ Q fever is caused by Coxiella burnetti and Rocky Mountain spotted fever by Rickettsia rickettsii −− These organisms have numerous reservoirs, which include arthropods, birds, and mammals ♦♦ Clinical manifestations include high fevers, chills, sweating, and myalgia −− Most patients present with pneumonia manifested by shortness of breath, cough, and sputum production ♦♦ The liver is involved in 85% of cases but most patients do not demonstrate liver disease −− Liver involvement is indicated by hepatomegaly and abnormal liver tests

Microscopic ♦♦ The distinctive lesion of Q fever is the fibrin ring granuloma, which consists of a central fat vacuole surrounded by a complete or partial fibrin ring with an outer cuff of epithelioid cells and macrophages (Fig. 44.23) ♦♦ This lesion is, however, not always present and, in many instances, only portal inflammation and prominent Kupffer cell hyperplasia may be seen ♦♦ The fibrin ring granuloma is not specific for Q fever and has been described in hepatitis C viral infection, lymphomas, and drug toxicity

Differential Diagnosis ♦♦ Other granulomatous diseases ♦♦ Fibrin ring granulomas have been described in hepatitis C viral infection, lymphomas, and drug toxicity

Fungal Infections Histoplasmosis Clinical ♦♦ Histoplasmosis is caused commonly by Histoplasma capsulatum and less commonly by H. dubosii

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Fig.  44.23. Rickettsial hepatitis showing a fat vacuole surrounded by a fibrin ring – the “fibrin ring granuloma.”

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 44.24. Histoplasmosis of the liver with an early granuloma containing numerous organisms.

♦♦ The organism is highly endemic in the Ohio and Mississippi River Valleys, and in South America −− It is carried by birds and is acquired by humans through inhalation ♦♦ The infection is asymptomatic in 90% of cases and does not cause significant pathology in immunocompetent individuals −− In immunocompromised patients such as those receiving corticosteroids or patients with AIDS, infection of the liver occurs as part of a disseminated systemic disease ♦♦ Mortality is high in untreated asymptomatic patients who have disseminated disease

Microscopic ♦♦ In most individuals living in endemic areas, the lesion consists of scarred and calcified granulomas, which are discovered incidentally on the surface of the liver during exploratory laparotomy ♦♦ In others, epithelioid granulomas may be seen, some of which may be necrotizing −− Necrotizing granulomas are usually found in active disease and contain organisms that are 2–5 mm round spores with rare broad-based buds (Figs. 44.24 and 44.25) ♦♦ In patients who are severely immunocompromised, abundant organisms may be found without well-formed granulomas, usually within Kupffer cells or loose collections of macrophages

Fig. 44.25. A high power view of Fig. 44.25 showing 2–5 mm nonbudding yeast forms of histoplasma. ♦♦ The infection is usually a benign, self-limited pulmonary disease ♦♦ Disseminated disease with liver involvement may occur in immunocompromised individuals ♦♦ The mortality is high in untreated symptomatic disease

Special Studies

Microscopic

♦♦ The organism can be easily demonstrated by the PAS and silver stains

♦♦ The main lesion of coccidioidomycoses consists of epithelioid granulomas with multinucleated giant cells containing the organism −− The organisms vary in size, from 20–200 nm spherules ♦♦ No calcifications are seen ♦♦ There may be an accompanying mild inflammatory infiltrate in portal tracts

Differential Diagnosis ♦♦ Other granulomatous infections

Coccidioidomycoses Clinical ♦♦ Coccidioidomycoses is caused by Coccidioides immitis, which is endemic in southwestern USA and South America

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Special Studies ♦♦ The PAS and silver stain demonstrate the organisms

Nonneoplastic Hepatobiliary Disease

Differential Diagnosis ♦♦ Other granulomatous infections

Parasite Infections Amebic Abscess Clinical ♦♦ Amebic abscess of the liver is caused by Entamoeba histolytica, which enters the liver from the intestine via the portal system ♦♦ The clinical manifestations are usually protean in the early stages and include fever and right upper quadrant pain ♦♦ As the abscess enlarges, there might be leukocytosis, pain, and hepatomegaly −− Most patients do not remember preceding bowel symptoms ♦♦ Most patients have positive serologies, even in the early stages of the disease

Macroscopic ♦♦ There is usually a single abscess, usually in the right lobe, which can vary from a few centimeter to up to 20  cm in diameter ♦♦ The abscess consists of a central necrotic area, which contains a reddish-brown fluid, which is often described as having an anchovy sauce appearance ♦♦ The periphery of the abscess shows shaggy necrotic walls ♦♦ Older abscesses may develop fibrous capsules

Microscopic ♦♦ The amebae are usually present at the advancing edge of the abscess but might also be present within necrotic fluid when it is aspirated ♦♦ The amebae are round unicellular organisms 20–50  mm in diameter −− They have a round, central to eccentric nucleus and clear to purple granular cytoplasm −− The nucleus has a sharp nuclear membrane and a prominent central karyosome −− Numerous phagocytosed erythrocytes are present within the cytoplasm and are pathognomic of amebic trophozoites

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Malaria Clinical ♦♦ Liver involvement in malaria is usually caused by Plasmodium falciparum of which 100 million cases are reported worldwide per year ♦♦ The malarial parasite requires multiplication within the liver after infection −− The schizonts develop within hepatocytes and then infect erythrocytes ♦♦ Liver damage occurs due to ischemic necrosis caused by adherence of the parasite to liver venules and engorgement of sinusoids by infected erythrocytes ♦♦ Malaria may be associated with a hypoglycemic state −− This is usually seen in African children and adult ­pregnant women −− In these cases, there is complete absence of glycogen in hepatocytes ♦♦ Individuals at increased risk of mortality from P. falciparum include children, pregnant women, and those who are immunocompromised

Microscopic ♦♦ Hemozoin is present extensively in Kupffer cells and in portal macrophages (Fig. 44.26) −− Hemozoin is an iron porphyrin protein complex, which is formed by breakdown of hemoglobin ♦♦ Scattered areas of necrosis are seen ♦♦ Sinusoidal congestion with parasite-filled Kupffer cells and red blood cells is present ♦♦ In patients with the hyperreactive malarial splenomegaly syndrome (tropical splenomegaly syndrome), the liver may show sinusoidal lymphocytosis

Special Studies ♦♦ The hemozoin pigment is negative with Prussian blue reaction

Special Studies ♦♦ An immunohistochemical stain is available for diagnosis of E. histolytica ♦♦ A PAS stain shows intense cytoplasmic staining due to accumulation of glycogen in the cytoplasm ♦♦ On an H&E stain, phagocytosed erythrocytes are diagnostic of ameba

Differential Diagnosis ♦♦ Pyogenic abscess ♦♦ Necrotic tumor mass

Fig.  44.26. Hemozoin deposition in Kupffer cells in malaria. Hemozoin appears as a dark brown pigment on H&E stain.

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Immunohistochemical stain for Plasmodium species is available

Differential Diagnosis ♦♦ The accumulated pigment can be differentiated from hemosiderin by the Prussian blue reaction ♦♦ A similar pigment can also be seen in Schistosomiasis

Hydatid Cyst Clinical ♦♦ Hydatid cyst is caused by Echinococcus granulosus and E. multiloculare, which are transmitted to humans by ingestion of foods contaminated by eggs of the parasite −− The oncospheres translocate to the liver via the portal vein ♦♦ The cyst is usually asymptomatic when small −− As it enlarges, the cyst may cause hepatomegaly and pain in the upper right quadrant ♦♦ Complications include biliary obstruction, cholangitis, and bacterial superinfection −− Rarely the cyst may rupture into the liver or into the peritoneal cavity and cause dissemination of the disease ♦♦ Treatment consists of PAIR – puncture, aspiration, injection, reaspiration −− The cyst is aspirated and injected with hypertonic saline to kill the scolices −− The cyst is reaspirated after 15 min

Fig. 44.27. Hooklets from the sediment of a hepatic hydatid cyst.

♦♦ ♦♦

Macroscopic ♦♦ E. granulosus causes unilocular cysts while E. multiloculare causes multilocular cysts ♦♦ Cysts may attain large sizes, up to 25 cm in diameter ♦♦ Calcifications in the wall of the cyst are common

♦♦

Microscopic

♦♦

♦♦ The cyst consists of two layers −− The outermost layer is an acellular laminated membrane about 1  mm thick, which is ivory white, friable, and slightly slippery −− The inner layer consists of a germinal membrane, which is transparent and consists of nucleated cells (a) Attached to the germinal membrane and budding from it are ovoid protoscolices, which contain hooklets and a sucker ♦♦ When aspirated, scolices and hooklets may be found in the aspirate fluid providing a diagnostic clue (Fig. 44.27)

Differential Diagnosis ♦♦ Amebic abscess

Clonorchiasis (Infection by Liver Flukes) Clinical ♦♦ Infection by the liver flukes, Clonorchis and Opisthorchis occurs in the Far East

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♦♦ ♦♦

−− C. sinensis is prevalent in China, Hong Kong, Korea, Vietnam, and Taiwan −− O. viverrini is frequent in Northeast Thailand The infection is acquired in humans by ingesting cercariae in uncooked freshwater fish Immature worms settle in the biliary tract and occasionally, within the pancreatic duct −− The worms live in the biliary tract for 10 years and, sometimes, up to 25 years where they release eggs (a) The eggs are shed in the bile and may be present in feces Most infections are asymptomatic −− Eosinophilia is present in most patients, even those who are asymptomatic Symptoms results from obstruction of the bile duct and infections secondary to obstruction −− Severe infections cause recurrent pyogenic cholangitis with repeated bouts of cholangitis Abdominal pain, hepatomegaly, and jaundice may also be present A long-term complication of clonorchiasis is cholangiocarcinoma

Macroscopic ♦♦ The liver is enlarged with gray and pale blue subcapsular cysts, which consist of dilated ducts with parasites ♦♦ The ducts are dilated, surrounded by fibrosis and contain parasites ♦♦ Intrahepatic and extrahepatic calculi may also be formed

Microscopic ♦♦ Microscopically, the intrahepatic and extrahepatic large bile ducts are dilated and contain parasites (Fig. 44.28) −− The parasites range from 8–25  mm in length and are 2–5 mm wide

Nonneoplastic Hepatobiliary Disease

Fig. 44.28. Clonorchis sinensis in a large bile duct, which shows proliferation of small peribiliary glands.

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Fig. 44.29. Schistosomiasis showing several eggs surrounded by an intense granulomatous inflammation.

♦♦ There is periductal inflammation and fibrosis ♦♦ Proliferation of the periductal glands is common ♦♦ The upstream, smaller bile ducts may show signs of obstruction with a ductular reaction ♦♦ Cholangitis may be present

Differential Diagnosis ♦♦ Mechanical duct obstruction

Schistosomiasis Clinical ♦♦ Schistosomiasis is a worldwide disease, caused by Schistosoma mansoni, S. japonicum, and S. mekongi ♦♦ The infection is acquired in humans when schistosomal cercariae infiltrate the skin from infected waters −− Following development, the adult worms settle in the mesenteric and portal veins and 4 weeks later, the females commence laying eggs −− While many eggs are excreted into feces, a significant number pass into the portal veins ♦♦ Most infections are asymptomatic with clinically evident disease present in approximately 10% of people −− The manifestations result from portal hypertension and its consequences −− During acute infection, some patients may have what is called “Katayama fever,” a syndrome characterized by fever, systemic upset, eosinophilia, and transient hepatomegaly

Microscopic ♦♦ The eggs are first trapped in the portal venules giving rise to an acute reaction of eosinophils (Figs. 44.29 and 44.30) −− The inflammation is followed by fibrosis

Fig.  44.30. Schistosomiasis showing intense eosinophilic inflammation. Deeper sections showed a schistosoma egg within this infiltrate.

♦♦ Extensive fibrosis of the portal veins and portal tracts leads to a characteristic “pipe-stem” fibrosis, which is the pathologic basis of portal hypertension seen clinically ♦♦ Eggs can be identified in early lesions before they undergo degeneration −− The eggs of S. mansoni bear a lateral spine whereas those of S. japonicum have a small lateral spine

Special Studies ♦♦ The eggs of Schistosoma stain with acid-fast stain; however, this is rarely required for diagnosis

Differential Diagnosis ♦♦ Infestation by other parasites and nematodes

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Essentials of Anatomic Pathology, 3rd Ed.

DRUG AND TOXIN-INDUCED LIVER INJURY General Features ♦♦ Drugs and toxins including herbal and alternative forms of therapy account for approximately 5% of all cases of liver injury and approximately 13% of all cases of acute liver failure ♦♦ These agents produce a wide array of hepatic lesions that mimic all known hepatobiliary diseases, and thus pose considerable challenges for differential diagnosis −− A number of clinical point scales have been devised to aid in the differential diagnosis −− The factors that are considered in the exclusion of druginduced liver injury are shown in Table 44.4 ♦♦ Drug-induced liver injury is usually classified according to the degree of certainty with which the drug can be related to the liver injury (Table 44.5) ♦♦ Screening with liver function tests and/or biopsy is recommended for patients on drugs with a known pattern of liver injury which is dose-dependent

−− An example is monitoring of liver tests in patients under methotrexate therapy

Pure Hepatocellular Necrosis Common Example: Acetaminophen ♦♦ This is the most common example of dose-related druginduced liver injury with a classic and known injury pattern ♦♦ Large doses results in liver cell necrosis with rapid development of liver failure −− This is usually the result of a suicide attempt or ­inadvertent use of large doses by patients with chronic and/or severe pain −− The injury is a result of glutathione depletion (a) Since the drug is metabolized in the centrilobular regions, necrosis is most evident in this region (zone 3)

Table 44.4. Diagnosis of Drug-Induced Liver Injury Temporal relationship

Time of initiation of drug use to time of onset of symptoms

Exclusion of competing causes

Clinical history, physical examination, laboratory tests and imaging studies should rule out known competing causes with identical clinical and pathologic features

Known potential for injury

Search of medial literature and web resources to identify history of the drug for similar or related injury

Precedent for pathologic injury pattern Dechallenge and rechallenge

Cessation of symptoms when the drug is withdrawn and reappearance if drug is reintroduced a

Pharmacologic studies

Analysis of enzyme polymorphisms b Serum level of drug and/or metabolitec

a Some drug-induced liver injuries may be self-progressive and cessation of the drug might not lead to ­discontinuation of symptoms b Pharmacologic studies are performed only rarely c Serum levels are only useful for dose-dependent toxicity and have no value in idiosyncratic reactions

Table 44.5. Degree of Certainty Linking Injury to a Drug or Toxin Degree of certainty

Criteria

Definite

Classic presentation by a known toxin with no competing cause

Very likely

Near classic presentation with no competing cause

Probable

Classic or near classic presentation but not all competing causes can be absolutely excluded No precedent for injury but no known competing cause

Possible

Atypical presentation or presence of competing cause with some features in favor of drug induced toxicity

Excluded

Agent can be reasonably excluded from consideration

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Nonneoplastic Hepatobiliary Disease

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♦♦ ♦♦ ♦♦ ♦♦

Fig.  44.31. Acetaminophen toxicity showing coagulative n­ ecrosis in the centrilobular region (acinar zone 3) in which hepatocytes have lost their nuclei but maintain their structure. (b) N-acetylcysteine repletes glutathione and administration can reverse drug damage if given up to 10 h following ingestion ♦♦ If the injury is less severe and the patient can be supported with medical therapy, regeneration of hepatocytes restores liver function to normal ♦♦ Liver transplantation offers a definitive therapeutic option in those with severe injury who are past the therapeutic window for benefit from N-acetylcysteine ♦♦ Microscopically, the classic features are centrilobular coagulative necrosis of hepatocytes (Fig. 44.31) −− In the early period following necrosis, there is no inflammatory infiltrate −− After 2–3 days, the necrotic hepatocytes disappear and are replaced by pigmented macrophages and a sparse mononuclear inflammatory infiltrate −− The surviving hepatocytes in zones 2 and 1 usually show steatosis

Other Drugs Causing Hepatocellular Necrosis ♦♦ Zone 1 (periportal) necrosis: ferrous sulfate, phosphorus ♦♦ Zone 2 (midzonal) necrosis: beryllium, dioxane, disulfiram, sulfasalazine, and indomethacin ♦♦ Zone 3 (centrilobular) necrosis: aflatoxin B1, chloroform, carbon tetrachloride, halogenated hydrocarbons, phalloidin, other alkaloids ♦♦ Diffuse necrosis: trinitrotoluene, tetrachloroethane, piroxicam, cimetidine, carbamazepine

Acute Hepatitis Common Example: Isoniazid ♦♦ The incidence of acute hepatitis and abnormal liver function tests with isoniazid in patients over 35 years of age is 3 and 30%, respectively

−− Hepatic failure occurs in about 10% of symptomatic patients and the overall mortality is approximately 0.1% Liver injury occurs 2–11 months after the initiation of therapy The hepatic injury resolves with withdrawal of the drug in approximately 70% of patients Therapy consists of supportive measures and liver transplantation The pathologic changes consist of a pattern of acute hepatitis with lobular injury that consists of inflammation, areas of hydropic change, and cell dropout −− In patients who have fulminant liver failure, there are extensive areas of panacinar and multiacinar cell loss −− Mild to moderate portal inflammatory infiltrate is seen, both in acute hepatitis as well as in fulminant hepatic failure

Common Example: Phenytoin ♦♦ The incidence of acute hepatitis with phenytoin use is 1% −− This is a hypersensitivity reaction ♦♦ Patients present with a viral hepatitis-like syndrome including jaundice, abdominal pain, and malaise −− There is also skin rash and eosinophilia consistent with a hypersensitivity reaction ♦♦ The prognosis is excellent and liver injury subsides on withdrawal of the drug −− The symptoms recur promptly on rechallenge with the drug ♦♦ The pathological features resemble an acute viral hepatitis or EBV infection when there is sinusoidal lymphocytosis

Common Example: Halothane ♦♦ Halothane and related halogenated inhalation anesthetic agents are known to cause severe liver dysfunction ♦♦ Two types of hepatotoxicity occur with halothane administration −− The two types are unrelated with no cross susceptibility between these two ♦♦ The first, known as type 1 hepatotoxicity, is benign, selflimiting and relatively common, occuring in up to 25-30% of individuals who receive halothane −− Patients are asymptomatic without jaundice or clinically evident hepatocellular disease −− Mild increase in serum transaminase levels is seen ♦♦ The second, known as type 2 hepatotoxicity, is an immunemediated hepatitis with a fatality rate estimated to be 1 in 35,000 patients −− The injury is a reaction to a drug metabolite–protein complex, which is immunogenic in genetically susceptible individuals −− Patients present 5–7  days following exposure, although presentation may be delayed up to 4 weeks (a) Patients have systemic manifestations such as fever, leukocytosis, nausea, and vomiting

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−−

−−

−−

(b) Rash, arthralgias, and eosinophilia may be present (c) Liver injury is manifested by jaundice, liver tenderness, hepatomegaly, and grossly elevated serum transaminase levels Reexposure triggers a more severe response (a) Prior exposure, especially at intervals of less than 6 weeks, is associated with the greatest risk of halothane hepatitis Females and middle-aged individuals are more susceptible to halothane toxicity (a) The incidence in children is dramatically less, but does exist Treatment consists of supportive therapy (a) Liver transplantation offers definitive cure Microscopically, features of an acute hepatitis and centrilobular cell loss are seen

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ These patients are susceptible to idiopathic cholestasis of pregnancy and severe pruritis of pregnancy, and may have family history of these disorders ♦♦ Patients present within 1–6 months −− Symptoms consist of cholestasis, jaundice, and pruritis −− There is gradual cessation of symptoms and signs upon withdrawal of the drug ♦♦ Microscopically, canalicular cholestasis is present in perivenular regions −− This unaccompanied by inflammation, necrosis, or portal tract changes (“bland cholestasis”)

Other Drugs Causing Cholestasis and Drug Injury

♦♦ Alpha methyldopa, diclofenac, tetracyclines, indomethacin, nitrofurantoin, phenylbutazone, rifampin, and sulfasalazine

♦♦ Pure cholestasis: anabolic steroids ♦♦ Cholestatic hepatitis: azathioprine, chlorpromazine, cimetidine, erythromycin, 6-mercaptopurine, flucloxacillin, nitrofurantoin, penicillin, sulfonamides, tamoxifen, and verapamil ♦♦ Acute cholangitis: allopurinol, chlorpromazine, and hydralazine ♦♦ Biliary cirrhosis: ajmaline, chlorpromazine, methyl testosterone, sulfonylurea, and tolbutamide

Chronic Hepatitis

Fibrosis

Common Example: Nitrofurantoin

Common Example: Methotrexate

−−

Other Drugs Causing Acute Hepatitis

♦♦ Nitrofurantoin is most commonly used to treat urinary tract infections ♦♦ Hepatic injury presents about 6 months after initiation of therapy and is indistinguishable from autoimmune hepatitis −− Patients present with features of chronic hepatitis such as jaundice, fatigue, and fever −− ANA and SMA are usually positive ♦♦ Withdrawal of the drug results in resolution of the hepatitis −− Some cases may not regress and may pursue a relentlessly progressive course ♦♦ The histological features are similar to autoimmune hepatitis with portal and periportal inflammation, which consists of lymphocytes and plasma cells −− Interface hepatitis of varying degree is seen −− Varying degree of lobular damage with liver cell necrosis and inflammation is seen −− Canalicular and cellular cholestasis may be seen −− Portal fibrosis, which may progress to bridging fibrosis and cirrhosis, occurs in patients with a progressive course

Other Drugs Causing Chronic Hepatitis ♦♦ Alpha methyldopa, aspirin, chlorpromazine, diclofenac, ­tetracyclins, disulfiram, isoniazid, methotrexate, propylthiouracil, and sulfonamides

Cholestasis and Duct Injury Common Example: Oral Contraceptives ♦♦ The overall incidence of cholestasis after oral contraceptive use is 1:10,000

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♦♦ Methotrexate is a folate antagonist used in the treatment of rheumatoid arthritis, psoriasis, and inflammatory bowel disease ♦♦ Methotrexate causes portal-based fibrosis, which may progress to periportal fibrosis, bridging fibrosis and cirrhosis ♦♦ Liver injury due to methotrexate is dose-dependent and therefore predictable −− It usually occurs at a cumulative dose of 2–4 g −− The risk of liver toxicity is exacerbated with heavy alcohol use, preexisting liver disease, daily dosing, and a high cumulative dose −− Monitoring of liver function tests is recommended every 6 months for patients on methotrexate (a) Liver enzymes may be elevated in 20–50% of patients (b) These elevations are usually minor and do not signify toxicity (c) Surveillance liver biopsies are recommended in longterm treatment ♦♦ Patients present with insidious hepatosplenomegaly and ascites ♦♦ Histologically, there is mild fatty change, anisonucleosis, mild portal inflammation, and varying degrees of portal fibrosis

Other Drugs Causing Liver Fibrosis ♦♦ Aflatoxin, copper, disulfiram, alpha methyldopa, and isoniazid

Steatosis Macrovesicular ♦♦ Bleomycin, l-asparaginase, methotrexate, steroids, cisplatin, sulfasalazine, warfarin, indomethacin, tamoxifen, amiodarone (Fig. 44.32)

Nonneoplastic Hepatobiliary Disease

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Granulomas

Fig.  44.32. Amiodarone toxicity showing numerous Mallory hyaline in damaged hepatocytes.

♦♦ Granulomas are a common finding in liver biopsies, being present in approximately 10% of liver biopsies ♦♦ Granulomas may occur due to a variety of causes including infections, connective tissue diseases, sarcoidosis, primary biliary cirrhosis, parasitic infections, and drugs −− The diagnosis of drug-induced granulomas requires exclusion of all other potential causes (a) It is especially important to rule out infections ♦♦ Drug-induced granulomas are usually nonnecrotizing microgranulomas that are distributed randomly within the parenchyma −− They are associated with other features of drug-induced damage such as inflammation, cholestasis, or both ♦♦ Drugs most often associated with presence of granulomas include allopurinol, alpha methyldopa, carbamazepine, hydra­ lazine, penicillin, phenylbutazone, phenytoin, quinidine, and sulfonamides

Microvesicular ♦♦ Aflatoxin, aspirin, phalloidin, tetracycline, valproic acid

Neoplasms

Vascular Abnormalities

Hepatocellular Adenoma

Peliosis-Like Lesions ♦♦ Anabolic steroids, phalloidin, vitamin A

Sinusoidal Dilatation ♦♦ Oral contraceptives

Veno-Occlusive Disease ♦♦ Aflatoxin, azathioprine, busulfan, mitomycin C, oral contraceptives, tamoxifen, vinyl chloride, vitamin A

♦♦ Anabolic steroids ♦♦ Oral contraceptives controversial

Hepatocellular Carcinoma ♦♦ Aflatoxin, anabolic steroids, mycotoxins, thorotrast, vinyl chloride

Cholangiocarcinoma ♦♦ Thorotrast, vinyl chloride

Vasculitis

Angiosarcoma

♦♦ Allopurinol, chlorothiazide, penicillin, phenylbutazone, phenytoin, sulfonamides

♦♦ Anabolic steroids, copper sulfate, diethylstilbestrol, thorotrast, vinyl chloride

ALCOHOLIC AND NONALCOHOLIC FATTY LIVER DISEASE Acute Alcoholic Liver Disease Steatosis Clinical ♦♦ Steatosis is the most common hepatic abnormality in alcoholics, present in >90% of individuals −− However, the finding is nonspecific as it may occur in many other clinical conditions ♦♦ The degree of steatosis is somewhat proportional to alcohol intake and deficiency of dietary protein ♦♦ Steatosis is completely reversible in 8 weeks following abstinence from alcohol ♦♦ Steatosis is clinically silent

−− Asymptomatic hepatomegaly may be the only clinical sign discovered on routine examination for an unrelated condition −− Steatosis may be demonstrable by ultrasound and CT, although these are not sensitive or specific for diagnosis

Microscopic ♦♦ Lipid droplets are seen on an H&E stain as empty intracytoplasmic vacuoles −− The steatosis is usually macrovesicular and characterized by a large single vacuole, which occupies and distends the cell, pushing and compressing the nucleus to the periphery

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Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The steatosis begins in zone 3 around the central venules −− With increasing accumulation, the entire lobule may be involved ♦♦ Parenchymal lipogranulomas may be present −− These are made up of a lipid vacuole which is surrounded by a sparse collection of macrophages and other inflammatory cells ♦♦ Simple steatosis is not associated with significant inflammation

Differential Diagnosis ♦♦ Nonalcoholic fatty liver disease associated with obesity, diabetes mellitus or the metabolic syndrome ♦♦ Jejunoileal bypass ♦♦ Drugs ♦♦ Malnutrition

Steatohepatitis Clinical ♦♦ Steatohepatitis is seen in patients with chronic alcohol consumption and usually occurs after several years of heavy drinking −− About one-third of patients have significant fibrosis or cirrhosis at presentation −− It is often precipitated by bouts of heavy drinking in a chronic alcoholic ♦♦ Nonalcoholic steatohepatitis (NASH) is a condition in which similar histological changes are seen in patients who do not have a history of alcohol use −− However, the clinical and histological changes are usually milder and a significant number of patients may be asymptomatic ♦♦ There is a wide range of possible presenting symptoms, including nausea, vomiting, hepatomegaly, fever, jaundice, ascites, and hepatic encephalopathy ♦♦ Therapy consists of supportive measures and abstinence from alcohol −− Some patients benefit from corticosteroid therapy −− Worsening of clinical symptoms may occur 2–4 weeks following abstinence ♦♦ The condition is associated with high mortality and there is definite progression to cirrhosis if alcohol use continues

Microscopic ♦♦ A variable, but usually marked degree of macrovesicular ­steatosis is present ♦♦ Hydropic or ballooning change of hepatocytes is common −− It is characterized by enlarged hepatocytes with pale staining cytoplasm −− This change is most prominent in perivenular (zone 3) hepatocytes

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Fig.  44.33. Steatohepatitis showing neutrophilic infiltrate and Mallory hyalin, which appears as amorphous, eosinophilic material in hepatocytes.

♦♦ Abundant Mallory hyaline is usually present in ballooned hepatocytes (Fig. 44.33) −− Mallory hyaline appears as an amorphous, eosinophilic material and consists of cytoskeletal filaments −− Mallory hyaline may be surrounded by a neutrophilic infiltrate (satellitosis) −− Neutrophils are also present in areas away from the Mallory hyaline ♦♦ There is usually a variable degree of fibrosis −− In milder cases, the fibrosis is perisinusoidal and pericellular and most prominent in the perivenular (zone 3) −− Advanced cases may show fibrous septa bridging adjacent central veins or central veins to portal tracts ♦♦ There is usually a variable degree of cholestasis −− In most cases, it is mild but may be a prominent finding in some cases ♦♦ A mild degree of ductular reaction is present in most cases ♦♦ Alcoholic foamy degeneration and acute sclerosing hyaline necrosis are histologic variants in which fatty change and ballooning degeneration are severe, and accompanied by necrosis in the latter condition

Special Studies ♦♦ The Masson trichrome stains highlights the typical pattern of perisinusoidal and pericellular fibrosis in perivenular regions ♦♦ The reticulin stain shows an increase in reticulin fibers, which surround individual hepatocytes in a “chicken-wire” pattern

Differential Diagnosis ♦♦ Nonalcoholic steatohepatitis ♦♦ Drug-induced liver injury (amiodarone)

Nonneoplastic Hepatobiliary Disease

Chronic Alcoholic Liver Disease Progressive Perivenular Fibrosis Clinical ♦♦ Progressive perivenular fibrosis is the precirrhotic stage of chronic alcoholic liver disease, which differs from the “usual” perivenular fibrosis in alcoholics by denseness and degree of perivenular fibrosis and by absence of regenerative nodules ♦♦ The involvement is uniform throughout the liver leading to severe venous outflow obstruction, which subsequently gives rise to clinical features of portal hypertension ♦♦ Patients present with jaundice and ascites, which is resistant to diuretics ♦♦ Treatment and prognosis are similar to cirrhosis

Microscopic ♦♦ The microscopic features are those of dense sclerosis of perivenular zones −− Varying degrees of pericellular fibrosis are also present ♦♦ The dense fibrosis in the perivenular areas contrasts with the minimal portal fibrosis ♦♦ These changes are not accompanied by regeneration of hepatocytes

Special Studies ♦♦ The Masson trichrome stain highlights the perivenular fibrosis

Cirrhosis Clinical ♦♦ Cirrhosis is the initial presentation in 40% of cases of ­alcohol-induced liver disease and follows several years of heavy drinking −− However, only a subset of chronic drinkers develop cirrhosis −− Dietary factors, especially reduced protein intake, is thought to play a role in variable susceptibility −− Women have a much lower threshold for developing alcoholic cirrhosis ♦♦ Patients may have normal laboratory tests unless acute liver disease or decompensation is present ♦♦ Hepatomegaly is present in the early stages but the liver is atrophic in the later stages ♦♦ Hepatocellular carcinoma occurs in 5–10% of cases of alcoholic cirrhosis ♦♦ The management of alcoholic cirrhosis is similar to cirrhosis from other causes −− Although abstinence does not influence patient survival in the cirrhotic stage, it is a prerequisite criterion for liver transplantation −− Transplantation is curative provided the patient continues to be abstinent ♦♦ The 1-year survival after onset of gastrointestinal hemorrhage or ascites is 30–50% while the 5-year survival after portacaval shunting is 25%

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Microscopic ♦♦ In active drinkers, the liver is micronodular (nodules varying from 1–4 mm in size) as alcohol use suppresses hepatocyte proliferation −− Proliferation, however, resumes following abstinence and the nodules become larger creating a macronodular or mixed macro- and micronodular pattern of cirrhosis ♦♦ Fibrous septa bridging adjacent central venules are seen −− In addition, there is pericellular fibrosis ♦♦ Varying degrees of steatosis may be present ♦♦ Inflammation is usually minimal in alcoholic cirrhosis unless there is superimposed steatohepatitis, in which case, ballooning change, Mallory hyaline and neutrophils are seen ♦♦ There may also be prominent cholestasis and mild ductular reaction

Special Studies ♦♦ The Masson trichrome stain highlights the fibrous septa ♦♦ Mallory hyaline may also be highlighted by this stain

Differential Diagnosis ♦♦ Cirrhosis of other etiologies

Nonalcoholic Fatty Liver Disease Clinical ♦♦ Nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseased in the USA −− Its prevalence is increasing globally due to an emerging epidemic of metabolic syndrome −− The term NAFLD encompasses simple steatosis, steatohepatitis, steatofibrosis, and cirrhosis related to fatty liver disease ♦♦ Nonalcoholic fatty liver disease is thought to affect approximately one-third of the adult population and approximately 10% of children in the USA −− The exact incidence is uncertain as there are no noninvasive specific or sensitive markers of NAFLD −− Definite diagnosis, as well as accurate grading and staging require a liver biopsy (a) Since this is an invasive test, it is usually restricted to patients who have signs or symptoms of liver disease, or to asymptomatic patients in whom there is a high suspicion of liver disease −− Imaging studies may detect steatosis but while they are good at detecting severe steatosis, the sensitivity drops markedly when steatosis is <50% −− Imaging studies detect fibrosis at the more severe end of the spectrum but are less sensitive at the lower end of the process ♦♦ Many patients may be asymptomatic and the disease, especially at its lower end of the spectrum, may present with incidental findings such of hepatomegaly or abnormal liver function tests, especially raised ALT, during investigation for an unrelated cause or routine examination

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Fig. 44.34. Steatohepatitis showing macrovesicular steatosis, perivenular and pericellular fibrosis (Masson trichrome stain). Changes are most pronounced in the centrilobular region (acinar zone 3).

Essentials of Anatomic Pathology, 3rd Ed.

Fig.  44.35. Steatohepatitis showing ballooning change of hepatocytes.

−− Clinical symptoms may be nonspecific such as fatigue and right upper quadrant pain −− The disease may follow an insidious course and patients may present for the first time with signs and symptoms of cirrhosis

Microscopic ♦♦ The microscopic features consists of variable degrees of steatosis, which is usually macrovesicular −− A single large fat vacuole is present within the cytoplasm of hepatocytes pushing the nucleus to the edge of the cell against the nuclear membrane (Fig. 44.34) ♦♦ Microvesicular steatosis may also been seen −− It consists of multiple small vacuoles, which indent the central nucleus −− Microvesicular steatosis is, however, not the predomina ♦♦ Medium-sized vacuoles of fat may also be seen −− These consists of a single droplet of fat present within the cytoplasm, which is not large enough to push the nucleus to one side or to enlarge the hepatocyte ♦♦ Steatosis begins in the centrilobular regions (zone 3) (Fig. 44.34) −− As the degree of steatosis increases, it involve zones 2 and 1, respectively ♦♦ Steatosis may not be progressive and can be reversed if the underlying metabolic syndrome is treated successfully ♦♦ Steatohepatitis is defined by evidence of cellular damage in a fatty liver −− Cell damage may be seen in the form of ballooning change (Fig. 44.35), Mallory hyaline, necrosis, and apoptosis of cells −− Ballooning change consists of enlarged hepatocytes with clear cytoplasm and well-defined cell membranes (a) This might represent membranous damage to hepatocytes

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♦♦

♦♦

♦♦

♦♦

−− Mallory hyaline consists of an aggregation of cytoskeleton filaments and appears as a ropy eosinophilic intracytoplasmic material −− Inflammation associated with steatohepatitis may consist of neutrophils but is very often lymphocytic (a) It is present in the lobules or within portal tracts (b) The degree of inflammation within the portal tracts is usually much less than that seen in chronic viral hepatitis −− Other features that might be seen in steatohepatitis including glycogenated nuclei and giant mitochondria −− Patients with steatohepatitis may accumulate variable degrees of iron (a) Not all of these patients have a mutation for the HFE gene The pattern of fibrosis is distinctive for NAFLD and consists of deposition of perisinusoidal or pericellular collagen fibers (Fig. 44.36) −− It begins in the centrilobular region and extends outward into the lobules (Fig. 44.34) −− There may be bridging fibrosis in advanced stages with bridging of adjacent central veins or central veins and portal tracts In long-standing cirrhosis, the features of steatohepatitis may not be present and the underlying etiology may not be evident −− These cases of “burned-out steatohepatitis” are thought to have accounted for a large number of “cryptogenic cirrhosis” in older literature Staging of NASH is shown in Box 44.1 −− The NASH activity index (NAS) (Box 44.2) is useful to assess the severity of NASH −− The numeric value of the NAS should not be used to establish the diagnosis of NASH The features of pediatric NAFLD are slightly distinct from those in adults

Nonneoplastic Hepatobiliary Disease

Fig.  44.36. Steatohepatitis showing extensive pericellular fibrosis (Masson trichrome).

Box 44.1. Staging of NASH 0 1   1A   1B   1C 2 3 4

None Perisinusoidal or periportal Delicate perisinusoidal Dense perisinusoidal Portal/periportal only Both perisinusoidal and portal/ periportal Bridging fibrosis Cirrhosis

Modified from Kleiner et al., 2005

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Fig. 44.37. Reticulin stain in steatohepatitis showing an increase in pericellular reticulin fibers. −− Lobular changes such as ballooning change and lobular inflammation are less frequent in children than they are in adults

Special Studies ♦♦ The Masson trichrome stain is useful for assessing the degree of fibrosis ♦♦ The reticulin stain shows an increase in pericellular reticulin fibers (Fig. 44.37)

Differential Diagnosis ♦♦ Drug-induced steatohepatitis ♦♦ Alcoholic steatohepatitis ♦♦ Jejunoileal bypass

Jejunoileal Bypass Box 44.2. NAS (NAFLD Activity Score) Steatosis 0 1 2 3

<5% 5–33% 34–66% >66%

Lobular inflammation (per 200x field) 1 2 3

<2 foci 2–4 foci >4 foci

Hepatocyte ballooning 1 2

Few cells Many cells/prominent ballooning

Modified from Kleiner et al., 2005

−− In children, steatosis begins around the portal tracts (zone 1) and there is more portal inflammation and more portalbased fibrosis than is seen in adults

♦♦ Jejunoileal bypass (JIB) was a bariatric procedure designed to decrease absorption of nutrients in the small intestine in morbidly obese patients −− JIB led to dramatic weight loss but was accompanied by morbidity and mortality related to profound alterations in gastrointestinal physiology and nutrition −− The high rate of early and late complications led to reversal of the procedure in almost 25% of cases −− The procedure has been replaced by other, relatively safer methods ♦♦ Liver failure was the main cause of short- and long-term mortality following JIB −− Approximately 5–10% of patients developed acute liver failure months after surgery and the risk persisted for years ♦♦ Steatosis and a rapidly progressive fibrosis leading to cirrhosis occurred within 1–2 years of the surgery −− This was thought to be the result of endotoxins released from bacterial colonies in the surgical blind loop

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Essentials of Anatomic Pathology, 3rd Ed.

Total Parenteral Nutrition

♦♦ Choledochal cyst ♦♦ Neonatal giant cell hepatitis

Clinical ♦♦ Total parenteral nutrition (TPN) is associated with variable degrees of steatosis and cholestasis −− One lesion may occur without the other in an individual patient ♦♦ Jaundice develops 4–40 days after initiation of total parenteral nutrition, which resolves with restoration of normal oral food intake −− Gallstones and sludge develop frequently ♦♦ Prolonged TPN may lead to increasing steatosis, cholestasis, and ductular reaction with progressive fibrosis and even cirrhosis ♦♦ Steatosis is thought to be induced by alterations in lipoprotein and fatty acid synthesis −− The disease mechanism is thought to be more complex in neonates and infants

Microscopic ♦♦ Variable degrees of macrovesicular steatosis are seen −− Other features of steatohepatitis such as ballooning change and Mallory hyaline may be present but are rare ♦♦ Variable degrees of canalicular cholestasis are present in the perivenular areas (zone 3) −− The portal tracts show mild ductular proliferation ♦♦ Giant cell transformation of hepatocytes may be seen in neonates on TPN ♦♦ Fibrosis may either be periportal, or perisinusoidal and centrilobular, depending on whether cholestatic or steatotic changes predominate

Differential Diagnosis

Acute Fatty Liver of Pregnancy Clinical ♦♦ Acute fatty liver of pregnancy usually manifests in the third trimester −− Postpartum presentation has also been reported ♦♦ The disorder is rare with a prevalence between 1 per 7,000 to 1 per 16,000 pregnancies ♦♦ The etiology is not certain but a certain number of cases are the result of recessively inherited fatty acid oxidation defects in the fetus or the mother, which are unmasked by pregnancy ♦♦ Mild cases are asymptomatic and discovered by the presence of abnormal liver tests −− Symptomatic patients may have nonspecific manifestations such as nausea, vomiting, lethargy, and abdominal pain −− Others may have jaundice, bleeding, and mental status changes −− Acute renal failure occurs in a significant number of patients ♦♦ Serum transaminases are moderately elevated ♦♦ Supportive treatment and prompt delivery reverse the liver injury in the majority of cases −− Certain fatty acid oxidation defects are associated with increased risk of fetal mortality

Microscopic ♦♦ The typical findings are a diffuse microvesicular steatosis, which is unaccompanied by inflammation, necrosis, or fibrosis

Differential Diagnosis ♦♦ Drug-induced steatosis ♦♦ Alcohol-induced foamy degeneration

♦♦ Extrahepatic biliary atresia

VASCULAR DISORDERS Hepatic Venous Outflow Obstruction Congestive Heart Failure Clinical ♦♦ Chronic right-sided heart failure causes sinusoidal dilatation and congestion due to back-pressure in the hepatic venous system −− This may eventually lead to centrilobular fibrosis, which may progress to bridging septa between adjacent central veins −− Extensive and diffuse bridging fibrosis is sometimes called “cardiac cirrhosis” (a) This is a misnomer because regenerative nodules are not a feature of this process

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♦♦ Jaundice is not a feature of this condition ♦♦ Serum LFTs are normal or mildly elevated ♦♦ Treatment of the underlying heart disorder resolves liver disease if fibrosis has not already set in −− Morbidity and mortality are usually due to the cardiac disease and its complications

Microscopic ♦♦ In the early phases, sinusoidal dilatation and congestion are seen in perivenular regions −− With time, there is compression of the hepatic cell plates, leading eventually to atrophy and loss of hepatocytes −− Further progression leads to centrilobular fibrosis, which may lead to bridging of adjacent central venules by fibrous septa

Nonneoplastic Hepatobiliary Disease

Fig.  44.38. An occluded sublobular hepatic vein in a patient with Budd–Chiari syndrome.

Special Studies ♦♦ Masson trichrome stain highlights the degree of fibrosis

Differential Diagnosis ♦♦ Budd–Chiari syndrome ♦♦ Veno-occlusive disease

Budd–Chiari Syndrome Clinical ♦♦ The Budd–Chiari syndrome is caused by obstruction of the main hepatic veins or the inferior vena cava (Fig. 44.38) ♦♦ Causes include membranous obstruction of large hepatic veins in South Africa, Japan, and India and fibrous obstruction due to malignancy, trauma, infection, and radiation in Western countries ♦♦ A significant cause of the Budd–Chiari syndrome includes coagulation defects, which lead to clots in the hepatic veins and/or inferior vena cava ♦♦ The clinical presentation may be acute with development of sudden ascites ♦♦ The outcome and complications are similar to cryptogenic cirrhosis in the chronic forms −− Acute Budd–Chiari syndrome may have a poor prognosis

Microscopic ♦♦ In the acute stage, there is severe perivenular sinusoidal ­dilatation and congestion (Fig. 44.39), which may be accompanied by hemorrhage −− There is no fibrosis at this stage ♦♦ In the chronic stages, perivenular and sinusoidal fibrosis develops which may progress to bridging fibrous septa

Special Studies ♦♦ The Masson trichrome stain highlights the degree of fibrosis

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Fig.  44.39. Centrilobular sinusoidal dilatation and congestion with hepatic plate atrophy in a patient with Budd–Chiari syndrome.

Differential Diagnosis ♦♦ Right-sided heart failure ♦♦ Veno-occlusive disease

Veno-Occlusive Disease Clinical ♦♦ Veno-occlusive disease may present either as an acute or a chronic disease ♦♦ Veno-occlusive disease is caused by endothelial damage to the central veins −− This is followed by intimal hyperplasia and fibrous deposition, leading finally to fibrosis of the central hepatic veins ♦♦ Veno-occlusive disease may be caused by radiation, chemotherapy, or graft vs. host disease −− It is endemic in the West Indies where it is associated with drinking bush tea which contains toxic alkaloids −− Veno-occlusive disease is a common finding in chronic alcohol-related liver disease ♦♦ Patients present with features of portal hypertension and ascites due to obstruction to venous outflow ♦♦ Liver tests are elevated and there may be jaundice

Microscopic ♦♦ In the acute phase, the terminal hepatic venules may show intimal hyperplasia, edema, and fibrin deposition (Fig. 44.40) −− The surrounding sinusoids show dilatation and congestion ♦♦ In the chronic phase, there is attenuation and atrophy of hepatocytes with perivenular and perisinusoidal fibrosis −− No changes are seen in the larger hepatic veins

Special Studies ♦♦ Masson trichrome stain highlights the thickening and obliteration of the central hepatic venules

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Fig. 44.40. Veno-occlusive disease showing intimal thickening and partial occlusion of a central vein in a patient on chemotherapy for leukemia. The remaining liver biopsy shows centrilobular congestion and necrosis.

Differential Diagnosis ♦♦ Budd–Chiari syndrome ♦♦ Right-sided heart failure

Hypotensive Anoxia Clinical ♦♦ Although the hepatic arterial blood flow is directly related to cardiac output, only severe hypotension leads to extensive liver cell necrosis −− Usually, there is mild ischemic necrosis throughout the liver, which might not clinically manifest −− In severe cases, there may be extensive necrosis leading to hepatic dysfunction, a process that is sometimes called “ischemic hepatitis” ♦♦ Full recovery occurs following a single hypotensive episode due to regeneration of hepatocytes ♦♦ The ultimate prognosis is related to the underlying disease causing hypotension

Microscopic

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 44.41. Thrombophlebitis showing purulent infiltrate within the wall and lumen of a large portal vein branch. ♦♦ Viral hepatitis −− Necrosis is usually nonzonal in distribution

Inflammatory Vascular Lesions Pylephlebitis Clinical ♦♦ Portal vein inflammation may occur secondary to intraabdominal suppurative infections such as appendicitis, diverticulitis, or pelvic abscess −− Pylephlebitis may lead to portal vein thrombosis and fibrous obliteration, which may be followed by cavernous transformation of the portal vein −− Hepatic abscesses may complicate inflammatory pylephlebitis −− Pylephlebitis and portal vein thrombosis occurs frequently in children in developing countries due to high incidence of infection of the umbilical stump ♦♦ The prognosis depends upon the underlying infection and mortality can be high if infection is not eradicated

Microscopic

♦♦ Hypertensive or ischemic liver disease is manifested by coagulative necrosis of hepatocytes −− This is most prominent in the perivenular regions ♦♦ The lesion usually heals without any residual damage when there is a single and transient episode of hypotension ♦♦ With continued ischemia, there might be perivenular ­collapse and fibrosis

♦♦ Inflammation within the wall and lumen of the portal vein is seen (Fig. 44.41) −− The inflammation includes neutrophils and chronic inflammatory cells ♦♦ Vascular thrombosis and fibrosis may be seen in later stages (Fig. 44.42) ♦♦ There might also be periportal neutrophilic infiltrate and microabscess formation

Special Studies

Differential Diagnosis

♦♦ The reticulin stain highlights collapse and loss of cells

Differential Diagnosis ♦♦ Drug-induced liver injury −− Acetaminophen toxicity closely mimics ischemic hepatitis

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♦♦ Acute cholangitis −− This may result in periportal inflammation and microabscesses ♦♦ Portal vein thrombosis may occur as a paraneoplastic pheno­ menon with some malignancies

Nonneoplastic Hepatobiliary Disease

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Miscellaneous Vascular Disorders Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Disease) Clinical ♦♦ This is an autosomal dominant disorder characterized by capillary arteriovenous malformations ♦♦ The number of lesions increases with age and liver involvement is usually not symptomatic

Microscopic ♦♦ Dilated and enlarged portal venules with herniation of the vessels into the adjacent parenchyma are seen ♦♦ Malformed vessels may be seen in the portal tracts ♦♦ Variable degree of accompanying fibrosis is seen Fig. 44.42. Same patient as in Fig. 44.41 showing a small portal vein branch replaced by fibrous scar. The hepatic arteriole and bile duct are seen on either side of the scarred vein.

Differential Diagnosis ♦♦ Idiopathic portal hypertension ♦♦ Cirrhosis of other etiologies

Idiopathic Portal Hypertension (Noncirrhotic Portal Hypertension) Clinical

Polyarteritis Clinical ♦♦ The hepatic arteries may be involved by necrotizing vasculitides that affect medium and small-sized arteries −− The hepatic artery is involved in approximately 60% of such cases and hepatic involvement may be symptomatic ♦♦ Inflammation may be followed by thrombosis and aneurysmal formation, which may give rise to ischemic hepatitis

Microscopic

♦♦ Idiopathic portal hypertension has been described most commonly in India and Japan −− It is rare in Western countries ♦♦ Patients present with typical complications of portal hypertension in the absence of cirrhosis −− The onset is insidious with nonspecific laboratory findings ♦♦ It is thought that the condition results from fibrous obliteration of the portal vein −− Alternatively, these cases may represent regressing cirrhosis

♦♦ Microscopic features consist of fibrinoid necrosis and inflammation of the arterial walls (necrotizing vasculitis) ♦♦ Secondary thrombosis and fibrosis may be present ♦♦ Ischemic necrosis of hepatocytes, involving predominantly zone 3, may be seen

Microscopic

Differential Diagnosis

Differential Diagnosis

♦♦ Ischemic necrosis due to other causes ♦♦ Pylephlebitis with secondary arterial changes

♦♦ Osler–Weber–Rendu disease ♦♦ Regressing cirrhosis

♦♦ There might be some portal fibrosis and the portal tracts contain an increased number of dilated vessels ♦♦ The portal veins may be attenuated but are not obliterated ♦♦ There is no inflammation and no bile duct anomalies are seen

CHOLESTASIS AND BILIARY TRACT DISORDERS Acute Mechanical Duct Obstruction Clinical ♦♦ Common causes of acute obstruction of the bile duct include choledocholithiasis, neoplasms, acute pancreatitis, postoperative iatrogenic duct stricture, and abdominal trauma ♦♦ Patients may present with pain, fever, and jaundice (Charcot triad) due to secondary cholangitis

♦♦ Treatment aims at relieving obstruction and treating the infection to prevent the development of chronic changes in the liver

Microscopic ♦♦ Canalicular cholestasis is present, which is most prominent in the perivenular regions ♦♦ The portal tracts show edema, ductular reaction and dilated bile ducts which may contain bile plugs

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♦♦ Bile lakes resulting from leakage of bile from damaged ducts and bile infarcts resulting from the toxic effects of bile on hepatocytes may rarely be seen

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Acute alcoholic hepatitis Pylephlebitis Toxic shock syndrome Septicemia Primary sclerosing cholangitis

Chronic Mechanical Duct Obstruction Clinical ♦♦ The common causes of chronic duct obstruction include chronic pancreatitis, neoplasms, parasitic infections, and extrahepatic biliary atresia −− Long-standing duct obstruction may lead to increasing fibrosis and cirrhosis −− The interval to biliary cirrhosis is 4–7  years (common duct stricture or choledocholithiasis) −− Cirrhosis develops rapidly within 6  months in neonates with extrahepatic biliary atresia ♦♦ Patients present with episodes of recurrent cholangitis or insidiously with features of decompensated cirrhosis ♦♦ Partial chronic obstruction commonly results in abscess formation and septicemia ♦♦ Relief of obstruction leads to reversal of hepatic pathology in noncirrhotic patients

Microscopic ♦♦ The portal tracts show increased numbers of bile ductules with bile plugs, with or without an accompanying neutrophilic infiltrate (Fig. 44.43)

Fig.  44.43. Ductular reaction in a patient with long-standing b­ iliary obstruction. Portal and periportal fibrosis were seen on trichrome stain.

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♦♦ Long-standing obstruction may lead to damage and loss of interlobular bile ducts ♦♦ Varying degrees of portal fibrosis with bridging fibrosis or cirrhosis is seen in the late stages ♦♦ Variable degrees of cholestasis, acute cholangitis, bile lakes, and bile infarcts may be present

Differential Diagnosis ♦♦ Primary biliary cirrhosis ♦♦ Primary sclerosing cholangitis ♦♦ Drug-induced liver injury

Primary Biliary Cirrhosis Clinical ♦♦ Primary biliary cirrhosis (PBC) is a chronic progressive and destructive granulomatous cholangitis leading to biliary cirrhosis ♦♦ The exact etiology of PBC is uncertain but is thought to involve an autoimmune reaction against antigens shared or unmasked by infectious agents ♦♦ The prevalence is 20–240 cases per million population, varying widely among geographic regions −− The disease is common in Europe and North America and is rarely reported in Africa or India ♦♦ The disease affects young to middle-aged women who may present with pruritus (50%), fatigue and pain (25%), or hepatic decompensation due to cirrhosis (25%) −− Portal hypertension may develop before the onset of cirrhosis ♦♦ Patients commonly have other associated autoimmune phenomena such as the sicca syndrome, thyroid disease, arthralgia, sclerodactyly, and Raynaud disease −− There is only a weak association with HLA DR8 ♦♦ Laboratory tests reveal a cholestatic liver test profile −− Serum immunoglobulins are increased and a variety of autoantibodies are reported ♦♦ The anti-mitochondrial autoantibody, M2-subtype, is specific and found in 96% of all cases −− It recognizes a mitochondrial antigen, PDC-E2, which is expressed aberrantly on small intrahepatic bile ducts ♦♦ Treatment consists of symptomatic treatment for pruritus, lethargy, and osteopenia −− Ursodeoxycholic acid is used to relieve cholestasis and slows development of cirrhosis ♦♦ Liver transplantation provides a definitive, life-saving therapeutic option −− The median time from diagnosis to transplantation (or death) is dependent on stage at presentation and varies from 3 to 10 years ♦♦ The disease recurs in the allograft and the incidence increases with duration of follow-up −− It is characterized by granulomatous cholangitis and presence of PDC-E2 in biliary epithelium −− Recurrent disease follows an indolent course

Nonneoplastic Hepatobiliary Disease

Microscopic ♦♦ The diagnostic lesion is a nonnecrotizing granulomatous inflammation surrounding and destroying a small-sized bile duct, the so-called florid duct lesion (Fig. 44.44) ♦♦ This lesion is very focal and may not be seen on a liver biopsy −− Lymphocytic cholangitis (Fig. 44.45) consisting of a lymphoplasmacytic infiltrate surrounding a damaged bile duct is a more frequent finding in liver biopsies ♦♦ Late stage PBC shows duct loss (ductopenia) ♦♦ Mild lobular inflammation with granulomas may be seen; however, the lobular changes do not predominate unless there is associated autoimmune hepatitis, the so-called overlap syndrome

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♦♦ The lobules show features of chronic cholate stasis such as pseudoxanthomatous change, copper deposition, and Mallory hyaline in periportal hepatocytes which result from retention of bile acids ♦♦ PBC is staged according to the Scheuer staging system into four stages as follows −− Stage 1: Florid duct lesion −− Stage 2: Ductular proliferation −− Stage 3: Portal and periportal fibrosis −− Stage 4: Cirrhosis

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Sarcoidosis Graft vs. host disease Chronic hepatitis C Primary sclerosing cholangitis

Primary Sclerosing Cholangitis Clinical

Fig.  44.44. Granulomatous inflammation is present around a damaged bile duct in primary biliary cirrhosis (“florid duct lesion”).

Fig.  44.45. Primary biliary cirrhosis showing lymphoplasmacytic inflammation around damaged bile ducts (“lymphocytic cholangitis”).

♦♦ Primary sclerosing cholangitis (PSC) is a slowly progressive cholestatic disease characterized by inflammation, fibrosis, and obliteration of large and medium-sized bile ducts ♦♦ The exact etiology is unknown and several factors such as chronic portal bacteremia, toxic bile acid metabolites, chronic viral infections, and ischemia are thought to play interdependent roles ♦♦ The prevalence is 2–7 per 100,000 population −− The disease occurs in young to middle-aged males (75%) −− The average age at diagnosis is 40 years ♦♦ Patients present with a variable combination of progressive fatigue, pruritus, or jaundice in two-thirds of cases −− The disease is typically associated with inflammatory bowel disease in 70% of individuals −− Chronic ulcerative colitis is a more common association than Crohn disease ♦♦ Complications of PSC such as fat-soluble vitamin deficiencies and metabolic bone disease result from compromised bile flow −− Others such as recurrent bacterial cholangitis (frequent), cholelithiasis (30%), bile duct strictures (20%), and ­cholangiocarcinoma (10–15%) are a consequence of the strictures themselves ♦♦ Liver function tests reveal a cholestatic profile −− The disease is associated with HLA B8/DR3 haplotype −− Antineutrophil nuclear and cytoplasmic antibodies, ANNA and ANCA, respectively, are usually present in serum ♦♦ Diagnosis is established by characteristic findings on ERCP or MRCP −− These consist of a “beaded” appearance of the biliary tree caused by multifocal strictures with intervening dilatations ♦♦ D-penicillamine, methotrexate, ursodeoxycholic acid, steroids, and other immunosuppressants have not been shown

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Fig. 44.46. Primary sclerosing cholangitis showing concentric periductal fibrosis (“onion-skinning”) around duct with marked epithelial damage and luminal narrowing. to have definite beneficial effects on the course of the disease −− Liver transplantation is the treatment of choice and PSC is the fourth leading cause for liver transplantation in the USA −− The median time to transplantation (or death) is 9 to 11 years from time of diagnosis −− Disease recurrence occurs in approximately 8% of cases at 3–5 years after transplantation

Microscopic ♦♦ PSC is a disease of large and medium-sized bile ducts such as the hilar and segmental ducts −− Pathognomic lesions may not be seen on liver biopsy specimens that sample smaller, peripheral bile ducts ♦♦ The large ducts show intense periductal inflammation consisting of lymphocytes and plasma cells −− When there is bile leakage, neutrophils and foamy macrophages may be present ♦♦ As the disease progresses, there is concentric periductal fibrosis (“onion-skin” appearance) (Fig. 44.46) and epithelial attenuation −− The final stages of this process consist of fibrous obliteration of the ducts, which are replaced by bile duct scars, and ductopenia (Fig. 44.47) ♦♦ The smaller portal tracts demonstrate portal edema and ductular reaction reflecting the downstream effects of obstruction −− Continued obstruction leads to portal fibrosis, which then progresses to bridging septa and cirrhosis ♦♦ Analogous to PBC, primary sclerosing cholangitis is divided into four stages, but these are not as well-defined as in PBC

Differential Diagnosis ♦♦ Sarcoidosis

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Fig. 44.47. Primary sclerosing cholangitis showing bile duct scar.

♦♦ Primary biliary cirrhosis ♦♦ Secondary sclerosing cholangitis

Intrahepatic Cholestasis Postoperative Cholestasis Clinical ♦♦ Postoperative cholestasis complicates approximately 0.2% of elective procedures and occurs 1–2 days following surgery −− It is seen after prolonged surgical procedures and is most common after cardiac surgery −− Postoperative cholestasis results from a combination of bilirubin overload due to hemolysis and/or transfusions as well as temporary compromise of liver function ♦♦ The condition is benign by itself and prognosis is related to the condition underlying the surgical procedure

Microscopic ♦♦ The microscopic features are those of “bland cholestasis” with canalicular and cellular cholestasis, which are most prominent in the centrilobular region ♦♦ The portal tracts do not show any changes such as bile duct damage, ductular reaction, or fibrosis −− Minimal portal inflammation may be present

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Drug-induced cholestasis Septicemia Early acute duct obstruction Intrahepatic cholestasis of pregnancy Benign recurrent intrahepatic cholestasis

Intrahepatic Cholestasis of Pregnancy Clinical ♦♦ Intrahepatic cholestasis of pregnancy occurs in the third trimester

Nonneoplastic Hepatobiliary Disease

♦♦ The incidence in 2–5% of all pregnancies −− However, a much higher prevalence exists in Chile and Sweden ♦♦ Some, but not all patients have mutations in MDR3, the same canalicular transporter, which is mutated in progressive intrahepatic cholestasis (PFIC) type 3 −− Some patients may have family members with PFIC-3 −− It is postulated that a partial functional deficiency of this transporter is unmasked by the hormonal changes of pregnancy ♦♦ Patients present with mild jaundice and variable degrees of pruritis −− The symptoms disappear after delivery −− The condition recurs in 50% of subsequent pregnancies −− The severity varies from pregnancy to pregnancy in the same patient and is unpredictable ♦♦ There are no long-term consequences for the mother −− Increased incidence of fetal distress and stillbirth has been reported ♦♦ Therapy consists of ursodeoxycholic acid which is thought to improve both maternal pruritus and fetal prognosis

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Microscopic ♦♦ The microscopic features are those of “bland cholestasis” with canalicular and cellular cholestasis, which are most prominent in the centrilobular region ♦♦ The portal tracts do not show any changes such as bile duct damage, ductular reaction, or fibrosis ♦♦ Giant cell transformation of hepatocytes may be seen but it is neither prominent nor a constant feature

Differential Diagnosis ♦♦ Drugs ♦♦ Septicemia ♦♦ Early acute duct obstruction

Paucity of Intrahepatic Bile Ducts ♦♦ Paucity of intrahepatic bile ducts is associated with a number of inherited/metabolic and acquired conditions −− Examples of inherited/metabolic conditions include alpha-1 antitrypsin deficiency, inborn errors of bile acid metabolism, Turner syndrome, trisomy 17, and trisomy 21 −− Examples of acquired conditions include viral hepatitis, drug-induced liver injury, allograft rejection, and graft vs. host disease

DEVELOPMENTAL, HEREDITARY, AND METABOLIC LIVER DISEASE

Cystic Liver Disease Solitary Unilocular Cyst Clinical ♦♦ Solitary unilocular cysts arise from aberrant bile ducts and may be congenital or developmental in origin ♦♦ These are usually asymptomatic, incidental findings −− Rarely, one might rupture or cause symptoms due to compression of adjacent structures ♦♦ Symptomatic cysts are treated by surgical excision

Macroscopic ♦♦ Solitary unilocular cysts are well-circumscribed, usually small and may contain several liters of fluid

Microscopic ♦♦ The wall is thin and lined by flat or cuboidal epithelium −− The lining epithelium may be partially denuded especially in large cysts, which may then be lined by fibrous or granulation tissue ♦♦ Cysts lined by cuboidal to low columnar biliary type epithelium are also called solitary bile duct cysts −− The lining epithelium stains with biliary cytokeratins, CK 7 and CK 19

♦♦ The cysts are well-demarcated from the hepatic parenchyma by a collagen capsule

Differential Diagnosis ♦♦ Mucinous cystadenoma ♦♦ Ciliated foregut cyst

Autosomal Recessive Polycystic Kidney Disease (ARPKD) Clinical ♦♦ ARPKD is associated with disease of kidney and liver −− The mutated gene is located on the short arm of chromosome 6 at 6p21 and encodes for fibrocystin ♦♦ The liver disease manifests as portal hypertension and is due to increasing microcystic changes associated with increasing degrees of fibrosis ♦♦ In patients with severe renal manifestations, death results from chronic renal failure and hypertension −− In those with milder forms of kidney disease, symptoms of portal hypertension may predominate

Microscopic ♦♦ The characteristic feature is the presence of irregularly shaped, dilated, and anastomosing biliary channels, which

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♦♦ ♦♦ ♦♦ ♦♦

are usually present at the periphery of expanded portal tracts in a configuration reminiscent of the ductal plate The dilated biliary channels extend into lobules Small fibrovascular cores protrude into the lumina of the dilated ducts True cyst formation is not seen (Figs. 44.48 and 44.49) The malformation is associated with fibrosis which progresses with age; older children show features of congenital hepatic features

Differential Diagnosis ♦♦ von Meyenburg complexes ♦♦ Congenital hepatic fibrosis

Essentials of Anatomic Pathology, 3rd Ed.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) Clinical ♦♦ Autosomal dominant disease (ADPKD) shows cysts in liver, kidney, and pancreas ♦♦ It is caused by mutations in one of two genes −− The first is the PKD1 gene located on chromosome 16 at 16p13, which accounts for 90% of cases and encodes for a protein called polycystin −− The second is the PKD2 gene located on chromosome 4 at 4q21-23, which encodes for polycystin 2 ♦♦ ADPKD is a multisystem disease characterized by cysts and connective tissue abnormalities −− Polycystic renal disease occurs in 50% of patients and cerebral aneurysms in 10% of patients ♦♦ The severity of liver disease varies from asymptomatic involvement to massive hepatomegaly, which causes abdominal discomfort and pain, and compresses the thoracic cavity resulting in difficulty in breathing −− The cysts enlarge over time and hepatic expression of the disease is influenced by age, female gender, pregnancy, and severity of renal lesions and function ♦♦ The cysts may be complicated by infection or cholangio­ carcinoma

Macroscopic ♦♦ Liver involvement is variable ♦♦ In patients with severe disease, there is massive hepatomegaly (Fig. 44.50) and the liver is completely replaced by cysts ranging in size from 1 mm to several centimeters −− The cysts contain clear to yellow cyst fluid

Fig. 44.48. ARPKD shows irregularly shaped, dilated, and anastomosing biliary channels without cyst formation.

Microscopic

Fig. 44.49. ARPKD showing a dilated malformed ductal structure containing numerous polypoid projection.

Fig.  44.50. ADPKD showing an enlarged liver almost totally replaced by varying sized cysts.

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♦♦ The cysts are lined by a single layer of flat or cuboidal epithelium ♦♦ The walls show small amounts of fibrous tissue and variably, mild chronic inflammation

Nonneoplastic Hepatobiliary Disease

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Fig.  44.51. Congenital hepatic fibrosis showing dilated malformed bile ducts in broad fibrous septa that lack inflammation.

Fig. 44.52. Congenital hepatic fibrosis showing dilated biliary channels containing bile casts at the interface with hepatic parenchyma.

Differential Diagnosis

Bile Duct Dilatation Choledochal Cyst Clinical

♦♦ von Meyenburg complexes ♦♦ Congenital hepatic fibrosis

Congenital Hepatic Fibrosis Clinical ♦♦ Congenital hepatic fibrosis is inherited as an autosomal recessive disease −− It is associated with renal cystic disease, usually ARPKD, in 50% of cases ♦♦ The liver disease is asymptomatic in childhood −− Clinical manifestations from liver disease occur in adolescents or young adults who have survived their renal disease −− Patients present with complications of portal hypertension, which bring the liver disease to clinical attention ♦♦ Shunt procedures are often helpful ♦♦ Liver transplantation offers definitive therapy ♦♦ Death results from esophageal variceal bleeding or renal failure and not from hepatic failure

Microscopic ♦♦ The portal tracts are markedly expanded and contain irregularly dilated biliary channels, which are arranged at the edge of the fibrous tracts in an interrupted circular arrangement resembling the embryonic ductal plate (Fig. 44.51) −− The dilated ducts characteristically contain inspissated bile (Fig. 44.52) ♦♦ Fibrous bands link adjacent portal tracts dividing the liver into nodules −− There is no regeneration as occurs in cirrhotic nodules distinguishing the fibrosis and nodularity of congenital hepatic fibrosis from that of cirrhosis due to other causes

♦♦ Choledochal cysts are caused by congenital dilatation of a part of the biliary tract ♦♦ Although congenital in origin, they may present at any age −− Approximately 20% present within the first year of life and 60% present before 10 years of age −− Presentation in late adulthood is not unusual ♦♦ There is a significant female predilection ♦♦ Choledochal cysts are often associated with other developmental abnormalities of the biliary tract ♦♦ Malformation of pancreatobiliary system (“common channel”) is also present in many patients −− Presence of a common channel with consequent damage of the wall by pancreatic juice leading to cyst formation is thought to be the likely etiopathogenetic mechanism ♦♦ Children present with jaundice while adults present with features of recurrent ascending cholangitis ♦♦ There is an increased incidence of cholangiocarcinoma −− This is thought to be due to bile stasis leading to bacterial overgrowth and the formation of secondary unconjugated bile acids; and reflux of pancreatic juice ♦♦ Treatment consists of complete resection and creation of a hepaticojejunostomy

Macroscopic ♦♦ Choledochal cysts vary in size, and may contain up to 5 L of bile (Fig. 44.53) ♦♦ The dilatation may be either saccular or fusiform in configuration

Microscopic ♦♦ Choledochal cysts are comprised of fibrotic walls, which show chronic inflammation and sometimes abundant mucinous glands

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Caroli Disease Clinical ♦♦ Caroli disease is a congenital nonobstructive segmental dilatation of the intrahepatic biliary tree −− It is thought to result from a malformation of the ductal plate −− Caroli disease may be associated with autosomal recessive polycystic kidney disease ♦♦ Caroli disease first presents in adolescence or young adulthood due to complications such as cholangitis and choledo­ cholithiasis ♦♦ Patients may have fever, nausea, abdominal pain, jaundice, and hepatomegaly −− Cholangitis can lead to sepsis −− There is an increased incidence of cholangiocarcinoma ♦♦ Therapy consists of controlling the cholangitis which is a significant cause of morbidity and mortality

Microscopic Fig. 44.53. Choledochal cyst appearing as a saccular dilatation of the common bile duct.

♦♦ The intrahepatic bile ducts are dilated −− A neutrophilic infiltrate indicative of cholangitis and pericholangitis may be present around the bile ducts as well as within the lumen and biliary epithelium −− Portal and periportal microabscesses may be present ♦♦ The portal tracts are expanded and contain dilated biliary structures present in an interrupted circular configuration at their edges in a pattern reminiscent of the ductal plate −− This is accompanied by varying degree of portal fibrosis

Differential Diagnosis ♦♦ Congenital hepatic fibrosis ♦♦ Recurrent pyogenic cholangiohepatitis ♦♦ Mechanical biliary obstruction

Extrahepatic Biliary Atresia Clinical

Fig. 44.54. Choledochal cyst in Fig. 44.53 shows a fibrotic wall lined by tall columnar epithelium.

♦♦ The cyst may be lined partially by epithelium (Fig.  44.54), which may be biliary or metaplastic, including intestinal or squamous epithelium ♦♦ Cholangiocarcinoma may be present in the cyst ♦♦ The liver may show features of biliary obstruction including ductular reaction, cholangitis, and even biliary cirrhosis in long-standing cases

Differential Diagnosis ♦♦ Other causes of biliary obstruction

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♦♦ Extrahepatic biliary atresia occurs in 1:15,000 births ♦♦ The exact etiology is not known −− Developmental and viral factors have been implicated in isolation or in combination with each other ♦♦ The process usually involves the entire extrahepatic biliary tree including the gallbladder, which is usually small and hypoplastic −− A minority of cases may have partial atresia or hypoplasia ♦♦ Patients present at 1–2 weeks after birth with jaundice, dark urine, and acholic stools −− Hepatomegaly may be present ♦♦ The condition proceeds rapidly to cirrhosis and mortality is 50% within 1 year if left untreated ♦♦ The Kasai procedure (hepatoportoenterostomy) restores bile flow and allows a fairly good quality of life for several decades

Nonneoplastic Hepatobiliary Disease

−− Most patients subsequently require liver transplantation −− The Kasai procedure is the first option of choice allowing good quality of life and normal development before transplantation is performed

Microscopic ♦♦ The microscopic features are those of mechanical obstruction with marked ductular reaction consisting of numerous ductules associated with a neutrophilic infiltrate −− Bile plugs are often seen (Fig. 44.55) −− Bile duct loss occurs in the late stages ♦♦ The lobules show marked canalicular and cellular cholestasis, which is most prominent in centrilobular regions −− Bile may be present in Kupffer cells ♦♦ Giant cell transformation of hepatocytes may be present but is not as extensive as in neonatal hepatitis ♦♦ There is extensive portal fibrosis which progresses rapidly to bridging fibrosis and cirrhosis

Differential Diagnosis ♦♦ Neonatal giant cell hepatitis ♦♦ Alpha-1 antitrypsin deficiency ♦♦ Progressive familial intrahepatic cholestasis

Alagille Syndrome Clinical ♦♦ Alagille syndrome consists of a variable combination of paucity of intrahepatic bile ducts, peripheral pulmonary stenosis, ocular posterior embryotoxon, vertebral arch deformities, and a characteristic facies with frontal bossing, hypertelorism, deep-set eyes, and pointed chin ♦♦ Alagille syndrome is inherited as an autosomal dominant condition and has an incidence of approximately 1:70,000 live births ♦♦ Alagille syndrome has been mapped to two genes; the first is the JAG1 located on chromosome 20 at 20p11 and

Fig. 44.55. Extrahepatic biliary atresia showing numerous bile ductules containing bile plugs.

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the second is the NOTCH2 gene located on chromosome 1 at 1p13 −− JAG/NOTCH interactions are important for development of intrahepatic bile ducts −− Mutations in both genes cause a similar clinical phenotype −− However, the phenotype varies widely between individuals, even among those with the same mutation, suggesting the role of modifier genes and the presence of complex pathways ♦♦ Patients present with jaundice and severe pruritis within the first 3 months of life −− Numerous xanthomas may be present ♦♦ Patients have hyperbilirubinemia, elevated serum bile acids and dyslipidemia ♦♦ Treatment consists of controlling pruritis and the dyslipidemia −− Liver transplantation offers definitive treatment for the liver disease; however, its feasibility depends on the presence of extrahepatic manifestations

Microscopic ♦♦ There is absence of bile ducts in portal tracts −− Bile ducts should be absent in 50% of portal tracts to render a definitive diagnosis of paucity of intrahepatic bile ducts (Fig. 44.56) ♦♦ The lobules show canalicular and cellular cholestasis, which is most prominent in the perivenular regions (Fig. 44.57) ♦♦ There is no accompanying inflammation either in the portal tracts or lobules ♦♦ A ductular reaction is not usually seen, although this has been described in the early stages of the disease ♦♦ Giant cell transformation of hepatocytes is not seen ♦♦ Portal fibrosis is usually mild, if present at all −− Mild centrilobular fibrosis may be seen in patients with severe and long-standing cholestasis

Fig. 44.56. Alagille syndrome showing absence of bile ducts in small portal tracts without significant inflammation or ductular reaction.

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Fig. 44.57. Alagille syndrome showing canalicular cholestasis in the lobules without inflammation.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 44.58. Dubin–Johnson syndrome showing pigment deposition in the perivenular region.

Differential Diagnosis ♦♦ Alpha-1 antitrypsin deficiency ♦♦ Extrahepatic biliary atresia ♦♦ Progressive familial intrahepatic cholestasis

Disorders of Bilirubin Metabolism Conjugated Hyperbilirubinemias Dubin–Johnson Syndrome Clinical ♦♦ Dubin–Johnson syndrome is an autosomal recessive disease that results from mutations in ABBC2 located on chromosome 10 at 10q24 −− ABBC2 encodes for multidrug resistance-associated protein 2 (MRP2) ♦♦ Patients may present at any age from infancy to their sixties with intermittent episodes of jaundice −− Episodes are precipitated by trauma, infection, pregnancy, or other stressors ♦♦ The only laboratory finding is conjugated hyperbilirubinemia in the range of 2–5 mg/dL ♦♦ Diagnosis is established by determining urine coproporphyrin levels with isomer fractionation −− The overall value is normal, but isomer I accounts for >80% of the total ♦♦ There are no long-term consequences and no specific therapy exists

Microscopic ♦♦ The liver shows a dark brown, granular pigment in hepatocytes, which is most prominent in the perivenular regions (Figs. 44.58 and 44.59) ♦♦ There is no inflammation, necrosis or fibrosis ♦♦ Immunohistochemistry for MRP2 shows absence of canalicular expression

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Fig. 44.59. Dubin–Johnson syndrome showing a brown, coarsely granular pigment that localizes to the pericanalicular membrane of hepatocytes.

Differential Diagnosis ♦♦ Excessive lipofuscin deposition

Rotor Syndrome ♦♦ Rotor syndrome is an autosomal disorder, which is clinically similar to Dubin–Johnson syndrome −− However, there is no pigment deposition in hepatocytes ♦♦ Patients present with fluctuating jaundice −− There is no other hepatic dysfunction ♦♦ Urinary coproporphyrin excretion is increased, with isomer I comprising <80% of the total ♦♦ The exact etiopathogenesis of Rotor syndrome is not known

Nonneoplastic Hepatobiliary Disease

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Unconjugated Hyperbilirubinemias Crigler–Najjar Syndrome Types I and II, and Gilbert Syndrome Clinical ♦♦ These syndromes are very rare and inherited as autosomal recessive traits −− All result from the inability to conjugate bilirubin due to mutations in UGT1A1 located on chromosome 2 at 2q37 (a) UGT1A1 encodes for the bilirubin-conjugating enzyme, uridine diphosphate glucuronosyl transferase (b) The degree of deficiency varies in the three syndromes and so do the clinical manifestations ♦♦ Type I Crigler–Najjar syndrome is the most severe form of UGT1A1 deficiency as patients lack all enzyme activity −− Presentation is within the first 3 days of birth with persistent jaundice and unconjugated hyperbilirubinemia, which is usually greater than 20  mg/dL and may be as high as 45 mg/dL −− The high bilirubin levels cause kernicterus and severe neurological damage leading to death within the first 2 years of life ♦♦ Type II Crigler–Najjar syndrome also presents with neonatal jaundice but the levels of unconjugated are lower, ranging between 7 and 20 mg/dL −− Levels rise during illness or other stressful events and may cause kernicterus, leading to neurological deficits even in adult patients ♦♦ Patients with Gilbert syndrome have approximately 25% of normal enzyme activity −− They present at puberty with jaundice and unconjugated hyperbilirubinemia ranging from 1 to 6 mg/dL −− These patients do not have any other clinical manifestations ♦♦ Phenobarbitol has no effect on type I Crigler–Najjar but it reduces bilirubin levels by about 30% in type II disease

Microscopic ♦♦ The microscopic features are not prominent, if at all present ♦♦ Minimal bright yellow canalicular and intracellular bile may be present in Crigler–Najjar syndrome (Figs.  44.60 and 44.61) ♦♦ Gilbert syndrome may show mild increase in hepatocyte lipofuscin pigment

Progressive Familial Intrahepatic Cholestasis Clinical ♦♦ The term progressive familial intrahepatic cholestasis (PFIC) is currently used for three autosomal recessive diseases, which are caused by mutations in genes that encode for transporters located on the canalicular membrane of hepatocytes ♦♦ The mutations cause abnormalities of bile formation and bile flow leading to a rapidly progressive biliary cirrhosis

Fig.  44.60. Crigler–Najjar syndrome showing occasional bile canalicular plugs without inflammation, necrosis or fibrosis.

Fig.  44.61. Crigler–Najjar syndrome showing canalicular bile plugs. −− PFIC-1 is caused by mutations in ATP8B1 located on chromosome 18 at 18q21-22, which encodes for a P-type ATPase (a) This is also called ATP8B1 disease or Byler syndrome −− PFIC-2 is caused by mutations in ABCB11 located on chromosome 2 at 2q24, which encodes for the bile salt export pump (BSEP) (a) This is also called ABCB11 disease −− PFIC-3 is caused by a mutations in ABCB4 located on chromosome 7 at 7q21, which encodes for the multidrug resistant protein 3 (a) This is also called ABCB4 disease ♦♦ All three forms of PFIC present with jaundice, pruritis and failure to thrive −− Diarrhea and foul-smelling stools result from fat malabsorption due to impaired bile flow

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♦♦

♦♦ ♦♦

♦♦

♦♦

♦♦

♦♦

−− Hemorrhage due to deficiency of Vitamin K may occur −− Jaundice is more severe and less likely to remit in PFIC-2 than in PFIC-1 −− PFIC-2 progresses more rapidly to cirrhosis than PFIC-1 PFIC-1 is marked by presence of extrahepatic manifestations such as recurrent pancreatitis, chronic respiratory disease, delayed sexual development, and sensorineural deafness PFIC-2 does not share these extrahepatic manifestations PFIC-2 patients have a disproportionately high risk of hepatocellular carcinoma −− This is not shared by patients with PFIC-1 Laboratory findings include conjugated hyperbilirubinemia and elevated serum bile acids in all three forms −− PFIC-1 and PFIC-2 have normal serum gGT values (low in comparison to the degree of hyperbilirubinemia) while serum gGT is elevated in PFIC-3 −− Analysis of bile shows low bile salt concentrations in PFIC-1 and PFIC-2 −− Analysis of bile in PFIC-3 shows low concentrations of phospholipids with elevated bile acid:phospholipid and bile acid:cholesterol ratios Prognosis is very poor in patients with PFIC with death resulting from hepatic failure and portal hypertension within 10 years Therapy consists of antipruritics, supplements of fat-soluble vitamins, and UDCA −− Surgical biliary diversion provides temporary relief −− Liver transplantation offers a definitive therapeutic option (a) However, while it ameliorates the hepatic manifestations in PFIC-1, the extrahepatic manifestations are exacerbated and the allograft itself develops steatosis with varying degrees of fibrosis It should be remembered that PFIC is only one clinical consequence of mutations in the above mentioned genes −− Mutations in ATP8B1 and ABCB11 also cause benign recurrent intrahepatic cholestasis (BRIC) and some cases of intrahepatic cholestasis of pregnancy (ICP) −− Mutations in ABCB4 are now known to cause a variety of other cholestatic diseases including adulthood idiopathic cirrhosis, cholesterol cholelithiasis, intrahepatic cholestasis of pregnancy, and drug-induced cholestasis

Microscopic ♦♦ PFIC-1 −− Shows bland cholestasis with presence of canalicular and hepatocellular bile without accompanying inflammation, necrosis, or ductular reaction −− Fibrosis develops on this background of bland cholestasis −− Electron microscopy shows “granular” bile in contrast to the normal amorphous or filamentous appearance (a) This appearance is highly typical of PFIC-1 (b) It is referred to as “Byler bile” and is not found in other forms of PFIC

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♦♦ PFIC-2 −− Shows features of neonatal hepatitis with marked cholestasis and giant cell changes of hepatocyte −− Bridging fibrosis and cirrhosis develop on this background of neonatal hepatitis ♦♦ PFIC-3 −− Shows cholestasis and mild ductular proliferation, which may mimic biliary obstruction −− Bridging fibrosis and cirrhosis develop on this background

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Alpha-1 antitrypsin deficiency Neonatal giant cell hepatitis Extrahepatic biliary atresia Idiopathic paucity of intrahepatic ducts

Benign Recurrent Intrahepatic Cholestasis Clinical ♦♦ Benign recurrent intrahepatic cholestasis (BRIC) is caused by mutations in ATP8B1 and ABCB11, which also cause PFIC-1 and PFIC-2, respectively −− However, these mutations do not account for all cases of BRIC ♦♦ BRIC is clinically characterized by recurrent episodes of jaundice and pruritus −− The episodes may be triggered by infections, pregnancy, or other factors that stress and decompensate the bile handling apparatus ♦♦ The intervals between episodes vary widely ranging from months to years, and the timing of their onset is unpredictable ♦♦ The word “benign” refers to the nonprogressive nature of this disease −− However, it has become apparent over recent years that some patients may develop fibrosis over variable periods of time but at a rate much slower than PFIC

Microscopic ♦♦ The features are those of bland cholestasis with canalicular and hepatocellular bile, most prominent in the centrilobular regions ♦♦ There is no inflammation, necrosis, ductular reaction, or bile duct damage

Differential Diagnosis ♦♦ Early acute duct obstruction

Cystic Fibrosis Clinical ♦♦ Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene located on chromosome 7 at 7q31, which encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) ♦♦ The incidence is 1:2,000 births and carrier frequency is 5% ♦♦ Liver disease is caused by viscous mucus production which causes plugging of bile ducts leading to obstruction of bile flow

Nonneoplastic Hepatobiliary Disease

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Alpha-1 Antitrypsin Deficiency Clinical

Fig.  44.62. Cystic fibrosis showing cirrhosis with dilated bile ductules containing a pale eosinophilic material.

Fig.  44.63. Cystic fibrosis showing dilated bile ductules containing inspissated, eosinophilic material. −− This leads to fibrosis and cirrhosis over the long-term −− In addition, strictures of the distal common bile duct have also been described ♦♦ Approximately 10% of patients develop cirrhosis by age 25 ♦♦ Death usually results from pulmonary complications

Microscopic ♦♦ The portal tracts are expanded by increased numbers of bile ductules lying at the edges of the portal tracts −− These are characteristically dilated and contain plugs of a light eosinophilic material ♦♦ Portal fibrosis is present which eventually progresses to bridging fibrosis and cirrhosis (Figs. 44.62 and 44.63)

Differential Diagnosis ♦♦ Extrahepatic biliary obstruction

♦♦ Alpha-1 antitrypsin is the major antiprotease in serum −− Its main physiologic function is to inhibit neutrophilic proteases (a) Absence results in unopposed action of neutrophil elastase in the lung leading to breakdown of ­connective tissue and development of emphysema (b) The condition is exacerbated in smokers as components in cigarette smoke cause accumulation of neutrophils in the lung parenchyma −− Alpha-1 antitrypsin is also an acute phase glycoprotein and serum levels are elevated during infections and other inflammatory conditions ♦♦ The enzyme is encoded by the Pi gene located on chromosome 14 −− Proteins coded by both alleles are produced (codominant expression) −− Approximately 95% of the global population is homozygous for the PiM allele (PiMM) and these individuals have normal physiological serum levels of 120–200 mg/dL −− About 100 mutations of the Pi gene are known (a) Deficiency alleles are PiZ, PiS, and the null variants (b) Lowest serum levels are found in PiZZ patients who manifest the “classic” deficiency phenotype * These patients have emphysema at a young age * Accumulation of the abnormal protein in hepatocytes in the form of eosinophilic globules leads to various forms of liver disease * However, the genotype has weak penetrance and the majority of patients never develop liver disease ♦♦ Patients with PiZZ may present at any age −− Alpha-1 antitrypsin deficiency is the most common cause of liver disease in children −− Approximately 10% of neonates present with neonatal jaundice (a) A minority of them progress to cirrhosis while the majority recover −− Patients may also present in late childhood with cirrhosis ♦♦ A second peak occurs in adults in their fifties who present with features of advanced chronic liver disease including cirrhosis −− Men are more often affected than women −− These patients are paradoxically those who have reached adulthood due to absence of significant pulmonary disease ♦♦ The risk or predisposition of heterozygotes (PiMZ) to liver injury is less than that of PiZZ individuals but this phenotype may cause cirrhosis and accentuate the course of other liver diseases ♦♦ Diagnosis is made by decreased levels of the protein in serum and enzyme phenotype analysis by isoelectric focusing

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♦♦ Treatment includes avoidance of smoking as well as replacement enzyme therapy for pulmonary disease −− Therapy of liver disease is symptomatic and supportive −− Liver transplantation offers a viable option for end-stage liver disease

Microscopic ♦♦ Neonatal hepatitis in children is characterized by cholestasis and giant cell transformation of hepatocytes −− Variable degrees of inflammation and ductular reaction are seen −− In some infants, the latter may predominate and be mistaken for biliary atresia −− In others, there may be paucity of intrahepatic bile ducts −− Intracytoplasmic eosinophilic inclusions characteristic of alpha-1 antitrypsin deficiency are not seen in very young children ♦♦ In other age groups, the disease shows mild to moderate chronic portal inflammatory infiltrate, mild-to-moderate ductular reaction, and mild steatosis −− Varying degrees of fibrosis are seen −− Intracytoplasmic eosinophilic inclusions are present in periportal hepatocytes (Fig. 44.64) ♦♦ Heterozygotes show smaller and less numerous cytoplasmic inclusions

Fig.  44.64. Alpha-1 antitrypsin deficiency shows eosinophilic cytoplasmic globules in periportal hepatocytes.

Special Studies ♦♦ PAS stain after enzyme digestion highlights the intracytoplasmic globules (Fig. 44.65) ♦♦ Immunohistochemical staining with specific antibodies provides definitive diagnosis

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Neonatal hepatitis of other causes Extrahepatic biliary atresia Paucity of intrahepatic bile ducts due to other causes Drug- and alcohol-induced liver disease

Genetic Hemochromatosis Clinical ♦♦ Genetic hemochromatosis is an autosomal recessive disease resulting from mutations in the HFE gene located on chromosome 6 at 6p213 −− The exact mechanism whereby this genetic mutation leads to failure of control of iron absorption has not been elucidated ♦♦ Genetic hemochromatosis is a disease of Caucasians, especially people of Celtic and Nordic descent ♦♦ The two common mutations are C282Y in which cysteine is replaced by tyrosine; and H63D in which histidine is replaced by aspartate −− Homozygosity for C282Y is present in 80–90% of patients with typical hemochromatosis −− Compound heterozygotes (C282Y/H63D) make up 5% of cases while approximately 5% of cases have as yet unidentified abnormalities

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Fig. 44.65. Alpha-1 antitrypsin globules stain with PAS and are resistant to digestion by diastase. ♦♦ The incidence of C282Y homozygosity in Caucasians is 0.1%; however, the penetrance is incomplete and only a small minority of homozygotes develop clinical disease −− The major factors that affect expression of the genotype include gender and alcohol consumption −− Genetic defects in other molecules involved in iron metabolism are also presumed to affect phenotypic expression ♦♦ A significant number of patients are identified by abnormal serum iron studies during investigation for other unrelated causes −− Others present with nonspecific complains such as fatigue, arthralgia or clinical signs and symptoms of chronic liver disease or diabetes ♦♦ The diagnosis is based on identifying known mutations −− However, the presence of mutation does not provide information on the presence or degree of iron overload

Nonneoplastic Hepatobiliary Disease

−− The degree of iron overload is estimated by levels of serum iron, serum ferritin, and the amount of iron in liver tissue ♦♦ Universal screening is not cost-effective as the mutation is racially restricted −− Screening is recommended for select racial groups or of family members of the proband ♦♦ Treatment consists of repeated phlebotomy to decrease iron overload followed by maintenance phlebotomy as required −− Serum iron and serum ferritin levels are used to monitor phlebotomy therapy

Microscopic ♦♦ Hemosiderin deposition begins in periportal hepatocytes (zone 1) and with continuing accumulation, gradually extends to involve zones 2 and 1 (Fig. 44.66) −− The iron is deposited along the canalicular membrane of hepatocytes ♦♦ As accumulation continues, iron is also seen in Kupffer cells −− Hepatocytes may undergo necrosis and the iron may be taken up by macrophages (sideronecrosis) −− Extensive iron accumulation is also associated with iron deposition in bile ducts −− Heavy iron deposition ultimately leads to portal fibrosis and even cirrhosis ♦♦ Hemosiderosis is not usually accompanied by an inflammatory infiltrate unless there is concomitant viral hepatitis ♦♦ There is a substantially increased risk of hepatocellular ­carcinoma, which exceeds the risk that can be attributed to cirrhosis alone −− Iron-free foci in an iron overloaded liver are ­preneoplastic lesions and may be associated with hepatocellular ­carcinoma elsewhere in the liver

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−− It also highlights iron-free foci ♦♦ The Masson trichrome stain provides information on the stage of fibrosis

Differential Diagnosis ♦♦ Secondary hemosiderosis from other etiologies such as transfusions, dyserythropoiesis, and hemolysis ♦♦ Alcohol-induced liver disease

Copper Storage Disorders Wilson Disease Clinical

♦♦ The Perls iron stain provides information on the degree of siderosis and the pattern of iron deposition (Fig. 44.67)

♦♦ Wilson disease is an autosomal recessive disorder of copper metabolism, which results in copper accumulation in the liver, cornea, and basal ganglia ♦♦ The mutated gene resides on chromosome 13 at 13q14 and encodes for ATP7B, a copper-transporting adenosine triphosphatase ♦♦ The carrier rate is 1% and the incidence varies geographically from 1 in 30,000 to 1 in 100 ♦♦ The presentation is varied with patients presenting with neurologic manifestations or liver disease −− In most cases, presentation is at 10–15 years of age with signs or symptoms of liver disease ♦♦ Neurologic manifestations occur approximately a decade after presentation of liver disease −− Neurologic symptoms include dystonia, tremors, personality changes, and cognitive impairment (a) They are a result of copper accumulation in the basal ganglia (b) Patients with neurologic manifestations almost ­always have Kayser–Fleischer ring, which are a ­result of copper accumulation within the Descemet membrane of the cornea

Fig. 44.66. Hemochromatosis showing hemosiderin deposition in periportal hepatocytes.

Fig. 44.67. Hemochromatosis showing hemosiderin deposition in periportal hepatocytes (Prussian blue stain).

Special Studies

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−− A rare but well-known presentation is acute liver failure accompanied by hemolysis (a) The hemolysis results from sudden release of ­copper from necrotic hepatocytes (b) The acute necrosis is presumed to be caused by superimposed acute injury such as an infection or an injurious drug (c) This presentation is more common in women ♦♦ Diagnosis is made by a combination of low ceruloplasmin (<20  mg/dL), increased 24-h urinary copper excretion and increased hepatic copper (>250 mg/g dry weight) ♦♦ A high index of suspicion is necessary for diagnosis of Wilson disease −− In young and middle-aged patients, if the liver biopsy shows chronic hepatitis or steatohepatitis and other liver diseases have been excluded, measurement of hepatic copper content is mandatory ♦♦ Therapy consists of chelation of copper by D-penicillamine and/or zinc −− Liver transplantation is a viable therapeutic option in patients without neurologic deficits

Essentials of Anatomic Pathology, 3rd Ed.

Special Studies ♦♦ The rhodanine stain highlights copper as orange-red granules within hepatocytes ♦♦ The orcein stain demonstrates copper-binding protein as dark brown granules

Differential Diagnosis ♦♦ All major chronic liver diseases ♦♦ Drugs (chlorpromazine) ♦♦ Indian childhood cirrhosis

Indian Childhood Cirrhosis Clinical

♦♦ The microscopic features of Wilson disease are not specific and may resemble chronic hepatitis or steatohepatitis ♦♦ Nonspecific inflammatory changes of variable degrees may be seen in the early stages ♦♦ The constellation of microvesicular steatosis, ballooning change, glycogenated nuclei, anisonucleosis, and binucleation is very suggestive of Wilson disease (Figs.  44.68 and 44.69) ♦♦ Cirrhosis with steatosis and chronic inflammation is seen in late stages ♦♦ Copper is variably demonstrable and is predominantly periportal but may be inapparent by special stains in early stages

♦♦ Indian childhood cirrhosis (ICC) is a disease of copper toxicity described in Indian children under 5 years of age due to excess dietary copper ♦♦ ICC was found to occur due to storage of milk in brass or copper containers from which copper was leached by casein in milk ♦♦ A similar disease also occurs sporadically in other parts of the world, especially in rural areas, and is also related to inadvertent excess dietary copper −− In these cases, it is associated with storage of water in copper vessels, copper pipes for delivery of drinking water and excess copper in well water ♦♦ A familial disposition cannot be absolutely ruled out although no genetic defect has as yet been identified ♦♦ Patients usually present when young (1–5 years with peak at 2 years of age) with jaundice and increasing signs and symptoms of liver disease ♦♦ Hepatomegaly is present −− As cirrhosis progresses, the liver assumes a very hard texture ♦♦ Alpha fetoprotein levels are elevated from birth ♦♦ Death occurs within 1–2 years of diagnosis, if untreated

Fig. 44.68. Wilson disease showing macro- and microvesicular fibrosis, glycogenated nuclei, anisonucleosis, and binucleation.

Fig.  44.69. Wilson disease showing scattered microvesicular steatosis, anisonucleosis, and binucleation of hepatocytes.

Microscopic

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Nonneoplastic Hepatobiliary Disease

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♦♦ Treatment consists of eliminating copper from the diet and chelation with penicillamine −− Regression of hepatic disease follows chelation

Differential Diagnosis

Microscopic

Amyloidosis Clinical

♦♦ Microscopically, there is extensive ballooning change of hepatocytes with extensive Mallory body formation (Fig. 44.70) ♦♦ Extensive fibrosis and micronodular cirrhosis occur with continued copper accumulation and progressive live injury ♦♦ There is minimal to mild portal mononuclear inflammatory infiltrate ♦♦ Cellular and canalicular cholestasis may be seen ♦♦ Increased copper and copper-binding protein can be demonstrated within hepatocytes (Fig. 44.71)

♦♦ Metabolic defects with fibrosis/cirrhosis ♦♦ Alpha-1 antitrypsin deficiency

♦♦ Systemic amyloidosis in present in 0.5% of cases at autopsy and approximately 50% show liver involvement ♦♦ Amyloidosis occurs most frequently secondary to systemic diseases such as multiple myeloma, connective tissue diseases, and long-standing infections −− Familial amyloidosis, also called primary amyloidosis, is rare and results from genetic mutations that produce amyloidogenic proteins −− The liver is often the site of production of these abnormal proteins and liver transplantation is the definitive therapy in these cases ♦♦ The commonest hepatic presentation of systemic amyloidosis is with hepatomegaly, which is most often asymptomatic but may be associated with right upper quadrant pain or discomfort ♦♦ The prognosis depends upon the course of the underlying disease and the extent of liver involvement

Microscopic

Fig.  44.70. Indian childhood cirrhosis showing micronodular cirrhosis without any regenerative activity in the nodules.

Fig. 44.71. Indian childhood cirrhosis showing accumulation of coarse granules of copper-associated protein (Orcein stain).

♦♦ Amyloid appears as an amorphous, lightly eosinophilic extracellular material ♦♦ There are two major patterns of amyloid deposition, which are not mutually exclusive −− Amyloid may either deposit in a perivascular pattern or in a perisinusoidal pattern −− With the latter, deposition begins in space of Disse (Fig. 44.72) ♦♦ As amyloid accumulates, it compresses the adjoining hepatocytes causing atrophy of the liver cell plates

Fig.  44.72. Amyloid appears as an amorphous, eosinophilic material that deposits in the space of Disse and eventually causes atrophy of the hepatic plates.

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Special Studies ♦♦ The Congo red stain confirms the presence of amyloid which appears brick-red in bright-field microscopy and demonstrates apple-green birefringence under polarized light ♦♦ Immunohistochemistry with specific antibodies such as those against kappa light chain, lambda light chain, amyloid-associated protein, transthyretin, and beta-2 microglobulin help to identify the abnormal protein and the specific underlying disease

Differential Diagnosis ♦♦ Collagen or fibrin deposition −− These do not stain with Congo red

Porphyrias Porphyria Cutanea Tarda Clinical ♦♦ Porphyria cutanea tarda (PCT) results from a deficiency of uroporphyrinogen decarboxylase ♦♦ It occurs in two forms, a “sporadic” form called PCT type I and an autosomal dominant inherited form called PCT II −− In the sporadic form, the enzyme deficiency occurs only in the liver while the deficiency exists in all tissues in the inherited form ♦♦ Inherited PCT is caused by mutations in the UROD gene encoding for uroporphyrinogen decarboxylase located on chromosome 6 at 6p21 −− The mutation results in enzyme levels, which are approximately 50% of normal ♦♦ The incidence is estimated to be 5:100,000 and the disease manifests in adulthood ♦♦ There is a strong association with chronic alcoholic liver disease in 90% of cases −− There is also an association with one or more of the mutations associated with hemochromatosis ♦♦ Patients present with light-sensitive dermatitis that usually occurs on the face, hands, and ears −− Dark urine likened to the color of port-wine or tea results from the excretion of uroporphyrin in urine

Essentials of Anatomic Pathology, 3rd Ed.

Erythropoietic Protoporphyria Clinical ♦♦ Erythropoietic protoporphyria (EPP) results from a deficiency of ferrochelatase, an enzyme that catalyzes the insertion of iron into protoporphyrin, the last step in heme biosynthesis −− This results in the accumulation of protoporphyrin in plasma, erythrocytes and in some patients, in the liver ♦♦ The inheritance is complex and is thought to be autosomal dominant with variable penetrance and in some cases, it is thought to be autosomal recessive −− Variable penetrance is explained by the presence of a mutation in one allele and the inheritance of a low-expression second allele in patients who have overt disease, while patients who are asymptomatic have a mutation in one allele while the second allele is normally expressed ♦♦ Patients present with painful light-sensitive dermatitis in childhood −− Later presentation with photosensitivity is also known ♦♦ Liver disease occurs in a minority of patients and presents many years after the dermatitis, usually after the age of 30 years, although presentation in teenage years is known −− Males are affected twice as often as females −− Patients present with right upper quadrant pain and/or jaundice −− Liver disease may progress to cirrhosis −− Macroscopically the liver appears black in color

Microscopic ♦♦ There is deposition of a dark brown pigment in bile canaliculi, bile ducts, Kupffer cells, and connective tissue (Fig. 44.73) ♦♦ This pigment shows orange-red autofluorescence on frozen sections −− When paraffin-embedded sections are viewed under polarized light, the crystals show red birefringence with “Maltese” cross profiles (Fig. 44.74)

Microscopic ♦♦ The diagnosis is made by the presence of uroporphyrin deposits in hepatocytes, which appear as needle-shaped birefringent crystals under polarized light ♦♦ Most patients are cirrhotic and have increased iron in the liver −− Macrovesicular steatosis is present in 50% of patients

Special Studies ♦♦ A Perls iron stain highlights the iron accumulation −− Polarized light demonstrates the characteristic needleshaped crystals

Differential Diagnosis ♦♦ Genetic hemochromatosis ♦♦ Chronic alcoholic liver disease

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Fig.  44.73. Erythropoietic protoporphyria showing deposition of a dark brown pigment.

Nonneoplastic Hepatobiliary Disease

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Fig.  44.75. Sickle cell disease showing dilated and congested sinusoids due to accumulation of sickled red blood cells.

Fig. 44.74. The pigment of erythropoietic protoporphyria is birefringent under polarized light and shows Maltese cross profiles. ♦♦ There may be variable degrees of chronic inflammation and necrosis ♦♦ Fibrosis and cirrhosis are seen

Differential Diagnosis ♦♦ Other cholestatic diseases

Sickle Cell Anemia Clinical ♦♦ The liver is involved in 2% of patients with sickle cell anemia by a variety of pathogenic mechanisms −− The commonest form of injury is ischemic necrosis due to sickling of erythrocytes in the sinusoids (a) Sickling of erythrocytes may also lead to obstruction of the hepatic venous outflow −− Approximately 50% of patients have gallstones and changes of biliary obstruction may occur −− Hyperbilirubinemia occurs due to hemolysis, which also leads to hemosiderin deposition within the liver ♦♦ The overall prognosis is not related to liver disease

Microscopic ♦♦ The sinusoids may appear dilated and congested containing clumps of sickled erythrocytes (Figs. 44.75 and 44.76) −− There may be necrosis of perivenular hepatocytes

Fig. 44.76. Sickled cell red in sinusoids. −− Sickled erythrocytes may be seen in Kupffer cells ♦♦ Hemosiderin deposition of varying degrees is present in Kupffer cells −− When severe, iron may also be deposited in hepatocytes ♦♦ Extramedullary hematopoiesis secondary to hemolytic anemia is present in approximately 50% of all cases

Differential Diagnosis ♦♦ Disseminated intravascular coagulation ♦♦ Passive congestion ♦♦ Budd–Chiari syndrome

Storage Disorders ♦♦ Glucocerebrosidoses – the two diseases with the most characteristics microscopic appearances are Gaucher disease and Niemann–Pick disease −− Gaucher disease

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(a) Shows storage cells with a striated appearance, sometimes referred to as “wrinkled tissue paper” appearance (Fig. 44.77) (b) These cells are highlighted by the PAS stain after enzyme digestion (Fig. 44.78) −− Niemann–Pick disease (a) Shows storage cells with a lightly basophilic foamy appearance (Fig. 44.79) (b) These cells are also highlighted by a PAS stain following enzyme digestion (Fig. 44.80) ♦♦ Glycogen storage diseases – examples include −− von Gierke disease, which is characterized microscopically by microvesicular steatosis, cirrhosis, hepatocellular adenoma, and carcinoma (Figs. 44.81 and 44.82) Fig. 44.79. Niemann–Pick disease showing accumulation of the abnormal glucocerebroside in both hepatocytes and Kupffer cells; the storage cells have a foamy appearance.

Fig. 44.77. Gaucher disease shows deposition of the abnormal glucocerebroside in Kupffer cells that demonstrate a striated “wrinkled tissue paper” appearance. Fig. 44.80. The storage cells of Niemann–Pick disease show a faintly basophilic appearance on PAS stain.

Fig. 44.78. The storage cells of Gaucher disease are highlighted by PAS stain following diastase digestion.

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Fig. 44.81. Von Gierke disease showing an enlarged, pale yellow liver with a hepatocellular carcinoma.

Nonneoplastic Hepatobiliary Disease

Fig.  44.82. Von Gierke disease showing macro- and microvesicular steatosis.

♦♦

♦♦

♦♦ ♦♦

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Fig. 44.83. Pompe disease, a glycogen storage disease showing extensive microvesicular steatosis.

−− Pompe disease, which shows cytoplasmic glycogen deposits (Fig. 44.83) −− Cirrhosis or significant fibrosis occur in types III and IV Mucopolysaccharidoses, e.g., Hurler disease – small lipid droplets are seen in hepatocytes (Fig.  44.84), Kupffer, and Ito cells; fibrosis is present Lipid and cholesterol storage disorders – small fat droplets are seen in hepatocytes, foamy macrophages with cholesterol deposits Glycosphingolipidoses, e.g., Fabry – hypertrophy of portal macrophages and Kupffer cells is seen Gangliosidoses, e.g., Tay-Sachs – laminated inclusions are seen in hepatocytes by electron microscopy Fig. 44.84. Hurler disease, a mucopolysaccharidoses, showing extensive vacuolization of hepatocytes.

MISCELLANEOUS CONDITIONS Autoimmune Hepatitis Clinical ♦♦ Autoimmune hepatitis occurs in young to middle-aged females who usually present with jaundice and hepato­ splenomegaly ♦♦ About half of all patients have other autoimmune diseases −− Some patients may have concomitant primary biliary ­cirrhosis or primary sclerosing cholangitis (overlap syndrome) ♦♦ Serum IgG is elevated

♦♦ Autoantibodies are present in serum, including ANA (antinuclear antibody), SMA (smooth muscle antibody), antiLKM (liver kidney microsomal), anti-LMA (liver membrane antibody), anti-LSP (liver-specific lipoprotein) −− These autoantibodies are sensitive, but not specific markers of autoimmune hepatitis −− AMA (anti-mitochondrial antibodies) are not seen in high titers unless there is overlap with primary biliary cirrhosis ♦♦ Corticosteroids form the mainstay of therapy

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♦♦ Prognosis is good in patients who respond to immunosuppressive therapy

Microscopic ♦♦ Microscopically, the most prominent feature is portal inflammation with prominent plasma cells −− Plasma cells may not be present in all cases of autoimmune hepatitis −− Lymphocytes, including lymphoid aggregates, may be the only cell type in a significant number of cases ♦♦ Severe interface hepatitis by a lymphoplasmacytic infiltrate is the hallmark of untreated autoimmune disease (Figs. 44.85–44.87) ♦♦ Lobular inflammation accompanies the periportal inflam­ mation Fig.  44.87. Autoimmune hepatitis showing an inflammatory infiltrate rich in plasma cells. −− It is variable in severity and in some patients there may be confluent areas of necrosis (collapse) ♦♦ Inflammation recedes with successful immunosuppression and biopsies in such patients may show minimal inflammation, if any at all ♦♦ Varying degrees of portal fibrosis may be seen −− Some patients may have significant fibrosis at presentation −− Disease that is inadequately treated or that is partially responsive may ultimately lead to cirrhosis

Special Studies ♦♦ Serum autoantibody assays

Differential Diagnosis Fig.  44.85. Autoimmune hepatitis showing severe interface activity.

♦♦ Viral hepatitis ♦♦ Drug-induced hepatitis

Granulomatous Liver Disease General Features

Fig. 44.86. Autoimmune hepatitis showing lymphoid aggregates in portal tracts.

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♦♦ Granulomas are present in approximately 10% of all liver biopsy specimens ♦♦ They are associated with a variety of causes including ­systemic diseases (70%), primary liver diseases (5%), and unknown etiologies (25%) −− Tuberculosis and sarcoidosis are the most common causes of liver granulomas worldwide −− Other associated conditions include fungal infections, schistosomiasis, hypersensitivity reactions to drugs, foreign body material in IV-drug users, and primary biliary cirrhosis ♦♦ Microscopically, the granulomas are composed of a collection of epithelioid macrophages with variable number of multinucleated giant cells −− They may be well-defined or poorly formed −− They may be necrotizing or nonnecrotizing

Nonneoplastic Hepatobiliary Disease

Fig.  44.88. Hepatic sarcoidosis showing large, nonnecrotizing granulomas without prominent lymphocytic inflammation (“naked granulomas”) in portal and periportal areas.

−− Other inflammatory cells may be present in variable numbers ♦♦ Lipogranulomas contain lipid vacuoles surrounded by epithelioid cells admixed with other inflammatory cells ♦♦ Fibrin ring granulomas consist of a central lipid vacuole surrounded by a fibrin ring and inflammatory cells

Sarcoidosis Clinical ♦♦ Liver granulomas occur in 60–90% of all cases of systemic sarcoidosis; however, most patients do not show clinical manifestations of liver disease ♦♦ Asymptomatic elevations in liver tests also occur in a significant number of patients ♦♦ Primary presentation with liver disease is rare but well known −− These patients usually have asymptomatic pulmonary and lymph node involvement ♦♦ Symptomatic liver disease may present as a cholestatic syndrome resembling primary biliary cirrhosis or primary sclerosing cholangitis; or with signs and symptoms of portal hypertension −− Rare presentations include the Budd–Chiari syndrome and extrahepatic biliary obstruction due to compression of the hepatic veins or bile ducts by enlarged lymph nodes ♦♦ Prognosis is usually determined by the pulmonary disease

Microscopic ♦♦ Microscopically, nonnecrotizing epithelioid granulomas, which often coalesce to form large masses, are seen ♦♦ The granulomas are usually located in the portal and periportal regions, but may also be lobular (Fig. 44.88) ♦♦ The granulomas contain multinucleated giant cells with asteroid bodies (Fig. 44.89)

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Fig. 44.89. Hepatic sarcoidosis showing an asteroid body within a giant cell.

♦♦ They are usually not surrounded by a lymphocytic infiltrate (“naked granulomas”) ♦♦ The granulomas fibrose as they age ♦♦ The granulomas may cause destruction and loss of interlobular bile ducts

Special Studies ♦♦ Masson trichrome stain highlights the degree of fibrosis ♦ ♦ Ziehl–Neelsen and Grocott methenamine silver exclude infections as the underlying cause for the granulomas ♦♦ Reticulin stain shows the granulomas to be rich in reticulin fibers

Differential Diagnosis ♦♦ Granulomas of other causes (tuberculosis, drug-induced) ♦♦ Primary biliary cirrhosis

Inflammatory Bowel Disease ♦♦ Approximately 50% of patients with chronic ulcerative colitis or Crohn disease exhibit hepatic dysfunction of varying degrees, most of which is not clinically significant −− Nonspecific reactive changes with mild elevations in serum LFTs and asymptomatic clinical course represent the majority of cases ♦♦ Clinically significant liver disease occurs in 5% of patients and is most often due to primary sclerosing cholangitis, which may progress to cirrhosis −− Colon resection for inflammatory bowel disease does not influence the course of primary sclerosing cholangitis −− Cholangiocarcinoma may complicate sclerosing cholangitis in patients with ulcerative colitis ♦♦ Autoimmune hepatitis may be associated in 1–2% of all cases of inflammatory bowel disease

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Neonatal Giant Cell Hepatitis Clinical ♦♦ Neonatal giant cell hepatitis refers to an injury pattern seen in neonates with a wide variety of liver diseases −− The most frequently associated disorder is alpha-1 antitrypsin deficiency −− Numerous other metabolic, infectious and inherited ­diseases can produce a similar clinical and microscopic picture ♦♦ Patients present with conjugated hyperbilirubinemia and signs and symptoms which reflect the underlying disease −− The biliary tree is usually normal on imaging ♦♦ The overall prognosis is variable and depends on the underlying cause

Microscopic ♦♦ The microscopic pattern is one of cholestasis with associated hepatocellular damage ♦♦ The hallmark is syncytial giant cell transformation of hepatocytes, which are present in a diffuse distribution −− They are accompanied by lobular disarray and portal and lobular inflammatory infiltrate (Fig. 44.90) −− The giant cells are thought to reflect hepatocyte cell fusion and/or mitotic inhibition ♦♦ Varying degrees of canalicular and cellular cholestasis are found −− There may be mild bile ductular reaction (a) Although a few multinucleated giant cells may be present, extrahepatic biliary atresia does not produce the classical findings of giant cell hepatitis (b) The portal tract changes in biliary atresia overshadow those in the lobules ♦♦ Varying degrees of extramedullary hemopoiesis is usually present

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Viral inclusions when present provide a clue to the etiology

Special Studies ♦♦ Immunohistochemical stains and/or PAS-diastase to rule out alpha-1 antitrypsin deficiency

Differential Diagnosis ♦♦ Extrahepatic biliary atresia ♦♦ Alpha-1 antitrypsin deficiency

Reye Syndrome Clinical ♦♦ Reye syndrome, described in 1963, was reported worldwide in children with a history of influenza or varicella who had received aspirin −− The disease is rarely seen nowadays due to avoidance of salicylates in young children −− A Reye-like syndrome may, however, occur due to other metabolic diseases, especially those related to mitochondrial and energy utilization pathways ♦♦ Reye syndrome is characterized by acute onset of encephalopathy and diffuse microvesicular steatosis in the liver −− Other organs may also contain fat ♦♦ Patients present with vomiting, lethargy, altered mental status, and hypoglycemia −− The neurological impairment progresses to seizures and coma −− Patients do not have jaundice, hepatomegaly, or spleno­ megaly ♦♦ The liver lesion is reversible with adequate supportive therapy ♦♦ Mortality results from cerebral edema

Microscopic ♦♦ There is extensive and diffuse microvesicular steatosis in hepatocytes −− This is not accompanied by inflammation −− Extensive necrosis is unusual (a) Spotty necrosis and rarely periportal necrosis may occur −− Significant cholestasis is not seen ♦♦ Microvesicular fat also accumulates in proximal tubules of the kidney, in myocardium, and in skeletal muscle ♦♦ Electron microscopy shows marked changes in mitochondria, which appear enlarged and misshapen −− The crista are attenuated; the matrix appears lucent and dense bodies are reduced in number −− The peroxisomes appear flocculent

Special Studies Fig. 44.90. Neonatal hepatitis showing multinucleated syncytial giant hepatocytes.

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♦♦ Fat stains ♦♦ Electron microscopy

Nonneoplastic Hepatobiliary Disease

Differential Diagnosis ♦♦ Metabolic diseases affecting mitochondrial and energy utilization pathways ♦♦ Drugs/toxins

44-55

♦♦ Vasospasms and/or disseminated intravascular coagulation are the initiating events ♦♦ Treatment strategies include supportive care and termination of pregnancy

Microscopic

Toxemia of Pregnancy Clinical ♦♦ Toxemia occurs in the third trimester and is responsible for 5% of jaundice in pregnancy

♦♦ The distinctive lesion which occurs in severe cases is hemorrhagic ischemic necrosis in the periportal regions ♦♦ This is accompanied by fibrin deposition along sinusoids in these areas and fibrin thrombi in portal veins

DISORDERS OF THE GALLBLADDER Acute Cholecystitis ♦♦ The most common cause of acute cholecystitis is obstruction of the cystic duct or Hartmann pouch by a gallstone leading to secondary bacterial infection −− Rarely occlusion may occur due to a neoplasm ♦♦ Cholecystitis may also occur in the absence of stones after trauma, burns, or major surgery (acalculous cholecystitis) −− Acalculous cholecystitis may also complicate hemolysis, typhoid fever, brucellosis, or pancreatitis ♦♦ The usual presentation is with biliary colic

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

−− Continuous pain, vomiting, fever, and mild jaundice are other presenting manifestations −− Elderly patients may be pain-free and afebrile at presentation Laboratory tests provide evidence of an inflammatory process Liver tests may be mildly elevated Diagnosis is established by imaging studies Treatment includes antibiotics and semielective cholecystectomy after 2–3 days of medical treatment Complications of untreated or long-standing acute cholecystitis include empyema, gangrene, abscess, and peritonitis

Chronic Cholecystitis ♦♦ Chronic cholecystitis is most commonly associated with stones in the gall bladder ♦♦ There is poor correlation between clinical features and pathologic findings ♦♦ The gallbladder wall is typically thickened; the mucosal surface becomes flattened and may ulcerate ♦♦ Microscopically, fibrosis, variable chronic inflammatory infiltrate and mucosal diverticula (Rokitansky–Aschoff sinuses) are usually present −− Various reactive and hyperplastic mucosal changes may develop; several polyps and tumor-like conditions can be seen −− Extensive wall calcifications lead to a “porcelain gallbladder”

♦♦ Patients experience episodes of biliary colic with sudden onset of pain (which is not colicky despite its name) after certain meals ♦♦ Oral cholecystography and ultrasound are diagnostic −− Ultrasound can detect stones 1–3 mm in size and is more sensitive ♦♦ Treatment consists of pain relief during acute episodes, ­followed by elective cholecystectomy

Cholelithiasis ♦♦ Cholelithiasis is the most common disorder of the biliary system −− Only 20% of patients with gallstones develop symptoms ♦♦ Although of global occurrence, the prevalence of gallstones varies considerably suggesting the combined influence of genetic predisposition, prevalence of hemolytic diseases, and differences in lifestyle −− They are rare in Africa and among Eskimos but common in Western countries −− There is a very high incidence among American Pima Indians ♦♦ The incidence of gallstones increases with age −− Females are two to three times more often affected than males −− Risk factors include obesity, high calorie diet, and longterm parenteral nutrition ♦♦ Gallstones are usually designated as cholesterol stones, mixed stones, or pigment stones (Fig. 44.91) −− However, there is a continuous spectrum of stone composition and most stones are mixed (a) Only 20% of stones are either pure cholesterol or pure pigmented stones (b) 10–20% of stones contain enough calcium to be radiopaque ♦♦ Pigment stones arise when excess unconjugated bilirubin leads to precipitation of calcium bilirubinate −− They are especially common in the Far East and have an equal incidence in men and women

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Fig.  44.91. Large faceted gallstones in a patient with cholelithiasis.

♦♦ ♦♦

♦♦

♦♦

−− They are associated with hemolytic anemia, cirrhosis, and cholangitis but also occur in the absence of known risk factors Gallstones are found in most patients with carcinoma of the gallbladder and in 50% of patients with acute pancreatitis Complications of gallstones include biliary colic, acute cholecystitis, acute pancreatitis, and biliary obstruction −− Rarer complications include carcinoma of the gallbladder, fistula formation, and gallstone ileus Dissolution therapy is only indicated in patients with small (<1.5 cm), cholesterol-rich stones −− Chenodeoxycholic acid is most widely used −− Stone formation recurs on cessation of therapy Cholecystectomy offers definite cure in symptomatic patients

Choledocholithiasis ♦♦ Choledocholithiasis (stones in the bile ducts) occur in 10% of patients who have gallbladder stones −− The incidence increases with age

♦♦ In most cases, the stones have migrated from the gallbladder to the bile duct where they increase in size −− Primary bile duct stones are rarer and typically associated with partial biliary obstruction due to strictures (a) These are usually single, ovoid, soft, and conform to the shape of the bile duct ♦♦ Patients present with episodes of obstructive jaundice or pancreatitis or classic Charcot triad of pain, obstructive jaundice, and fever −− There may be recurrent episodes of acute cholangitis and septicemia may occur ♦♦ Changes secondary to obstruction and infection may develop in the liver depending on the degree of obstruction, time present, and amount of biliary infection ♦♦ Diagnosis is established by ultrasound and/or ERCP ♦♦ The treatment of choice is ERCP-based stone extraction or cholecystectomy with bile duct exploration ♦♦ Cholecystectomy does not cure symptoms

Postcholecystectomy Syndrome ♦♦ Postcholecystectomy syndrome describes recurrent pain or discomfort in the upper abdomen following cholecystectomy −− The syndrome occurs in approximately 30% of patients following cholecystectomy (a) 2–5% of patients have severe symptoms ♦♦ Management consists of identifying and treating known causes related to −− Extrabiliary pathology including reflux esophagitis, peptic ulceration, chronic pancreatitis, irritable colon, and functional pain −− Biliary tract such as retained common bile duct stones and biliary stricture ♦♦ Suspected causes include long cystic duct remnant, papillary stenosis, adhesions, and traumatic neuromas, spasm of sphincter of Oddi ♦♦ When no cause is identified, treatment is uncertain and includes debatable procedures such as sphincterotomy −− Only 50% of patients benefit from surgical intervention

SUGGESTED READING Abdalian R, Heathcote EJ. Sclerosing cholangitis: a focus on secondary causes. Hepatology 2006;44:1063–1074.

Burt AD. Primary biliary cirrhosis and other ductopenic diseases. Clin Liver Dis 2002;6:363–380, vi.

Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med 2009;11:307–313.

Carpenter HA, Czaja AJ. The role of histologic evaluation in the diagnosis and management of autoimmune hepatitis and its variants. Clin Liver Dis 2002;6:685–705.

Baalmann-Mangano L, Brunt EM. Evaluating liver disease in chronic hepatitis C – the role of the liver biopsy. Med Gen Med 2003;5:21. Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995;19:1409–1417. Bhardwaj SS, Saxena R, Kwo PY. Granulomatous liver disease. Curr Gastroenterol Rep 2009;11:42–49. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3–20.

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Chevaliez S, Pawlotsky JM. Hepatitis C virus: virology, diagnosis and management of antiviral therapy. World J Gastroenterol 2007;13:2461–2466. Czaja AJ. Autoimmune liver disease. Curr Opin Gastroenterol 2009;25:215–222. Denk H, Scheuer PJ, Baptista A, et al. Guidelines for the diagnosis and interpretation of hepatic granulomas. Histopathology 1994;25:209–218.

Nonneoplastic Hepatobiliary Disease

Devaney K, Goodman ZD, Epstein MS, Zimmerman HJ, Ishak KG. Hepatic sarcoidosis. Clinicopathologic features in 100 patients. Am J Surg Pathol 1993;17:1272–1280. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Clin Chem 2000;46: 2050–2068. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem 2000;46:2027–2049. Durazzo M, Premoli A, Fagoonee S, Pellicano R. Overlap syndromes of autoimmune hepatitis: what is known so far. Dig Dis Sci 2003;48:423–430. Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. Am J Gastroenterol 2008;103:2136–2141; quiz 42. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47–58. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374. Gitlin JD. Wilson disease. Gastroenterology 2003;125:1868–1877. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol 2007;47:598–607. Heathcote J. Variant syndromes of autoimmune hepatitis. Clin Liver Dis 2002;6:669–684. Hubscher SG. Iron overload, inflammation and fibrosis in genetic haemochromatosis. J Hepatol 2003;38:521–525. Ishak KG. Inherited metabolic diseases of the liver. Clin Liver Dis 2002;6:455–479, viii. Ishak KG, Zimmerman HJ. Morphologic spectrum of drug-induced hepatic disease. Gastroenterol Clin North Am 1995;24:759–786. Kahi CJ, Saxena R, Temkit M, et al. Hepatobiliary disease in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:117–123. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313–1321. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet 2003;362:2089–2094. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology 2006;44:746–764. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349:474–485. Lefkowitch JH. Recent developments in liver pathology. Hum Pathol 2009;40:445–455. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology 2009;50:291–308. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–662.

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Marion AW, Baker AJ, Dhawan A. Fatty liver disease in children. Arch Dis Child 2004;89:648–652. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55. Mendes FD, Lindor KD. Primary sclerosing cholangitis. Clin Liver Dis 2004;8:195–211. Pachkoria K, Lucena MI, Molokhia M, et  al. Genetic and molecular factors in drug-induced liver injury: a review. Curr Drug Saf 2007;2: 97–112. Perlmutter DH. Liver injury in alpha 1-antitrypsin deficiency. Clin Liver Dis 2000;4:387–408, vi. Pietrangelo A. Hereditary hemochromatosis–a new look at an old disease. N Engl J Med 2004;350:2383–2397. Pietrangelo A. Inherited metabolic disease of the liver. Curr Opin Gastroenterol 2009;25:209–214. Pittler MH, Ernst E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003;18: 451–471. Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003;362:2095–2100. Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009;62:481–492. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089–2111. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49:1017–1044. Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003;7:453–473. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007;11:577–596, vii. Seeff LB. The history of the “natural history” of hepatitis C (1968-2009). Liver Int 2009;29 Suppl 1:89–99. Selmi C, Invernizzi P, Keeffe EB, et al. Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 2004;38:264–271. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007;11: 477–505, v. Sherman KE. HCV and HIV: a tale of two viruses. Rev Gastroenterol Disord 2004;4 Suppl 1:S48–S54. Sherman KE, Peters M, Koziel MJ. HIV and liver disease forum: conference proceedings. Hepatology 2007;45:1566–1577. Smyth C, Kelleher D, Keeling PW. Hepatic manifestations of gastrointestinal diseases. Inflammatory bowel disease, celiac disease, and Whipple’s disease. Clin Liver Dis 2002;6:1013–1032. Theise ND. Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach. Mod Pathol 2007;20 Suppl 1:S3–S14. Vergani D, Choudhuri K, Bogdanos DP, Mieli-Vergani G. Pathogenesis of autoimmune hepatitis. Clin Liver Dis 2002;6:727–737.

Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758–2769.

Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2009;49:306–317.

Mani H, Kleiner DE. Liver biopsy findings in chronic hepatitis B. Hepatology 2009;49:S61–S71.

Zafrani ES. Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch 2004;444:3–12.

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45 Neoplasms of the Liver and Biliary System Romil Saxena, mbbs, frcpath

Contents

I. Tumors of the Liver and Intrahepatic Bile Ducts..........................................45-2

Benign Epithelial Tumors................................45-2 Hepatocellular Adenoma.......................45-2 Bile Duct Adenoma................................45-2 Mucinous Cystic Neoplasm...................45-4 Intraductal Papillary Neoplasm...........45-6 Malignant Epithelial Tumors..........................45-6 Hepatocellular Carcinoma....................45-6 Fibrolamellar Carcinoma......................45-8 Hepatoblastoma....................................45-10 Cholangiocarcinoma............................45-12 Intraductal Papillary Neoplasm with Invasive Carcinoma................45-14 Benign Mesenchymal Tumors.......................45-14 Hemangioma.........................................45-14 Infantile Hemangioma.........................45-15 Angiomyolipoma..................................45-15 Malignant Mesenchymal Tumors.................45-16 Angiosarcoma.......................................45-16 Epithelioid Hemangioendothelioma..................45-17 Undifferentiated Sarcoma...................45-18 Embryonal Rhabdomyosarcoma........45-19 Hematopoietic Neoplasms.............................45-19 Primary Malignant Lymphoma..........45-19 Secondary Hematopoietic Neoplasms........................................45-19 Metastases.......................................................45-19 Tumor-like Lesions.........................................45-19

Cysts......................................................45-19 Focal Nodular Hyperplasia.................45-19 Nodular Regenerative Hyperplasia....45-20 Mesenchymal Hamartoma..................45-21 Biliary Hamartoma (von Meyenburg Complex).............45-22 Peliosis Hepatis.....................................45-22 Inflammatory Pseudotumor................45-22

II. Tumors of the Gallbladder and Extrahepatic Bile Ducts....................45-23 Benign Epithelial Tumors and Lesions.........45-23 Polyps....................................................45-23 Hyperplasia and Metaplasia...............45-24 Papillary Hyperplasia..........................45-24 Adenoma...............................................45-24 Malignant Epithelial Tumors........................45-24 Carcinoma of the Gallbladder............45-24 Carcinoma of the Extrahepatic Bile Ducts.........................................45-25 Miscellaneous Malignant Epithelial Tumors............................45-25 Benign and Malignant Nonepithelial Tumors........................................................45-25 Tumor-like Lesions.........................................45-25 Adenomyoma........................................45-25

III. Tnm Classification of Liver Tumors (2010 Revision)................................45-25 IV. Suggested Reading...........................45-26

L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_45, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Essentials of Anatomic Pathology, 3rd Ed.

TUMORS OF THE LIVER AND INTRAHEPATIC BILE DUCTS Benign Epithelial Tumors Hepatocellular Adenoma Clinical ♦♦ Hepatocellular adenoma (HCA) occurs most commonly in women of reproductive age group taking oral contraceptive steroids with a causal link related to dose, duration of use, and patient’s age −− There is an absolute risk of <3 per 100,000 oral contraceptive users per year for women under 30 years of age ♦♦ HCA also occurs in adult men and children and is associated with a variety of other factors such treatment with anabolic/ androgenic steroids, glycogenosis type 1, familial adenomatosis polyposis, maturity-onset diabetes of the young (MODY3), and obesity ♦♦ Although initially considered a homogenous group, recent molecular investigations have delineated four types of HCA with distinct clinical, morphological, and molecular characteristics (Table 45.1) ♦♦ Spontaneous regression after discontinuation of use drug is rare, as are instances of malignant transformation −− Malignant transformation is most likely to occur in the subgroup of tumors with beta-catenin mutations (Table 45.1) ♦♦ Patients may be asymptomatic or present with episodic right upper quadrant pain and discomfort −− Rupture may lead to severe abdominal pain, hemorrhage, and shock ♦♦ The tumor does not produce alpha fetoprotein and elevated levels are not found in serum ♦♦ Treatment consists of surgical resection

♦♦

♦♦ ♦♦ ♦♦

♦♦

−− The hepatic plates are separated by endothelial-lined sinusoids, which may not be conspicuous (Figs. 45.1 and 45.2) −− The stroma is rich in reticulin fibers which surround individual hepatocytes (Fig. 45.3) −− Pseudoacinar (pseudoglandular) structures may be seen in beta-catenin mutated HCA The tumor cells are generally larger than hepatocytes and have uniform nuclei −− Nuclear pleomorphism may be seen in beta-catenin mutated HCA −− The cytoplasm may be pale or clear (a) Steatosis is a common finding in adenomas with HNF-1 alpha mutations −− Mitoses are absent in HCA Bile may be present as cytoplasmic droplets or plugs in distended canaliculi Thick-walled arterioles lying randomly within the tumor are a characteristic feature of HCA (Fig. 45.2) Sinusoidal dilatation and peliosis are a common finding −− Areas of telangiectasia are particularly common in the telangiectatic/inflammatory subtype Rare features include epithelioid and giant cell granulomas, steatohepatitic, and extramedullary hematopoiesis

Immunohistochemistry ♦♦ HCA with mutations in HNF-1 alpha show loss of staining for liver fatty acid-binding protein (LFABP) ♦♦ Telangiectatic/inflammatory HCA show staining with serum amyloid A (SAA) and C-reactive protein (CRP)

Macroscopic

Differential Diagnosis

♦♦ Macroscopically, HCA is usually solitary and occasionally pedunculated −− The tumors may become very large, and assume sizes up to 30 cm −− The tumor appears as a bulging mass with dilated blood vessels coursing on its surface ♦♦ On cut surface, the tumor appears soft, well-demarcated but seldom encapsulated −− They are usually yellow to tan-brown in color, and frequently show areas of hemorrhage −− Tumors associated with HNF-1 alpha mutations are steatotic and appear yellow in color; whereas, the telangiectatic/inflammatory subtype appear dark-brown ♦♦ HCA are not associated with cirrhosis and the remaining liver is usually normal

♦♦ Focal nodular hyperplasia ♦♦ Well-differentiated hepatocellular carcinoma ♦♦ Hepatocellular carcinoma arising in HCA

Bile Duct Adenoma Clinical ♦♦ Bile duct adenomas are an incidental finding present in up to 30% of individuals at laparotomy or autopsy ♦♦ They may be mistaken grossly for metastases, especially at surgery for abdominal tumors, when they appear as small white nodules studding the surface of the liver

Macroscopic ♦♦ Macroscopically, they present as small, white, and firm subcapsular nodules

Microscopic

Microscopic

♦♦ Microscopically, HCA are made up purely of hepatocytes arranged in two- to three-cells thick plates −− The hepatic plates are never more then three-cell thick

♦♦ Microscopically, bile duct adenomas demonstrate small tubules set in a fibrous stroma with lymphocytes (Fig. 45.4) −− Normal portal tracts are often present (Fig. 45.5)

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45-3

Table 45.1. Molecular Subtypes of Hepatocellular Adenoma

Subtype

Molecular abnormalities

Distinctive microscopic features

Distinctive IHC features

Associations

HCA with mutations in HNF1a

Biallelic inactivation of HNF1a; both somatic, or 1 germline and 1 somatic

Marked steatosis

LFABP negative

Germline mutations associated with   Younger age   MODY3   Adenomatosis

HCA with mutations in b-catenin

Mutation in b-catenin gene

Cytological atypia Pseudoglandular pattern

Aberrant nuclear and cytoplasmic positivity for b-catenin in a heterogenous distribution

Androgen intake Glycogenosis type 1 Familial adenomatosis polyposis

Inflammatory/ telangiectatic HCA

Inframe deletions of gp130 (60%)

Inflammatory infiltrates Sinusoidal dilatation Telangiectasia

SAA and CRP positive

Obesity Alcohol intake Inflammatory syndrome with increased serum levels of CRP

Hepatocellular adenoma, not otherwise specified

None defined

Negative for   Steatosis  Cytological abnormalities  Inflammatory infiltrates

Normal LFABP positivity No other specific findings

None defined

Fig. 45.1. Hepatocellular adenoma showing hepatocytes arranged as two- or three-cell thick plates with thick-walled arterioles scattered within the lesion. The tumor cells are slightly larger than normal hepatocytes and have regular nuclei.

Fig.  45.2. Areas of sinusoidal dilatation are commonly seen within hepatocellular adenomas. Arrow points to a thick-walled arteriole.

♦♦ The tubules are lined by a single layer of cuboidal cells −− They may contain mucin secretion but bile is not present (a) This reflects their origin from peribiliary glands; “peribiliary gland hamartoma” is a more accurate term ♦♦ Considerable nuclear atypia and desmoplasia may be present

−− This should not be mistaken for metastatic carcinoma, especially in frozen sections (Figs. 45.6 and 45.7)

Differential Diagnosis ♦♦ Biliary hamartoma (von Meyenburg complexes) ♦♦ Mesenchymal hamartoma

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Fig.  45.3. Reticulin stain of a hepatocellular adenoma shows reticulin fibers around individual hepatocytes.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 45.6. Bile duct adenoma showing considerable nuclear atypia and desmoplasia. The lesion was detected while the patient was undergoing Whipple excision for pancreatic carcinoma.

Fig. 45.4. Bile duct adenoma consists of small benign tubules with regular nuclei and no mitoses in a fibrous stroma. Fig. 45.7. Bile duct adenoma showing considerable nuclear atypia and desmoplasia. High power of lesion shown in Figure 45.6.

Mucinous Cystic Neoplasm ♦♦ Formerly hepatobiliary cystadenoma

Clinical ♦♦ Mucinous cystic neoplasm is a tumor of middle-aged women who present with pain and discomfort −− The tumor grows slowly and tends to become symptomatic with increasing size ♦♦ There is a small risk of malignant transformation ♦♦ Surgical resection is curative

Macroscopic Fig. 45.5. Bile duct adenoma with a portal tract within the lesion (left lower corner).

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♦♦ Macroscopically, the tumor is usually multilocular and may assume a large size (Fig. 45.8)

Neoplasms of the Liver and Biliary System

Fig. 45.8. Mucinous cystic neoplasm showing a multiloculated cystic structure. An opened cyst in the foreground shows smooth inner wall without any excrescences.

45-5

Fig. 45.10. Mucinous cystic neoplasm lined by intestinal epithelium with goblet cells.

Fig. 45.9. Mucinous cystic neoplasm lined by a single layer of columnar mucinous cells with underlying ovarian-type stroma.

♦♦ The inner surface of the cyst wall is usually smooth but may sometimes be trabeculated and show small projec­ tions ♦♦ The cysts may contain clear to cloudy mucinous fluid

Microscopic ♦♦ Microscopically, the cysts are lined by mucinous simple columnar epithelium −− The epithelium may become cuboidal or atrophic in large cysts −− Intestinal metaplasia with goblet cells may occasionally be seen (Figs. 45.9 and 45.10) −− Mucinous cystic neoplasm may contain cellular, “ovariantype” stroma in women −− This stroma is positive for estrogen and/or progesterone receptors (Fig. 45.11) ♦♦ The tumor should be adequately sampled to rule out invasion, indicative of malignant transformation

Fig. 45.11. Immunohistochemical stains show estrogen (A) and progesterone (B) receptor positivity in the ovarian-type stroma of a mucinous cystic neoplasm.

Differential Diagnosis ♦♦ Developmental cysts ♦♦ Cystadenocarcinoma

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Intraductal Papillary Neoplasm ♦♦ Formerly biliary papillomatosis

Clinical ♦♦ Intraductal papillary neoplasm is a very rare lesion characterized by multifocal involvement of the intra- and extrahepatic bile ducts −− It occurs in middle-aged patients ♦♦ The clinical course is progressive

Macroscopic ♦♦ Macroscopically, the involved ducts are dilated and contain friable papillary excrescences

Microscopic ♦♦ Microscopically, the lesion consists of papillae with thin fibrovascular stalks covered by mucus-secreting columnar epithelium ♦♦ The epithelial changes encompass the entire spectrum from benign to in situ and invasive malignant change

Malignant Epithelial Tumors Hepatocellular Carcinoma Clinical ♦♦ Hepatocellular carcinoma (HCC) is globally the fifth commonest malignancy and the third leading cause of death ♦♦ The incidence of HCC varies widely around the world reflecting the varying incidence of the underlying risk factors −− The incidence is highest in Africa and South-East Asia due to the high incidence of hepatitis B virus (HBV) infection −− The incidence is low in risk Europe, North and South America, and Australia −− Japan, North Africa, and Middle East constitute areas of intermediate risk ♦♦ Most HCC develop on a background of cirrhosis of varied etiology ♦♦ The etiologic factors underlying the development of cirrhosis may impart additional and independent risk for HCC −− HBV DNA integrates into the host genome and transactivates oncogenes −− Aflatoxin B1 causes a specific change (molecular “fingerprint”) in the p53 gene (G > T at codon 249) −− Alpha-1 antitrypsin and tyrosinemia confer a risk greater than what can be ascribed to cirrhosis alone ♦♦ There is a weak association with xenobiotics such as organochlorine pesticides, polychlorinated biphenyls, thorotrast, and vinyl chloride ♦♦ Clinical presentation includes −− Middle-to-early old age patients with longstanding cirrhosis and rapidly developing liver failure (low incidence areas) −− Young adults presenting with pain, weight loss, or hemorrhage (high incidence areas)

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Fig. 45.12. Hepatocellular carcinoma seen as a soft green-yellow nodule arising in a cirrhotic liver. ♦♦ Significantly elevated serum AFP may be diagnostic, but is only moderately sensitive −− Imaging studies have better sensitivity but may miss small lesions, especially in a cirrhotic background ♦♦ Lymph node metastases are common and treatment results are poor ♦♦ Most patients die within months of presentation, although better results are seen with small and incidental tumors

Macroscopic ♦♦ Most hepatocellular carcinomas arise in a background of cirrhosis (Fig. 45.12) ♦♦ Hepatocellular carcinoma appears as a soft, yellow-green or reddish mass of varying size ♦♦ The tumor occurs as one of three basic patterns −− Multinodular −− Solitary massive −− Diffuse ♦♦ Satellite nodules are common and are defined as smaller tumor nodules situated <1 cm around a large mass ♦♦ The tumor has a high propensity to invade into portal veins

Microscopic ♦♦ The most characteristic pattern recapitulates normal liver architecture with trabeculae and intervening sinusoidal vascular channels (Figs. 45.13 and 45.14) ♦♦ The tumor cells are large with abundant cytoplasm, high nucleocytoplasmic ratio, and large nucleoli −− There are slightly more basophilic cytoplasm than normal liver cells and prominent nucleoli −− Intracellular inclusions are common and include eosinophilic inclusions of alpha-1 antitrypsin and pale bodies, some of which stain for fibrinogen −− Mallory hyaline and Fat droplets may be present ♦♦ The presence of bile is diagnostic of hepatocellular carcinoma ♦♦ Several histologic patterns may occur, usually in combination with each other −− Major histological patterns include trabecular, pseudoglandular, and solid growth (Figs. 45.15 and 45.16)

Neoplasms of the Liver and Biliary System

45-7

Fig. 45.13. Hepatocellular carcinoma showing a macrotrabecular pattern consisting of hepatocytes arranged as thick trabecula separated by sinusoids.

Fig. 45.15. Hepatocellular carcinoma showing pseudoglandular pattern with eosinophilic secretions within the gland-like structures.

Fig. 45.14. Hepatocellular carcinoma showing a microtrabecular pattern consisting of slender trabecula separated by sinusoids.

Fig.  45.16. Poorly differentiated hepatocellular carcinoma growing in a solid pattern.

−− Less common patterns include clear cell, steatohepatitislike, inflammatory, anaplastic giant cell, and spindling, clear cell (Figs. 45.17–45.20) −− These variant patterns as well as histologic grade are of little or no clinical or biological significance ♦♦ Diagnosis on fine needle aspiration cytology is made by the presence of endothelial cells around clusters of malignant cells and the presence of bile (Figs. 45.21 and 45.22) −− Fine needle aspiration yields a low rate of false-positive, but a rather high false-negative rate

Immunohistochemistry

Special Stains ♦♦ A reticulin stain shows thick trabecula of hepatocytes distinguishing HCC from a hepatocellular adenoma or regenerative nodule which show two- to three-cell thick plates (Fig. 45.23) ♦♦ A mucin stain is negative in hepatocellular carcinoma distinguishing it from adenocarcinoma and cholangiocarcinoma

♦♦ HCC is positive for Hepar1, also known as hepatocyte specific antigen and glypican-3 ♦♦ Polyclonal CEA and CD10 highlight the bile canaliculi ♦♦ Alpha fetoprotein is positive in approximately 25% of HCC ♦♦ Cytokeratin 7 is positive in approximately 20% of HCC

Variants ♦♦ Rarely, HCC may be pedunculated −− This variant has a better prognosis if the tumor is localized and surgically resectable ♦♦ Small (<2 cm) and early hepatocellular carcinoma comprise 15% of all liver cell cancers from South-East Asia) −− These have a better prognosis because they have not yet attained an angioinvasive phenotype

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Fig.  45.17. Hepatocellular carcinoma showing macrovesicular fatty change.

Fig. 45.19. Hepatocellular carcinoma with bizarre, multinucleated giant tumor cells. Fig.  45.18. Hepatocellular carcinoma showing steatohepatitislike areas with fatty change and Mallory hyalin.

Differential Diagnosis ♦♦ Hepatocellular adenoma −− Reticulin stain and in some cases, glypican-3 may aid in the differential diagnosis ♦♦ Cholangiocarcinoma −− Presence of bile and absence of mucin diagnostic of hepatocellular carcinoma ♦♦ Metastatic tumors ♦♦ Mixed hepatocellular carcinoma and cholangiocarcinoma

Fibrolamellar Carcinoma Clinical

Fig. 45.20. Hepatocellular carcinoma with a clear cell pattern.

♦♦ Fibrolamellar carcinoma (FLC) occurs in patients between the ages of 18 and 45 years ♦♦ Patients do not have cirrhosis, and hepatitis B infection is infrequent

♦♦ Patients present with abdominal pain, malaise, and weight loss −− A mass is usually readily palpable

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Fig. 45.21. Hepatocellular carcinoma from a fine needle aspiration specimen showing the characteristic covering of tumor groups by an endothelial lining.

Fig. 45.22. Hepatocellular carcinoma showing presence of bile which is a definitive diagnostic feature for this tumor. ♦♦ The tumor has a better prognosis than usual HCC −− This is related to early stage at presentation when the tumor is localized to the liver and often resectable −− The prognosis is however the same as usual HCC when compared stage to stage −− The 5-year survival rate is 10–50%

Macroscopic ♦♦ Macroscopically, FLC appears as a well-defined, solitary mass −− The mass has a lobulated appearance with a central scar and interconnecting fibrous bands −− Small satellite nodules may be present around the main mass ♦♦ Metastases to regional lymph nodes and lungs may be present in late stages

45-9

Fig. 45.23. Reticulin staining of hepatocellular carcinoma shows scant reticulin fibers within the tumor.

Fig. 45.24. Fibrolamellar carcinoma consists of sheets of tumor cells separated by lamellar fibrosis.

Microscopic ♦♦ FLC shows a characteristic microscopic appearance of sheets of hepatocytes separated by lamella of dense, hyalinized collagen (Figs. 45.24 and 45.25) −− The tumor cells are large and contain abundant granular, eosinophilic cytoplasm with central nuclei containing prominent eosinophilic central nucleoli −− The granular, eosinophilic cytoplasm corresponds to abundant mitochondria −− Numerous intracytoplasmic inclusions are present −− These correspond to eosinophilic globules of alpha-1 antitrypsin and “pale bodies,” some of which stain for fibrinogen (Figs. 45.26 and 45.27) ♦♦ Bile production may be seen ♦♦ Fat droplets may be occasionally present

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Fig.  45.25. Fibrolamellar carcinoma consists of large tumor cells with abundant eosinophilic cytoplasm and large eosinophilic nucleoli.

Essentials of Anatomic Pathology, 3rd Ed.

Fig. 45.27. Fibrolamellar carcinoma with intracytoplasmic eosinophilic inclusions.

−− Nephroblastoma:neuroblastoma:hepatoblastoma = 6:3:1 ♦♦ There is a significant association with familial colonic polyposis, nephroblastoma, and Down syndrome ♦♦ Patients present with failure to thrive, weight loss, and ­rapidly enlarging upper abdominal mass with markedly elevated serum levels of alpha fetoprotein ♦♦ Prognosis depends on complete surgical resection −− Since most tumors are large and unresectable at presentation, preoperative chemotherapy is commonly employed to decrease size and “down-grade” the tumor

Macroscopic

Fig. 45.26. Fibrolamellar carcinoma with pale body (arrow).

♦♦ Macroscopically, HB appears as a single, large mass up to 25 cm in size ♦♦ The cut surface is variegated with areas of necrosis, cystic degeneration, and hemorrhage ♦♦ The liver is noncirrhotic

Microscopic Immunohistochemistry ♦♦ Polyclonal CEA outlines the bile canaliculi ♦♦ Cytokeratin 7 is positive in most cases ♦♦ Alpha fetoprotein is usually negative

Hepatoblastoma Clinical ♦♦ Hepatoblastoma (HB) is a tumor of young children −− The majority of cases occur in children younger than 5 years of age −− The peak incidence is in the first 2 years of life −− Rare cases have been reported in adolescents and young adults ♦♦ The relative incidence of childhood tumors is fairly identical worldwide

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♦♦ Microscopically, HB may be either epithelial or mixed epithelial-mesenchymal in type (Box 1) −− Epithelial HB tries to recapitulate the developing liver (a) Four epithelial variants are described – fetal (Figs.  45.28 and 45.29), embryonal (Figs.  45.30 and 45.31), small cell undifferentiated (SCUD) (Fig. 45.32), and macrotrabecular −− Mesenchymal elements include bone, cartilage, squamous epithelium, glandular epithelium, undifferentiated mesenchyme, and muscle (Fig. 45.33) ♦♦ The various elements usually occur in a combination with each other −− Fetal and embryonal elements are invariably present in most tumors in varying proportions (a) Mixed fetal-embryonal HB represents the commonest variant of HB (Fig. 45.31)

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Box 1: Histological Classification of Hepatoblastoma Epithelial Fetal (standard risk) Embryonal (standard risk) Small cell undifferentiated (bad prognostic subtype even when present focally) Macrotrabecular (bad prognosis but not a well characterized subtype) Mixed epithelial-mesenchymal With teratoid features Without teratoid features

Fig. 45.30. Hepatoblastoma showing areas that resemble embryonal hepatoblasts with pseudorosetting.

Fig. 45.28. Fetal hepatoblastoma showing cells slightly increased nucleocytoplasmic ratio, eosinophilic cytoplasm and central, round, regular nuclei. Fig. 45.31. Hepatoblastoma with admixture of fetal and embryonal pattern.

Fig. 45.29. Fetal areas of hepatoblastoma often consist of cells with clear cytoplasm.

♦♦ Fetal HB consists of large, polygonal fetal-type cells with oval nuclei, single nucleoli, and granular or clear cytoplasm organized into irregular plates with bile canaliculi and sinusoids (Figs. 45.28 and 45.29) −− Islands of extramedullary hematopoiesis are commonly seen in fetal HB ♦♦ Embryonal HB consists of smaller, darkly staining cells with scant cytoplasm resembling embryonal-type hepatoblasts (Figs. 45.30 and 45.31) −− Mitoses are frequent in these areas and the cells form with cords, ribbons, or rosette-like structures ♦♦ Small cell undifferentiated HB consists of “small blue cells” with a high nuclear-cytoplasmic ratio, scant cytoplasm, and no nucleoli (Fig. 45.32) −− The cells are arranged as sheets or clusters of cells −− Mitoses are frequent

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♦♦ The macrotrabecular pattern of HB resembles hepatocellular carcinoma −− The macrotrabecular variant is morphologically and clinically not well-defined ♦♦ Histological types with prognostic significance include the purely fetal variant which has a better prognosis; SCUD which has a bad prognosis even when present in small foci; and the macrotrabecular variant which has a bad prognosis −− SCUD is not infrequent and extensive sampling is required to exclude its presence due to the adverse prognostic implications

Immunohistochemistry Fig. 45.32. Hepatoblastoma with anaplastic (small cell) component.

♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Alpha fetoprotein positive (fetal and embryonal cells) Beta-hCG positive (giant cells) Vimentin positive (anaplastic cells) Hepatocyte specific antigen positive Beta-catenin positive

Cholangiocarcinoma Clinical

Fig.  45.33. Hepatoblastoma with admixture of epithelial and mesenchymal elements; the latter is seen as an undifferentiated spindle cell component.

♦♦ Cholangiocarcinoma is a tumor that arises from biliary epithelium ♦♦ The tumor is associated with liver flukes (Clonorchis sinensis: Hong Kong, Canton; Opisthorchis viverrini: Thailand), hepatolithiasis, primary sclerosing cholangitis (Fig. 45.34), congenital anomalies, and Thorotrast exposure ♦♦ There is no association with cirrhosis, HBV infection, or mycotoxins ♦♦ The tumor occurs in patients in their fifth and sixth decade with pain, weakness, and weight loss ♦♦ Serum AFP is usually normal while CEA is elevated ♦♦ This tumor usually presents at a late stage and is frequently not resectable −− Metastases to the regional lymph nodes are common at presentation −− Hematogenous spread occurs late in the course of the disease ♦♦ The prognosis is very poor

Macroscopic

Fig. 45.34. A duct with concentric periductal fibrosis in a patient with PSC and infiltrating glands of cholangiocarcinoma.

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♦♦ Macroscopically, cholangiocarcinoma appears as a solitary, sometimes multinodular gray-white, firm mass with central sclerosis and calcifications −− This color and firm texture correspond to the abundant sclerosis seen microscopically −− Finger-like extensions from main mass, corresponding to lymphatic spread, may be seen ♦♦ The tumor is characteristically avascular in contrast to the highly vascular HCC ♦♦ Growth into major bile ducts or blood vessels may be seen rarely

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Microscopic ♦♦ The tumor shows well- to moderately differentiated tubules and glands in abundant fibrous stroma (Fig. 45.35) −− Many different architectural growth patterns may be seen, which have no biological or clinical significance −− Mucin production (Fig. 45.36) and squamous metaplasia may be seen in the tumor ♦♦ The PAS and mucicarmine stains demonstrate intracellular or extracellular mucin (Fig. 45.36) ♦♦ Dysplasia and carcinoma in situ may be seen in bile ducts adjacent to the tumor ♦♦ Distinction from metastases requires demonstration of carcinoma in situ in adjacent ducts, which may not be possible in needle biopsies (Figs. 45.37 and 45.38)

Immunohistochemistry ♦♦ Mucin positive (Fig. 45.39)

Fig. 45.37. Severe dysplasia in a duct with concentric periductal fibrosis in a patient with PSC and cholangiocarcinoma.

Fig.  45.35. Cholangiocarcinoma showing irregularly shaped glands with pleomorphic nuclei in a desmoplastic stroma.

Fig. 45.38. Severe dysplasia in a patient with PSC and cholangiocarcinoma.

Fig. 45.36. Cholangiocarcinoma with signet ring cells and mucin production.

Fig. 45.39. Mucin production in cholangiocarcinoma (Mucicarmine stain).

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♦♦ Alpha fetoprotein negative ♦♦ EMA positive ♦♦ CEA positive (cytoplasmic pattern, in contrast to canalicular pattern in HCC) ♦♦ Cytokeratins 7 and 19 positive

Variants ♦♦ Hilar adenocarcinoma (Klatskin tumor) −− This arises from the main hepatic duct or lobar branches and presents early in its course with obstructive jaundice −− The tumor has a better prognosis

Differential Diagnosis ♦♦ Metastatic adenocarcinoma ♦♦ Hepatocellular carcinoma ♦♦ Atypical benign bile duct proliferation in hepatolithiasis or duct malformations

Fig. 45.40. Stromal invasion in a intraductal papillary neoplasm with invasive carcinoma.

Intraductal Papillary Neoplasm with Invasive Carcinoma ♦♦ Formerly hepatobiliary cystadenocarcinoma

Clinical ♦♦ This is a very rare malignant tumor that represents the malignant spectrum of intraductal papillary tumor ♦♦ The tumor occurs equally in men and women who do not present with symptoms until the tumor is very large ♦♦ The tumor is usually well-demarcated and resectable, imparting good prognosis

Macroscopic ♦♦ Macroscopically, the tumor is usually multilocular and may assume a large size ♦♦ The inner surface of the cyst wall is smooth with focal excrescences or focal areas of thickness ♦♦ The cysts may contain clear, mucinous, or hemorrhagic fluid

Microscopic ♦♦ The microscopic appearances are similar to mucinous cystic neoplasm but include invasion of the cyst wall and adjacent liver by tumor (Fig. 45.40)

Immunohistochemistry ♦♦ Similar to cholangiocarcinoma

Differential Diagnosis ♦♦ Mucinous cystic neoplasm ♦♦ Carcinoma arising in developmental cysts

Benign Mesenchymal Tumors Hemangioma Clinical ♦♦ Hemangioma is the most common benign liver tumor, occurring as an incidental finding in all ages and both genders ♦♦ It is usually solitary and <5 cm in size

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Fig. 45.41. Cavernous hemangioma consists of anastomosing vascular channels lined by flattened, inconspicuous endothelial cells. −− Most tumors remain stable or involute spontaneously ♦♦ “Giant” hemangiomas >10 cm in size are symptomatic and present with pain and discomfort ♦♦ Resection only if symptoms or rare complications (rupture, thrombocytopenia) occur

Macroscopic ♦♦ The tumor appears as a subcapsular flat or circumscribed red-blue lesion −− The tumor may be pedunculated ♦♦ Fibrosis and calcifications may occur; large lesions have a central scar ♦♦ The lesions collapse upon sectioning

Microscopic ♦♦ Microscopically, the tumor consists of cavernous vascular spaces with flattened endothelium (Fig. 45.41)

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♦♦ Fibrous septae, thrombosis, and calcifications corresponding to the macroscopic findings may be seen

Differential Diagnosis ♦♦ Peliosis hepatis ♦♦ Angiosarcoma ♦♦ Hereditary hemorrhagic telangiectasia

Infantile Hemangioma ♦♦ Formerly infantile hemangioendothelioma

Clinical ♦♦ Infantile hemangioma is the most common mesenchymal liver tumor of infancy −− It presents within the first 6 months of life, and may be present at birth ♦♦ Patients present with a hepatic mass, failure to thrive and high output cardiac failure (A-V shunting in the tumor) −− It is often associated with cutaneous hemangiomas −− Complications which include rupture and thrombocytopenia are rare ♦♦ Tumor tends to regress gradually over a few months −− Patients with high output cardiac failure or thrombocythemia may require treatment which consists of surgery and embolization −− The overall prognosis is good

Fig. 45.42. Infantile hemangioma showing anastomosing vascular channels lined by plump, prominent endothelial cells.

Macroscopic ♦♦ The tumor appears as a large, lobulated, spongy, red-brown mass ♦♦ The tumor does not have well-defined borders and often extends into the adjacent liver parenchyma ♦♦ Areas of scarring may be seen

Microscopic ♦♦ The tumor consists of interconnecting vascular channels lined by prominent endothelial cells (Fig. 45.42) ♦♦ Thrombosis and infarction common ♦♦ Small bile ducts are present throughout the lesion (Fig. 45.43) ♦♦ The presence of nuclear atypia, multilayering, and endothelial hyperplasia suggests low grade angiosarcoma ♦♦ These findings were classified as type II hemangioendothelioma but are now considered to be angiosarcoma ♦♦ The interface of the tumor with adjacent parenchyma is not well-defined and lobules of the tumor extend into the adjacent parenchyma

Differential Diagnosis ♦♦ Angiosarcoma ♦♦ Hemangioma

Angiomyolipoma Clinical ♦♦ Angiomyolipoma usually occurs in middle-aged individuals

Fig. 45.43. Infantile hemangioma with interspersed normal bile ducts. ♦♦ There is a female predominance ♦♦ The tumor is usually solitary ♦♦ Unlike renal angiomyolipomas, there is no association with tuberous sclerosis ♦♦ Patients with tuberous sclerosis and hepatic angiomyolipomas also have renal angiomyolipomas −− These patients may have multiple lesions in the liver

Macroscopic ♦♦ The tumor is nonencapsulated but well-defined ♦♦ The tumor usually occurs in the vicinity of the hepatic hilum ♦♦ The cut surface may be soft and yellow or firm and tan depending on the relative proportions of the lipomatous and myoid component ♦♦ There is no necrosis or hemorrhage

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Microscopic

Immunohistochemistry

♦♦ The tumor consists of a combination of fat, muscle, and blood vessels which are present in varying amounts (Fig. 45.44) ♦♦ The lipomatous component consists of mature adipose tissue; there are no lipoblasts ♦♦ The angiomatous component consists of thick-walled vessels surrounded by s mantle of smooth muscle ♦♦ The myoid component takes on variety of appearances and may consist of spindle, epithelioid, clear, or oncocytic cells (Fig. 45.45) ♦♦ Depending on the predominant component, the tumors may be classified as lipomatous, myomatous (<10% fat), angiomatous, or inflammatory pseudotumor-like types

♦♦ The myomatous component is positive for desmin, smooth muscle actin, and HMB 45 −− HMB 45 positivity is diagnostic of angiomyolipoma

Differential Diagnosis ♦♦ Leiomyosarcoma ♦♦ Malignant fibrous histiocytoma ♦♦ Inflammatory pseudotumor

Malignant Mesenchymal Tumors Angiosarcoma Clinical ♦♦ Angiosarcoma is the most common sarcoma arising in the liver ♦♦ The peak age incidence is in the sixth and seventh decades of life ♦♦ Angiosarcoma is strongly associated with exposure to Thorotrast, a radioactive contrast medium used between 1920 and 1955, vinyl chloride monomer and chronic arsenic exposure −− Vinyl chloride monomer produces a molecular fingerprint in the p53 gene, similar to aflatoxin ♦♦ Patients present with abdominal pain, hemorrhage, jaundice, and coagulopathy ♦♦ The tumor is highly aggressive with no effective treatment −− Death occurs within 6 months of diagnosis

Macroscopic Fig. 45.44. Angiomyolipoma showing an admixture of fat cells and epithelioid myoid cells.

Fig.  45.45. Angiomyolipoma dominated by epithelioid myoid cells with low nucleocytoplasmic ratio, abundant eosinophilic cytoplasm, and small regular nuclei.

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♦♦ Angiosarcoma consists of ill-defined, spongy nodules with hemorrhage −− Extensive and diffuse involvement of the liver is usually present (Fig. 45.46) ♦♦ Regional and distant metastases are present in 20% of cases

Fig. 45.46. Angiosarcoma appearing as a spongy, hemorrhagic mass in a noncirrhotic liver.

Neoplasms of the Liver and Biliary System

Microscopic ♦♦ The tumor consists of malignant endothelial cells which grow along the sinusoids using the latter as a scaffold (tectorial growth) ♦♦ The liver cell plates atrophy and disappear as the tumor progresses ♦♦ The tumor may also form solid sheets of cells or large cavernous spaces with coarse reticulin pattern ♦♦ Necrosis and hemorrhage are usually present ♦♦ The tumor cells are usually plump and spindle in shape and contain large, pleomorphic nuclei (Fig. 45.47)

Immunohistochemistry ♦♦ The tumor is positive for factor VIII, CD31, and CD34

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Hemorrhagic liver cell carcinoma Diffuse metastatic disease in sinusoids Kaposi sarcoma Epithelioid hemangioendothelioma

Epithelioid Hemangioendothelioma Clinical ♦♦ Epithelioid hemangioendothelioma occurs across a wide age range but the commonest presentation is in the sixth decade of life ♦♦ There is a slight female preponderance ♦♦ The tumor presents with vague clinical symptoms such as malaise, weight loss, and upper abdominal discomfort ♦♦ The tumor follows an indolent course with a 5-year survival rate of 50% ♦♦ Complete surgical resection is the treatment of choice for solitary tumors

Fig.  45.47. Angiosarcoma consists of anastomosing vascular channels lined by malignant endothelial cells with hyperchromatic, pleomorphic nuclei.

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♦♦ Liver transplantation offers a good therapeutic option in patients with multifocal tumors

Macroscopic ♦♦ Solitary or multiple firm, fibrous masses which may show central calcification or ossification

Microscopic ♦♦ The center of the tumor appears sclerotic and hyalinized with few scattered tumor cells −− The center may show calcification and ossification ♦♦ Tumor cells are best visualized at the periphery of the tumor where they grow along the sinusoids gradually replacing the liver parenchyma (Fig. 45.48) −− The tumor cells have an epithelioid appearance and are mildly pleomorphic −− They typically show intracytoplasmic vascular lumina which contain red blood cells (a) The intracytoplasmic lumina impart a “signet ring” appearance which may be mistaken for an adenocarcinoma (Fig. 45.49) (b) The presence of red blood cells differentiates them from signet ring cell adenocarcinoma which contains intracellular mucin ♦♦ The tumor typically forms papillary tufts and glomeruloid structures within adjacent portal venules and sinusoidal spaces (Fig. 45.50)

Immunohistochemistry ♦♦ The tumor is positive for Factor VIII, CD31, and CD34 ♦♦ Keratin may be positive ♦♦ The tumor is negative for mucin

Differential Diagnosis ♦♦ Angiosarcoma ♦♦ Hemorrhagic hepatocellular carcinoma

Fig. 45.48. The center of an epithelioid hemangioendothelioma consists of myxoid, paucicellular tissue containing spindle tumor cells.

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Fig.  45.49. Single cells with intracytoplasmic lumina (signet ring cells) (arrow) are characteristic of epithelioid hemangioendothelioma, especially when the lumina contain red blood cells (arrowhead).

Fig. 45.50. At the periphery of the lesion, epithelioid hemangioendothelioma tends to infiltrate sinusoids producing papillary tufts and glomeruloid structures. ♦♦ Diffuse metastatic disease in sinusoids ♦♦ Cholangiocarcinoma

Undifferentiated Sarcoma Clinical ♦♦ Undifferentiated sarcoma is the third most common malignant liver tumor in children ♦♦ The typical age distribution is between 6 and 10  years of age ♦♦ Patients present with weight loss and abdominal swelling ♦♦ The tumor appears as a large, hypodense, avascular mass on imaging

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Fig.  45.51. Undifferentiated sarcoma consisting of sheets of undifferentiated spindle cells.

Fig.  45.52. Undifferentiated sarcoma showing plump, epithelioid cells, some multinucleated, within a myxoid stroma. ♦♦ The prognosis is very poor even with aggressive chemotherapy ♦♦ Multicenter collaborative studies are underway to study the efficacy of newer chemotherapeutic agents

Macroscopic ♦♦ The tumor appears as a large globular, solitary mass, usually in the right lobe ♦♦ The cut surface is variegated with solid and cystic areas ♦♦ Necrosis and hemorrhage are common

Microscopic ♦♦ Microscopically, the tumor consists of loosely arranged, spindle-shaped, pleomorphic cells embedded in an abundant mucopolysaccharide-rich myxoid matrix (Figs.  45.51 and 45.52)

Neoplasms of the Liver and Biliary System

♦♦ Dilated, benign-appearing bile ducts and PAS positive ­diastase-resistant globules are characteristically found ­scattered amidst the tumor cells

Immunohistochemistry ♦♦ The tumor is uniformly positive for vimentin ♦♦ Keratin may be focally positive

Differential Diagnosis ♦♦ Rhabdomyosarcoma ♦♦ Metastatic tumors

Embryonal Rhabdomyosarcoma Clinical ♦♦ Embryonal rhabdosarcoma occurs in children <5  years of age ♦♦ The tumor arises from major bile ducts at the hilum ♦♦ Patients present with obstructive jaundice, fever, and weight loss ♦♦ Treatment and prognosis similar to undifferentiated sarcoma

Macroscopic ♦♦ Grossly, the tumor consists of gelatinous, grape-like (botryoid) masses which protrude into the bile duct lumina

Microscopic ♦♦ The tumor consists largely of a myxoid stroma-containing tumor cells ♦♦ The tumor cells consist of small, dark round cells which are concentrated in a “cambium” layer just beneath the surface −− Numerous mitoses are present −− “Typical” cross-striation are seldom seen

Immunohistochemistry ♦♦ The tumor is positive for smooth muscle actin, myosin, myoglobin, and desmin

Differential Diagnosis ♦♦ Undifferentiated sarcoma

Hematopoietic Neoplasms Primary Malignant Lymphoma Clinical ♦♦ Primary lymphoma of the liver shows a biphasic age incidence, occurring in children/adolescents, and older adults ♦♦ There is a slight male predominance ♦♦ Patients present with pain, abdominal mass, or hepatomegaly −− Systemic symptoms (B-symptoms) are present in 50% of individuals −− Acute liver failure is an uncommon but known presentation of hepatic lymphoma ♦♦ There is an association with hepatitis C virus infection and AIDS ♦♦ Treatment options include surgery, chemotherapy, and radiotherapy

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Macroscopic ♦♦ Tumors may be solitary, multifocal, or diffuse in distribution ♦♦ The cut section shows a soft, fish-flesh appearance

Microscopic ♦♦ Primary hepatic lymphomas are high grade non-Hodgkin lymphomas ♦♦ They may be of B- or T-cell lineage, the latter typically invade the hepatic parenchyma diffusely

Differential Diagnosis ♦♦ ♦♦ ♦♦ ♦♦

Metastatic carcinoma Metastatic malignant melanoma Inflammatory pseudotumor Chronic hepatitis

Secondary Hematopoietic Neoplasms ♦♦ ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

Hodgkin lymphoma Non-Hodgkin lymphoma Leukemias Multiple myeloma Histiocytosis Mast cell disease

Metastases ♦♦ The liver is a common site for metastases, particularly from the lung, breast, and GI tract ♦♦ Metastases are usually multiple and typical appear on the surface of the liver as umbilicated nodules ♦♦ In rare cases, metastatic disease may infiltrate the liver along the sinusoids −− This pattern has been reported with malignant melanoma and lung carcinoma −− This pattern may be mistaken for primary liver tumors as well as for lymphoma/leukemia

Tumor-like Lesions Cysts ♦♦ Cysts in the liver may be solitary or multiple ♦♦ Multiple cysts are most often encountered in ductal plate malformative syndromes such as polycystic disease and Caroli disease ♦♦ The commonest solitary cysts are bile duct cysts (simple cyst) ♦♦ A rare but morphologically distinct solitary cyst is the ciliated hepatic foregut cyst which is lined by ciliated bronchial epithelium and is thought to arise from a foregut remnant

Focal Nodular Hyperplasia Clinical ♦♦ Focal nodular hyperplasia (FNH) is thought to represent parenchymal hyperplasia in response to the presence of an aberrant artery

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Fig.  45.53. Focal nodular hyperplasia consisting of a wellcircumscribed, lobulated lesion with a central stellate scar arising in a noncirrhotic liver.

♦♦ It may occur at all ages and in both genders but is commonest in young women −− An association with oral contraceptives is not wellestablished ♦♦ FNH may be discovered incidentally or may present with pain and/or a palpable mass −− The lesion may occasionally reach a large size of up to 15 cm) −− It may sometimes be pedunculated ♦♦ Treatment consists of surgical resection −− Resection is not always necessary and is usually indicated for symptomatic relief −− FNH does not undergo malignant transformation and does not have a propensity to rupture

Macroscopic ♦♦ FNH appears as a solitary mass, usually <5 cm in size ♦♦ The lesion is well circumscribed but unencapsulated ♦♦ It consists of lobulated yellow-brown nodules of liver parenchyma separated by fibrous septae (Fig. 45.53) which radiate out from a radial scar ♦♦ The scar is eccentrically located in small, early lesions but assumes a central location as the lesion enlarges

Microscopic ♦♦ The typical feature is the presence of abnormal vessels with eccentrically thickened walls which lie within the radial scar and the fibrous septa (Fig. 45.54) −− Bile ductules and a mild inflammatory infiltrate are present within the fibrous tissue −− No bile ducts are present within the lesion ♦♦ The proliferative nodules of hepatic parenchyma consist of crowded hepatocytes which are of similar size or are smaller in size than normal hepatocytes −− These hepatocytes often contain medium or large droplet fat

Differential Diagnosis ♦♦ Hepatocellular adenoma ♦♦ Mesenchymal hamartoma

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Fig. 45.54. Focal nodular hyperplasia showing atypical vessels with eccentrically thickened walls.

Nodular Regenerative Hyperplasia Clinical ♦♦ Nodular regenerative hyperplasia (NRH) occurs in both genders and at all ages ♦♦ NRH is associated with a large number of extrahepatic diseases, the commonest associations being connective tissue diseases, vascular disorders, and chemotherapeutic agents ♦♦ NRH is thought to represent a secondary, nonspecific tissue adaptation to uneven distribution of total hepatic blood flow ♦♦ In some instances, damage to the endothelium of the central venules causes atrophy of the centrilobular hepatocytes and secondary proliferation of periportal hepatocytes leading to nodularity ♦♦ NRH is not a neoplastic or preneoplastic condition ♦♦ Patients present with noncirrhotic portal hypertension ♦♦ Diagnosis by liver biopsy is difficult but possible

Macroscopic ♦♦ The liver with NRH appears diffusely nodular ♦♦ The nodules are small and in contrast to cirrhosis, there is no fibrosis ♦♦ Large regenerative nodules are not seen

Microscopic ♦♦ The hepatic architecture is maintained −− Portal tracts are evenly distributed throughout the liver ♦♦ The nodules are of the same size or only slightly larger than the normal hepatic lobules −− The nodules show periportal regeneration of hepatocyte alternating with centrilobular atrophy of hepatocytes −− This pattern is best appreciated on a reticulin stain (Figs. 45.55and 45.56) ♦♦ There are no fibrous septae ♦♦ Obliterative portal or hepatic venular changes may be seen

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Fig. 45.55. Reticulin stain of nodular regenerative hyperplasia showing alternate areas of parenchymal atrophy and hyperplasia creating nodular liver architecture in the absence of fibrosis.

Fig.  45.57. Mesenchymal hamartoma containing haphazardly arranged bile ducts and blood vessels in a loose myxoid stroma.

Fig. 45.56. Reticulin stain of nodular regenerative hyperplasia.

Fig. 45.58. Mesenchymal hamartoma showing bile ducts in a loose myxoid stroma.

Mesenchymal Hamartoma Clinical ♦♦ Mesenchymal hamartoma occurs exclusively in young children −− The median age at presentation is 15 months ♦♦ Patients present with progressive abdominal enlargement ♦♦ Surgical resection is curative ♦♦ The lesion is thought to result from a prenatal localized abnormality of ductal plate development with subsequent enlargement due to fluid accumulation

Macroscopic ♦♦ The lesion presents as a large and soft cystic mass with a smooth surface and gelatinous cut surface contents

Microscopic ♦♦ Microscopically, the lesion consists of a haphazard and variable admixture of normal liver structures ♦♦ The predominant component is loose and edematous mesenchymal tissue (Figs.  45.57 and 45.58) which contains randomly scattered ductal structures, nodules of hepatocytes and vascular channels −− The ductal structures are typically surrounded by a collar of fibroblastic tissue

Differential Diagnosis ♦♦ Focal nodular hyperplasia ♦♦ Hepatocellular adenoma

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Biliary Hamartoma (von Meyenburg Complex) Clinical ♦♦ Biliary hamartomas are a common incidental finding at surgery or autopsy ♦♦ During surgery, they might be mistaken for metastases and are a frequent biopsied for frozen section diagnosis ♦♦ They often occur as multiple lesions scattered randomly in the liver ♦♦ They are thought to represent a localized form of ductal plate malformation

Macroscopic

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ The pathogenesis is not known but endothelial cell injury is postulated ♦♦ Patients may present with hemorrhage or liver failure ♦♦ The lesion is distinctly uncommon

Macroscopic ♦♦ Macroscopically, multiple, blood-filled spaces may be seen throughout the liver ♦♦ They range in size from 1 mm to several cm

Microscopic ♦♦ Microscopically, the lesion consist of blood-filled spaces surrounded by “capsule” of fibrin/early collagen ♦♦ An endothelial lining is seen only rarely

♦♦ Biliary hamartomas appear as small whitish nodules, a few mm in size

Differential Diagnosis

Microscopic

♦♦ Bacillary angiomatosis

♦♦ Microscopically, the lesions consist of irregularly shaped, dilated ducts in a fibrous stroma (Fig. 45.59) ♦♦ The ducts may contain bile ♦♦ There is no cytologic atypia or mitotic activity

Inflammatory Pseudotumor Clinical

Differential Diagnosis ♦♦ Bile duct adenoma −− More compressed ducts, less fibrous stroma −− Lumens may contain mucin (not bile)

Peliosis Hepatis Clinical ♦♦ Peliosis hepatis is associated with exposure to anabolic steroids, tuberculosis, and AIDS ♦♦ Similar lesions occur in the spleen, lungs, and lymph nodes

♦♦ Inflammatory pseudotumor usually occurs in young adults and is associated with ascending cholangitis, primary sclerosing cholangitis, and local autoimmune processes −− The lesion has been known by a variety of synonyms such as plasma cell granuloma, reflecting the range of histologic patterns −− The lesion is similar to such lesions which present in other parts of the body ♦♦ Some examples consist of IgG4 plasma cells and are usually associated with autoimmune pancreatitis −− They are part of the spectrum of IgG4 autoimmune diseases ♦♦ Patients present with intermittent fever, pain, and weight loss ♦♦ Laboratory markers of inflammatory are positive −− Alkaline phosphatase is usually elevated ♦♦ The lesion is almost always mistaken for malignancy by radiography ♦♦ Treatment consists of steroid therapy for IgG4 associated lesions and surgical excision for non-IgG4 associated symptomatic lesions −− Surgical excision leads to relief of systemic symptoms

Macroscopic ♦♦ The lesion appears as a solitary mass which may attain a large size, up to 25 cm in diameter ♦♦ The lesion may compress adjacent structures ♦♦ Multiple lesions may be found in some patients

Microscopic Fig. 45.59. von Meyenburg complex consisting of dilated ducts containing eosinophilic material in a fibrotic stroma.

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♦♦ The tumor consists of spindle-shaped fibroblastic or myofibroblastic cells admixed with a variable number of inflammatory cells (Fig. 45.60)

Neoplasms of the Liver and Biliary System

Fig.  45.60. Inflammatory pseudotumor consisting of spindle cells in a whorled arrangement.

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Fig.  45.61. Inflammatory pseudotumor showing numerous plasma cells.

−− The spindle cells may show a whorled pattern −− Sclerosis may be seen in the stroma ♦♦ Inflammatory cells include variable proportions of plasma cells, eosinophils, lymphocytes, and macrophages (Figs. 45.61 and 45.62) −− Plasma cells and eosinophils are the predominant cell types

Immunohistochemistry ♦♦ Plasma cells are polyclonal for kappa/lambda light chains

Differential Diagnosis ♦♦ Malignant lymphoma ♦♦ Malignant fibrous histiocytoma Fig.  45.62. Inflammatory pseudotumor showing a mixture of plasma cells and eosinophils.

TUMORS OF THE GALLBLADDER AND EXTRAHEPATIC BILE DUCTS Benign Epithelial Tumors and Lesions Polyps ♦♦ Lymphoid polyps are small sessile or pedunculated lesions ranging from 2 to 4 mm in size −− They are usually found in older people −− Microscopically, they consist of hyperplastic lymphoid tissue covered by normal biliary epithelium ♦♦ Granulation tissue polyps are small lesions and usually associated with acute and chronic cholecystitis

−− Microscopically, they have the typical appearance of granulation tissue with proliferating blood vessels and variable number of inflammatory cells (a) The overlying epithelium is typically denuded ♦♦ Fibrous polyps are large enough to be detected by ultra­ sonography −− Microscopically, they consist of abundant edematous ­connective tissue stroma-containing scattered glands/ ducts (a) The surface is covered by normal biliary epithelium

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♦♦ Cholesterol polyps are small pedunculated yellow lesions −− They represent 50% of all gallbladder polyps −− They are usually not associated with cholesterolosis −− Microscopically, they consist of lipid-laden macrophages covered by normal biliary epithelium

Hyperplasia and Metaplasia ♦♦ Nodular hyperplasia of pseudopyloric glands appears as small, sessile nodules, often adjacent to adenomas and carcinomas −− They consist of poorly demarcated areas of tall, mucinproducing cells, and Paneth cells ♦♦ Intestinal metaplasia is characterized by replacement of the normal surface epithelium by intestinal-type cells −− The process may be focal, segmental, or diffuse and may coexist with adenomas and carcinomas

Papillary Hyperplasia ♦♦ Primary papillary hyperplasia can be focal, segmental, or diffuse in the gallbladder and/or extrahepatic bile ducts −− Microscopically, it consists of papillary structures lined by biliary epithelium (a) Intestinal-type cells and dysplasia are not seen ♦♦ Secondary papillary hyperplasia is typically associated with cholecystitis and cholelithiasis −− Microscopically, it consists of numerous crowded mucosal folds lined by tall mucin-secreting columnar cells interspersed with goblet cells and Paneth cells

Adenoma ♦♦ Adenomas are rare lesions seen in association with familial polyposis coli or Gardner syndrome ♦♦ Adenomas of the gallbladder are often incidental findings while those in the common bile duct may be symptomatic with jaundice, cholangitis, or hemobilia ♦♦ They are usually solitary lesions <2 cm in size, and may be sessile or pedunculated ♦♦ Microscopically, they may have a tubular, papillary, or mixed architectural pattern; with a pyloric or colonic type epithelium (Fig. 45.63) −− Paneth cells and neuroendocrine elements may be seen −− Variable degree of dysplasia is present

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ Gallbladder carcinoma is usually discovered incidentally during surgery −− Metastatic spread to lymph nodes and the adjacent liver bed is already present in 50–70% of cases −− There may be metastatic involvement of liver, peritoneum, and lungs at presentation; or it may occur later in the course of the disease ♦♦ The prognosis is poor with 5–10% overall survival at 5 years −− Prognosis is favorable in the absence of muscular invasion

Macroscopic ♦♦ Macroscopically, the tumor consists of diffuse thickening of the gallbladder wall ♦♦ Polypoid or discrete lesions are uncommon

Microscopic ♦♦ Microscopically, the tumor consists of tubules and well to moderately differentiated glandular structures embedded in a desmoplastic stroma ♦♦ The adjacent mucosa may show hyperplastic changes, antral, or intestinal metaplasia; and dysplasia or carcinoma in situ ♦♦ Perineural invasion common

Immunohistochemistry ♦♦ The tumor is positive for cytokeratin 7 and CEA positive

Variants ♦♦ ♦♦ ♦♦ ♦♦

Intestinal, mucinous, signet ring types Clear cell and aggressive small cell carcinoma Adenosquamous and pure squamous cell carcinoma Undifferentiated (spindle cell) carcinoma

Differential Diagnosis ♦♦ Dysplasia extending into the cystic duct, Luschka ducts, and Aschoff–Rokitansky sinuses ♦♦ Adenoma/cystadenoma ♦♦ Adenomyoma

Malignant Epithelial Tumors Carcinoma of the Gallbladder Clinical ♦♦ Carcinoma of the gallbladder is the fourth most common malignant neoplasm of the GI tract ♦♦ There is an etiological association with gallstones/chronic inflammation −− Gallstones are present in 80–90% of all cases ♦♦ Gallbladder carcinoma arises from flat dysplasia of the adjacent epithelium and not from adenomas

1852

Fig.  45.63. Tubular adenoma arising in a gallbladder appears very similar to the intestinal counterpart.

Neoplasms of the Liver and Biliary System

45-25

Carcinoma of the Extrahepatic Bile Ducts Clinical ♦♦ Carcinoma of the extrahepatic bile ducts is a distinct entity from gallbladder carcinoma ♦♦ It occurs in older individuals and is less commonly associated with cholelithiasis −− Choledochal cysts prone to develop carcinoma ♦♦ Patients present with obstructive jaundice, cholangitis, and hemobilia ♦♦ Resectability and prognosis are poor −− Metastatic spread to lymph nodes and liver are frequent at diagnosis −− Prognosis is better for distal lesions

Macroscopic ♦♦ Macroscopically, the appearance may vary from diffuse segmental thickening to a stricture to a polyp

Microscopic ♦♦ The appearances are similar to those described for gallbladder carcinoma ♦♦ The adjacent mucosa may show metaplasia and/or dysplasia

Immunohistochemistry ♦♦ The tumor is positive for cytokeratin 7 and CEA

Differential Diagnosis ♦♦ Nonneoplastic fibrous stricture ♦♦ Primary sclerosing cholangitis

Miscellaneous Malignant Epithelial Tumors ♦♦ Carcinosarcoma/undifferentiated spindle cell carcinoma ♦♦ Carcinoid tumor ♦♦ Metastatic tumors (breast, stomach, pancreas)

Benign and Malignant Nonepithelial Tumors ♦♦ Granular cell tumor ♦♦ Malignant melanoma

Fig. 45.64. Adenomyoma in the wall of a gallbladder appears as a fibrous nodule with slit-like spaces. ♦♦ All others are exceedingly rare, including: lipoma, hemangioma, neurofibroma, paraganglioma, leiomyo-/rhabdomyosarcoma, MFH, and malignant lymphoma

Tumor-like Lesions Adenomyoma Macroscopic ♦♦ Adenomyoma may occur anywhere in the gallbladder or extrahepatic bile ducts (Fig. 45.64) but is onset in the fundus of the gallbladder ♦♦ It usually appears as a distinct but unencapsulated nodule in the fundus of the gallbladder −− On cut section, small slit-like lumina may be seen There may be associated cholelithiasis

Microscopic ♦♦ The lesion consists of ductal or cystic glandular structures embedded in a stroma consisting of hyperplastic smooth muscle cells ♦♦ The lumina usually contains bile ♦♦ Granulomatous inflammation and fibrosis may be present around ruptured glands

TNM CLASSIFICATION OF LIVER TUMORS (2010 REVISION) ♦♦ T: Primary Tumor −− Tx: Primary tumor cannot be assessed −− T0: No evidence of primary tumor −− T1: Solitary tumor without vascular invasion −− T2: Solitary tumor with vascular invasion or multiple tumors none more than 5 cm

−− T3a: Multiple tumors more than 5 cm −− T3b: Single tumor or multiple tumors of any size involving a major branch of the portal or hepatic vein −− T4: Tumor with direct invasion of adjacent organs other than gallbladder or with perforation of visceral peritoneum

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45-26

Essentials of Anatomic Pathology, 3rd Ed.

♦♦ N: Regional Lymph Nodes −− NX: Regional lymph nodes cannot be assessed −− N0: No regional lymph node metastasis −− N1: Regional lymph node metastasis

♦♦ M: Distant Metastasis −− MX: Distant metastasis cannot be assessed −− M0: No distant metastasis −− M1: Distant metastasis

SUGGESTED READING Aishima S, Nishihara Y, Kuroda Y, et al. Histologic characteristics and prognostic significance in small hepatocellular carcinoma with biliary differentiation: subdivision and comparison with ordinary hepatocellular carcinoma. Am J Surg Pathol 2007;31:783–791. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485–1491. Berthiaume EP, Wands J. The molecular pathogenesis of cholangiocarcinoma. Semin Liver Dis 2004;24:127–137. Brunt EM. Benign tumors of the liver. Clin Liver Dis 2001;5:1–15. Coston WM, Loera S, Lau SK, et al. Distinction of hepatocellular carcinoma from benign hepatic mimickers using Glypican-3 and CD34 immunohistochemistry. Am J Surg Pathol 2008;32:433–444. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674–687. Goodman ZD. Neoplasms of the liver. Mod Pathol 2007;20 Suppl 1: S49–60. Hytiroglou P. Morphological changes of early human hepatocarcinogenesis. Semin Liver Dis 2004;24:65–75.

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Katzenstein HM, Krailo MD, Malogolowkin MH, et  al. Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 2003;97: 2006–2012. Mas VR, Maluf DG, Stravitz R, et al. Hepatocellular carcinoma in HCVinfected patients awaiting liver transplantation: genes involved in tumor progression. Liver Transpl 2004;10:607–620. Mortele KJ, Ros PR. Benign liver neoplasms. Clin Liver Dis 2002;6:119–145. Saxena R, Albores-Saavedra J, Bioulac-Sage P, Hytiroglou P, Sakamoto M, Theise ND, Sui WMS. Diagnostic algorithms for tumors of the liver. In Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.) WHO Classification of Tumours of the Digestive System, IARC, Lyon 2010 Shaib, Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:115–125. Stocker JT. Hepatic tumors in children. Clin Liver Dis 2001;5:259–281. Suriawinata A, Xu R. An update on the molecular genetics of hepatocellular carcinoma. Semin Liver Dis 2004;24:77–88. von Schweinitz D. Neonatal liver tumours. Semin Neonatol 2003;8:403–410. Yan BC, Hart JA. Recent developments in liver pathology. Arch Pathol Lab Med 2009;133:1078–1086.

Index Abrasion, 422 Abscess, bacterial infection, neuropathology, 661–662 Abscess, fungal infection, neuropathology, 663 Absidia species, 362–363 Acanthamoeba corneal ulcer, 1133 Acanthamoeba species, 385–386 Acetaminophen, 451 Acetones, 446–447 Acetylsalicylic acid (Aspirin), 451 Achalasia, 1683 Achondroplasia, 553 Acinar cell carcinoma, 51, 83–85, 250, 254, 1762–1763 Acinar cell cystadenoma, 1763 Acinetobacter baumannii, 339 Acinic cell carcinoma, 51–53, 55, 259, 1066–1067 Acne keloidalis nuchae, 899–900 Acquired progressive lymphangioma, 835–836 Acquired renal cystic disease, 1485 Acral A-V tumor, 834 Acral-lentiginous melanoma, 843 Acrochordons, 828 Acrodermatitis enteropathica, 577 Actinic keratosis (senile, solar), 801 Actinomyces, 353 respiratory cytology, 39, 40 Actinomycosis, 353, 1232, 1345 Acute disseminated encephalomyelitis (ADEM), 661 Acute EBV infection, 745 Acute inflammatory demyelinating polyneuropathy (AIDP), 661 Acute megakaryoblastic leukemia (AMkL), 763–764 Acute myeloid leukemia (AML), 736, 759–766 Acute promyelocytic leukemia (APML), 760–761 Acute tubular necrosis (ATN), 1477 Adamantinoma, 989 Adamantinomatous craniopharyngioma, 643 Adenocarcinoma, 251–253, 259, 260, 1243–1244, 1258, 1603 of anal duct/gland, 1744 with atrophic features, prostate, 1607 benign lesions of, prostate, 1585–1594 bladder, 530–531, 1552–1554 early invasion (microinvasion), uterus, 1357 esophagus, 1692 gastrointestinal tract, 1737–1738, 1744, 1745 glomeruloid features, prostate, 1607 in-situ (AIS), uterus, 1357 microvacuolated cytoplasm, prostate, 1608 nasal cavity, paranasal sinuses and nasopharynx, 1111 neuroendocrine differentiation, prostate, 1605

pancreatic ductal, 530 putative precursor of, prostate, 1588 of skin appendage, 1328 specific variants, gastrointestinal tract, 1738 with spindle cell metaplasia, breast, 1291 stomach, 1692 uterus, 1358–1361 Adenocarcinoma with microvacuolated cytoplasm, 1608 Adenofibroma, 1363, 1385, 1390 Adenoid basal carcinoma, uterus, 1361–1362 Adenoid cystic carcinoma, 259, 1241–1243, 1597, 1604 breast, 1292 larynx and trachea, 1118 nasal cavity, paranasal sinuses and nasopharynx, 1108–1109 salivary gland, 54–55, 1067–1068 skin, 815 uterus, 1361 Adenoma, 249, 259–261 breast, 1273–1274, 1298, 1299 extrahepatic bile duct, 1853 gallbladder, 1853 prolactin producing, 676 stomach, 1703 Adenomatoid hyperplasia, 1092 Adenomatoid tumor epididymis, 1641 fallopian tube, 1384 odontogenic, 1097 uterus, 1384 Adenomatosis polyposis coli (APC), 522 Adenomatous polyp, 81 Adenomyoepithelioma, 1299–1300 Adenomyoma, 1363, 1384, 1853 Adenomyosis, uterus, 1368 Adenosarcoma, uterus, 1363, 1385 Adenosine deaminase, 579 Adenosis, 267–269, 1337, 1590 Adenosquamous carcinoma, 1244–1245 breast, 1291 esophagus, 1693 prostate, 1606 uterus, 1361 Adenovirus, 378, 1231 Adipocyte-derived tumors and proliferations, 817–818 Adipose neoplasms, 260 Adipose tissue tumors, 74 Adrenal aplasia, 935 Adrenal cortical carcinoma (ACC), 945–947 hyperplasia, 939–940 neoplasms, 260 rests ovary, 1401 testis, 1620

Adrenal gland adrenal insufficiency (Addison's disease), 938 cysts, 936 cytomegaly, 936, 937 heterotopia, 935 leukodystrophy, 937 medullary hyperplasia, 941–942 Adrenoleukodystrophy, 579–580, 673 Adult rhabdomyoma, 1022 Adult small round blue cell tumors, 212, 219 Adult T-cell leukemia/lymphoma (ATLL), 72, 706–707, 782–783 Aerobic, facultatively anaerobic (or microaerophilic) bacteria, 317–345 Agenesis of corpus callosum, 669 Aggressive angiomyxoma, 1004, 1321–1322 Aggressive digital papillary adenoma/ adenocarcinoma, 811 Airway and obstructive diseases emphysema, 1215–1218 large, 1216–1217 small, 1218 Alagille's syndrome, 1809–1810 Albinism, 564, 838 Alcoholic liver disease, 1793–1795 Alcoholism, 467 Alcoholism, chronic, 417 Alcohol, malnutrition, 671–672 Alcohols, 446–447 Algor mortis (body cooling), 410–411 Allergic angiitis granulomatosis. See ChurgStrauss syndrome Allergic fungal sinusitis, 1103 Alopecia areata, 898 non-scarring, 897–898 scarring, 898–900 syringoma-like proliferations associated with, 809 Alpha-1-antitrypsin deficiency, 1813–1814 Alpha-hemolytic streptococci (Viridans streptococci), 323 Alport syndrome, 557, 1472–1473 Alternaria species, 372 Alveolar adenoma, 1238–1239 rhabdomyosarcoma, 517–519, 1023–1024 soft part sarcoma, 260, 517, 520, 1039–1041 Alzheimer's disease (AD), 653, 655 Amalgam tattoo, 1092 Amebic abscess, 1787 Amebic meningoencephaliti, 666 Ameloblastic carcinoma, 1099 Ameloblastic fibroma, 1098 Ameloblastoma, 1096–1097 Amiodarone induced changes, 41–42 Amitriptyline, 450 AML. See Angiomyolipoma

1855



Amphetamines, 449 Amplification, 492, 493, 496 AMR. See Antibody-mediated rejection Amyloid, breast, 1272 Amyloidoma, 1036–1037 Amyloidosis, 789–790 eyelid, 1148–1149 glomerular diseases, 1464–1465 heart, 1197 hepatobiliary disease, 1817–1818 Amyotrophic lateral sclerosis (ALS), 657 Anaerobic bacteria and diseases, 345–353 Analgesics, 451 Anal intraepithelial neoplasia (AIN), 1743 Anaphylaxis, 419 Anaplastic carcinoma, 62–63, 922–923 Anaplastic large cell lymphoma (ALCL), 72–73, 711–712, 781–782 Anatomic pathology analysis, data biological pathway, 477 class discovery and comparison, 476–477 class prediction, 477 integrative/systems biology approaches, 477 data management, 476 historical perspective 1960–2000, 470–471 2000, 471 imaging, 472 laboratory information systems, 471–472 medical error classification, 484 definition, 484 detection methods, 484 health care impact, 484 molecular data analysis and sharing, 478 cancer biomarker, 477–478 clinical annotations, 478 laboratory procedures, 478 tissue resources, 478 quality assurance (QA) quality control (QC), 482 quality improvement (QI), 482–483 regulations, accreditation hospital, 487 laboratory, 485–487 ROLE, information management, 470 synoptic reporting, 474–476 telepathology, 472–473 whole slide imaging, 473–474 Ancylostoma duodenale, 396 Androblastoma, 1414 Androgen deprivation therapy, prostate, 1611–1612 Androgenetic alopecia, 898 Anemia of chronic disease, bone marrow, 793 Anencephaly, 666, 667 Aneurysmal bone cyst (ABC), 969–970 Aneurysms, 1205–1206 Angelman syndrome, 539–540 Angiodysplasia, 1729 Angiofibroma, 828–829 Angioimmunoblastic T-cell lymphoma, 710

1856

Index

Angioinvasive forms, 663 Angiokeratoma, 1198, 1320–1321 Angioleiomyoma, 822 Angiolipoma, 817, 1016–1017 Angiolymphoid hyperplasia, 833 Angioma serpiginosum, 834 Angiomatoid MFH, 1037–1038 Angiomatosis, 836, 1026, 1302 Angiomyofibroblastoma, 1322 Angiomyolipoma (AML), 88 kidney, 1509–1510 liver and biliary system, 1843–1844 Angiomyxoma, 1037 Angiosarcoma, 1250–1251 bone and joints, 984 breast, 1302–1303 cardiac, 1203 hepatobiliary disease, 1793 liver and biliary system, 1844–1845 skin, 836–837 soft tissue, 74–77, 1028 spleen, 742–743 Angiostrongylus species, 400 Anisakis species, 400 Anorchidism, 1619 Anovulation, glandular and stromal breakdown associated with, 1366 Anoxic encephalopathy (global ischemic injury), 648–649 Anthracycline cardiotoxicity, 1198 Anti-basement membrane antibody disease (ABMA). See Goodpasture's syndrome Antibody-mediated rejection (AMR), 1238 Antidepressants, 450 Antigen receptor gene rearrangements as markers of clonality, 501–503 Antipsychotics, 450–451 Anus, 1742–1745 Aortic dissection, 415 stenosis, 413, 1194 valve stenosis, 1199 APC. See Adenomatosis polyposis coli Aphthous stomatitis, 1092 Apical periodontal cyst, 1094 Aplasia, thymic, 1167 Aplastic anemia (AA), bone marrow, 794–795 Apocrine carcinoma, 69, 815–816, 1287 derived tumors and proliferations, 815–816 intraductal carcinoma, 1279–1280 nevus, 815 Apoplexy, 676 Appendix, 1730–1732 Aqueductal stenosis, 667 Arias-stella reaction, 24, 1348, 1365–1366 Arnold-Chiari (Chiari II) malformation, 666–667 Arrythmogenic right ventricular cardiomyopathy (ARVD), 1196–1197 Arsenic poisoning, 451–452, 672 Arteriolosclerosis, 650 Arteriosclerosis, 1204–1205 Arteriovenous malformation (AVM), 651–652 Arthritides, 962–964

Arthropod bite reaction, 891 Asbestos related reactions berylliosis, 1226–1227 CWP, 1226–1227 hard metal pneumoconiosis, 1226–1227 Ascaris lumbricoides (roundworm), 396 ASD. See Atrial septal defect Aspergillosis, 44, 1234 Aspergillus species, 361–362 Aspermatogenesis, 1624 Asphyxia, 435–442 Asthma, 44, 1217, 1228 Astrocytoma, 99–100, 609–619 Ataxia-telangiectasia, 543 a-thalassemia, 557–558 Atherosclerosis, 1204, 1480 Atherosclerotic aneurysm of the abdominal aorta, 1205–1206 Atmospheric pressure changes, 442–443 ATN. See Acute tubular necrosis Atresia, 1683 Atrial septal defect (ASD), 1194 Atrophy, prostate, 1593 Atypia, 1347 Atypical adenomatous hyperplasia (AAH), 1240–1241, 1587–1589 Atypical basal cell hyperplasia (ABCH), prostate, 1586 Atypical chronic myeloid leukemia (aCML), 774 Atypical lipomatous tumor (ALT), 1018–1019 Atypical small acinar proliferation (ASAP), 1597–1598 Autoerotic asphyxia, 437–438 Autopsy ancillary procedures, 465 brain, 463 complete and partial, 458 consent, 457 donation, organ and tissue, 458 external examination, 459–461 female reproductive system, 465 gastrointestinal tract, 465 heart, 463–464 hepatobiliary and hematopoietic system, 465 in-situ block dissection, 461–463 internal examination, 461–463 lungs, 465 medical record review, 459 medicolegal jurisdiction, 456–457 neck, 463 organ-by-organ removal, 461 organs and tissues, retention, 458 restrictions, 458 universal precautions, 456 urinary tract, male reproductive system, and adrenal glands, 465 Autosomal dominant polycystic kidney disease (ADPKD), 1483–1484 Babesia microti, 386 Bacillary angiomatosis, 1024 lymph node, 718 skin, 833 spleen, 746

Index

Bacillus anthracis (etiologic agent of anthrax), 323–325 Bacillus cereus, 325 Bacteremia, 348–349 Bacteria, 317–361 Bacterial infections cervicitis, 1345 hepatobiliary disease, 1782–1783 neuropathology, 661–662 ovary, 1400 ulcers, eye, 1133 vaginosis, 11 Bacteroides fragilis group, 351–352 Balanitis, 1659 Balantidium coli, 386 Barbiturates, 449 Barotrauma, 443 Barrett's esophagus, 79, 1688–1690 Bartholin's duct cyst, 1316 Bartholin's glands, carcinoma of, 1327–1328 Bartonella, 358–360, 746 Basal cell adenocarcinoma, 1065–1066 Basal cell adenoma, 1059, 1587 Basal cell carcinoma (BCC), 73, 807, 1326 Basal cell hyperplasia (BCH), prostate, 1586 Basal cell nevus syndrome (Gorlin syndrome), 588–589 Basal cell proliferations, prostate, 1585 Basaloid follicular hamartoma, 805 Basaloid squamous cell carcinoma (BSCC), 1116, 1356 B-cell acute lymphoblastic leukemia (B-ALL), 766–767 B-cell lymphoma of MALT, 1741–1742 B-cell lymphoproliferative disorders, 775–780 B-cell prolymphocytic leukemia (B-PLL), 692, 776–777 Becker's nevus, 821, 839 Beckwith-Wiedemann syndrome, 567, 594, 936–937 Behcet's disease, 1312–1313 Benign/hyperplastic lesions, 1251 Benign metastasizing leiomyoma, 1256 Benign nephrosclerosis, kidney, 1479 Benign ovary, 1408, 1416, 1421 Benign papillary mesothelioma, 1642 Benign prostatic hyperplasia (BPH), 1585–1591 Benign tumors epithelial, 1238–1239 mesenchymal, 1239–1240 Berry (saccular) aneurysm, 647, 651 Berry aneurysm of cerebral arteries, 1206 Berylliosis, 1227 Bethesda System (2001), 8 Bile duct adenoma, 1830–1832 cells, 81, 82 dilatation, 1807–1808 hamartoma, 82 Biliary cirrhosis, primary, 1802–1803 colic, 1825, 1826 hamartoma (von Meyenburg complex), 1850 papillomatosis, 1834 Binswanger disease, 650 Biphasic tumors, 211

Biphasic tumors, breast, 1295–1297 Bizarre parosteal osteochondromatous proliferation (Nora's lesion), 977–978 B-K mole, 841 Black adenoma, 260 Black thyroid nodule, 59 Bladder adenocarcinoma fibroblast growth factor receptor 3 (FGFR3) gene, 530 UroVysion, 531 Blastic NK-cell lymphoma, 717 Blastomyces dermatitidis, 365 Blastomycosis respiratory cytology, 38–51 spleen, 746 Blood vessels, pathology of, 1204–1209 Bloom syndrome, 543 Blue nevi, skin, 839–840 Blue nevus, uterus, 1363 B-lymphoblastic leukemia (B-ALL)/ lymphoblastic lymphoma (B-LBL), 689–690 Bone cysts, 968–970 Bone, cytology, 77–78 Bone-forming lesions, 970–976 Bone infections, 960–962 Bone marrow anemias, 793–794 general considerations, 753 infections, 792–793 reactive conditions, treatment changes, 794–795 storage diseases, 791 transplantation (BMT), 273, 302–305 Bordetella pertussis, 341 Botryomycotic abscesses, 317 Botulism, 350 Bowenoid papulosis, 804 BP. See Bullous pemphigoid BPD. See Bronchopulmonary dysplasia Brain autopsy, 463 Brain death syndrome (“respirator brain”), 649 Brainstem avulsion, 429 Branchial cleft cysts, 53, 56, 799–800 Breast adenocarcinoma CCND1, 526 CDH1/E-cadherin, 526 CSRC, 525 FGF1/FGF4, 525 gene expression profiling, 527 HER2/neu overexpression, 524–525 MMPs, 526 sentinel lymph nodes, molecular analysis, 526 TP53, 526 Breast, cytology, 63–69 Breast, IHC adenoid cystic carcinoma, 173 adenomyoepithelioma, 170 angiosarcoma, 174 biphasic tumors: fibroadenoma, phyllodes tumors, 173 breast carcinoma micrometastasis, sentinel lymph node, 172

complex sclerosing lesion/radial scar, 169–170 fibromatosis, 173–174 granular cell tumor, 173 infiltrating ductal carcinoma, 172 lobular carcinoma, 172 intraductal papillary tumors, 170–171 lobular in situ carcinoma, 171–172 lymphoma, 174 malignant myoepithelioma, 173 mesenchymal tumors, 174 metaplastic carcinoma, 172–173 metastatic disease, 116 microglandular adenosis, 170 myofibroblastoma, 174 nipple adenoma, 169–170 Paget's disease, nipple, 173 pseudoangiomatous stromal hyperplasia, 174 sclerosing adenosis, 169–170 tubular adenoma/adenosis tumor, 169–170 Brenner tumor ovary, 87, 1406, 1411, 1419 vagina, 1336 Bronchial asthma, 417 brushings, 39, 46 washings, 39 Bronchiectasis, 1216–1217 Bronchiolo-alveolar carcinoma (BAC), 1214 Bronchoalveolar lavage (BAL), 39, 40, 42 Bronchocentric granulomatosis, 1217 Bronchogenic cysts, 1164–1165, 1213, 1214 Bronchogenic cyst, skin, 800 Bronchopulmonary dysplasia (BPD), 1214–1215 Brucella species, 341–343 Brugia malayi, 399 BSLE. See Bullous systemic lupus erythematosus b-thalassemia, 558–559 Bubonic plague, 334 Budd-Chiari syndrome, 1799 Buerger's disease. See Thromboangiitis obliterans Bullet track, low velocity missles, 646 Bullous keratopathy, 1130–1131 Bullous pemphigoid (BP), 851–852 Bullous systemic lupus erythematosus (BSLE), 854–855, 864 Burkholderia, 339 Burkitt's lymphoma/leukemia (BL), 71–72, 505–506 bone marrow, 767–768 gastrointestinal tract, 1742 lymph node, 704–705 spleen, 730–731 Burns. See Local hyperthermia Café-au-lait spot, 839 Calcifying aponeurotic fibroma, 1006 Calcifying epithelial odontogenic tumor (Pindborg tumor), 1097 Calcifying odontogenic cyst (Gorlin cyst), 1094

1857



Calcium pyrophosphate crystal deposition disease (pseudogout, chondrocalcinosis), 963–964 Calymmatobacterium granulomatis, 336 Campanacci's disease (osteofibrous dysplasia), 988–989 Campylobacter jejuni, 336–337 Canalicular adenoma, 1060 Cancer breast, 496, 589–590 head and neck, 532 lung (see Lung cancer) thyroid (see Thyroid cancer) urinary bladder, 1561 Cancer, benign lesions and mimics ectopic prostatic tissue, 1569 endometriosis, 1568–1569 fibroepithelial polyp, 1568 idiopathic retroperitoneal fibrosis, 1570 urethral caruncle, 1569 urethral diverticula, 1569 urethral inflammatory polyp, 1569 Cancer biomarker data and information, 477–478 molecular diagnosis, 477 Candida albicans, 10–11, 79, 373–374 Candida species, 373–374, 1686 Candidiasis oral cavity, 1084 respiratory cytology, 38–51 vulva, 1314–1315 Capillaria philippinensis, 400–401 Capillary hemangioma (Infantile hemangioendothelioma), 1024–1025 Carbohydrate metabolism disorders, 574–575 Carbon dioxide, 440 Carbon monoxide, 441, 651, 672 Carcinoid atypical, 49 bladder, 1560 heart disease (CHD), 1200 islet cell tumors, 260 ovary, 1406, 1419 stomach, 1709–1710 thymic, 1174–1176 tumors, 1732, 1738–1739 typical, 49 uterus, 1362 Carcinoma bladder, 1521, 1541, 1551, 1560 with chondroid metaplasia, 1291 duct collecting, 89–90, 1503 ex-pleomorphic adenoma, 1061 fallopian tube, 1391 nasopharynx, 262 papillary, 1405, 1407–1409, 1411, 1422, 1426–1427 salivary gland, 1061, 1075 secretory, 1288 serous, 1376–177 thymic, 1167, 1173–1175 thyroid, 913–926, 950–951 uterus, 1354–1356, 1361–1362, 1370–1378, 1391, 1393–1394 Carcinosarcoma bladder, 1554

1858

Index

salivary gland, 1062–1063 uterus, 1363, 1386 vagina, 1339 Cardiac neoplasms, 1201–1204 Cardiac rhabdomyoma, 1022 Caroli disease (intrahepatic), 1808 Carotid sleeper hold (Lateral Vascular Neck Restraint), 437 Cartilage, cytology, 77–78 Cartilagenous lesions, 977–983 Cartilaginous tumors, 1251 Castleman's disease, 685–686, 1184–1186 Cat scratch disease, 70, 687 Cavernous angioma (“Cavernoma”), 652 Cavernous hemangioma, 1025 Cavernous lymphangioma, 832 C-cell hyperplasia, 923 CD30+ lymphoproliferative disorders: lymphomatoid papulosis; CD30+ large, T-cell lymphoma, 847–848 CD45 positive and CD45 negative hematolymphoid neoplasms, 208 Celiac disease, 1721–1723 Cell surface (plasmalemma), 257–258 Cellular angiofibroma, 1322 Cellular neurothekeoma, 820, 1036–1037 Cellular rejection, 274, 277, 282–283, 287–288, 293, 295, 306, 308, 311 Cementoblastoma, 1098 Cemento-osseous dysplasia, 1095 Central cemento-ossifying fibroma, 1098 Central corneal ulcers, 1133 Central nervous system (CNS), 98–101, 605, 607–608, 644, 645, 663 Central nervous system tumors, IHC choroid plexus tumors, 189 dural hemangiopericytoma, 190 meningioma, atypical meningioma and malignant meningioma, 189–190 glial tissue astrocytoma, anaplastic astrocytoma and glioblastoma multiforme, 188 ependymoma, 188–189 gliosarcoma, 189 oligodendroglioma, 188 subependymoma, 189 infection, 193 miscellaneous atypical teratoid/rhabdoid tumor, 192 germ cell tumors, 193 hemangioblastoma, 192–193 lymphoma, 193 metastatic disease, 193 neural tissue central neurocytoma, 190 dysembryoplastic neuroepithelial tumor, 191–192 ganglioglioma and gangliocytoma, 190 pineoblastoma, medulloblastoma, retinoblastoma and supratentorial (central) primitive neuroectodermal tumor, 191 pineocytoma, 190–191 sella craniophayngioma, 192

pituitary adenoma, 192 Central neurocytoma, 628–629 Central pontine myelinolysis (CPM), 671–672 Cephalic histiocytosis, 827 Cerebellar degeneration, 671 Cerebral amyloid angiopathy (CAA), 651, 652 contusion, 427–428 edema, 606 infarct, 648 malaria, 666 swelling, 429 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), 650–651 Cerebral infarct, 648–649 Cerebrospinal fluid (CSF), cytology, 98–101 Cerebrovascular disease, 416–41 Cervical intraepithelial neoplasia (CIN), 1353–1354 Cervical squamous cell carcinoma (SCC), 21–23 Cervicitis, 1345 Cestodes (tapeworms), 394–396 Chalazion, 1147 Charcot-Marie-tooth disease, 550 Chemical asphyxia, 440–441 Chemicals, 452–453 Chemotherapy-induced atypia, 41 Cherry angiomas, 834 Cherubism, 1096 Chief cell hyperplasia, 928 Chlamydial cervicitis, 1345 Chlamydia trachomatis, 12 Choke hold (Shime-Waza), 437 Choking, 439 Cholangiocarcinoma, 83, 260, 1840–1842 Cholangitis, recurrent pyogenic, 1783–1784 Cholecystitis, 1825 Choledochal cyst (extrahepatic), 1807–1808 Choledocholithiasis, 1826 Cholelithiasis, 1825–1826 Cholestasis and biliary tract disorders, 1801–1805 and duct injury, 1792 post-operative, 1804 of pregnancy, intrahepatic, 1804–1805 Chondroblastoma, 979–980 Chondroid, 77, 78 chordoma, 991 syringoma (benign mixed tumor), 810–811 tumors, 250, 260 Chondroma, 978–979 Chondromyxoid fibroma, 980–981 Chondro-osseous tumors, 1001, 1035–1036 Chondrosarcoma bone and cartilage, 78 and its variants, 981–983 jaws, 1100 larynx and trachea, 1118 Chop wound, 435 Chordoma, 990–991 Chorioamnionitis, 1437–1439 Choriocarcinoma mediastinum, 1180 ovary, 1418

Index

placenta, 1434–1435 testis, 1635 Choroid plexus neoplasms, 637–638 Choroid plexus papilloma, 100 Chromoblastomycosis, 372–373 Chromophobe renal cell carcinoma, 89, 1502–1503 Chromosomal disorders, 537–544 Chromosomal sarcomas, 490 Chromosome breakage syndromes, 542–544 Chronic bronchitis, 1217 cellular rejection, 274 cervicitis, 1345 endometritis, 1367, 1368 eosinophilic leukemia (CEL), 757 follicular cervicitis, 15–16 follicular conjunctivitis, 1138 gastritis, 80 gliosis, 606 granulomatous inflammation, eye, 1128 histiocytic intervillositis (massive chronic intervillositis), 1449 idiopathic myelofibrosis (CIMF), 736–737 lymphocytic leukemia (CLL), 504 bone marrow, 775–776 lymph node, 691–692 spleen, 728 multifocal recurrent osteomyelitis, 961 myelogenous leukemia (CML), 753–754 myelomonocytic leukemia (CMML), 773 myeloproliferative disorders, 774 neutrophilic leukemia, 757–758 nongranulomatous inflammation, eye, 1127–1128 osteomyelitis, 960–961 pancreatitis, 84 papillary conjunctivitis, 1138 pyelonephritis, 1475–1476 salpingitis, 1388, 1389 sclerosing sialadenitis of submandibular gland (Küttner's tumor), 1053 spongiotic dermatitis, 878 thyroiditis, 58 vascular rejection, 275 Chronic sclerosing sialadenitis of submandibular gland, 1053 Churg-Strauss syndrome, 1227–1228 Churg-Strauss syndrome, blood vessels, 1207 Cicatricial pemphigoid, 852 Cigarette smoking, 41 Ciliated cell change (tubal metaplasia), uterus, 1369 Ciliocytophthoria, 44, 95 CIN. See Cervical intraepithelial neoplasia Cingulate (subfalcine) herniation, 607 Circumscribed astrocytomas, 612–617 Cirrhosis, 1795, 1802–1803 Clark's nevus, 841 Classical Hodgkin lymphoma (CHL), 507 Clear cell acanthoma, 803 adenocarcinomas, 251, 260, 1360, 1372 carcinoma bladder, 1554 breast, 1288

kidney (CCSK), 1493–1494 odontogenic, 1099 ovary, 86 renal, 88–89, 260–261, 1493–1494 uterus, 1377 vagina, 1337 metaplasia, 1267 sarcoma, 261, 517, 520, 1039–1040, 1490 tumor benign, lung, 1410–1411 myomelanocytic, bladder, 1410–1411, 1560–1561 ovary, 1410–1411 Clinical Laboratory Improvement Act (CLIA '88), 485, 487 Clonality, 501 Clonorchiasis, 1788–1789 Clonorchis sinensis, 402 Clostridial cellulitis, 347 Clostridial myonecrosis (gas gangrene), 346 Clostridial suppurative myositis, 347 Clostridium, 349–350 Clostridium botulinum, 350 Clumped cytoid bodies and shaggy deposition of fibrinogen along the basement membrane zone, 866–867 CMV. See Cytomegalovirus CNS tumors, 223, 243–244 Coal worker's pneumoconiosis (CWP), 1226–1227 Coarctation of aorta, 1194 Coats disease, 1128–1129 Cobalt, 452 Cocaethylene, 447–448 Cocaine, 447–448 Coccidioides immitis, 365–367 Coccidioidomycosis, 45, 746 Colitis collagenous, 1726 diversion, 1726 ischemic, 1724, 1725, 1729 lymphocytic, 1725–1726 microscopic, 1725–1728 radiation, 1727 Collagenous spherulosis, 1270–1271 College of American Pathologists (CAP) anatomic pathology requirements, 485–486 autopsy requirements, 487 cytopathology requirements, 486–487 Colloid carcinoma, pancreas, 1754–1755 Colloid cyst of third ventricle, 418–419 Colloid nodule, 59–60 Colon, cytology, 81 Comedonal cyst, 799 Common melanocytic nevi, 840 Comparative genomic hybridization (CGH), 497 Complex choristomas, 1135–1136 Complex sclerosing lesion/radial scar, 1270 Condyloma, 272, 1335, 1351, 1352, 1534, 1651, 1743, 1744 Congenital adrenal hyperplasia (adrenogenital syndrome), 937–938 anomalies, 1517 dyserythroblastic anemias (CDA), 794 epulis, 820

gingival granular cell tumor, 1088–1089 heart disease, 1194–1195 hydrocephalus, 666–667 infection, 1447–1448 mesoblastic nephroma (CMN), 1491–1493 nephrotic syndrome, 1473–1474 nevus, 842 pneumonia, 322 self-healing reticulohistiocytosis, 826–827 Congenital anomalies and pediatric lesions bronchogenic cysts, 1213, 1214 bronchopulmonary dysplasia (BPD), 1214–1215 congenital pulmonary airway malformation (CPAM), 1213–1214 diffuse pulmonary lymphangiomatosis, 1214 infantile (congenital) lobar emphysema, 1215 pediatric interstitial lung disease, 1215 pulmonary sequestration, 1213 Congenital pulmonary airway malformation (CPAM), 1213–1214 Congestive heart failure, 1798–1799 Conjunctiva, 1135–1139 Conjunctival cysts, 1137 inflammation, 1137–1139 intraepithelial carcinoma, 1140 papillomas, 1140 Conjunctivitis, 1137–1139 Connective tissue disorders, 554–557 Contact dermatitis, 878–879 Contact ulcer, 1115 Contrecoup contusion, 427–428 Contusion, 422–424 Copper storage disorders, 1815–1818 Cornea, 1129–1135 Corneal degenerations and dystrophies, 1134–1135 Corneal ulcers, 1132–1133 Corpora amylacea, 42–43 Corpus luteum cyst, 86, 1401 Cortical adenoma, 942–945 contusion, 646 dysplasia, 668, 669 hyperplasia, 939–940 infarcts, 1480–1481 Corticobasal (ganglionic) degeneration (CBD), 657 Corticotrophic (ACTH) adenomas, 675–676 Corynebacterium diphtheriae, 326 Corynebacterium jeikeium (formerly Group “JK” bacilli), 326 Coup contusion, 427 Cowden's syndrome (Multiple hamartoma syndrome), 591 Cowper's glands, 1594 CPAM. See Congenital pulmonary airway malformation Craniopharyngioma, 100, 643, 676 Craniorachischesis, 666, 667 Creola bodies, 40, 44, 47 Crescentic glomerulonephritis, 1457, 1462–1463 Creutzfeldt-Jakob disease (CJD), 378, 655–657

1859



Cribriform carcinoma, prostate, 1604 Cri du Chat syndrome, 541 Crohn's disease, 1724–1725 Crooke's hyaline change, 675 Cryoglobulinemic glomerulonephritis, 1465–1467 Cryptococcosis, 44–45 Cryptococcus neoformans, 374–375 Cryptogenic organizing pneumonia (COP)/ bronchiolitis obliterans organizing pneumonia (BOOP), 1219–1220 Cryptorchidism, 1619 Cryptosporidium parvum, 386 Crystal arthropathies, 963–964 C. tetani, 350–351 Cushing's syndrome, 675 Cutaneous ciliated cyst, 800 entrance wound, 430 exit wounds, 431 lymphoid hyperplasia (lymphocytoma cutis), 893 lymphomas, classification of, 844 meningothelial heterotopias/meningiomas, 821 myxoid cyst See Digital myxoma neoplasms and developmental anomalies, 799–850 CWP. See Coal worker's pneumoconiosis Cyclin D1, 526 Cyclospora cayetanensis, 386–387 Cylindroma, 813 Cystadenoma, 53, 84, 87 Cystic fibrosis, 564, 1749, 1812–1813 granulosa cell tumor, 86 hygroma, 832 lesions eyelid, 1148 inflammatory, 1054–1055 mediastinum, 1164–1167 neoplastic/developmental, 799–801 salivary gland, 1055 vulva, 1316–1317 liver disease, 1805–1807 lymphangioma, ovary, 1401–1404 lymphoid hyperplasia (HIV+ subjects), 1053 neoplasms, salivary gland, 1054 nephroma, 1511 partially differentiated nephroblastoma, 1491 tumor of the atrioventricular node, 1203 Cysticercosis, 665, 671 Cystinosis, 576–577 Cystinuria, 576 Cystitis acute, 1517–1518 BCG-induced, 1521–1522 chronic, 1518–1519 cystica, 1527 cytoxan-induced hemorrhagic, 1521–1522 eosinophilic, 1523–1524 granulomatous, 1519 interstitial, 1522–1523, 1539 radiation, 1520–1521 special variants of, 1522–1523 treatment-induced, 1520–1521

1860

Index

tuberculous, 1520–1521 urinary bladder, 1517–1524 Cyst of müllerian origin, 1527 Cysts esophagus, 1684 liver, 81–82, 1847 non-hematopoietic lesions, 738 peritoneum, 1425–1429 thymic, 1166–1167, 1181 Cytogenic karyotyping, 508 Cytokine effects, bone marrow, 795 Cytologic/histologic variants, 609–610 Cytologic smear, evaluation of, 36 Cytomegalovirus, 1316 esophagus, 1687 infection, hepatobiliary disease, 1781 lymph node, 685 microbiology, 378 neuropathology, 664 Cytomegalovirus (CMV), 1230 Cytoplasm, 249–256 Cytotoxic edema, 606 Dabska's tumor (malignant endovascular papillary angioendothelioma), 836 Dacryocystitis, 1151 Dacryolithiasis, 1151 DAG. See Diffuse antral-predominant gastritis Dandy walker malformation, 667, 668 Death, cardiovascular causes of, 413–416 Death, non-vascular causes of, 417–421 Decidual cells, 16 Decidual pseudopolyp and decidualization, 1351 Decidual reaction, uterus, 1366 Decomposition, 411 Decompression sickness, 442–443 Decoy cells, 91, 93 Decreased atmospheric pressure, 422 Dedifferentiated liposarcoma, 1019 Defense wound, 435 Degenerations, conjunctiva, 1136–1137 Deletion syndrome, 541 Dematiaceous fungi, 371–372 Demyelinating disorders, 660–661 Demyelinating viral infections, 661 De novo carcinogenesis, 272 De-novo osteosarcoma, 972–974, 981 Dentigerous cyst, 1093–1094 Dentinogenic ghost cell tumor (included here given similarity to Gorlin cyst), 1095 Dermal analogue tumor (membranous adenoma), 1059–1060 Dermal nerve sheath myxoma, 1032 Dermatitis herpetiformis (DH), 865–866 Dermatofibroma, 75, 823, 830, 1011 Dermatofibrosarcoma protuberans (DFSP), 519 Dermatomyofibroma, 829 Dermatomyositis, 867, 885 Dermatopathic lymphadenopathy, 687 Dermatophytes, 371 Dermatophytosis, 883 Dermatoses, 894–895 Dermoid cyst immunodermatology, 799 oral cavity, 1092 testis, 1635

Desmoplastic fibroma, 987 Desmoplastic small round cell tumor (DSRCT), 517, 518 Desmoplastic tumor, 261, 1043 Desquamative interstitial pneumonitis (DIP), 1220 Destructive malformations, 668–669 DFSP. See Dermatofibrosarcoma protuberans DH. See Dermatitis herpetiformis Diabetes mellitus, 411, 419, 1128, 1463–1464, 1748–1749 Diffuse alveolar damage (DAD)/acute interstitial pneumonia (AIP), 1218–1219 (infiltrative) astrocytomas, 609–612 axonal injury, 428–429 idiopathic pulmonary neuroendocrine cell hyperplasia, 1241 large B-cell lymphoma (DLBLC), 72, 702–703, 735, 780 large B-cell lymphoma, stomach, 1709 large cell lymphoma, 1180 lymphoid hyperplasia/lymphocytic interstitial pneumonitis, 1252 mesangial sclerosis, 1474–1475 neurofibroma, 1031 panbronchiolitis, 1218 pulmonary lymphangiomatosis, 1214 Diffuse antral-predominant gastritis (DAG), 1700 Digestive tract, IHC anus anal gland adenocarcinoma, 135 Bowen disease, 135 infection, 135 leiomyoma, leiomyosarcoma, 135–136 lymphoma, 136 malignant melanoma, 135 mesenchymal tumors, 136 metastatic disease, 136 Paget's disease, 135 squamous cell carcinoma, 135 esophagus adenocarcinoma, 130 granular cell tumor, 131 high-grade dysplasia, Barrett, 130 infection, 130 leiomyoma, leiomyosarcoma, 131 lymphoma, 131 malignant melanoma, 131 mesenchymal tumors, 131 metastatic disease, 131 small cell carcinoma, 130–131 squamous cell carcinoma, 130 small intestine, colon and rectum adenocarcinoma, 133–134 endocrine neoplasms, well differentiated, 134 fibromatosis, 134 gastrointestinal stromal tumor (GIST), 134 granular cell tumor, 134 infection, 133 inflammatory myofibroblastic tumor, 134 lymphoma, 135 mesenchymal tumors, 134–135

Index

metastatic disease, 135 small cell neuroendocrine carcinoma, 134 stomach adenocarcinoma, 132 endocrine neoplasms, well differentiated, 132 gastrointestinal stromal tumor (GIST), 132–133 glomus tumor, 133 hepatoid adenocarcinoma, 132 lymphoma, 133 metastatic disease, 133 Digital fibrokeratoma, 828–829 Digital mucous cyst, 801 Digital myxoma (cutaneous myxoid cyst), 1037 Digital pacinian neuroma, 1030 Dilated cardiomyopathy, 414 Dilated pore of Winer, 805 Dimorphic fungi, 365–370 DIP. See Desquamative interstitial pneumonitis Diphyllobothrium latum, 394 Direct immunofluorescence (DIF), 850 Dirofilarial granulomas, 1237 Dirofilaria species, 401 Discoid lupus erythematosus (DLE), 863–864 Disease classification, 683–684 Dissecting cellulitis, 899 Dissection, blood vessel, 1206 Disseminated fungal infection, 1085, 1114 Diverticulae, 1696, 1727–1728 Diverticulosis, urinary bladder, 1530 DNA diagnostic methodologies, 495–496 Döderlein bacilli (Lactobacillus acidophilis), 12 Dog heart worm. See Dirofilarial granulomas Dowling-Degos disease, 838 Down syndrome, 537, 670 Dracunculus medinensis, 396–397 Drowning, 441–442 Drugs and toxins, hepatobiliary disease, 1790–1793 Drug toxicity, 275, 280 Dry drowning, 441 DSRCT. See Desmoplastic small round cell tumor Dubin-Johnson syndrome, 1810 Duchenne/Becker muscular dystrophy (DMD/ BMD), 548–549 Ductal adenocarcinoma, 85 (endometrioid) adenocarcinoma, prostate, 1603–1604 carcinoma, 65–69, 1750, 1752–1754 cysts, conjunctiva, 1137 intraepithelial neoplasia (DIN), 1276–1277 neoplasia, pre-invasive, 1756–1761 Duct ectasia (periductal mastitis), 1270 Dural metastases, 642 Duret (secondary brainstem) hemorrhage, 607–608 Dysembryoplastic neuroepithelial tumor (DNT) (WHO Grade I), 629–630 Dysfunctional uterine bleeding, 1366–1367 Dysgenetic cysts, 1054–1055 Dysgerminoma, 87, 263, 1406, 1417 Dysplasia, 19–21, 27, 79

thymic, 1167 Dysplastic nevus, 841 E-cadherin, 526 Eccrine angiomatous hamartoma, 831 -derived tumors and proliferations, 809–815 duct carcinoma, 813–814 poroma, 812 spiradenoma, 813 syringofibroadenoma, 809–810 Echinococcus, 394, 746 Ectopic decidual reaction, 1335, 1404, 1429 pregnancy, 1389 prostatic tissue, 1533, 1594 supernumerary ovary, 1401 Eczematous dermatitis, 878–879 Edward syndrome, 538, 670 EGFR. See Epidermal growth factor receptor Ehlers-Danlos syndrome, collagen related, 556 Ejaculatory ducts, 1593 Elastofibroma, 829, 1002–1003 Elisa, 111, 271, 358, 386, 388, 392, 394, 401, 851 Embolism, 421–422, 429 Embryonal rhabdomyosarcoma, 1023, 1847 tumors, 634–636 Embryonal carcinoma, 261 mediastinum, 1180 ovary, 1406, 1418 testis, 1632–1633 Emphysema, 1215–1216, 1226 Emphysematous vaginitis, 1335 Empty Sella syndrome, 677 Encephalitis, 606, 663–664, 671 Encephalocele, 666 Endocarditis, 319 infectious, 1200 non-infectious, 1200 Endocardium valves, 1199–1201 Endocervical adenocarcinoma, 25–28 cells, 23–25 polyps, 1352 transformation zone component (TZ), 9–10 Endocervicosis, 1408, 1527–1530 Endocrine carcinoma (small cell), poorly differentiated, 1764 Endocrine neoplasm, pancreas, 1763–1764 Endometrial adenocarcinoma, 14, 28, 30–31 carcinoma, 1371–1378 cells, cytologically normal, 28–29 cellular changes (metaplasias), 1368–1369 cycle, 1364–1365 cytology, 28–32 hyperplasia, 1370–1371 intraepithelial carcinoma, 1371–1373, 1377 polyps, uterus, 1369–1370 stromal and related tumors, 1381–1384 Endometrial cells, 28–30 Endometrioid adenocarcinoma, 1338, 1360, 1375 carcinoma, 87, 1375

polyp, 1390–1391 tumors, 263 tumors, ovary, 1406, 1409–1410 Endometriosis ovary, 1404 skin, 800–801 uterus, 1350 vulva, 1323 Endometriotic cyst, 86, 1404, 1409, 1410 Endometritis, 1345 Endometrium, 1364–1366 Endophthalmitis, 1126 Endosalpingiosis, 800–801, 1401, 1426 End-stage scarring alopecia, 877, 900 Entamoeba histolytica, 12, 387 Enteritis, 1719, 1729 Enterobius vermicularis (pinworm), 12, 397–398 Enterococcus species, 323 Enterocolitis, 1719, 1725 Enterohemorrhagic E. coli (O157:H7), 1720 Enteropathy-associated T-cell lymphoma (EATL), 707–708 Entrance wound, 646 Entrapment (environmental suffocation), 438–439 Enzyme-linked immunosorbent assay (ELISA), 851 EORTC classification, 844 Eosinophilic pneumonia, 1222 Eosinophils cellulitis (Wells' syndrome), 893 Ependymomas, 100, 618–621, 623 Epidermal cyst, 56, 799, 1317 tumors and proliferations, 801–804 Epidermal growth factor receptor (EGFR), 522–524, 528–529 Epidermoid cyst, 1635, 1766 Epidermolysis bullosa acquisita (EBA), 853–854 Epididymis, 1621, 1641–1642 Epidural hematoma, 646 Epidural hemorrhage, 426 Epilepsy, 417 Epithelial cell abnormalities, 8 inclusion glands/cyst in ovarian cortex, 1401, 1405–1407, 1412, 1414, 1426, 1428 -myoephithelial carcinoma, 1071–1072 neoplasms and developmental anomalies, 799–817 sarcoma, 1329–1330 tumors adenocarcinoma, 1243–1244 adenosquamous carcinoma, 1244–1245 bronchioloalveolar carcinoma, 1214 fallopian tubes, 1390–1393 large cell undifferentiated carcinoma, 1245 salivary glands, 1061–1074 small cell carcinoma, 1243 squamous cell carcinoma, 1243 uterus, 1351–1363, 1369–1378, 1384–1386

1861



Epithelioid hemangioendothelioma, 983–984, 1845–1846 immunodermatology, 836 soft tissue, 1028 hemangioma, 1025 immunodermatology sarcoma, 261, 831, 1041 soft tissue, 1025, 1028 Epithelioid cell tumors, 211, 216 Epstein-Barr virus (EBV), 378–380, 1231, 1780–1781 Erdheim-Chester disease, 992 Error detection methods active vs. passive, 484 prospective vs. retrospective, 484 traditional, 484 Eruptive histiocytoma, 827 Eruptive vellus hair cyst, 800 Erysipelas, 321 Erythema multiforme, 867 Erythema nodosum, 895 Erythroleukemia, 764 Erythropoietic protoporphyria (EPP), 1818–1819 Escherichia coli, 330–331 Esophageal cyst, 1165 Esophagitis caustic (corrosive), 1684–1685 eosinophilic, 1685–1686 infectious, 1686–1687 pill-induced, 1685 radiation, 1685 Esophagus, 1685–1711 cytology, 78–80 non-neoplastic anomalies, 1683–1684 Essential thrombocythemia (ET), 756–757 Ethanol (drinking alcohol), 446–447 Ethidium bromide (EtBr) staining of gels, 492, 493 Ethylene glycol, 447 Ewing sarcoma/primitive neuroectodermal tumor, 517, 518 Ewing's sarcoma, 78, 251, 261, 989–990 Exit wound, 646 Exstrophy, 1517, 1525, 1526, 1552 Extaspinal (soft tissue) ependymoma, 1034 External hordeolum or stye, 1147–1148 External otitis, chronic, suppurative, 338 Extrahepatic bile ducts, 1851–1853 Extrahepatic biliary atresia, 1808–1810 Extramedullary hematopoiesis (EMH), 735–736 Extramedullary plasmacytoma, 1184 Extranodal lymphoma, 696, 697, 707 Extrarenal rhabdoid tumor, 1042 Extraskeletal myxoid chondrosarcomas, 520 Extraskeletal osteosarcoma, 1035–1036 Extraskeletal sarcoma, 950 Extra-uterine metastatic adenocarcinoma, 31–32 Extrinsic allergic alveolitis (hypersensitivity pneumonitis), 1221–1222 Eye acute inflammation, 1126–1127 diseases that affect multiple structures in the eye, 1125–1129

1862

Index

inflammation of the eye, 1126–1128 tumors of the eye, 1142–1147 Eyelids, 1147–1150 Fabry disease, 587, 1467–1468 Factor V Leiden, 493 Failed corneal graft, 1131 Fallopian tubes, 1334 epithelial tumors, 1390–1392 germ cell tumors, 1392 lymphoid and hematopoetic tumors, 1392 mesenchymal tumors, 1392 mixed epithelial mesenchymal tumors, 1392 nonneoplastic lesions, 1387–1390 secondary tumors, 1393 trophoblastic disease, 1392 tumors of the uterine ligaments, 1393 Familial adenomatous polyposis, 587–588 cancer syndromes, 587–595 hypophosphatemic rickets, 575–576 medullary thyroid carcinoma (FMTC), 592–593 Fanconi anemia, 542–543 Fasciitis, 828, 998–1002 Fasciola hepatica, 402 Fasciolopsis buski, 402 Fatal familial insomnia (FFI), 656 Fat embolism, 429 Fat necrosis, 63–64, 1272 Ferruginous bodies, 44 Fetal alcohol syndrome, 672 Fetal/perinatal insults, 669–670 Fetal rhabdomyoma, 1022 Fetal thromboocclusive lesions, 1446–1447, 1451 Fetal vascular obstruction (fetal thrombotic vasculopathy), changes consistent with, 1446–1447 Fibrillary glomerulonephritis, 1463 Fibroadenoma, 65–67, 69, 1295–1296 Fibrocystic changes, 64–66, 69, 1265 Fibroepithelial polyp, 1320, 1351 Fibroepithelioma of pinkus, 808 Fibrofolliculoma, 807 Fibrohistiocytic lesions, 74–75, 987 Fibrohistiocytic tumors, 1011–1015 Fibroid polyp, inflammatory, 1697–1698 Fibrolamellar carcinoma, 1836–1838 Fibroma, 261 cardiac, 1202 ovary, 1406, 1415 of tendon sheath, 828, 1003 Fibromatosis, 1007–1009 breast, 1274–1275 colli, 1005–1006 skin, 829, 830 soft tissue, 75–76 Fibromuscular dysplasia (FMD), 1205, 1480 Fibrosarcoma, 261 bone, 1009–1011, 1033 soft tissue, 75, 830–831, 1009–1011, 1033–1034 Fibrosing mediastinitis, 1162–1164 Fibrosis, hepatobiliary disease, 1792 Fibrothecoma, 87

Fibrous hamartoma of infancy, 829–830, 1005 histiocytoma, 261, 823–825, 987 lesions, 74–75, 987 papule, 828–829 proliferations and tumors, 827–831 thyroiditis (Riedel's thyroiditis), 908–909 tumors, 1186–1187 calcifying, 1009–1007 solitary, 1004–1005 Fibrous dysplasia (FD, Jaffe-Lichtenstein syndrome), 988 Fibrous histiocytoma, 1011–1012 Fibroxanthoma, 825, 1014–1015 FIGO staging of the vulva and vagina, 1330–1331, 1341 Fine needle aspiration (FNA), 38, 39 Firearms injuries, 430–434 FISH. See Fluorescence in situ hybridization Fissure, 1742–1743 Fistula, 1743 Fixed drug eruption, 888 Flat urothelial lesions with atypia, 1538–1541 Florid cystitis glandularis, 1527–1528 FLT3 abnormalities, 510–511 Flukes. See Trematodes Fluorescence in situ hybridization (FISH), 490–491, 517 Fluoxetine (Prozac), 450 FMD. See Fibromuscular dysplasia Foamy gland carcinoma. See Adenocarcinoma with microvacuolated cytoplasm Focal “adrenalitis,” 935–936 Focal nodular hyperplasia, 82, 1847 Focal segmental glomerulosclerosis (FSGS), 1458 Folic acid deficiency, 16 Follicle cysts, ovary, 1401–1403 Follicular adenoma, 917–918 carcinoma, 905, 916, 918–919, 922, 1507 cervicitis, 1345 cyst, 86 dendritic cell, 261, 739 hyperplasias, 683–686 infundibulum, tumor of the, 805 lymphoma, 504–505 bone marrow, 778 lymph node, 684, 698–700 spleen, 729–730 neoplasm favor benign, 60–61 Folliculitis decalvans, 899, 900 Forensic entomology, 411–412 Fox-Fordyce disease, 1313 Fracture contusion, 428 Fractures, 424–425 Fragile X syndrome, 545, 670 Francisella tularensis, 343–344 Freckle (ephelid), 838 Freons, 423 Friedreich's ataxia, 546–547, 658 Frontotemporal lobar degeneration (FTLD), 653 FSGS. See Focal segmental Glomerulosclerosis Fuchs adenoma, eye, 1145–1146 Fuchs dystrophy, 1134 Fumarylacetoacetic acid hydrolase (FAH), 568

Index

Fundic gland polyp, 1697 Fungal diseases, uterus, 1347 Fungal infection, 1234–1236 hepatobiliary disease, 1785–1787 lymph node, 688 neuropathology, 662–663 Fungal osteomyelitis, 961 Fungi, 361–378 Funiculitis, 1643–1644 Fusarium species, 362 Fusobacterium genus, 351–352 Galactokinase deficiency, 575 Galactosemia, 575 Gallbladder, 1825–1826, 1851–1853 Ganglion, 605, 625–627 Ganglion cyst, 1037 Ganglioneuroblastoma, 949, 1177 Ganglioneuroma adrenal gland, 948–949 gastrointestinal tract, 1737 mediastinum, 1177–1178 soft tissue, 76, 1032 Gangliosidosis, 582–583 Gastric antral vascular ectasia (GAVE), 1699–1700 emptying, 411 marginal zone B-cell lymphoma, stomach, 1707–1709 ulcer, 80, 1703 Gastritis, 1700–1703 acute hemorrhagic, 1701 autoimmune, 1701 granulomatous, 1702–1703 lymphocytic, 1702 Gastroenteric cyst, 1165 Gastroenteritis (by itself), 337 Gastroesophageal reflux disease (GERD), 1687–1688 Gastrointestinal autonomic nerve (GAN) tumor, 261 lymphoma, 1741 specific bacterial infection, 1719–1720 stromal tumors (GIST), 261, 1706–1707, 1740 Gastrointestinal stromal tumor (GIST), 520–521 Gastropathy, 1697 Gaucher disease, 585, 968 Gene expression profiling with microarray, 497 Gene rearrangements, 501–503 Genital rhabdomyoma, 1022 Genitourinary system adrenal gland cortical adenoma and carcinoma, 145–146 metastatic disease, 146 neuroblastoma, 146 pheochromocytoma, 146 kidney adult epithelial tumors, 142–144 leiomyoma/leiomyosarcoma, 145 lymphoma, 145 mesenchymal tumors, 145 miscellaneous tumors, 144–145 pediatric tumors, 141–142 prostate gland

adenoid cystic/basal cell carcinoma, 149–150 androgen deprivation and radiation therapy changes, 149 atypical small acinar proliferation, 149 basal cell hyperplasia, 148 benign prostatic hyperplasia, 148 leiomyoma, leiomyosarcoma, 150 lymphoma, 150 mesenchymal tumors, 150 mucinous (urothelial type) adenocarcinoma, 150 phyllodes tumor, 150 prostatic adenocarcinoma, 149 sclerosing adenosis, 148 seminal vesicle adenocarcinoma, 150 urothelial carcinoma, 150 testis adenomatoid tumor, 150 germ cell tumors, 150–153 lymphoma, 153 mesenchymal tumors, 153 metastatic disease, 153 sex cord stromal tumors, 153 solitary fibrous tumor, 153 urinary bladder adenocarcinoma, 147 clear cell adenocarcinoma, 147 clear cell carcinoma, 147 endocervicosis and endometriosis, 146–147 inflammatory myofibroblastic tumor, 148 leiomyoma, leiomyosarcoma, 148 lymphoma, 148 mesenchymal tumors, 148 metastatic disease, 148 nephrogenic adenoma, 146 post-operative spindle cell nodule, 147–148 rhabdomyosarcoma, 148 sarcomatoid carcinoma, 147 small cell carcinoma, 147 urothelial carcinoma, 147 Geographic tongue, 803, 1092 Germ cell tumors, 1174, 1175, 1178–1180 fallopian tube, 1392 mixed, testis, 1626–1636 neuropathology, 644 ovary, 1417–1420 ovary, gynecological tract choriocarcinoma, 167 dysgerminoma, 166 embryonal carcinoma, 167 yolk sac tumor, 166 testis, 1626–1636 testis, genitourinary system choriocarcinoma, 153 embryonal carcinoma, 152–153 seminoma, 150–151 spermacytic seminoma, 151–152 yolk sac tumor, 152 uterus, 1364, 1387 Germinal centers, progressive transformation of, 685 Germinoma, 100

Gerstmann-Sträussler-Scheinker disease (GSS), 656 Gestational trophoblastic disease (GTD), 1432–1437 g-Hydroxybutyrate (GHB), 450 Giant cell arteritis/aortitis, 1207 carcinoma, osteoclastic, pancreas, 1755, 1756 fibroblastoma, 519, 830 granuloma, 1087, 1095–1096 jaws, 1095–1096 lesions, 984–987, 1095–1096 osteoclastoma, 984–986 reparative granuloma, 986–987 tendon sheath, 76, 828, 1012–1013 tumor, 984–986 Giant condyloma, 1651–1652, 1744 Giardia lamblia, 387–388 Gingival cyst/lateral periodontal cyst, 1101 GIST. See Gastrointestinal stromal tumor Gitter cells, 604–605 Glandular cell abnormalities, 24–28 Glandular tumors and precursor lesions, uterus, 1357–1361 Glassy cell carcinoma variant, uterus, 1361–1362 Glaucoma, 1125 Glioma of the optic nerve (pilocytic astrocytoma of the optic nerve), 1154 Gliosis (reactive astrocytosis), 606 Glomerular diseases, 1457–1475 Glomeruloid hemangioma, 835 Glomerulopathies, 1470 Glomus tumor bone and joints, 984 skin, 837–838 soft tissue, 1029 stomach, 1710 Glycogen acanthosis, 1683–1684 Glycogen storage diseases, 1197 Gnathostoma species, 401 Gonadal dysgenesis, 1401, 1420 Gonadoblastoma, 1416, 1420, 1639 Gonadotrophic (FSH/LH) adenomas, 676 Gonorrhea, 344, 345 Goodpasture's syndrome, 1224–1225 Gorham disease (massive osteolysis), 983 Gorlin cyst. See Calcifying odontogenic cyst Gout and gouty arthritis, 963 Graft vs. host disease, 867, 886 Gram-negative bacilli, 330–344 Gram-negative cocci, 344–345 Gram-positive bacilli, 323–330 Gram-positive cocci, anaerobic, 352–353 Granular cell tumor, 251, 252, 261 breast, 1275 cytopathology esophagus, 1694 neuropathology, 677 oral cavity, 1088–1089 skin, 819–820 soft tissue, 1032–1033 vulva, 1320–1321 Granular dystrophy, 1134 Granulocytic sarcoma, 1184, 1304

1863



Granuloma annulare, 892 bone marrow, 795 fungal infection, 663 hepatobiliary disease, 1793 inguinale, 336 Granulomatous mastitis, 1271 mediastinitis (localized fibrosing mediastinitis), 1162, 1164 prostatitis, 1583–1584 salpingitis, 1388–1389 slack skin, 847 thyroiditis (de Quervain's), 907–908 Granulosa cell tumor, 87, 261, 1406, 1412– 1414, 1416, 1638–1639 Graves' disease, 910–912, 1153–1154 Gray matter, 668, 669 Growth hormone adenoma, 676 GTD. See Gestational trophoblastic disease Guillain-Barré syndrome (GBS), 661 Gunshot wounds, 646–647 Gynandroblastoma, 1416 Gynecological tract, IHC cervix endocervical adenocarcinoma, non-intestinal type, 156 endocervical intestinal-type adenocarcinoma, 157 high-grade squamous dysplasia/ carcinoma in situ, 156 lymphoma, 158 mesenchymal tumors, 158 mesonephric remnants, hyperplasia and carcinoma, 155–156 metastatic disease, 158 small cell carcinoma, 157–158 squamous cell carcinoma, 156 ovary carcinoid tumor, 165 carcinosarcoma, 166 clear cell carcinoma, 163–165 endometrioid carcinoma, 162–163 endometriosis, 162 germ cell tumors, 166–167 lymphoma, 168 mesenchymal tumors, 168 metastatic disease, 168 mucinous carcinoma, 163 serous carcinoma, 163 sex cord stromal tumors, 167–168 small cell carcinoma, hypercalcemic type, 165–166 small cell carcinoma, pulmonary type, 165 struma ovarii, 167 transitional cell carcinoma, 166 peritoneum adenomatoid tumor, 168 desmoplastic small round cell tumor, 169 fibromatosis, 169 inflammatory myofibroblastic tumor, 169 mesothelioma, 168–169 primary serous carcinoma, 168 solitary fibrous tumor, 169 uterus, corpus

1864

Index

adenomatoid tumor, 160 carcinosarcoma, 159 choriocarcinoma, 159 clear cell carcinoma, 159 endometrial intraepithelial carcinoma, 158 endometrial stromal nodule and sarcoma, 160–161 endometrioid carcinoma, 158 leiomyoma, leiomyosarcoma, 160 lymphoma, 162 mesenchymal tumors, 162 metastatic disease, 162 mucinous carcinoma, 158–159 nodule and trophoblastic tumor, placental site, 159 serous carcinoma, 158 sex cord elements, endometrial stromal tumor, 161–162 small cell carcinoma, 159 undifferentiated endometrial sarcoma, 162 vulva and vagina Bowen's disease, 154 clear cell carcinoma, 154 deep aggressive angiomyxoma, 154 leiomyoma, leiomyosarcoma, 155 lymphoma, 155 malignant melanoma, 154 mesenchymal tumors, 155 metastatic disease, 155 Paget's disease, 153–154 post operative spindle cell nodule, 155 sarcoma botryoides, 154–155 squamous cell carcinoma, 154 Gynecologic cytology, 8–33 Gynecomastia, 66, 1266–1267 Gyral defects, 667–668 Haemophilus influenzae, 340 Hairy cell leukemia, 262, 695, 731, 779–780 Halo nevus, 842 Haloperidol (Haldol), 451 Hamartoma, 738–739, 1239–1240, 1274 Hamartomatous polyp, 1732–1733 Handguns, 430–431 Hanging, 435 Hantavirus, 380 Hantavirus pulmonary syndrome, 1231 Hard metal pneumoconiosis, 1227 Hartnup disease, 576 Hashimoto's thyroiditis, 58–59, 909–910 HD. See Hodgkin's disease Head and neck cancer MEC, 532 PA, 532 SCC, 532 eye and ocular adnexa lymphoma, 120 malignant melanoma, 120 mesenchymal tumors, 120 metastatic disease, 120 retinoblastoma, 120 miscellaneous tumors paraganglioma/carotid body tumor, 120, 121

pleomorphic and spindle cell lipoma, 120 nasopharynx lymphoma, 115–116 mesenchymal chondrosarcoma, 115 mesenchymal tumors, 115 metastatic disease, 116 nasopharyngeal carcinoma, 114 olfactory neuroblastoma, 115 sinonasal adenocarcinoma, intestinal type, 114 sinonasal undifferentiated carcinoma, 114 oropharynx granular cell tumor, 116 lymphoma, 116 mesenchymal tumors, 116 metastatic disease, 116 rhabdomyoma, 116 parathyroid gland, 120 salivary gland adenoid cystic carcinoma, 116 epithelial-myoepithelial carcinoma, 117 lymphoma, 117 mesenchymal tumors, 117 metastatic disease, 117 myoepithelial carcinoma, 117 salivary duct carcinoma, 116–117 thyroid gland follicular adenoma and carcinoma, 118 Hürthle cell neoplasms, 118 lymphoma, 120 medullary thyroid carcinoma, 118 mesenchymal tumors, 119 metastatic disease, 120 papillary thyroid carcinoma, 118 poorly differentiated squamous carcinoma, 119 undifferentiated thyroid carcinoma, 118–119 upper respiratory tract angiosarcoma, 113–114 infection, 112 kaposi sarcoma, 114 langerhans cell histiocytosis, 114 lymphoma, 114 mucosal malignant melanoma, 113 rhabdomyosarcoma, 113 small and large cell neuroendocrine carcinoma, 112–113 squamous cell carcinoma, 112 Head, gunshot wounds of, 431 Head injuries blunt, 646 closed, 607, 645 complications of, 429 open, 645 Health Insurance Portability and Accountability Act of 1996 (HIPAA), 487 Heart disease, atherosclerotic, 413 Heart, pathology of, 1194–1204 Heart transplantation, 282–287 Heat loss, mechanism of, 444–445 Helicobacter pylori, 337, 1700 Helminths, 394–403 Hemangioblastoma (WHO Grade I), 642–643

Index

Hemangioendothelioma, 742, 1843 Hemangioma, 1842–1843 bladder, 1556 cavernous, capillary, 640–641, 834 deep, 834 hobnail, 833, 835 infantile, 834 liver, 82 mediastinum and thymus, 1186 salivary gland tumors in children, 1075–1077 solitary, 983 superficial, 834 Hemangiopericytoma, 261, 640–643 breast, 1302 musculoskeletal, 984 skin, 838 soft tissue, 1005 tumor of the nasal cavity, 1106–1107 Hematologic disorders, 557–563 Hematolymphoid neoplasms, IHC histiocytic and dendritic cell neoplasms disseminated juvenile xanthogranuloma, 200 follicular dendritic cell sarcoma, 200 histiocytic sarcoma, 199 interdigitating dendritic cell sarcoma, 200 langerhans cell histiocytosis and sarcoma, 199–200 Hodgkin lymphoma classical, 199 nodular lymphocyte predominant, 198–199 mature B-cell B-cell prolymphocytic leukemia, 194 Burkitt lymphoma, 196 chronic lymphocytic leukemia/small lymphocytic lymphoma, 194 diffuse large B-cell lymphoma, NOS, 195 extranodal marginal zone lymphoma, 195 follicular lymphoma, nodal, 195 hairy cell leukemia, 194 lymphomatoid granulomatosis, 196 lymphoplasmacytic lymphoma, 195 mantle cell lymphoma, 195 nodal marginal zone lymphoma, 195 plasmablastic lymphoma, 195 plasma cell neoplasms, 195 primary cutaneous follicle center lymphoma, 195 primary effusion lymphoma, 196 primary mediastinal lymphoma, 195 splenic marginal zone lymphoma, 194 mature T-and NK-cell adult T-cell leukemia/lymphoma, 196 aggressive NK-cell leukemia, 196 anaplastic large cell lymphoma, ALK-positive, 198 angioimmunoblastic T-cell lymphoma, 197 enteropathy-associated T-cell lymphoma, 196 extranodal NK-T-cell lymphoma, nasal type, 196

hepatosplenic T-cell lymphoma, 196 mycosis fungoides/Sézary syndrome, 197 peripheral T-cell lymphoma, NOS, 198 primary cutaneous anaplastic large cell lymphoma, 198 subcutaneous panniculitis-like T-cell lymphoma, 197 T-cell large granular lymphocytic leukemia, 196 T-cell prolymphocytic leukemia, 196 myeloid tumors blastic plasmacytoid dendritic cell neoplasm, 200 myeloid sarcoma, 200 precursor lymphoid neoplasms B lymphoblastic leukemia/lymphoma, 194 T lymphoblastic leukemia/lymphoma, 194 Hematopoietic disorder, 760t neoplasms, 497, 499–500, 1640, 1847 tumors, 1330, 1339, 1767 Hemochromatosis, 578–579, 1197, 1814–1815 Hemopericardium, 1198 Hemophagocytic syndrome (HPS), 686, 738–739, 790–791 Hemophilia, 560–561 Hemophilic pseudotumor, 983 Hemorrhagic telangiectasia (Osler-Weber-Rendu disease), hereditary, 1801 Hemorrhoids, 1742, 1743 Hemosiderin-laden macrophages, 42, 63 Hepatic encephalopathy, 672 Hepatic fibrosis, congenital, 1807 Hepatic venous outflow obstruction, 1798–1800 Hepatitis acute, 1791–1792 autoimmune, 1821–1822 chronic, 1792 neonatal giant cell, 1824 steatohepatitis, 1794 viral, 1773–1782 viruses, 380 Hepatobiliary cystadenocarcinoma, 1842 Hepatobiliary cystadenoma, 1832–1833 Hepatobiliary disease, 1771–1826 Hepatobiliary system, IHC gallbladder and extra-hepatic bile ducts adenocarcinoma, 141 liver angiomyolipoma, 138 cholangiocarcinoma, 138 embryonal rhabdomyosarcoma, 138 hemangioma, infantile hemangioendothelioma, epithelioid hemangioendothelioma and angiosarcoma, 138 hepatic adenoma, 136 hepatoblastoma, 138 hepatocellular carcinoma, 136–138 infection, 136 lymphoma, 138 mesenchymal tumors, 138 metastatic disease, 139

undifferentiated sarcoma, 138 pancreas acinar cell carcinoma, 139 intraductal papillary mucinous neoplasms, 139 invasive ductal carcinoma, 139 mucinous cystic neoplasms, 139 neuroendocrine neoplasms, 139–140 serous cystic neoplasms, 139 solid pseudopapillary neoplasm, 140 Hepatoblastoma, 83, 1838–1840 Hepatocellular adenoma, 82, 83, 261–262 carcinoma, 1793, 1834–1836 necrosis, pure, 1790–1791 Hepatocytes, 81, 89 Hepatoid carcinoma, 1421 Hepatosplenic T-cell lymphoma, 708, 733, 783–784 HER2. See Human epidermal growth factor receptor 2 Hereditary hemorrhagic telangiectasia (Osler-WeberRendu syndrome), 832 liver disease, 1805–1821 nephritis, 1472–1473 neuropathy with liability to pressure palsies, 551 non-polyposis, colon cancer, 590–591 Polyposis syndromes and gastric manifestations, 1698t Hereditary hemochromatosis (HH), 494 Hereditary hemorrhagic telangiectasia, 832, 1801 Herniation, 428 Herniation syndromes, 607 Herpes gestationis (pemphigoid gestationis), 852–853 Herpes simplex virus (HSV), 1230–1231 1 and 2 (HSV), 380 cytopathology, 12, 79, 93 esophagus, 1686–1687 infection, 1315, 1346, 1367, 1781–1782 keratitis, 1133 neuropathology, 663 oral cavity, 1084 Heterotopic gastric mucosa (“inlet patch”), 1684 meningeal lesions (ectopic meningioma), 1033 nasal glioma, 821, 1033 ossification, 957 pancreas, 1696 thyroid, 905–906 Heterozygotes, 562, 1814 Hibernoma, 818, 1018 Hide and Die syndrome, 443–444 Hidradenitis suppurativa, 1313 Hidradenocarcinoma (malignant nodular hidradenoma), 812 Hidradenoma papilliferum (HP), 815 Hidroacanthoma simplex (intraepidermal poroma), 812 Hidrocystoma, 801 High-grade prostatic intraepithelial neoplasia (HGPIN), 1595–1597

1865



High grade squamous intraepithelial lesion (HSIL), 20–21 High-grade surface osteosarcoma, 975 Hilar Leydig cell hyperplasia, 1403, 1410 Hilus cell tumor, 262 Hippocampal necrosis, 649 Histiocytic and macrophage disorders, bone marrow, 790–792 Histiocytic lymph node tumors, 684 Histiocytoid carcinoma, 1287 Histiocytosis X (Langerhans' cell histiocytosis), 677 Histology clues, sellar/suprasellar pathology, 673–677 Histoplasma capsulatum, 367–368 Histoplasmosis, 45, 746, 1785–1786 HIV/AIDS, 380, 663–664, 685, 746 Hodgkin lymphoma (HL), 72–73, 684, 712–716, 734–735, 786 Hodgkin's disease (HD), 1164, 1180, 1181 Holoprosencephaly, 666 Homocystinuria, 569 Homozygotes, 563 Hordeolum, 1147–1148 Hormone administration, effects of, 1366 Hortaea werneckii, 370 Hospital gangrene. See Necrotizing fasciitis HPV. See Human papilloma virus HSV. See Herpes simplex virus Human epidermal growth factor receptor 2 (HER2) determining methods, 524–525 overexpression, 524–525 Human immunodeficiency virus (HIV) / Acquired immune deficiency syndrome (AIDS), 1467 Human immunodefi ciency virus infection and AIDS, 1779–1780 Human papilloma virus (HPV), 380–382, 1085, 1314, 1346–1347 Human t-cell lymphotropic virus 1 and 2 (HTLV), 382 Humoral (“vascular”) rejection, 283–284, 294–295 Humoral rejection (hyperacute rejection), 271, 274, 283 Huntington's disease (HD), 547, 653 Hürthle cell, 59, 61, 919–921 Hyaline arteriosclerosis, 1204 Hyaline fungi, 361–365 Hybrid cyst, 801 Hydatid cyst, 1788 Hydatidiform mole, 1432–1434 Hydranencephaly, 669 Hydrocele, 1642 Hydrocephalus, 607, 666–667 Hydrocystomas (“water cysts”), 1148 Hydrogen cyanide, 441 Hydrogen sulfide, 441 Hymenolepis species, 394–395 Hyperacute rejection, 271, 274, 294 Hyperbilirubinemias, 1810–1811 Hyperkeratosis (HK), 15, 1115–1116 Hyperkeratotic squamous papilloma, 1105 Hyperparathyroidism, 965

1866

Index

Hyperplasia, 24, 40, 41, 48, 59, 60, 67, 70, 82, 94, 1357, 1524–1525, 1585–1591 Hyperplastic arteriolosclerosis, 1204–1205 Hyperplastic polyp (HPP), 80, 1697, 1733–1734 Hyperreactio luteinalis, 1402 Hypertensive cardiovascular disease, 413 heart disease, 1197 intracerebral hemorrhage, 651 vascular disease, 1204–1205 Hypertrophic cardiomyopathy, 414 pyloric stenosis, 1696 scar and keloid, 827 Hypoglycemic brain injury, 651 Hypospermatogenesis, testis, 1623–1624 Hypotensive anoxia, 1800 Hypothalamic hamartoma, 677 Hypothermia, local, 443 Hypoxic ischemic encephalopathy, 429 I-cell disease, 582 Idiopathic dilated cardiomyopathy, 1196 granulomatous mastitis, 1271 granulomatous orchitis, 1623 guttate hypomelanosis, 839 hypertrophic cardiomyopathy, 1195–1196 inflammatory bowel disease, 1723–1725 interstitial pneumonias, 1220–1221 Parkinson's disease (IPD), 653 paucity of intrahepatic bile ducts, 1805 portal hypertension (non-cirrhotic portal fibrosis), 1801 pulmonary hemosiderosis, 1225 “Id” reaction, 879 IgAN. See IgA nephropathy IgA nephropathy (IgAN), 1459–1460 IgA pemphigus, 860, 861 Ileal conduit, 91 Immersion hypothermia, 443 Immune-mediated disease, oral cavity, 1085–1086 Immune thrombocytopenic purpura (ITP), 795 Immunoblastic reaction, 687 Immunobullous diseases, 851 Immunocytoma (marginal zone lymphoma), 844–845 Immunodermatology, 850–870 Immunoglobulin and T-cell receptor gene rearrangements, 501 Immunohistochemical (IHC) diagnosis applications, 111–112 methods, 109–111 principles, 109 Immunophenotypic distinction between Hodgkin lymphoma and anaplastic large cell lymphoma, 712t Immunosuppression, 270 Impetigo, 321 IMT. See Inflammatory myofibroblastic tumor Incised wound, 434 Inclusion body fibromatosis (infantile digital fibromatosis), 1006 Inclusion cysts and Walthard nests, 1389 Increased atmospheric pressure, 442–443

Indeterminate cell histiocytosis, 827 Indirect immunofluorescence (IIF), 850–851 Infantile digital fibroma/fibromatosis, 829 fibromatosis (desmoid-type), 1006 lobar emphysema, 1215 myofibromatosis, 1005 Nephrotic syndrome, 1473–1475 Refsum disease, 579–580 Infarcted appendix epiploica, 1428 Infections bacteria, 1231–1232 contaminants, 44, 49 fungal, 1234–1236 larynx and trachea, 1114 mycobacterial, 1232–1234 nasal cavity, sinuses and nasopharynx, 1102–1103 organisms, 10, 12 protozoan, 1236–1237 uncommon, ovary, 1400 viral, 1230–1231 Infectious lesions, vulva, 1314–1316 mononucleosis, 70, 687, 727, 745 processes, respiratory, 44–45, 78, 79 sinusitis, other forms of, 1103 Infectious pyelonephritis (ascending or hematogenous infection), 1475 Infertility, 1623–1626 Infiltrating carcinoma, 1282–1293 Infiltrative diseases, 1197 Inflammatory bowel disease, 1823 carcinoma, breast, 1282 disorder, gastrointestinal tract, 1719–1728 fibrous polyp, 1734 hepatobiliary disease, 1800–1801, 1823 lesions appendix, 1730–1731 miscellaneous, ovary, 1400–1401, 1428–1429 ovary, 1400–1401 prostate, 1583–1854 vulva, 1312–1313 myofibroblastic tumor soft tissue, 1008–1009 spleen, 740 urinary bladder, 1531–1533 non-neoplastic lesions, 1086–1088, 1103–1105, 1114–1115, 1162–1164 pancreas, 1749–1752 pseudopolyp, 1733 liver and biliary system, 1850–1851 orbit, 1152–1153 pseudotumor lymph node, 719 spleen, 739 vascular lesions, hepatobiliary disease, 1800–1801 Inflammatory disease, gastrointestinal tract, 1719–1720 Inflammatory myofibroblastic tumor (IMT), 1248 Inflammatory pseudotumor, 1247–1249

Index

Injuries blunt force, 422–430 electrical, 445–446 physical, 421–446 road traffic, 424–425 sharp force, 434–435 toxic, 672–673 Instrument artifact and lithiasis, 91 Insular carcinoma, 921 Interdigitating dendritic cell neoplasm, 262 Interface dermatitis, 883–888 Internal hordeolum, 1148 Interstitial diseases acute lung injury, 1218–1220 eosinophilic pneumonia, 1222 extrinsic allergic alveolitis, 1221–1222 goodpasture's disease, 1224–1225 idiopathic interstitial pneumonias, 1220–1225 idiopathic pulmonary hemosiderosis, 1225 lymphangioleiomyomatosis, 1224 pneumoconioses, 1225–1227 pulmonary alveolar proteinosis, 1223–1224 pulmonary langerhans cell histiocytosis (PLCH), 1222–1223 sarcoidosis, 1223 Interstitial pattern, 892–894 Intervillous thrombus (fetomaternal hemorrhage), 1443–1444 Intestinal ischemia, 1728 Intestinal polyps, 1732–1737 Intra-abdominal desmoplastic small round cell tumor, 1406, 1427 Intracerebral hemorrhage (apoplexy), 416 Intracortical osteosarcoma, 975 Intracranial hemorrhage, 426–427, 651 Intracystic papillary carcinoma, 67 Intraductal carcinoma with secretory features, 1280 clear cell carcinoma, 1280 epithelial proliferations, breast, 1276–1282 oncocytic papillary neoplasms, 1759–1760 papillary mucinous neoplasms, 1758–1759 papilloma, 66, 1294 papillomatosis, 1294 signet ring carcinoma, 1280 spindle cell carcinoma, breast, 1280 Intrahepatic bile ducts, tumors of the, 1830–1853 Intrahepatic cholestasis, 1804–1805, 1811–1812 Intralobar nephrogenic rests (ILNR), 1488 Intramuscular hemangioma, 1026 Intramuscular myxoma, 1037 Intraosseous ganglion, 968–969 Intraosseous well-differentiated osteosarcoma, 975 Intratubular germ cell neoplasia, unclassified (IGCNU), testis, 1628–1629 Intrauterine devices, changes related to, 1368 Intravascular large B-cell lymphoma, 845 Intravascular lymphoma, 652 Intravascular lymphomatosis/angiotropic lymphoma, 1254 Intravascular papillary endothelial hyperplasia (Masson's hemangioma), 833 Intravenous leiomyomatosis, 1380, 1383

Intraventricular hemorrhage, 669, 670 Invasive carcinoma, 66–69 Invasive fungal sinusitis, 1103 Invasive squamous cell carcinoma (ISCC), vulva, 1324–1325 Inverted follicular keratosis, 802 Inverted papilloma, 1536–1537, 1594 Iron deficiency anemia, bone marrow, 793 Irregular shedding, uterus, 1367 Ischemic fasciitis (atypical decubital fibroplasia), 1002 Ischemic heart disease, 1195 Ischemic injury, 1477, 1728–1729 Islet cell tumor, 86 Isopropyl (rubbing alcohol), 447 Isospora belli, 388 Isovaleric acidemia, 570 IUD-associated change, 14 Jaffe-Lichtenstein syndrome. See Fibrous dysplasia (FD, Jaffe-Lichtenstein syndrome) JC virus, 664–665 Jejunoileal bypass (JIB), 1797 Juvenile hyaline fibromatosis, 1006 hypertrophy, breast, 1266 myelomonocytic leukemia, 774 nephrophthisis (medullary cystic disease), 1484–1485 xanthogranuloma, 824, 1012 Juxtaarticular myxoma, 1037 Juxtaglomerular cell tumor, 1510–1511 Kaposiform hemangioendothelioma, 835, 1026 Kaposi's sarcoma, 77, 718, 836, 1027 Kawasaki's disease (Mucocutaneous Lymph Node syndrome), 1207 Keloid scar, 998 “Keratinizing dysplasia,” 21 Keratitis, 339, 1132–1133 Keratoacanthoma, 804, 1326 Keratoconus, 1135 Kernicterus, 670 Kidney, 88–90, 1475–1485 adult epithelial tumors chromophobe renal cell carcinoma, 144 collecting duct carcinoma, 144 mucinous tubular and spindle cell carcinoma, 144 oncocytoma, 142 papillary renal cell carcinoma, 144 renal cell carcinoma, conventional type, 143–144 renal medullary carcinoma, 144 urothelial carcinoma, 144 leiomyoma/leiomyosarcoma, 145 lymphoma, 145 mesenchymal tumors, 145 miscellaneous tumors angiomyolipoma, 145 juxtaglomerular cell, 145 metanephric adenoma, 144 renomedullary interstitial cell tumor, 144–145 pediatric tumors

clear cell sarcoma, 141–142 congenital mesoblastic nephroma, 142 Ewing sarcoma, 142 neuroblastoma, 142 rhabdoid tumor, 142 Wilms tumor, 141 Kidney transplantation, 275–282 Kikuchi-Fujimoto disease, 688 Kitamura's reticulate hyperpigmentation, 838 Klebsiella pneumoniae, 335–336 Klinefelter syndrome (XXY), 538–539 Krabbe disease, 584–585 Küpffer cells, 81 Kuru, 656–657 Küttner's tumor. See Chronic sclerosing sialadenitis of submandibular gland Labor pneumonia, 322 Laceration, 424 Lacrimal tumors, 1151 Lactating adenoma, 1273 Lactational changes, 64, 1267 Lafora's disease (myoclonic epilepsy), 659–660 Laminar/pseudolaminar necrosis, 649 Langerhans' cell histiocytosis (LCH), 78, 262, 716, 790, 826, 827, 991–992 Large airway disease, 1216–1217 Large B-cell lymphoma, 845, 846 Large cell acanthoma, 803 carcinoma neuroendocrine, 50 neuroendrocrine, 1117–1118 salivary gland, 1073–1074 undifferentiated, 46, 48 cutaneous T-cell lymphoma, 844 neuroendocrine carcinoma, 1247 undifferentiated carcinoma, 1245 Large granular lymphocytic (LGL) leukemias, 706, 733–734, 784–785 Large solitary luteinized follicle cyst of pregnancy and puerperium, 1401–1402 Laryngeal nodule/polyp, 1114–1115 Laryngocele, 1114 Larynx and trachea, 1114–1118 Lattice dystrophy, 1134 LCAT deficiency. See Lecithin cholesterol acyltransferase (LCAT) deficiency LCH. See Langerhans' cell histiocytosis Lead, 452 Lead poisoning, 673 Lecithin cholesterol acyltransferase (LCAT) deficiency, 1468–1470 Legionella pneumophila, 339–340 Legionnaires' disease, 1231–1232 Leiomyoma bladder, 1556 esophagus, 1693 eye, 1146 soft tissue, 1020–1021 stomach, 1707 uterus, 1362, 1378–1380 vulva, 1322–1323 Leiomyomatous peritonealis disseminata, 1021

1867



Leiomyosarcoma, 1249 bladder, 1557–1558 prostate, 1609–1610 skin, 822–823 soft tissue, 77, 1021 spermatic cord, 1644 uterus, 1362, 1381 vagina, 1339 variants, uterus, 1381 Leishmaniasis, 746 Leishmania species, 388–389 Lentiginous melanosis, 1655 Lentigo maligna melanoma, 843 Lentigo simplex, 840 Leprosy, testis, 1622 Leptothrix, 12 Lesch-Nyhan, 579 Lesions benign anus, 1742–1743 breast, 63–66 discolored, vulva, 1317–1319 liver, 81–82 lymphoepithelial, 1052–1053 non-neoplastic, vagina, 1334–1335 respiratory, 39–44 squamous cell, uterus, 1351–1352 thyroid, 58–60 urinary bladder, 91–92, 1524–1534 uterus, 1352 hemorrhagic, placenta, 1443–1444 lacrimal drainage system and lacrimal glands, 1150–1152 miscellaneous, 1092–1093, 1100–1101, 1112–1113 peritoneum, 1428–1429 reactive, 743–748 spermatic cord, 1642–1644 tumor-like liver and biliary system, 1847–1853 salivary glands, 1052–1054 vascular, 1301–1303 bone and joints, 983–984 gastrointestinal tract, 1728–1730 Leukemia, 504–506, 644, 1640 Leukemia cutis, 850 Leukemias of ambiguous lineage, 765–766 “Leukoaraiosis,” 651 Leukodystrophies, 673 Leukoedema, 803 Leukoplakia, oral cavity, 1084–1085, 1089–1090 Leydig cell tumor, 262, 1636–1637 Lichenoid dermatitis, 867 Lichenoid drug, 867, 887–888 Lichenoid keratosis (lichen planus-like keratosis), 801–802 Lichen planus, 866–867, 887, 1085–1086, 1318 Lichen sclerosus, 894–895, 1317, 1657–1658 Lichen simplex chronicus (LSC), vulva, 1312 Li-Fraumeni syndrome, 591–592 Light chain cast nephropathy (myeloma kidney), 1478 Light chain deposition disease, glomerular diseases, 1465 Lightning, 446

1868

Index

Ligneous conjunctivitis, 1138–1139 Limbal (epibulbar) dermoids, 1135 Lineage determination, 503 Linear epidermal nevus, 802 Linear IgA bullous dermatosis (chronic bullous disease of childhood), 855–856 Lingual thyroid, 1092 Lipid (steroid) cell tumors, ovary, 1415, 1416 Lipid degeneration, 1134–1135 Lipid-laden macrophages in bronchial lavage, 42 Lipid-rich carcinoma, breast, 1287 Lipoblastoma, 817, 1017–1018 Lipoblastomatosis, 817 Lipodermatosclerosis (lipomembranous panniculitis, sclerosing panniculitis), 895–896 Lipodystrophy, 1472 Lipofibromatous hamartoma of nerve, 817 Lipoma, 260, 1240 skin, 817 soft tissue, 74, 116 thymus, 1176, 1186 Lipomatosis, 818, 1018 Lipomatous hypertrophy of the interatrial septum, 1202–1203 Lipomatous tumors, 1016–1020 Liposarcoma, 260 mediastinum, 1187 skin, 818 soft tissue, 74, 1018–1020 spermatic cord, 1644 Liposclerosing myxofibrous tumor (LSMTF), 987 Lissencephaly/pachygyria, 667–668 Listeria monocytogenes, 326–327 Littoral cell angioma, 741 Liver cell adenoma, 1852 cytology, 81–83 disease, 1793–1798, 1805–1821 reactive/regenerative changes, 82 tumors of the, 1830–1851 Liver transplantation, 291–299 Loa loa, 399 Lobar hemorrhage, 651, 652 Lobar pneumonia, 335 Lobular capillary hemangioma, 1025, 1105 Lobular carcinoma, 67, 68 Lobular intraepithelial neoplasia (LIN), 1281–1282 Local hyperthermia, 444 Localized fibrous tumor of the pleura, 1258 Long QT syndrome (LQTS), 413 Low-grade B-cell lymphoma of MALT type, 1184 Low-grade fibromyxoid sarcoma, 519 Low grade myofibroblastic sarcoma, 1009 Low grade squamous intraepithelial lesion (LSIL), 19–20 Lung cytology, normal cellular components of, 39 injury, acute, 1218–1220 Lung cancer malignant mesothelioma, 529 non-small cell, 528–529 small cell, 529

Lung fluke. See Paragonimiasis Lung transplantation, 287–291, 1237–1238 Lupus erythematosus, 863–865, 884–885, 890, 898–899 Lupus panniculitis (lupus profundus), 896–897 Lupus variants, immunobullous diseases, 863 Luteal phase, inadequate, 1366–1367 Lymphadenitis, 70 Lymphangiogram effect, 686 Lymphangioma, 741, 831–832, 835–836, 983, 1186, 1766 Lymphangio(leio)myomatosis, 1224 Lymph node, 70–73, 681–719 Lymphoblastic leukemia/lymphoma (ALL/ LBL), 732, 766–769 Lymphoblastic lymphoma (LBL), thymus, 1173, 1183 Lymphocyte Hodgkin lymphoma, 712–713 Lymphocytic hypophysitis, 677 interstitial pneumonitis (diffuse lymphoid hyperplasia), 1252 leukemia, 262 mastitis (diabetic mastopathy, fibrous mastopathy), 1271–1272 thyroiditis (painless thyroiditis), 909, 910 Lymphocytic leukemia/lymphoma (ALL/LBL), 99 Lymphoepithelial carcinoma, 262, 1074, 1101 Lymphoepithelial cell variant (Lennert lymphoma), 711 Lymphoepithelial cyst, 1092, 1766 Lymphoepithelioma-like carcinoma, 1117, 1357, 1548–1549, 1607 Lymphogranuloma venereum (LGV), 688, 1316 Lymphoid hematopoietic tumors, 1364 hyperplasias, 683–688, 1167–1168, 1176 lesions, 1303–1304 neoplasms, 727–735, 1707–1709 tumors, 1135 Lymphoma, 262, 727–735 bladder, 1559–1560 breast, 1303 cardiac, 1203 central nervous system, 644, 645 common variants of, 71–73 cutaneous follicular center cell, 845 diagnosis, 504–507, 511–512 esophagus, 1694 lesion, uterus, 1351, 1368 leukemia, 32, 50, 1387, 1423 liver and biliary system, 1847 neuropathology, 644 prostate, 1611 salivary gland, 1075 stomach, 81 testis, 1640 Lymphoma malignant (WHO classification), 689–716 Lymphomatoid papulosis (LyP), 891 Lymphoplasmacytic lymphoma, 504, 692–694, 728–729, 777 Lymphoproliferative disorders, 775–785, 844–850, 1180–1185

Index

Lymphoproliferative lesions, lung benign/hyperplastic, 1251 intravascular lymphomatosis, 1254 lymphomas, 1252–1253 primary pulmonary hodgkin disease, 1253, 1254 LyP. See Lymphomatoid papulosis Lysergic acid diethylamide (LSD), 449 Lysosomal storage diseases/disorders, 580–587, 673 Macrophage/microglial reactions, 605–606 Macroscopic, esophagus achalasia, 1683 adenocarcinoma, 1692 barrett esophagus, 1688 Candida species, 1686 caustic (corrosive), 1685 cysts, 1684 cytomegalovirus, 1687 eosinophilic, 1685 fibrovascular polyp, 1694 GERD, 1687 glycogen acanthosis, 1684 granular cell tumor, 1694 herpes simplex virus, 1686 heterotopic gastric mucosa (inlet patch), 1684 leiomyoma, 1693 lymphoma, 1694 melanoma, 1694 pill-induced, 1685 radiation, 1685 small cell carcinoma, 1693 squamous cell carcinoma, 1691 squamous papilloma, 1690 varices, 1688 Macular dystrophy, 1134 Malabsorptive disorder, gastrointestinal tract, 1719–1728 Malakoplakia, 1519–1520, 1622–1623 Malaria, 746, 1787–1788 Malassezia furfur, 370 Male breast, carcinoma of the, 1293 Malignancy, mimics of, urinary bladder, 91–92 Malignant (anaplastic) meningioma, 640 chondroid syringoma, 810–811 cylindroma, 813 eccrine spiradenoma, 813 fibrous histiocytoma (MFH), 75, 825, 987, 1015 hyperthermia, 445 lesions, 82–83 lymphoma eye, 1145 lymph node, 71–73, 683–684, 689–716 nasal cavity, paranasal sinuses and nasopharynx, 1108 melanoma, 262, 843–844, 870 eye, 1142–1143 nasopharynx, 1110 oral cavity, 1091 skin, 73–74, 843–844, 870 uterus, 1364

vagina, 1338 vulva, 1329 mesothelioma, 529, 1257–1258, 1427, 1642 myoepithelioma (myoepithelial carcinoma), 1300–1301 neoplasms jaws, 1099–1100 nasal cavity, paranasal sinuses and nasopharynx, 1107–1112 oro/hypopharynx, 1101–1102 salivary glands nephrosclerosis, 1479 pilomatricoma, 807, 808 tumors epithelial, 1061–1073, 1323–1328, 1336–1338, 1391–1392 gastrointestinal tract, 1737–1742 mesenchymal, 1176, 1187 mixed Müllerian, 32, 1412, 1421 non-epithelial, 1329–1330 peripheral nerve sheath, 76, 263, 821, 1033–1034, 1177 prostate, 1599–1611 serous, 1405–1408 triton, 1034 trophoblastic, 1434–1437 Malignant tumors cartilaginous, 1251 epithelial, 1243–1245 lymphoproliferative lesions, 1251–1254 masses and tumor-like lesions, 1255–1256 mesenchymal, 1247–1256 neuroendocrine, 1245–1247 neurogenic, 1251 salivary gland type, 1241–1243 uncertain histogenesis, 1254–1255 vascular, 1227–1230, 1249–1251 MALT. See Mucosa Associated Lymphoid Tissue MALT lymphomas, 504 Mansonella perstans, 399 Mantle cell lymphoma (MCL), 71, 505, 700–702, 730, 779, 1741–1742 Maple syrup urine disease, 568–569 Marfan syndrome, fibrillin related, 554–555 Marginal zone lymphoma (MZL), 777–778, 844–845 Marijuana, 450 Marijuana smoking, habitual, 41 Massive ovarian edema, 1403–1404 Massive perivillous fibrinoid deposition (maternal floor infarction), 1449–1450 Massive retinal gliosis, 1129 Masson's tumor. See Papillary endothelial hyperplasia Mastitis, lung, 1271–1272 Mastitis/periareolar abscess, 1271 Mastocytoma, 889, 890 Mastocytosis, 894 Maternal arteriopathies and preeclampsia, 1441–1444 Matrix metalloproteinases (MMPs), 526

Maturation arrest, 1624–1625 Mature B-cell neoplasms, 683, 691–705 Mature cystic teratoma, 86 Mature peripheral T-cell lymphoma/leukemia, 506 Mature T-cell and NK-cell neoplasms, 683–684, 705–712 MCD. See Minimal change disease Measles, 382 MEC. See Mucoepidermoid carcinoma Mechanical asphyxia, 440–441 Mechanical duct obstruction, 1801–1802 Meconium and subacute hypoxia, 1440–1441 Mediastinal (thymic) large B-cell lymphoma, 505, 703–704 Mediastinal parathyroid lesions, 1168–1169 Mediastinitis, 1162–1164 Medullary carcinoma, 56, 62, 69, 924, 925, 1286–1287, 1755 Medulloblastoma, 634, 635 Medulloepithelioma, 1146 Megaloblastic anemia, bone marrow, 794 Melanoacanthoma, 1092 Melanocytic nevi, 1319 Melanocytic proliferations, 838–844 Melanocytic proliferations and pigmentary disorders, 838–839 Melanocytic tumors, uterus, 1363–1364 Melanoma, 1694, 1744–1745 Melanotic neuroectodermal tumor of infancy, 1100 Melanotic paraganglioma, 1387 Melasma, 838 Membranoproliferative (mesangiocapillary) glomerulonephritis (MPGN), 1460–1461 Membranous nephropathy (MN), 1458–1459 Meningioma, 638–641 Meningiomas, 100, 262, 1154–1155 Meningitis, 345, 661–663 Menke's disease, 578 Mercury, 452 Merkel cell carcinoma, 74, 262, 816–817 Merkel cell tumor (MCT), 1330 Mesenchymal chondrosarcomas, 1100, 1113 hamartoma, 1849 lesions, 988–992 neoplasms, kidney, 1508–1511 tumors benign (low-grade), mediastinum, 1186 fallopian tube, 1392 fibrous and fibro-histiocytic, 1247–1249 inflammatory pseudotumor, 1247–1248 malignant fibrous histiocytoma, 1248–1249 mediastinum, 1185 pancreas, 1766–1767 salivary glands, 1075 skeletal muscle, 1249 smooth muscle, 1249 uterus, 1362–1363, 1378–1386 Mesenchymal cystic hamartoma, 1240

1869



Mesenchymal tissue, IHC bone chordoma, 180 Ewing sarcoma/peripheral neuroectodermal tumor, 181 langerhans cell histiocytosis, 181 metastatic disease, 182 plasma cell dyscrasia, plasmacytoma and multiple myeloma, 181 small cell osteosarcoma, 180–181 cartilage mesenchymal chondrosarcoma, 179–180 fibrous and fibrohistiocytic atypical fibroxanthoma, 176 benign fibrous histiocytoma, 175 deep (desmoid) fibromatosis, 177 dermatofibrosarcoma protuberans, 176 desmoplastic small round cell tumor, 176–177 fibrosarcoma, 177 inflammatory myofibroblastic tumor, 176 juvenile xanthogranuloma, 175 myofibromatosis, myofibroma, 176 nodular, proliferative and ischemic fasciitis, 174–175 solitary fibrous tumor and hemangiopericytoma, 175–176 miscellaneous alveolar soft part sarcoma, 182 angiomyolipoma, 182 clear cell sarcoma, 182 epithelioid sarcoma, 182–183 gastrointestinal stromal tumor (GIST), 182 pleomorphic and spindle cell lipoma, 182 synovial sarcoma, 182 undifferentiated high-grade pleomorphic sarcoma, 183 neural tissue granular cell tumor, 179 malignant peripheral nerve sheath tumor, 179 neurofibroma, 179 schwannoma, 179 skeletal muscle rhabdomyoma, 177 rhabdomyosarcoma, 177–178 smooth muscle, 177 vessels angiosarcoma, epithelioid hemangioendothelioma and hemangioma, 178 glomus tumor, 178 kaposi sarcoma, 178 Mesial temporal sclerosis (MTS; hippocampal sclerosis), 670 Mesodermal stromal polyp (pseudosarcoma botryoides), uterus, 1351 Mesonephric adenocarcinoma, 1338, 1360 Mesonephric (Gartner's duct) cyst, 1317 Mesonephric remnants and mesonephric hyperplasia, 1349–1350 Mesothelial hyperplasia, 94, 1426 tumors, fallopian tube, 1392

1870

Index

Mesothelial cells, 94–95 Mesothelioma, 47, 95–96, 262 Metabolic bone disease, 964–968 Metabolic disorders, 567–580, 671–674 Metabolic liver disease, 1805–1821 Metachromatic leukodystrophy, 586 Metal metabolism disorders, 577–579 Metals, 451–452 Metanephric tumor family, 1508 Metaphyseal fibrous defect (non-ossifying fibroma), 987 Metaplasia esophagus, 1688–1690 gallbladder, 1852 intestinal, 1517, 1526, 1553 nephrogenic, bladder, 1525–1526 nephrogenic, prostate, 1592–1593 prostate, 1591–1592 urinary bladder, 1525–1526 Metaplastic carcinomas, 69, 1290–1291 Metaplastic changes, breast, 1267 Metaplastic papillary tumor, 1390 Metastases, 642, 644–645, 1847 Metastases from distal sites, 1188 Metastasizing leiomyoma, benign, 1256 Metastasizing pleomorphic adenoma, 1063 Metastatic adenocarcinoma, 31–32, 83, 96–98, 100 bone disease, 992 carcinoid, 83 carcinoma, 50–51, 63, 101 disease, 743, 744, 792, 1100 esophagus, 1695 tumors, 1146–1147, 1187–1188, 1407, 1408, 1422, 1429 Methane, 440 Methanol, 447, 651, 672 Methotrexate toxicity, 673 Methylmalonic acidemia, 571 Microadenomatous hyperplasia (primary pigmented nodular adrenocortical disease, PPNAD), 940–941 Microaerotolerant, histotoxic species, 348 Microcalcifications, lung, 1265 Microcystic adnexal carcinoma, 814 Microdeletion syndromes, 539–542 Microfilaria (tissue roundworms), 399 Microglandular adenosis (MGA), 1268–1269 Microglandular endocervical hyperplasia, 1348–1349 Microglandular hyperplasia, 24 Microglial activation (rod cells, microglial nodules), 606 Microinvasive breast carcinoma, 1282 Microsatellites, 522, 523 Microscopic hemangioma, breast, 1301 Microsporidia, 389–390 Microvenular hemangioma, 835 Migrational/gyral defects, 667–668 Milia, 799 Miller-Dieker syndrome, 542 Minimal change disease (MCD), 1457–1458 Minimal residual disease, 497, 507 Miscellaneous tumors, 1577 Mitochondrial disorders, 595–596 Mitral regurgitation, 1200

Mitral stenosis, 1200–1201 Mitral valve prolapse, 414 Mixed carcinoid-adenocarcinoma, gastrointestinal tract, 1738, 1739 Mixed carcinomas, pancreas, 1766 Mixed cell adenocarcinoma, uterus, 1377 Mixed cellularity Hodgkin lymphoma (MCHL), 714–715 Mixed endometrial stromal and smooth muscle tumor, 1384 Mixed epithelial and mesenchymal tumors, 1392 Mixed epithelial and stromal tumor, kidney, 1512 Mixed epithelial mesenchymal tumors, fallopian tube, 1392 Mixed epithelial neoplasms, kidney, 1511–1512 Mixed oligoastrocytoma, 618 Mixed tumor, malignant, 1061–1063 MMPs. See Matrix metalloproteinases MN. See Membranous nephropathy Molecular determination of clonality of non-lymphoid malignancies, 501, 503 Molecular pathology assays, guidelines for rational use of, 498–500 Mollaret meningitis, 99 Molluscum contagiosum, 12, 382–383, 1315 Mönckeberg's medial calcific sclerosis, 1205 Mondor's phlebitis, 1301 Mongolian spot, 839 Monoclonal gammopathy of undetermined significance (MGUS), 789 Morbilliform drug eruption, 884, 886–888 Morphea, 894 Morton's neuroma (localized interdigital neuritis), 1030 Motor neuron disease, 657 Mountain sickness, 442 MPGN. See Membranoproliferative (mesangiocapillary) glomerulonephritis Mucinous adenocarcinoma, 1359, 1372, 1375–1376, 1604–1605, 1723 (Colloid) carcinoma, breast, 68–69, 1286 change, uterus, 1369 cystadenocarcinoma, 87 cystadenoma, 87, 1239 cystic neoplasms, pancreas, 84–85, 1756–1758 eccrine carcinoma, 814 metaplasia, 1267, 1591 tubular carcinoma, 1505 tumors, 263, 1406, 1408, 1409, 1414, 1421–1422 Mucocele, 1055, 1088, 1103, 1266 Mucoepidermoid carcinoma, 54–55, 815, 1069–1070, 1241 Mucoepidermoid carcinoma (MEC), 532 Mucolipidoses, 582 Mucopolysaccharidoses, 580–582, 968 Mucor species, 362–363 Mucosa Associated Lymphoid Tissue (MALT), 1252–1253 Mucosal melanotic macules, 839 Mucosal neuroma, 1030

Index

Mucous extravasation phenomena (mucocele/ ranula), 1088 Mucous gland adenoma, 1239 Mucous membrane (cicatricial) pemphigoid, 1086 Müllerianosis, 1529–1530 Müllerian papilloma, 1334, 1352–1353 Multicentric reticulohistiocytosis, 824–825 Multifocal intestinalized pangastritis, 1700–1701 Multifocal osteosarcoma, 974 Multi-infarct dementia, 650, 653 Multilocular cystic renal cell carcinoma, 1499–1500, 1506 Multilocular peritoneal inclusion cysts (multicystic benign mesothelioma), ovary, 1426, 1427 Multilocular thymic cyst (acquired [reactive] process), 1166–1167 Multiple endocrine neoplasia type 1, 592–593 Multiple endocrine neoplasia types 2A, 2B (MEN2A and MEN2B), 592–593 Multiple follicular cysts, ovary, 1402 Multiple pregnancy, 1450–1451 Multiple sclerosis (MS), 660–661 Multistep carcinogenesis: the colorectal cancer (CRC) paradigm APC (FPC, DP2) and CTNNB1 (B-catenin gene), 522 DCC, SMAD2 and SMAD4, 524 early lesions, 521–522 KRAS and EGFR, 522–524 microsatellite instability, 522 multistage tumorigenesis, 522 TP53/p53, 524 Multisystem atrophy (MSA), 657 Musculoskeletal neoplasms, 968–993 Musculoskeletal neoplasms, staging of, 992–993 Mutational analyses, 500 Mycobacteria, 1103 Mycobacterial infections mycobacterial tuberculosis, 1232–1233 nontuberculous mycobacteria, 1233–1234 Mycobacterial tuberculosis (TB), 1225, 1232–1233 Mycobacterium avium-intracellulare, 745, 747 infection, 1785 species, 353 Mycoplasma pneumoniae, 1234 Mycosis fungoides (MF) bone marrow, 782 with follicular mucinosis, 847 lymph node, 709–710 skin, 845–847 Mycotic ulcers, 1133 Myelocytic (granulocytic sarcoma) leukemia, 262 Myelodysplastic/myeloid proliferative diseases, 773–774 Myelodysplastic syndromes, 737, 769–773 Myeloid dysplastic syndrome (MDS), 509 Myelolipoma, 948 Myelomeningocele, 666 Myelomonocytic leukemia, 262

Myeloproliferative disorders (MPD), 735, 773–774 MYH-associated polyposis, 588 Myiasis, 403 Myocardial ischemia (approximate), sequence of certain microscopic changes in, 1196t Myocarditis, 414, 1197–1198 Myocardium, 1195–1198 Myoepithelial carcinoma, 1063–1064 Myoepithelial lesions, 1299–1301 Myoepithelioma, 1057 Myoepitheliosis, breast, 1299 Myofibroblastoma, 1275 Myofibroma/myofibromatosis, 829 Myositis, 828 Myositis ossificans, 957, 1035 Myospherulosis, 1104 Myotonic dystrophy, 545–546 Myxoid liposarcoma, 1019–1020 Myxoid medial degeneration, 1205 Myxoid/round cell liposarcoma, 520 Myxoma, 1037–1038, 1201, 1421 Nabothian cyst, 1349 Naegleria fowleri, 390 Nail-Patella syndrome, 1470–1472 Nasopalatine cyst, 1093 Nasopharyngeal angiofibroma, 1107 Nasopharyngeal carcinoma (NPC), 57, 1112 Natural killer (NK) leukemias and lymphomas,bone marrow, 785 Navicular cells, 16 Near drowning, 441–442 Necator americanus, 396 Neck compression, 435–438 Necrobiosis lipoidica, 892 Necrotizing capillaritis, 1228–1229 fasciitis (gangrene), 321 granulomatous lymphadenitis, 70, 683, 687–688 non-granulomatous lymphadenitis, 683, 688 sarcoid granulomatosis (NSG), 1228 sialometaplasia, 1052, 1088, 1112 Necrotizing fasciitis, 321, 322, 351 Necrotizing sarcoid granulomatosis (NSG), 1228 Neisseria gonorrhoeae, 344–345 Neisseria meningitidis, 345 Nelson's syndrome, 675 Nematodes (roundworms), 396–402 Neonatal adrenoleukodystrophy, 579–580 Neoplasia, 1752–1767 Neoplasiatransplantation pathology, 272 Neoplasms benign jaws, 1096–1099 larynx and trachea, 1115 nasopharynx, 1105–1107 oral cavity, 1088–1089 urothelial, 1535–1537 vascular, 834–836 of the bladder, 1535–1556 breast, 1273–1276

B/T-cell, 683, 689–691 epithelial, breast, 1273–1274 hepatobiliary disease, 1793 mediastinal, 1168–1169 mesenchymal, 641–642 metastatic to heart, 1203–1204 not limited to thymus, 1177–1188 ovary, 1420–1423 premalignant/malignant, 1089–1092, 1115–1118 soft tissue, 817–831 testis, 1626–1640 thymus, 1169–1177 thyroid gland, 907 ultrastructural features of, 261 Neoplastic adenomas, 1734–1737 epithelial, 1690–1693 lung disease benign tumors, 1238–1240 malignant tumors (see Malignant tumors) pre-invasive lesions, 1240–1241 mesenchymal, 1693–1694 miscellaneous tumors, esophagus, 1694–1695 Neoplastic lesions benign, salivary glands, 52–53 head and neck, 56–57 respiratory, 45–51 thyroid, 60–63 Nephroblastoma (Wilms' tumor), 1488–1491 Nephroblastomatosis, 1488 Nephrogenic rests, 1488 Nephrotoxic injury, kidney, 1477 Nerve sheath myxoma (NSM), 820 Nerve sheath tumors, 1177, 1185–1187 Nesidioblastosis, 1748 Neural-derived tumors and proliferations, 818–821 Neural tube defects, 666 Neural tumors, 75–76, 1030–1034 Neurilemoma (schwannoma), 1276 Neuroaxonal dystrophy, 659 Neuroblastoma, 529–530 adrenal gland, 949–950 mediastinum, 1177 soft tissue, 76 staging, 1491 Neuroectodermal tumors, uterus, 1387 Neuroendocrine carcinoma, 1110–1111, 1117–1118 derived tumors, 816–817 neoplasm, 263 tumors, 1362 Neuroendocrine tumors carcinoid tumorlet, 1245–1246 differentiation, 1247 large cell neuroendocrine carcinoma, 1247 small cell carcinoma, 1246–1247 typical and atypical carcinoid, 1246 Neurofibroma, 1031–1032 bladder, 1556–1557 mediastinum, 1177 skin, 818 soft tissue, 75–76

1871



Neurofibromatosis type 1 (von Recklinghausen), 564–565 Neurofibromatosis type II, 565–566 Neurogenic tumors, 1177–1178, 1251 Neuroleptic malignant syndrome, 445 Neuroma, circumscribed, 1030 Neuronal tumors, derivations/definitions used in, 625 Neuropathic arthropathy (Charcot's joints), 963 Neuropathology anoxic disorders, 648–652 chromosomal syndromes, 670 general reactions to injury, 605–607 gliomas, 607–625, 627 glioneuronal neoplasms, 625–631 infectious diseases, 660–666 inflammatory diseases, 660–666 ischemic disorders, 648–652 malformations, 651–652, 666–671 meningeal neoplasms, 638–642 neurodegenerative disorders, 653–660 neuronal neoplasms, 625–631 non-glial neoplasms, 642–645 seizure, 666–671 sellar/suprasellar pathology, 673–677 toxic/metabolic disorders, 671–674 trauma, 645–647, 671 vascular disorders, 648–652 Neuropathy, 671 Neurosarcoidosis, 661 Neurosyphilis, 662 Nevus anemicus, 831 atypical, 841 comedonicus, 803 depigmentosus, 839 flammeus, 831 of ito and ota, 839 lipomatosus superficialis, 818 sebaceous, 808 New variant CJD (nvCJD), 656 Nicotine stomatitis, 1092 Niemann-Pick, type C (NP-C), 584–585 Niemann-Pick, types A and B, 584 Nipple lesions, 1298–1299 NK-cell neoplasms, 507 Nocardia species (nocardiosis), 327–328 Nocardiosis, 327–328, 1232 Nodal marginal zone B-cell lymphoma, 697–698 Nodal marginal zone lymphoma, spleen, 730 Nodal MZL, 504 Nodular fasciitis, 74, 75, 828, 998 Nodular fibrous periorchitis, 1642–1643 Nodular goiter, 59–60 Nodular hidradenoma (clear cell hidradenoma, solid-cystic hidradenoma, and eccrine acrospiroma), 811–812 Nodular hyperplasia, 939–940, 944 Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), 507, 712–713, 734, 786 Nodular lymphoid hyperplasia (pseudolymphoma), 1251 Nodular malignant melanoma, 843 Nodular or diffuse infiltrates, 893–894

1872

Index

Nodular regenerative hyperplasia, 1848–1849 Nodular sclerosis Hodgkin lymphoma, 714 Nodular vasculitis (erythema induratum), 896 Non-gynecologic cytology, overview, 36–101 Non-Hodgkin's lymphoma, 991 Noninfectious granulomatous inflammation, ovary, 1127 Non-necrotizing granulomatous lymphadenitis, 70 Non-neoplastic diseases, 1265–1272 alopecia, 897–900 general concepts, 877 interface dermatitis, 883–888 interstitial pattern, 892–894 lung airways and obstructive diseases, 1215–1218 congenital anomalies and pediatric lesions, 1213–1215 infections, 1228, 1230–1237 interstitial, 1218–1227 transplantation, 1237–1238 vascular conditions, 1227–1230 panniculitis, 895–897 psoriasiform dermatitis, 880–883 reactive, 1095 sclerosing dermatoses, 894–895 spongiotic dermatitis, 878–880 superficial and deep perivascular dermatitis, 890–891 superficial perivascular dermatitis, 888–890 Non-neoplastic disorders, 1162–1169 Non-neoplastic hyperplasias, 1697–1700 Non-neoplastic lesions fallopian tubes, 1387–1390 head and neck, 56 salivary glands, 51–52 testis, 1619–1626 thymus, 1167–1169 uterus, 1345–1351, 1367–1369 Non-odontogenic cysts/pseudocysts, jaws, 1093 Nonopportunistic infection, 271 Non-specific interstitial pneumonia/fibrosis (NSIP), 1221 Nontuberculous mycobacteria, 1233–1234 Nontyphoidal Salmonella infections, 332–333 Nonviral infection, hepatobiliary disease, 1782–1789 Nora's lesion. See also Bizarre parosteal osteochondromatous proliferation, 977–978 NPC. See Nasopharyngeal carcinoma NSG. See Necrotizing sarcoid granulomatosis NSIP. See Non-specific interstitial pneumonia/ fibrosis Nuchal fibroma, 1004 Nucleus, 248–249 Null cell (IP-) adenomas, 676 Nummular dermatitis (nummular eczema), 879 Obesity and diabetes mellitus, 1794 Obstruction of airway, 438–440 Occupations Safety and Health Administration (OSHA), 487 Odontogenic disorders, 1093 Olfactory neuroblastoma, 57, 1109 Olfactory neuroblastoma (WHO Grade III), 635

Oligodendroglioma, 529, 617–619, 621, 622 Onchocerca volvulus, 399 Onchocerciasis, 1132 Oncocytic carcinoma, 1064 Oncocytic cyst, 1114 Oncocytoma, 53, 88, 249, 263, 944, 1057–1058, 1495–1496 Oncocytosis, 1052 Oncotype Dx, 527 Opiates, 448–449 Opportunistic infection, 271–272 Optically clear nuclei, 1366 Oral cavity, 857, 1084–1093, 1118–1119 Orbital tumors, 1145 Orchidoepididymitis, granulomatous, 1621–1623 Organic acidemias, 570–571 Organophosphates, 452 Oro/hypopharynx, 1101–1102 Osler-Weber-Rendu syndrome. See Hereditary hemorrhagic telangiectasia Ossifying fibroma, 1086–1087, 1098 Ossifying fibromyxoid tumor, 1038–1039 Osteitis (sclerosing osteomyelitis), 961 Osteoarthritis (OA), 962–963 Osteoblastic neoplasms (osteoma, osteoblastoma,osteosarcoma), 263 Osteoblastoma, 971 Osteochondritis “juvenilis,” 959 Osteochondroma (osteocartilaginous exostosis), 977 Osteochondromyxoma, 981 Osteoclast-like giant cells, carcinoma with, 1288–1289 Osteogenesis imperfecta, 553–554, 967–968 Osteoid osteoma, 970–971 Osteoma cutis, 1035 Osteomyelitis, 318, 960–962 Osteonecrosis (avascular, aseptic, ischemic necrosis), 958–959 Osteoporosis, 964–965 Osteosarcoma, 78, 972–976, 1099–1100 Ovarian cancer, 589–590 cysts, 1409, 1412, 1417, 1418, 1422 cytology, 86–87 surface epithelial neoplasms, 263 thecal metaplasia, 941 tumors, 1404, 1406, 1410, 1417, 1419, 1421, 1429, 1642 Ovary germ cell tumors, 1417–1420 inflammatory Lesions, 1400–1401 miscellaneous tumors, 1420–1423 nonneoplastic lesions, 1401–1404 sex cord-stromal tumors, 1412–1416 surface epithelial tumors, 1405–1412 PA. See Pleomorphic adenoma Pachygyria, 667–668 Pagetoid reticulosis, 847 Paget's disease, 966–967, 1298, 1326–1327 Palisaded encapsulated neuroma, 819, 1092–1093 Palisaded myofibroblastoma, 718–719, 1021 Palisading granulomatous dermatitis, 892

Index

Palpable hemangioma, 1301–1302 PAN. See Polyarteritis nodosa Pancreas, 1747–1768 acinar metaplasia, stomach, 1696 cytology, 83–86 islet cell transplantation, 299–302 in metabolic and other medical disorders, 1748–1749 neoplasia, 1752–1767 tumors, 1763–1764, 1766–1767 Pancreatic ductal adenocarcinoma HER1/EGFR and HER2/neu, 530 KRAS, 530 Pancreatitis, 84, 1749–1751 Pancreatoblastoma, 1765–1766 Pankeratin and vimentin positive tumors, 208, 210 Pankeratin positive, vimentin negative tumors, 208, 209 Panmyelosis with myelofibrosis, 765 Panniculitis, 895–897 Panophthalmitis, 1127 Papillary adenoma, 1495 carcinoma, 61–62, 913–917, 1295, 1667 craniopharyngioma (WHO Grade I), 643 cystadenoma, 1642 cystadenoma lymphomatosum, 53 eccrine adenoma, 811 endocervicitis, 1345 endothelial hyperplasia (Masson's tumor), 1024 fibroelastoma, 1201, 1202 hyperplasia, 1852 lesions, breast, 1293–1295 renal cell carcinoma, 89, 1500–1502 serous adenocarcinoma, 31 serous cystadenocarcinoma, 87 squamous cell carcinoma, 1091, 1102, 1117, 1357 urethritis, proliferative, 1594 urothelial tumors, non-invasive, 1541–1544 Papillary adenoma, type 2 cells, 1238 Papillary endothelial hyperplasia, 1024 Papilloma, 1294, 1525, 1534 Papillomatosis, 1654 Pap test, adequate, 9–11, 32, 33 Paracoccidioides brasiliensis, 368 Paracortical hyperplasias, 683, 687 Paradoxical undressing, 443 Paraganglia, prostate, 1594 Paraganglioma, 263 bladder, 1560 head and neck cytology, 56 heart, 1203 mediastinum, 1178 Paraganglioma neuropathology, 630–631 Paragonimiasis, 1237 Paragonimus westermani, 402–403 Parakeratosis (PK), 15–18 Paraneoplastic encephalomyelitis, 661 Paraneoplastic pemphigus, 862, 867 Paraphimosis, 1659 Paraproteinemia, 1464–1467 Parasites, 385–403, 665–666 Parasitic diseases, 1347

Parasitic infections, 1367, 1731 Parathyroid gland, 926–935 Paratubal cysts, 1390 Parosteal osteosarcoma, 976 Paroxysmal nocturnal hemoglobinuria (PNH), 794 Parvovirus B19, 383 Patau syndrome, 537–538, 670. See also Trisomy Patent ductal artery (patent ductus arteriosis, PDA), 1194 Paucity of intrahepatic bile ducts, 1805 PDA. See Patent ductal artery Pearly penile papules, 828–829 Pediatric fibrous tumors, 1005–1007 Pediatric interstitial lung disease, 1215 Pediatric small round blue cell tumors, 212, 219 Peliosis hepatis, 1850 Peliosis, spleen, 740 Pemphigus erythematosus, 858–860 foliaceus, 858, 859 variants, 856 vulgaris, 856–858, 1086 Penetrating wound, 646 Penicillium marneffei, 363 Penile intraepithelial neoplasia, 1656–1657 Penis benign conditions, 1651–1655 cancer, 1659 congenital anomalies, 1650 inflammatory conditions, 1653 putative precursor lesions of the, 1655–1658 Peptostreptococci, 352–353 Perforating wound, 646 Pericardial cyst (coelomic cyst), 1165–1166 Pericardial effusion, 1198 Pericarditis, 1198–1199 Pericardium, 1198–1199 Periductal stromal sarcoma, 1297 Perifollicular fibroma, 807 Perilobar nephrogenic rests (PLNR), 1488 Perinatally acquired pneumonia, 322 Perineurioma, 820–821, 1032 Periosteal osteosarcoma, 975 Peripheral separation (marginal abruption), 1444–1445 Peritoneal fluid, cytology, 91–98 Peritoneal leiomyomatosis, 1021 Peritoneum epithelial tumors of müllerian type, 1428 mesothelial lesions, 1426–1427 miscellaneous peritoneal lesions, 1428–1429 Perivascular dermatitis, 888–891 Perivascular infiltrate, 884–887 Perivascular tumors, 837–838, 1029, 1384 Perivenous encephalomyelitis, 661 Periventricular leukomalacia (PVL), 669–670 Perivenular fibrosis, progressive, 1795 Peroxisomal disease, 579–580 Peroxisomal disorders, 673 Persistent hyperplastic primary vitreous, 1126 Peutz-Jeghers syndrome, 593 Peyronie's disease, 1654 PH. See Pulmonary hypertension Phacoantigenic endophthalmitis, 1128

Phaeohyphomycosis, 373 Phakomatosis pigmentovascularis, 831 Pharyngitis, 321 Phencyclidine (PCP), 449–450 Phenothiazine, 450–451 Phenylketonuria (PKU), 567–568 Pheochromocytoma, 252, 263, 947–948 Phimosis, 1659 Phthisis bulbi, 1129 Phycomycosis, 45 Phyllodes tumor, 69, 1296–1297, 1610 Pick's disease (lobar atrophy), 653–655 Piebaldism, 838–839 Piedraia hortae, 370 Pigmented spindle cell nevus of reed, 841 Pigmented terminal hair cyst, 800 PIGN. See Post-infectious glomerulonephritis Pilar and pilosebaceous-derived tumors, 805–809 Pilar sheath acanthoma, 805 Pilocytic astrocytoma (WHO Grade I), 612–614 Pilocytic gliosis, 606 Piloleiomyoma (pilar leiomyoma), 822 Pilomatricoma (calcifying epithelioma of Malherbe), 73, 807 Pindborg tumor. See Calcifying epithelial odontogenic tumor Pineal parenchymal tumors, 631–633 Pineoblastoma, 632 Pineocytoma, 631–632 Pinguecula, 1136 Pinworm. See Enterobius vermicularis Pituitary adenoma, 673–676 Pityriasis lichenoides et varioliformis acuta (PLEVA), 890 Pityriasis rosea, 879–880 Placenta, 1437–1450 Plague, 334 Plasma cell, 787–790 neoplasms, 696 vulvitis, 1312 Plasmacytoma breast, 1303 testis, 1640 Plasmodium species, 390–391 PLCH. See Pulmonary langerhans cell histiocytosis Pleomorphic adenoma, 52, 54, 1056–1057, 1273 fibroma, 828 lipoma, 817, 1017 liposarcoma, 1020 lipsarcoma, 1020 rhabdomyosarcoma, 1024 small/medium-sized cutaneous T-cell lymphoma, 849 xanthoastrocytoma (PXA) (WHO Grade II–III), 614–616 Pleomorphic adenoma (PA), 532 Pleomorphic tumors, 212, 218 Pleura localized fibrous tumor, 1258 malignant mesothelioma, 1257–1258 Pleural fluid, cytology, 94–98 Pleuropulmonary blastoma, childhood, 1251, 1252

1873



PLEVA. See Pityriasis lichenoides et varioliformis acuta Plexiform fibrohistiocytic tumor, 824, 1014 Plexiform neurofibroma, 1032 Pneumoconioses asbestos-related reactions, 1226 silicosis, 1225 Pneumocystis jiroveci, 375–377 Pneumocystitis carinii (PCP), 45 Pneumomediastinum, 1169 Pneumonia, 39–42 Poliomyelitis, 665 Polyarteritis, 1207, 1208, 1801 Polyarteritis nodosa (PAN), 897, 1207–1208 Polycystic disease, 1805–1807 Polycystic ovarian disease (POCD), 1366 Polycythemia vera (PV), 755 Polymerase chain reaction (PCR), 492–493 detection of IgH and TCR, 502–503 dHPLC screening assay, 494 PCR-FRET, 493–494 PCR-RFLP assay, 493 Polymicrogyria, 667, 668 Polymorphous low grade adenocarcinoma, 55–56 Polyomavirus, 383–384 Polyorchidism, 1619–1620 Polypoid adenomyoma, 1384 Polyps, gallbladder, 1852 Polyps, nasal cavity, paranasal sinuses and nasopharynx, 1104–1105 Pompholyx (dyshidrotic eczema), 897 Pontomedullary transection (brainstem avulsion), 646 Porencephaly, 669 Porocarcinoma (malignant eccrine poroma), 812–813 Porphyrias, 867, 1818–1819 Porphyromonas species, 351–352 Positional asphyxia, 440 Post-atrophic hyperplasia, prostate, 1589–1590 Post-cholecystectomy syndrome, 1826 Post-infectious glomerulonephritis (PIGN), 1461–1462 Post-inflammatory hyperpigmentation, 838 Post-inflammatory pigment alteration, 888 Post-mortem chemistry, 412 Poststreptococcal glomerulonephritis, 321 Post-surgical granuloma, 1522, 1523 Posttransplant lymphoproliferative disease (PTLD), 272–274, 291, 299, 302, 305–306, 308–310 Post-transplant lymphoproliferative disorder, 1253–1254 Pox virus. See Molluscum contagiosum Prader-Willi syndrome, 540–541 Pregnancy luteoma, 1402 related changes, 16, 24, 64, 1365–1366 Pre-invasive lesions, 1240–1241 Prevotella species, 351–352 Priapism, 1676 Primary pulmonary Hodgkin's disease, 1254 Primitive neuroectodermal tumor (PNET), 76, 100, 259, 263, 1041–1042, 1339 Prion diseases, 456 Proctitis, radiation, 1727

1874

Index

Progressive multiform leukoencephalopathy (PML), 664–665 Prolactinoma (lactotrophic adenoma), 675 Proliferative myositis, 1002 Prolymphocytic leukemia (PLL), 732 Propionic acidemia, 570–571 Prostate cancer, 1613t immunohistochemical profiles of, 1588t, 1597t treatment effects, 1611–1613 Prostate adenocarcinoma, 528 Prostatic adenocarcinoma, 1598 Prostatic urethral polyp, 1594 Prostatitis, 1583 Prosthetic valves, 1201 Prothrombin G20210A mutation, 563 Prototheca wickerhamii, 377 Protozoa, 385–394 Protozoal diseases, uterus, 1347 Protozoan infections dirofilarial (dog heart worm) granulomas, 1237 Paragonimiasis, 1237 Pneumocystis jiroveci, 1236–1237 Toxoplasma gondii pneumonia, 1237 Psammocarcinoma, 1407, 1428 Pseudallescheria/scedosporium, 363–365 Pseudoangiomatous hyperplasia, 1301 Pseudocyst, 84, 1751–1752 Pseudo-hurler polydystrophy, 582 Pseudo-hyperplastic pattern of carcinoma, 1608 Pseudo-Kaposi's sarcoma, 833–834 Pseudo-membranous colitis, 1720 Pseudomonas, 338–339 Pseudomyxoma peritonei, 1409, 1429 Pseudo-tumors, inflammatory, 1053–1054 Psoriasiform dermatitis, 880–883 Psoriasis vulgaris, 880–881 Psychoactive drugs, 449–450 Pterygium, 1136–1137 Pulmonary alveolar proteinosis, 1223–1224 amyloidosis, 1255–1256 disease, 327 hyalinizing granuloma, 1256 infarct, 40, 46 neuroendocrine tumors, 48–50 sequestration, 1213 stenosis, 1194 thromboembolism, 415–416 Pulmonary hypertension (PH) clinical and microscopic, 1229–1230 pulmonary capillary hemangiomatosis, 1229 pulmonary veno-occlusive disease with secondary pulmonary arterial hypertension, 1229 thrombotic arteriopathy, 1229–1230 Pulmonary langerhans cell histiocytosis (PLCH), 1222–1223 Purine metabolism disorders, 579 Purkinje cell necrosis (cerebellar cortex), 649 Pustular psoriasis, 881 Pyelitis, ureteritis and urethritis, 1568 Pyelonephritis, 1475 Pylephlebitis, 1800

Pyogenic granuloma, 833, 1534 Pyogenic infection, 1782 Pyogenic osteomyelitis, 960–961 5q-syndrome, 772 Quantitative RT-PCR, 496 Rabies, 384, 665 Radiation, 14, 41, 79, 91, 1612–1613 Rasmussen's encephalitis, 671 Rathke's cleft cyst, 676 RB-ILD. See Respiratory bronchiolitisassociated interstitial lung disease Real-time quantitative reverse transcription PCR, 494–495 Reflex sympathetic dystrophy (algodystrophy), 958 Reflux esophagitis, 79 Refractory anemia (RA), 771, 772 Regressed tumor, testis, 1635–1636 Renal cell carcinoma (RCC), 1496–1506 cholesterol microembolism syndrome, 1481 dysplasia, 1482–1483 medullary carcinoma, 1503–1505 neoplasms, 1488–1512 neuroblastoma, 1490 peripheral neuroectodermal tumor (PNET), 1490 synovial sarcoma, 1490 Renal cell carcinoma TFE3, 531 VHL, 531 Renal pelvis and ureter neoplasms adenocarcinoma, 1573 benign urothelial, 1570 flat urothelial lesions, atypia, 1570 squamous cell carcinoma, 1573 urothelial carcinoma, 1570–1573 tumors,TNM classification, 1577–1578 Renomedullary interstitial cell tumor (medullary fibroma), 1508–1509 Renovascular hypertension (renal artery stenosis), 1479–1480 Respiratory bronchiolitis, 1218 Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), 1220 Respiratory cytology, 38–51 Respiratory syncytial virus, 384, 1231 Restrictive cardiomyopathy, 414 Rete ovarii (rete adenoma/cyst), 1403 Reticulohistiocytoma, 824–825, 1012 Retiform hemangioendothelioma, 836 Retinoblastoma (RB), 593–594, 635–636, 1143–1145 Retinopathy of prematurity (retrolental fibroplasia), 1125–1126 Retroplacental hemorrhage, 1444 Revolvers, 430–431 Reye's syndrome, 1824–1825 Rhabdoid tumor of kidney, 1490, 1494 Rhabdoid tumors, 212, 220 Rhabdomyoma, cardiac, 1202, 1203 Rhabdomyomatous mesenchymal hamartoma, 1022

Index

Rhabdomyosarcoma, 1249, 1252 alveolar and embryonal, 263 bladder, 1558–1559 nasal cavity, paranasal sinuses and nasopharynx, 1111 orbit, 1154 soft tissue, 77, 1022–1024 spermatic cord, 1644 Rheumatic fever, 321 Rheumatic heart disease, acute, chronic, 1199 Rheumatoid arthritis (RA), 685, 964 Rheumatoid nodule, 892 Rheumatoid pleuritis/pericarditis, 95 Rhinospordiosis, 1139 Rhinosporidium seeberi, 377–378 Rhizopus species, 362–363 Rhodococcus equi, 328–330 Rickets and osteomalacia, 965 Rickettsial infection, 1785 Rickettsia rickettsii, 360–361 Rifles, 434 Rigor mortis (rigidity), 410 Ring abscess, 1132–1133 Ring ulcer, 1132–1133 Ritter disease, 318 Rocky mountain spotted fever (RMSF), 360–361 Rosai-Dorfman disease, 716 Roundworms. See Nematodes Ruptured berry aneurysm, 416–417 Salivary duct carcinomas, 56, 1070–1071 Salivary duct cysts, 1093 Salivary glands cysts, 54–56, 1054–1055 secondary cysts, 1055 tumors, 1047–1078 Salmonella typhi (Typhoid fever), 333 Salmonellosis, gastrointestinal tract, 1719 Salpingitis, 1387–1388 Salpingitis isthmica nodosa, 1389 Sandfly vector (phlebotomus), 360 Sandhoff disease, 583, 584 Sarcocystis, 391 Sarcoidosis, 1223 conjunctiva, 1139 hepatobiliary disease, 1823 nasal cavity, paranasal sinuses and nasopharynx, 1104 respiratory cytology, 43–44 testis, 1622 Sarcomas alveolar rhabdomyosarcoma, 518–519 alveolar soft part sarcoma, 520 chromosomal translocations, 517–518 clear cell, 520 congenital/infantile fibrosarcoma, 519–520 DFSP and giant cell fibroblastoma, 519 DSRCT, 518 EWS/PNET, 518 extraskeletal myxoid chondrosarcoma, 520 FISH, 517, 518 GIST, 520–521 low-grade fibromyxoid, 519 myxoid/round cell liposarcoma, 520 ovary, 1412, 1421 spermatic cord, 1644

synovial, 519 thymic, 1176 undifferentiated endometrial, 1381–1384 liver and biliary system, 1846–1847 Sarcomatoid carcinoma, 1116–1117, 1554, 1606–1607 Sarcoptes scabiei, 403–404 S. aureus endocarditis, 318 Scalp injuries, external, 425 Scarlet fever, 321 SCC. See Squamous cell carcinoma Schamberg's disease, 888–889 Schistosoma species, 403 Schistosomiasis, 1789 Schistosomiasis, 1520 Schwannoma, 263 breast, 1276 head and neck cytology, 57 mediastinum, 1177 skin, 818–819 soft tissue, 75–76, 1030–1031 Scleroderma, 894, 1730 Sclerosing hemangioma, 1254 Sclerotic fibroma, 828 Sclerotic ulegyria, 669 Scuba diving, 442 Sebaceous gland adenoma, 808, 1059 carcinoma, 809, 1150 epithelioma, 808–809 hyperplasia, 808 lymphadenoma, 1058–1059 metaplasia, esophagus, 1690 Seborrheic dermatitis, 880 Seborrheic keratosis, 802, 1318–1319 Seizure-associated pathology, 670–671 Selective neuronal necrosis, 649 Seminal vesicles, 1593 Seminoma, 1179–1180, 1626, 1629–1631 Senile seminal vesicle amyloidosis, 1593–1594 Septicemia, 337 Septic spleen, 745 Sertoli cell tumor, 1637 Sex cord stromal tumors ovary, gynecological system fibroma, fibrothecoma and thecoma, 167 granulosa cell tumor, 167–168 sertoli cell tumor, 168 Sertoli-Leydig cell tumor, 168 steroid/lipid cell tumor, 168 testis, genitourinary tract Leydig cell, 153 Sertoli cell, 153 Sexual development, abnormalities of, ovary, 1420 Sézary syndrome (SS), 709–710, 782, 847 Shaken baby syndrome (SBS), 429–430, 463 Shigella species (cause bacillary dysentery), 331–332 Shigellosis, 1719 Shotguns, 431–434 Sialadenitis, 52, 1052 Sialadenosis, 51–52, 1052 Sialoblastoma, 1077 Sialolithiasis, 1052 Sickle cell anemia, 559, 1819

Signet ring cell carcinoma, prostate, 1605–1606 Silent corticotroph adenoma, 676 Silicone reaction, breast, 1271 Silicosis, 1225 Simple cyst, kidney, 88 Sinonasal neoplasm, 1090t Sinonasal papilloma, 1105–1106 Sinonasal undifferentiated carcinoma (SNUC), 1109–1110 Sinus histiocytosis, 1304 Sinus histiocytosis with massive lymphadenopathy (SHML), 716–717 Sinus hyperplasias, 683, 686–687 Sinusitis, 1102–1103 Sinusoidal dilatation, 1793 Six-sigma-method, 483 Sjögren's syndrome, 1053 Skeletal angiomatosis, 983 Skeletal disorders, 551–554 Skeletal muscle tumor, 1247 Skeletal muscle tumors, 1022–1024 Skeletal trauma and other common conditions, 957–959 Skene's duct cyst, 1316–1317 Skin adnexal tumors, 1299 cytology, 73–74 pigmentary disorders of the, 838–839 Skin, IHC angiosarcoma, epithelioid hemangioendothelioma and hemangioma, 187 basal cell carcinoma, 184 glomus tumor, 187 granular cell tumor, 186 Kaposi sarcoma, 187 lymphoma, 187 melanoma, 186 melanoma micrometastasis, sentinel lymph node, 186 Merkel cell carcinoma, 185 mesenchymal tumors, 187 metastatic disease, 187 squamous cell carcinoma, 184 Skull fracture, 425–426, 645 SLE. See Systemic lupus erythematosus Small airway disease constrictive (obliterative) bronchiolitis, 1218 diffuse panbronchiolitis, 1218 follicular bronchiolitis, 1218 respiratory bronchiolitis, 1218 Small B-cell lymphoproliferative disorders, 693t Small bowel transplantation, 305–310 Small cell carcinoma, 22, 23, 50, 57, 1246–1247 anus, 1744 bladder, 1554–1556 esophagus, 1693 gastrointestinal tract, 1744 larynx and trachea, 1117 lung, 1187–1188 ovarian hypercalcemic type, 264 ovary, 1420–1421 prostate, 1605 salivary gland, 1073 uterus, 1362, 1377–1378

1875



Small cell osteosarcoma, 975 Small lymphocytic lymphoma (SLL), 504, 691–692, 728 Smallpox. See Variola major Small vessel disease/deep infarcts, 650–651 Smith-Magenis syndrome, 541–542 Smoke inhalation, 444 Smokeless tobacco-induced keratosis, 1093 Smooth muscle hamartoma, 821 Smooth muscle tumors, 821–823, 1249 classification, 1001t leiomyosarcoma, 1249 soft tissue, 1020–1021 uncertain malignant potential (STUMP), 1380 uterus, 1362, 1378–1382, 1384 Smothering, 438 SNUC. See Sinonasal undifferentiated carcinoma Soft tissue chondroma, 1035 cytology, 74–77 neoplasms, 817–818 tumors, bladder, 1556–1559 Soft tissue tumors, 1577 Solar lentigo, 840 Solid-pseudopapillary neoplasm, 85, 1764–1765 Solitary Rectal Ulcer syndrome (SRUS), 1726–1727 Solitary unilocular cyst, 1805 Southern blotting, 502 Specimen adequacy terminology/reporting, 9–10 Spectral karyotyping (SKY), 497 Sperm granuloma, 1641 Sphingolipidoses, 582–587 Spider angioma (nevus araneus), 832 Spina bifida occulta, 666 Spinal and bulbar muscular atrophy (SBMA, Kennedy disease), 548 Spinal cerebellar ataxia (SCA), 547–548 Spinal cord, subacute combined degeneration of, 672 Spinal cord trauma, 647 Spinal muscular atrophy (SMA), 549–550, 657–658 Spindle cell carcinoid, 49 carcinoma, kidney, 1505 hemangioendothelioma, 835 hemangioma, 1026 lesions of lymph nodes, 684, 718–719 lipoma, 817, 1017 nodule, post-operative, 1334–1335, 1351, 1369, 1530–1531 Spindle cell tumors, 211, 217 Spinocerebellar ataxia (SCA), 658–659 Spirometra species (sparganosis), 395 Spironolactone bodies, 256 Spitz nevus (spindle and epithelioid cell nevus), 841 Spleen autoimmune conditions, 748 examination and evaluation of the, 725–726 hyperplasias, 743–744 infections, 745–746 lymphoid neoplasms, 727–735

1876

Index

myeloid and related disorders, 735–738 non-hematopoietic lesions, 738–743 red blood cell disorders, 744–745 storage diseases, 746–747 systemic disorders, 747–748 vascular disorders, 740 Splenic disorders ectopia, 727 gonadal fusion, 1620 marginal zone lymphoma (SMZL), 694–695, 727–728, 744 MZL, 504 rupture, 726–727 Splenomegaly, 726 Spongiform encephalopathies (SE), 655–657 Spongiotic dermatitis, 878–880 Spontaneous splenic rupture : associations and etiologies, 726t Sporothrix schenckii, 368–370 Sputum, 39 Squamotransitional cell carcinoma, 1357 Squamous cell abnormalities, 17–23 Squamous cell carcinoma (SCC) anus, 1744 basaloid type, 1661–1663 bladder, 1551–1552 Bowen's disease, 803–804 breast, 1291 esophagus, 79–80, 1690–1692, 1695 head and neck, 57 invasive, 1140, 1347, 1354–1356 jaws, 1099 keratinizing/non-keratinizing, 21, 22, 45–46, 1356 larynx and trachea, 1116 nasal cavity, paranasal sinuses, and nasopharynx, 1107 oral cavity, 1090, 1091 oro/hypopharynx, 1101, 1102 papillary, 1117 penis, 1659–1674 primary, 1072–1073 prostate, 1597, 1606 sarcomatoid (spindle cell) subtype, 1667–1668 skin, 73, 803, 804, 871 uterus, 1356, 1377 vagina, 1336–1337 Squamous cell hyperplasia, vulva, 1317–1318 Squamous cell papilloma, bladder, 1551–1552 Squamous cells, atypical (ASC), 17–19 Squamous dysplasia/carcinoma in situ, 1089, 1116, 1240 Squamous hyperplasia, penis, 1655–1656 Squamous intraepithelial lesions (SIL), 19–21 Squamous metaplasia breast, 1267 prostate, 1591 urinary bladder, 1525 Squamous papilloma esophagus, 1690 eyelids, 1149 and papillomatosis, 1238 urinary bladder, 1525 uterus, 1351–1352 Squamous tumors, 1097, 1098, 1353–1357

Squamous vestibular papillomatosis, 1320 SRUS. See Solitary Rectal Ulcer syndrome Stab wound, 434–435 Stafne defect, 1100 Staphylococcal scalded skin syndrome (Ritter disease), 318 Staphylococcus aureus, 317–319 Staphylococcus epidermidis and other coagulase-negative staphylococci (CNS), 319 Stasis dermatitis, 880 Steatocystoma, 799 Steatohepatitic liver disease, 1794 Steatohepatitis, 1794 Steatosis, 82, 1792–1794 Steele-Richardson-Olszewski disease, 657 Stein-Leventhal syndrome, 1402–1403 Stenotrophomonas maltophilia, 339 Stickler syndrome, 556 Stomach, 1696–1711 Strangulation, 435–437 Streptococcus, 320–321 Stroke. See Cerebral infarct Stromal hyperplasia, 1403, 1585 luteoma, 1415–1416 scarring, eye, 1131 tumor, 1412–1416, 1420, 1423 Strongyloides stercoralis, 397–398 Struma ovarii, 1419 Strychnine, 452 Subacute cutaneous lupus erythematosus (SCLE), 864 Subacute gliosis, 606 Subacute lymphocytic thyroiditis, 58 Subacute sclerosing panencephalitis (SSPE), 665 Subacute thyroiditis, 58 Subarachnoid hemorrhage (SAH), 427, 646, 647, 651 Subareolar abscesses, 64 Subcutaneous lymphoma, 708–709, 848 morphea, 896 mycoses, 371–373 Subdural hematoma, 426–427 Subependymal giant cell astrocytoma (SEGA), 616–617 Subependymoma, 621–622, 624 Subscalpular hemorrhage, 425 Sudden death from natural disease, 412–421 Sudden infant death syndrome (SIDS), 419–421 Superior limbic keratoconjunctivitis, 1138 Sweet's syndrome, 890 Swimmer's ear. See External otitis, chronic, suppurative Sympathetic uveitis, 1128 Syncytiotrophoblasts, 16 Synovial sarcoma, 77, 264, 831, 1043–1044, 1187 Syphilis, 883, 1784 lymph node, 685 vulva, 1316 Syphilitic keratitis, 1132 Syringobulbia, 669 Syringocystadenoma papilliferum, 815

Index

Syringoid eccrine carcinoma (eccrine epithelioma), 814 Syringoma, 810 Syringomatous adenoma, 1299 Syringomyelia, 647, 669 Systemic hyper/hypothermia, 443 Systemic lupus erythematosis (SLE), 688, 865, 1467 Systemic lupus erythematosus (SLE), 865 Systemic mastocytosis, 737–738, 758 T(12;21)(p13;q22), 512 Taenia species, 395–396 Tailgut cyst (retrorectal cystic hamartoma), 1428–1429 Takayasu's disease, 1207 Tamoxifen, 1366 Tapeworms. See Cestodes TB. See Tuberculosis TCC. See Transitional cell carcinoma T-cell acute lymphoblastic leukemia (T-ALL), 769 histiocyte rich variant, 703 lymphoma, 690–691, 703, 707–711, 769, 782–785, 1742 prolymphocytic leukemia (T-PLL), 705–706, 781 receptor gene arrangements, 501 Telangiectatic osteosarcoma, 831–834, 975 Telepathology, 472–473 Telogen effluvium, 897–898 Temporal arteritis (giant cell arteritis), 1207, 1208 Teratoma mature/immature, 1179, 1364 ovary, 1418–1420 testis, 1634 Terminal duct carcinoma (TDC), 1070, 1072 Testicular torsion and infarct, 1620 Testicular “tumor” of Adrenogenital syndrome (TTAGS), 1639 Testis neoplasms, 1626–1640 nonneoplastic lesions acquired abnormalities, 1620–1621 congenital abnormalities, 1619–1620 fungal orchidoepididymitis, 1623–1626 granulomatous orchidoepididymitis, 1621–1623 Tetanus, 350–351 Tetralogy of Fallot, 1194 Thallium, 452 Thermal injuries, 443–445 Thin Glomerular Basement Membrane syndrome, 1473 Thorax, IHC heart fibroma, 129 hemangioma, epithelioid hemangioendothelioma and angiosarcoma, 129 lymphoma, 129 mesenchymal tumors, 129 mesothelioma, 129 metastatic disease, 129 myxoma, 129

rhabdomyoma, rhabdomyosarcoma, 129 lung adenocarcinoma, 121–123 bronchial salivary gland type neoplasms, 125 carcinoid and atypical carcinoid tumors, 123–124 clear cell tumor (sugar tumor), 125 inflammatory myofibroblastic tumor, 125 lymphoma, 125 mesenchymal tumors, 125 metastatic disease, 125 pleomorphic, spindle cell, giant cell and sarcomatoid carcinoma, 123 pulmonary blastoma, 124–125 sclerosing hemangioma, 125 small and large cell neuroendocrine carcinoma, 124 squamous cell carcinoma, 121 synovial sarcoma, 125 mediastinum Ewing sarcoma, 129 germ cell tumors, 128–129 lymphoma, 129 mesenchymal tumors, 129 metastatic disease, 129 thymic carcinoid and atypical carcinoid tumors, 128 thymic carcinoma, 127–128 thymic small cell carcinoma, 128 thymoma, 127–128 pleura mesenchymal tumors, 127 mesothelioma, 126–127 metastatic disease, 127 solitary fibrous tumor, 127 Thrombic arteriopathy: pulmonary infarction, 1230 Thromboangiitis obliterans (Buerger's disease), 1208 Thromboembolic diseases, 1480–1482 Thromboembolism, 415–416 Thrombophlebitis, 897 Thrombotic microangiopathy, 1481–1482 Thymolipoma, 1176–1177 Thymoma, 264, 1167, 1170–1174, 1187 Thyroglossal duct cyst, 56, 800, 906–907 Thyroid cancer follicular, 528 papillary, 527 Thyroid gland, 905–935 carcinoma, 913–926 cytology, 57–63 Thyroiditis, 58–59, 907–910, 927 Thyrotrophic adenoma/hyperplasias, 676 Tissue roundworms. See Microfilaria T-lymphoblastic leukemia/lymphoma (T-ALL/TLBL), 690–691 TNM classification bladder cancer, 1561 colorectal adenocarcinoma, 1745 FIGO staging system, 1393, 1394 larynx, 1119–1120 lip/oral cavity, 1118–1119 orbit sarcoma, 1154 pancreatic tumors, 1767–1768

prostate cancer, 1613 retinoblastoma, 1158 salivary gland, 1079 skin melanoma, 870 testicular tumors, 1644 thymoma, 1188 uvea melanoma, 1156–1157 TNM classification of carcinoma breast, 1304–1305 conjunctiva, 1155–1156 eyelid, 1158 lacrimal gland, 1159 ovarian, 1429 skin, 871 TNM staging of renal cell carcinoma, 1513 Tonsillar herniation, 607 Tonsillitis, 321 Tori, 1100 Total parenteral nutrition (TPN), 1798 Total quality management, 483 Toxic diffuse hyperplasia (Graves' disease), 60 Toxic epidermal necrolysis, 884 Toxicology, 419, 446–453 Toxic shock syndrome (TSS), 318 Toxocara canis (visceral larva migrans), 401–402 Toxoplasma gondii, 391–392 Toxoplasmosis, 665, 684 Toyota production system, 483 TPN. See Total parenteral nutrition Tracheobronchopathia osteoplastica, 1256 Tracheoesophageal fistula//esophageal atresia, types of, 1683t Transbronchial FNA, 39 Transitional cell carcinoma (TCC), 259, 1377, 1411 Transitional cell metaplasia, 1348 Transitional cell tumors, 1406, 1411 Transplantation, 269–311 Transport disorders, 575–577 Transposition of great arteries, 1194 Trauma, mechanical, 421–422 Traumatic asphyxia, 440 Traumatic bone cavity, jaws, 1093 Traumatic neuroma, 819, 1030 Traumatic ulcerative granuloma with stromal eosinophilia, 1087–1088 Trematodes, 402–403 Trematodes (flukes), 402–403 Trichinella spiralis, 398 Trichofolliculoma, 805 Trichomonas vaginalis, 10, 392 Trichosporon beigelii, 370–371 Trichotillomania, 898 Trichuris trichiura (whipworm), 398 Tricyclic antidepressants, 450 Trinucelotide repeat disorders, 544–548 Trisomy, 537–538, 670 Trophoblastic disease, 1392 Trophoblastic tumor, 1434–1437 Tropical Sprue syndrome, 1722 True thymic hyperplasia, 1167 Trypanosoma species, 392–394 Tubal metaplasia, 23–24, 1348, 1369 Tubal prolapse, 1390 Tubercular osteomyelitis, 961

1877



Tuberculosis (TB) bone marrow, 792 hepatobiliary disease, 1784–1785 lymph node, 688 neuropathology, 662 pleural and peritoneal fluid, 94–98 spleen, 745 uterus, 1345–1346, 1367 Tuberous sclerosis, 566–567, 669, 671 Tuboendometrioid metaplasia, 1348 Tubular adenoma, 815, 1273, 1335 Tubular carcinoma, 66, 69, 1285–1286 Tubular hyalinization, 1625–1626 Tubulocystic carcinoma, kidney, 1500, 1505–1506 Tubulointerstitial diseases of the kidney, 1475–1478 Tubulointerstitial nephritis, 1476–1477 Tubulovillous adenoma, vagina, 1335 Tufted angioma (tufted angioblastoma), 834 Tularemia, 343–344, 688 Tumoral calcinosis, 1036 Tumors anus, 1743–1745 appendix, 1731–1732 benign epithelial, 1390–1391 mesenchymal, 1274–1276 mixed (spindle cell epithelioma), vagina, 1336 serous, 1408 bone, 221, 236 borderline, 1391, 1405–1408 CNS, 223, 243 histogenesis, 1254–1255 immunohistochemical analysis, 1078t liver, 220–221, 233 lung, 220, 231 lymph node, 222, 239, 240 molecular diagnostics of, 497–512 pancreas, 85–86 pleura, 1257–1258 pleural, 220, 230 salivary gland, 1047–1079 serous, 1407, 1422 sex cord stromal, 1386, 1412–1416, 1420, 1636–1639 solitary fibrous, 1004–1005 surface epithelial-stromal, 1405 sympathetic nervous system, 1177–1178 synovial, 1043–1044 teratoid/rhabdoid, 634, 636 unknown origin, 532 uterine, 1384, 1386, 1393 Tumors with hemangiopericytomatous vascular pattern, 214 Tunga penetrans, 404 Tunics, lesions of, 1641–1642 Tunnel clusters, 1349 Turner syndrome, 539 Typhoid fever, 333 Tyrosinemia type 1, 568 Ulcerative colitis, 1723–1724 Ulcerative Jejunitis, 1722 Uncal (transtentorial) herniation, 607

1878

Index

Uncertain histogenesis, tumors benign clear cell (sugar), 1254 granular cell, 1255 minute pulmonary meningothelial-like lesion, 1254–1255 sclerosing hemangioma, 1254 Undifferentiated tumor, screening panel, 205 Unicameral bone cyst (UBC), 968 Unilocular thymic cyst (developmental origin), 1166 Unknown primary cancer (UPC) organ specific and markers, 206–207 pitfalls, 207 Unknown primary, tumors approach, 204 definition, 204 limitations, 205 organization, 204 Unsatisfactory specimen, 10 UPC. See Unknown primary cancer Urachal abnormalities, 1517, 1529 Urachal remnant, 1517 Urea cycle disorders, 569–570 Ureter endometriosis, 1568–1569 fibroepithelial polyp, 1568 Urethra caruncle, 1569 congenital anomalies, 1568 diverticulum, 1569 inflammatory polyp, 1569 neoplasms adenocarcinoma, 1576 benign epithelial tumors, 1574 carcinoma, 1574–1575 squamous cell carcinoma, 1575–1576 urothelial carcinoma, 1575 tumor classification, 1574 tumor, TNM classification, 1578 Urethral polyp, 1517 Urinary bladder, 90–94 Urinary tract infection, 330 Urothelial adenocarcinoma, 93–94 atypia of unknown significance, 1538 carcinoma, 91–93, 1539–1541, 1608–1609 cells, 90, 91 dysplasia, 1538–1539 hyperplasia, 1524–1525 metaplasia, 1592 papilloma, 1535–1536, 1594 tumors, 1535t Urticaria, 868–869, 889 Usual interstitial pneumonitis (UIP), 1220–1221 Uterine gas gangrene, 347 Uterus cervix epithelial tumors and precursors, 1351–1362 lymphoid and hematopoietic tumors, 1364 melanocytic tumors, 1363–1364 mesenchymal tumors, 1362–1363 mixed epithelial and mesenchymal tumors, 1363 nonneoplastic lesions, 1345–1351

secondary tumor, 1364 tumors, germ cell type, 1364 corpus dysfunctional uterine bleeding, 1366–1367 epithelial tumors and related lesions, 1369–1378 lymphomas and leukemias, 1387 mesenchymal tumors and related lesions, 1378–1384 metastatic (secondary) tumors, 1387 miscellaneous tumors, 1386–1387 mixed epithelial and mesenchymaltumors, 1384–1386 morphology of the endometrium, 1364–1366 nonneoplastic lesions, 1367–1369 tumors, germ cell type, 1387 Vacuolar myelopathy of AIDS, 664 Vagina benign nonneoplastic lesions, 1334–1335 benign tumors, 1335–1336 other malignant tumors, 1338–1340 premalignant and malignant epithelial tumors, 1336–1338 Vaginal adenosis (VA), 1334 Vaginal intraepithelial neoplasia (VAIN), 1336 Varicella-Zoster virus (VZV), 384 Varices, 1688 Varicocele, prostate, 1620–1621 Variola major (smallpox), 384–385 Vascular malformations, 651–652, 671–672 proliferations, 831–838 stasis, 1447 tumors eye, 1146 immunocompromised patients, 984 low-grade malignancy, 836, 1026–1027 related conditions, 1249–1251 soft tissue, 1001, 1024–1029 Vascular conditions pulmonary hypertension, 1229–1230 vasculitides, 1227–1229 Vascularization, 1131 Vascular lesions, breast, 1302 Vascular rejection, 275 Vascular tumors angiosarcoma, 1250–1251 epithelioid hemangioendothelioma, 1249–1250 Kaposi's sarcoma, 1250 Vasculitides Churg-Strauss syndrome, 1227–1228 necrotizing capillaritis, 1228–1229 NSG, 1228 Wegener's Granulomatosis, 1227, 1228 Vasculitis blood vessel, 1206–1209 breast, 1301 gastrointestinal tract, 1729–1730 immunodermatology, 869–870 kidney, 1482 neuropathology, 652 non-infectious, 1207–1209

Index

Vasitis nodosa, 1643 Vasogenic edema, 606 VC. See Verrucous carcinoma Veno-occlusive disease, 1793, 1799–1800 Venous infarcts, 650 Venous lake, 832 Ventricular septal defect (VSD), 1194–1195 Verruciform xanthoma, 1087 Verrucous carcinoma (VC) larynx and trachea, 1116 oral cavity, 1090–1091 penis, 1663–1665 skin, 804 uterus, 1356 vulva, 1325–1326 Verrucous leukoplakia, 1089–1090 Verumontanum mucosal gland hyperplasia, 1591 Vesicular dermatophytosis, 879 Vibrios, gastrointestinal tract, 1719 Vibrio vulnificus, 337–338 Villitis of unknown etiology (VUE), 1448–1449 Villous adenoma, bladder, 1335, 1537–1538 Vimentin positive, pankeratin negative tumors, 208, 213 Viral exanthem, 887 Viral hepatitis, 1773–1782 Virchow method, organ removal, 461 Viruses, 378–385 Vitiligo, 838 Von Brunn's nests, 1527 Von Hippel-Lindau (VHL), 594

Von Willebrand disease, 561–562 VSD. See Ventricular septal defect VUE. See Villitis of unknown etiology Vulva benign discolored lesions, 1329–1330 benign tumors, 1320–1323 condyloma accuminata, 1314 cystic lesions, 1316–1317 infectious lesions, 1314–1316 inflammatory lesions, 1312–1313 malignant nonepithelial tumors, 1329–1330 premalignant and malignant epithelial tumors, 1323–1328 vestibulitis, 1312 Vulva intraepithelial neoplasia (VIN), 1323–1328 Waldenström macroglobulinemia, 692–694 Walthard nest, 1428 Warthin's tumor, 53–55, 1058 Warty carcinoma, 1357, 1665–1667 Warty dyskeratoma, 802 Water cysts. See Hydrocystomas Waterhouse-Friederichsen syndrome, 418 Watershed (borderzone) infarct, 649 Webs and rings, esophagus, 1683 Wegener's granulomatosis, 1208–1209, 1217, 1234, 1253 Well-differentiated liposarcoma (WDLS), 1018–1019 Wernicke-Korsakoff syndrome, 671 Western immunoblotting, 851

Whipple's disease, 662, 686, 1720 Whipworm. See Trichuris trichiura White sponge nevus, 803 Whole slide imaging, 473–474 William syndrome, 542 Wilms' tumor, 90, 594–595 Wilson's disease, 577, 1815–1816 Wind hypothermia, 443 Wound infections, 337 Wuchereria bancrofti, 399–400 Xanthelasma, 825–826, 1149–1150 Xanthoma, 825–826, 1012 Xeroderma pigmentosum, 543–544 Yeasts, 373–375 Yersinia, 333–335, 688 Yersinia enterocolitica, 333–334 Yersiniosis, 1719 Yolk sac tumor mediastinum, 1180 ovary, 1406, 1417–1418, 1421 testis, 1633–1634 uterus, 1364 vagina, 1339 vulva, 1330 Zellweger syndrome, 579–580 Zero defects, 483 Zollinger-Ellison syndrome, 1699 Zoonotic roundworms, 400 Zygomycetes, 45

1879